Diacylglycerol kinase modulating compounds

Abstract

The present disclosure provides diacylglycerol kinase modulating compounds, and pharmaceutical compositions thereof, for the treatment of cancer, including solid tumors, and viral infections, such as HIV or Hepatitis B virus infections. The compounds can be used alone or in combination with other agents. JPEG2024524210000143.jpg56128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 213,884, filed June 23, 2021, which is incorporated herein in its entirety for all purposes.

[0002] The present disclosure relates to compounds that modulate diacylglycerol kinase. The disclosure also relates to processes and intermediates for the preparation of such compounds, methods of using such compounds, and pharmaceutical compositions comprising the compounds described herein. [Background technology]

[0003] Diacylglycerol (DAG) is known as a second messenger of signaling molecules and plays an important role in cell proliferation, differentiation and / or metabolism (Carrasco, S., Merida, I. Trends Biochem. Sci. 2007, 32, 27-36). The intracellular concentration and localization of DAG are tightly controlled, and diacylglycerol kinase (DGK) is one of the enzymes that control them. DGK is an enzyme that synthesizes phosphatidic acid (PA) by transferring a phosphoryl group to DAG. Ten human isozymes (α, β, γ, δ, ε, ζ, η, θ, ι, κ) are known (Joshi, RP, Koretzky, GAINt. J. Mol. Sci., 2013, 14, 6649-6673.). Each isozyme is localized and is thought to be associated with different proteins and / or different cell types. DGK has been reported to be involved in the pathogenesis of multiple diseases, including cancer, immune diseases, neurodegenerative diseases, and diabetes (Sakane, F., et al. Front. Cell Dev. Biol., 2016, 4, 82.).

[0004] DGKα has been the subject of research, including studies on its potential for cancer therapy. For example, inhibitory activity against glioblastoma cell proliferation was reported as a result of knockdown caused by RNA interference targeting DGKα (Dominguez, CL, et al. Cancer Discov., 2013, 782-797). Inhibitory effects were also reported in human colon cancer cell lines in three-dimensional cell culture, and knockdown of DGKα was further reported to inhibit tumor growth in mouse models (Torres-Ayuso, P., et al. Oncotarget, 2014, 5, 9710-9726). Inhibition of DGKα has been disclosed in WO 2007 / 114239. Thus, compounds with inhibitory activity against DGKα may be useful as therapeutic agents, such as for the treatment of cancers in which DGKα is involved in their proliferation.

[0005] In recent years, cancer immunotherapy has attracted attention as a candidate for cancer treatment. Immune checkpoint inhibitors, such as anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibodies, anti-PD-1 (programmed death receptor 1) antibodies, and anti-PD-L1 (programmed death ligand 1) antibodies, can be administered to enhance antitumor immune responses in patients. Some immune checkpoint inhibitors have already been approved as medicines for antitumor therapy. However, the antitumor effect is often limited to a small number of patients. Furthermore, some patients become resistant to the inhibitors (Spranger, S., Gajewski, TF, Nat. Rev. Cancer., 2018, 18, 139-147).

[0006] DGKα is expressed in T cells, mediates T cell receptor (TCR) signal transduction, and is believed to play a role in T cell activation (Joshi et al. (supra) and Merida, I. et al., Adv. Biol. Regul., 2017, 63, 22-31). When T cells are in an immunologically unresponsive state such as anergy, the expression of DGKα may increase, and it has been reported that overexpression of DGKα induces an anergic state (Zha, Y. et al., Nat. Immunol., 2006, 7, 1166-1173). Furthermore, it has been reported that knockdown of DGKα in T cells by RNA interference results in activation of T cells (Avila-Flores, A., et al. Immunol. Cell. Biol., 2017, 95, 549-563.). Therefore, compounds having activity regulating DGKα may be useful for preventing and / or treating diseases associated with T cells, such as immune diseases or inflammatory diseases. Recently, CAR (chimeric antigen receptor) T cell therapy has attracted attention as a promising immuno-cancer therapy. It has been reported that DGKα-deficient CAR T cells have high effector function and antitumor effect against solid cancers (Riese, MJ et al. Cancer Res., 2013, 73, 3566-3577; Jung, IY, et al. Cancer Res., 2018, 78, 4692-4703.). Therefore, the use of compounds with inhibitory effects against DGKα may complement CAR T cell therapy. However, there remains a need, for example, for DGKα inhibitors that have desirable pharmaceutical and therapeutic properties. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2007 / 114239 [Non-patent literature]

[0008] [Non-Patent Document 1] Carrasco, S., Merida, I. Trends Biochem. Sci. 2007, 32, 27 - 36 [Non - Patent Document 2] Joshi, R.P., Koretzky, G.A. Int. J. Mol. Sci., 2013, 14, 6649 - 6673. [Non - Patent Document 3] Sakane, F., et al. Front. Cell Dev. Biol., 2016, 4, 82. [Non - Patent Document 4] Dominguez, C.L., et al. Cancer Discov., 2013, 782 - 797 [Non - Patent Document 5] Torres - Ayuso, P., et al. Oncotarget, 2014, 5, 9710 - 9726 [Non - Patent Document 6] Spranger, S., Gajewski, T.F., Nat. Rev. Cancer., 2018, 18, 139 - 147 [Non - Patent Document 7] Merida, I. et al., Adv. Biol. Regul., 2017, 63, 22 - 31 [Non - Patent Document 8] Zha, Y. et al., Nat. Immunol., 2006, 7, 1166 - 1173 [Non - Patent Document 9] Avila - Flores, A., et al. Immunol. Cell. Biol., 2017, 95, 549 - 563. [Non - Patent Document 10] Riese, M.J. et al. Cancer Res., 2013, 73, 3566 - 3577 [Non - Patent Document 11] Jung, I.Y., et al. Cancer Res., 2018, 78, 4692 - 4703. [Summary of the Invention] [Means for Solving the Problems]

[0009] In one embodiment, the present disclosure provides a compound of formula (I):

[0010] [ka] or a pharma- ceutically acceptable salt thereof, wherein Z 1 is N or CR 1 and Z 2 is N or CR 2 and R 1 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or -CN; R 2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 2a , -C(O)OR 2a , -OC(O)R 2a , -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -C(=NR 2a )N(R 2b )(R 2c ), -N(R 2a )(R 2b ), -N(R 2a )N(R2b )(R 2c ), -N(R 2a )N=C(R 2b )(OR 2c ), -OR 2a , -SR 2a , -S(O)R 2a , -S(O)(NR 2a )(R 2b ), -S(NR 2a )(NR 2b )(R 2c ), -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ), -N(R 2a )S(O) 2 (R 2b ), -P(R 2a )(R 2b ), -P(O)(R 2a )(R 2b ), -P(O)(OR 2a )(R 2b ), -P(O)(OR 2a )(OR 2b ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where each alkyl, alkenyl, or alkynyl is independently the same or different, and 1 to 3 R 2d Each cycloalkyl may be optionally substituted with 1 to 3 R 2e Each aryl may be optionally substituted with 1 to 3 R 2f Each heterocycloalkyl may be optionally substituted with 1 to 3 R 2gEach heteroaryl may be optionally substituted with 1 to 3 R 2h group, Each R 2a , R 2b , and R 2c are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where aryl or heteroaryl, which may be the same or different, are each selected from 1 to 3 R 2j and optionally substituted with Or, R 2a , R 2b , and R 2c when attached to the same atom, can be combined with the atom to which they are attached to form a heterocycloalkyl, Each R 2d are independently -CN, -C(O)R 2d1 , -C(O)OR 2d1 , -OC(O)R 2d1 , -C(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)R 2d2 , -OC(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)OR 2d2 , -N(R 2d1 )(R 2d2 ), =O, -OR2d1 , -SR 2d1 , -S(O)R 2d1 , -S(O)(NR 2d1 )(R 2d2 ), -S(O) 2 R 2d1 , -S(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )S(O) 2 R 2d2 , C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 2d1 and R 2d2 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, or C 1~6 is haloalkyl, Each R 2e , R 2f , R 2g , and R 2h are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, -CN, or -OH; Each R 2j is independently 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6Haloalkyl or C 1~6 is haloalkoxy; R 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)OR 3b , -C(=NR 3a )N(R 3b )(R 3c ), -N(R 3a )(R 3b ), -N(R 3a )N(R 3b )(R 3c ), -N(R 3a )N=C(R 3b )(OR 3c ), -OR 3a , -SR 3a , -S(O)R 3a , -S(O)(NR 3a )(R 3b ), -S(NR 3a )(NR 3b )(R 3c ), -S(O) 2 R 3a , -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 (R 3b ), -P(R 3a)(R 3b ), -P(O)(R 3a )(R 3b ), -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where each alkenyl or alkynyl is independently selected from 1 to 3 R 3d Each cycloalkyl may be optionally substituted with 1 to 3 R 3e Each aryl may be optionally substituted with 1 to 3 R 3f Each heterocycloalkyl may be optionally substituted with 1 to 3 R 3g Each heteroaryl may be optionally substituted with 1 to 3 R 3h group, Each R 3a , R 3b , and R 3c are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 aryl, heterocycloalkyl, or heteroaryl; Or, R 3a , R3b , and R 3c when attached to the same atom, can be combined with the atom to which they are attached to form a heterocycloalkyl, Each R 3d are independently -N(R 3d1 )(R 3d2 ), -OR 3d1 , C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 aryl, heterocycloalkyl, or heteroaryl; Each R 3d1 and R 3d2 are independently hydrogen, C 1~6 Alkyl, or -C(O)O-(C 1~6 alkyl), Each R 3e , R 3f , R 3g , and R 3h are independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl or C 1~6 is haloalkoxy; R 4 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or -CN; R 5 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where alkyl is R 5a and optionally substituted with R 5a is -OSi(R 5a1 )(R 5a2 )(R 5a3 ) and R 5a1 , R 5a2 , and R 5a3 are each independently 1~6 is alkyl, R 6 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 6~12 aryl, or heteroaryl, where the aryl or heteroaryl may be the same or different; 1 to 3 R 6a each of which is optionally substituted; Each R 6a is independent, C 1~6 Alkyl, C 2~6 Alkenyl, C 2-8 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO 2 , -C(O)R 6b , -C(O)OR 6b , -OC(O)R 6b , -C(O)N(R 6b )(R 6c ), -N(R 6b )C(O)R 6c , -C(=NR 6b )N(R 6c )(R6d ), -N(R 6b )(R 6c ), -OR 6b , -SR 6b , -S(O)R 6b , -S(O) 2 R 6b , -S(NR 6b )(NR 6c )R 6d , -S(O)(NR 6b )(R 6c ), -S(O) 2 N(R 6b )(R 6c ), -N(R 6b )S(O) 2 (R 6c ), -P(R 6b )(R 6c ), -P(O)(R 6b )(R 6c ), -P(O)(OR 6b )(R 6c ), -P(O)(OR 6b )(OR 6c ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each represent 1 to 3 R 6e and alkyl is optionally substituted with R 6f and alkynyl is optionally substituted with 1 to 4 R 6j and optionally substituted with Each R 6b , R 6c and R 6d are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6k and optionally substituted by Each R 6k is independently 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl); Each R 6e is independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO 2 , -C(O)R 6e1 , -C(O)OR 6e1 , -OC(O)R 6e1 , -C(O)N(R 6e1 )(R6e2 ), -N(R 6e1 )C(O)R 6e2 , -OC(O)N(R 6e1 )(R 6e2 ), -N(R 6e1 )C(O)OR 6e2 , -C(=NR 6e1 )N(R 6e2 )(R 6e3 ), -N(R 6e1 )(R 6e2 ), =O, -OR 6e1 , -SR 6e1 , -S(O)R 6e1 , -S(NR 6e1 )(NR 6e2 ), -S(O)(NR 6e1 )(R 6e2 ), -S(O) 2 R 6e1 , -S(O) 2 N(R 6e1 )(R 6e2 ),-SCIENCE FICTION 5 , -N(R 6e1 )S(O) 2 (R 6e2 ), -P(R 6e1 )(R 6e2 ), -P(O)(R 6e1 )(R 6e2 ), -P(O)(OR 6e1 )(R 6e2 ), -P(O)(OR 6e1 )(OR 6e2 ), -Si(R 6e1 )(R 6e2 )(R 6e3 ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-heterocycloalkyl, heteroaryl, or C 1~6 alkyl-heteroaryl, where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6heach of which is optionally substituted, and alkyl is the same or different, 1 to 3 R 6m and optionally substituted with Each R 6e1 , R 6e2 , and R 6e3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6n and optionally substituted with Each R 6n is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6n1 , -C(O)OR 6n1 , -OC(O)R 6n1 , -C(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)R 6n2 , -OC(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)OR 6n2, -C(=NR 6n1 )N(R 6n2 )(R 6n3 ), -N(R 6n1 )(R 6n2 ), =O, -OH, -SR 6n1 , -S(O)R 6n1 , -S(NR 6n1 )(NR 6n2 )R 6n3 , -S(O)(NR 6n1 )(R 6n2 ), -S(O) 2 R 6n1 , -S(O) 2 N(R 6n1 )(R 6n2 ), or -N(R 6n1 )S(O) 2 (R 6n2 ) and Each R 6n1 , R 6n2 and R 6n3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 6h is independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R6h1 , -C(O)OR 6h1 , -OC(O)R 6h1 , -C(O)N(R 6h1 )(R 6h2 ), -N(R 6h1 )C(O)R 6h2 , -OC(O)N(R 6h1 )(R 6h2 ), -N(R 6h1 )C(O)OR 6h2 , -C(=NR 6h1 )N(R 6h2 )(R 6h3 ), -N(R 6h1 )(R 6h2 ), =O, -OH, -SR 6h1 , -S(O)R 6h1 , -S(NR 6h1 )(NR 6h2 )R 6h3 , -S(O)(NR 6h1 )(R 6h2 ), -S(O) 2 R 6h1 , -S(O) 2 N(R 6h1 )(R 6h2 ), -N(R 6h1 )S(O) 2 (R 6h2 ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl); Each R 6h1 , R 6h2 , and R 6h3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 6m are independently halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6m1 , -C(O)OR 6m1 , -OC(O)R 6m1 , -C(O)N(R 6m1 )(R 6m2 ), -N(R 6m3 )C(O)R 6m2 , -OC(O)N(R 6m1 )(R 6m2 ), -N(R 6m1 )C(O)OR 6m2 , -C(=NR 6m3 )N(R 6m1 )(R 6m2 ), -N(R 6m1 )(R 6m2 ), =O, -OH, -SR 6m1 , -S(O)R 6m1 , -S(NR 6m1 )(NR 6m2 )R 6m3 , -S(O)(NR 6m1 )(R 6m2 ), -S(O) 2 R 6m1 , -S(O) 2 N(R 6m1 )(R 6m2 ), or -N(R 6m3 )S(O) 2 (R 6m2 ) and Each R 6m1 , R 6m2 , and R 6m3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), R 6f is -OSi(R 6f1 )(R 6f2 )(R 6f3 ) and R 6f1 , R 6f2 , and R 6f3 are each independently 1~6 is alkyl, Each R 6j is independently 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6j1 , -C(O)OR 6j1 , -OC(O)R 6j1 , -C(O)N(R 6j1 )(R 6j2 ), -N(R 6j3 )C(O)R 6j2 , -OC(O)N(R 6j1 )(R 6j2 ), -N(R 6j1 )C(O)OR 6j2 , -C(=NR 6j3 )N(R 6j1 )(R 6j2 ), -N(R 6j1 )(R 6j2 ), =O, -OR 6j1 , -SR 6j1 , -S(O)R 6j1 , -S(NR 6j1 )(NR 6j2 ), -S(NR 6j1 )(NR 6j2 )R 6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O) 2 R 6j1 , -S(O) 2 N(R 6j1 )(R 6j2 ), -N(R6j1 )S(O) 2 (R 6j2 ), -Si(R 6j1 )(R 6j2 )(R 6j3 ), C 3~10 Cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, where the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6p and optionally substituted with Each R 6j1 , R 6j2 , and R 6j3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 C optionally substituted with haloalkyl 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 6p is independently 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6p1 , -C(O)OR 6p1 , -OC(O)R 6p1 , -C(O)N(R 6p1 )(R 6p2 ), -N(R 6p1 )C(O)R 6p2, -OC(O)N(R 6p1 )(R 6p2 ), -N(R 6p1 )C(O)OR 6p2 , -C(=NR 6p3 )N(R 6p1 )(R 6p2 ), -N(R 6p1 )(R 6p2 ), =O, -OH, -SR 6p1 , -S(O)R 6p1 , -S(NR 6p1 )(NR 6p2 )R 6p3 , -S(O)(NR 6p1 )(R 6p2 ), -S(O) 2 R 6p1 , -S(O) 2 N(R 6p1 )(R 6p2 ), or -N(R 6p1 )S(O) 2 (R 6p2 ) and Each R 6p1 , R 6p2 , and R 6p3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Or R 5 and 1 R 6a together with the atom to which they are attached form a heterocycloalkyl, and 1 to 3 R 6g and optionally substituted with Each R 6gis independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or -CN; R 7 is hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl or C 1~6 alkyl-(heterocycloalkyl); each heterocycloalkyl is a 3- to 20-membered ring having 1-4 heteroatoms which are each independently N, O, or S; Each heteroaryl is a 5-18 membered ring having 1-4 heteroatoms which are each independently N, O, or S.

[0011] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0012] In another embodiment, the present disclosure provides a method of treating an HIV or Hepatitis B virus infection in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] I. Definition "Alkyl" means a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group can be one having 1 to 18 carbon atoms (i.e., C 1~18 alkyl) or 1 to 8 carbon atoms (i.e., C 1~8 alkyl) or 1 to 6 carbon atoms (i.e., C 1~6 alkyl) or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2), and 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3. Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0014] "Alkylene" refers to a straight or branched chain saturated aliphatic radical, i.e., a divalent hydrocarbon radical, having the number of carbon atoms indicated and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene is -(CH 2 ) n - can be a divalent radical of 、 where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. The alkylene group can be substituted or unsubstituted.

[0015] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl can be any number of carbons, e.g., C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6The alkenyl group may have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. The alkenyl group may be substituted or unsubstituted.

[0016] "Alkynyl" refers to either a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl is a C 2 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C 3 , C 3~4 , C 3~5 , C 3~6 , C 4 , C 4~5 , C 4~6 , C 5 , C 5~6 , and C 6 Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

[0017] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. With respect to the alkyl group, an alkoxy group is one having a C 1~6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further substituted with a variety of substituents as described. Alkoxy groups can be substituted or unsubstituted.

[0018] "Alkoxyalkyl" refers to an alkoxy group linked to an alkyl group which is linked to the remainder of the compound, such that the alkyl group is divalent. Alkoxyalkyl has 2 to 6 (C 2~6 Alkoxyalkyl), 2 to 5 (C 2~5 alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3 The number of carbons refers to the total number of carbons in the alkoxy and alkyl groups. For example, C 6 Alkoxyalkyl is butyl (C 4 Ethoxy (C alkyl) 2 Alkoxy), and isopropyl (C 3 n-propoxy (C 3 Alkoxy and alkyl are as defined above, where the alkyl is divalent, including but not limited to methoxymethyl (CH 3 OCH 2 -), methoxyethyl (CH 3 OCH 2 CH 2 -) etc. may be mentioned.

[0019] "Aminoalkyl" refers to an amino group linked to an alkyl group which is linked to the remainder of the compound, such that the alkyl group is divalent. An amino group is an unsubstituted amino (-NH 2) or alkyl groups, for example, monosubstituted amino (e.g., -NHCH 3 ), or disubstituted amino (e.g., -N(CH 3 ) 2 The aminoalkyl may be 1 to 8 (C 1~8 aminoalkyl), 1 to 6 (C 1~6 aminoalkyl), 2 to 6 (C 2~6 aminoalkyl), 2-4 (C 2~4 aminoalkyl), or 2 to 3 (C 2~3 The number of carbons refers to the total number of carbons in the amino and alkyl groups. For example, C 6 Aminoalkyl is butyl (C 4 -N(CH alkyl) 3 ) 2 (C 2 amino), and isopropyl (C 3 -NHCH linked to alkyl 2 CH 2 CH 3 (C 3 Aminoalkyl refers to the alkyl group of the aryl group, such as aminomethyl (H 2 NCH 2 -), methylaminomethyl (CH 3 NHCH 2 -), dimethylaminomethyl ((CH 3 ) 2 NCH 2 -), dimethylaminoethyl ((CH 3 ) 2 NCH 2 CH 2 -), but are not limited to these.

[0020] "Alkoxy-alkoxy" refers to an alkoxy group linked to a second alkoxy group which is linked to the remainder of the compound. Alkoxy is as defined above and includes, but is not limited to, methoxy-methoxy (CH 3 OCH 2 O-), methoxy-ethoxy (CH3 OCH 2 CH 2 O-) and the like.

[0021] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0022] As used herein, "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by halo substituents, which may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 Alkyl, 1~4 One or more of the alkyl hydrogen atoms are replaced by a halo substituent. 1~4 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0023] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. 1~6 The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, or more halogens. If all hydrogens are replaced by halogens, such as fluorine, the compound is persubstituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0024] "Cycloalkyl" refers to an alkyl group having 3 to 20 cyclic carbon atoms (i.e., C 3-20Cycloalkyl) refers to a saturated or partially unsaturated all-carbon monocyclic ring having, for example, 3 to 12 ring atoms, for example, 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also encompasses saturated and partially unsaturated all-carbon multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to 20 ring carbon atoms). The rings of a multiple condensed ring system may be connected together by fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0025] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene in order to link the cycloalkyl component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any of the groups listed below. 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6The cycloalkyl moiety is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0026] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or multiple ring system having at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur) in the ring, where the multiple ring system includes at least a non-aromatic ring containing at least one heteroatom. The multiple ring system may also include other aromatic and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has 3 to 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term encompasses saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having 1 to 6 annular carbon atoms and 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The heteroatoms are optionally oxidized to -N(-OH)-, =N(-O)-, -N(-OH)-, -N(-O ... - )-, -S(=O)-, or -S(=O) 2-. The rings of fused polycyclic (e.g., bicyclic heterocyclyl) systems can be connected to each other through fused, spiro, and bridged bonds, if permitted by valence requirements. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinacridine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl. , 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like.

[0027] Heterocycloalkyl rings also include 9-15 membered fused ring heterocycloalkyls having two, three or more rings, where at least one ring is an aryl ring and at least one ring is a non-aromatic ring containing at least one heteroatom. Representative fused bicyclic heterocycloalkyls include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenzo[b]dioxine, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the following structure:

[0028] [ka]

[0029] A fused bicyclic heterocycloalkyl can also be represented by the structure:

[0030] [ka] In the formula, Y 1 , Y 2 , Y 3 and Y 4 are each independently absent, -CH 2 -, -NH-, -O- or -S-; Y 1 , Y 2 , Y 3 and Y 4 At least one of is -NH-, -O-, or -S-, and the dashed circle represents a saturated or partially unsaturated non-aromatic ring. A fused bicyclic heterocycloalkyl is optionally substituted.

[0031] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene in order to link the heterocycloalkyl component and the point of attachment. The alkyl component is selected from the group consisting of C 0~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6In some cases, the alkyl component may be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may be substituted or unsubstituted.

[0032] As used herein, "aryl" refers to an all-carbon aromatic monocyclic ring or an all-carbon multiple fused ring system in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such multiple fused ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the multiple fused ring system. The rings of the multiple fused ring system may be connected to each other by fused bonds, spiro bonds, and bridged bonds, where valency requirements permit. When referring to an aryl with a particular range of atom members (e.g., 6-10 membered aryl), it is also understood that the atom range is for the total ring atoms of the aryl. For example, 6 membered aryl includes phenyl, and 10 membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0033] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to link the aryl component to the point of attachment. The alkyl component is selected from the group consisting of C 0~6 , C 1~2 , C 1~3 , C 1~4, C 1~5 , C 1~6 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 In some cases, the alkyl component may be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethylbenzene. The alkyl-aryl group may be substituted or unsubstituted.

[0034] As used herein, "heteroaryl" refers to an aromatic monocyclic ring having at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur, and "heteroaryl" also encompasses multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" encompasses a monoaromatic ring of 1-6 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also encompasses multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group as defined above is fused with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a multiple condensed ring system. Thus, a heteroaryl (aromatic monocyclic or multiple condensed ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms in the heteroaryl ring. Such condensed polycyclic systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of the multiple condensed ring system may be connected to each other by fused bonds, spiro bonds, and bridge bonds, if allowed by valency requirements. It is understood that the individual rings of the multiple condensed ring system may be connected to each other in any order. It is understood that the attachment point of the heteroaryl or heteroaryl to the multiple condensed ring system may be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). When a heteroaryl with a particular range of atom member numbers (e.g., 5-10 membered heteroaryl) is mentioned, it is also understood that the atom range is for the total ring atoms of the heteroaryl, including carbon atoms and heteroatoms.For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.

[0035] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to link the heteroaryl component and the point of attachment. The alkyl component is selected from the group consisting of C 0~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0036] "Compounds of the disclosure" include compounds disclosed herein, for example, compounds of the disclosure include compounds of formula (I), (Ia-1), (Ia-2), and (Ia-3), including the compounds of the Examples.

[0037] As used herein, a "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0038] "Pharmaceutically effective amount" refers to the amount of a compound of the present disclosure, in a formulation or combination thereof, that results in a desired therapeutic or pharmaceutical result.

[0039] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0040] As used herein, "treatment" or "treat" or "treating" refers to an approach for obtaining a beneficial or desired result. For purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the extent of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In some embodiments, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the extent of a disease or condition); b) delaying or inhibiting the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, slowing the worsening or progression of a disease or condition); and c) alleviating a disease or condition, e.g., causing regression of clinical symptoms, ameliorating pathology, slowing disease progression, improving quality of life, and / or prolonging survival.

[0041] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective to induce a desired biological or medical response when administered to a subject to treat a disease, including an amount of a compound sufficient to achieve such treatment of the disease. An effective amount may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. An effective amount may include a range of amounts. As is understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be achieved or is achieved in combination with one or more other agents. The suitable dose of any co-administered compound may be reduced, in some cases, due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0042] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject. Administration may be carried out according to a schedule that dictates frequency of administration, dosage, and other factors.

[0043] As used herein, "co-administration" refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., administration of a compound disclosed herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the co-administration or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0044] "Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0045] "Disease" or "condition" refers to a physical state or health condition of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein. The disease can be an autoimmune, inflammatory, cancer, infectious (e.g., viral infection), metabolic, developmental, cardiovascular, hepatic, intestinal, endocrine, neurological, or other disease. In some embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, renal cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

[0046] "Cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, renal cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), Examples of cancer include ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophageal), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0047] Additional examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, or uterus, or cancer of the medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant pulmonary fibrosis, and malignant pulmonary fibrosis. thyroid cancer, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, carcinoma of the pancreatic stellate cells, carcinoma of hepatic stellate cells, or prostate cancer.

[0048] "Leukemia" broadly refers to progressive, malignant diseases of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and character of the disease: acute or chronic; (2) the type of cells involved: bone marrow (myeloid), lymphocytes (lymphoid), or monocytic; and (3) the increase or absence of an increase in the number of abnormal cells in the blood: leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, and leukocytic leukemia. leukemia), basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hematoblastic leukemia, hematoblastic leukemia Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia , lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0049] "Sarcoma" generally refers to a tumor composed of embryonic connective tissue-like material and generally composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid rhabdomyosarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, and idiopathic multiple pigmented hemorrhagic sarcoma. sarcoma), immunoblastic sarcoma of B cell, lymphoma, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0050] "Melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0051] "Carcinoma" refers to a malignant new growth composed of epithelial cells that tend to invade surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma of the adrenal cortex, alveolar carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, comedocarcinoma, uterine carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, scirrhous carcinoma, durum, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, glandular epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, childhood embryonal carcinoma, intraepithelial carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, Chrompecher's carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma carcinoma), mucinous carcinoma, mucocytic carcinoma, mucoepidermoid carcinoma, mucous carcinoma (carcinoma mucosum), mucous carcinoma (mucosoma-like carcinoma), nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, follicle carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tubular carcinoma, nodular carcinoma (tuberous carcinoma), verrucous carcinoma, or choriocarcinoma.

[0052] "Metastasis", "metastatic" and "metastatic cancer" may be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ to another non-adjacent organ or body part. Cancer begins at a site of origin, e.g., the breast, which is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to invade and invade surrounding normal tissues in the local area and / or to invade the walls of the lymphatic or vascular system and spread through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of the primary tumor is referred to as a metastatic tumor or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, when lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells, not abnormal breast cells. A secondary tumor in the breast is referred to as a metastatic lung cancer. Thus, the term metastatic cancer refers to a disease in which the subject has or has had a primary tumor and has one or more secondary tumors.The term non-metastatic cancer or the subject with non-metastatic cancer refers to a disease in which the subject has a primary tumor but does not have one or more secondary tumors.For example, metastatic lung cancer refers to a disease in a subject who has or has had a history of a primary lung tumor and has one or more secondary tumors at a second site or multiple sites, for example, in the breast.

[0053] In the context of a substance or the activity or function of a substance associated with a disease (e.g., diabetes, cancer (e.g., prostate cancer, renal cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophageal), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)), "associated with" or "associated with" means that the substance or the activity or function of the substance causes (in whole or in part) the disease (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, renal cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) or causes (in whole or in part) a symptom of the disease.

[0054] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0055] The compounds of the present disclosure described herein may be prepared and / or formulated as pharmaceutically acceptable salts, or as free bases, where appropriate. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that has the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or inorganic or organic bases. Examples of pharmaceutically acceptable salts of the compounds of formula (I) of the present disclosure include inorganic acid salts such as hydrochloride, sulfate, carbonate and phosphate, and organic acid salts such as fumarate, maleate, methanesulfonate and p-toluenesulfonate. Also included are salts of alkali metals such as sodium, potassium, alkaline earth metals such as magnesium or calcium, organic amines such as lower alkylamines or lower alcoholamines, and basic amino acids such as lysine, arginine, ornithine or ammonium salts. For example, compounds containing a basic nitrogen may be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-diol, hexaphosphate ... Examples of suitable pharma- ceutically acceptable salts include phenyl-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma- ceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 stEdition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0056] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX 4 + (Wherein, X is C 1 -C 4 Also included are salts derived from appropriate bases, such as alkyl groups, etc. Also included are base addition salts, such as sodium or potassium salts.

[0057] Also provided are compounds described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may have enhanced resistance to metabolism and thus may be useful for increasing the half-life of the compounds described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol.Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0058] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N,15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I can also be mentioned. 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I), (Ia-1), (Ia-2) or (Ia-3) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples below, using the appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0059] The compounds of the embodiments disclosed herein, or pharma- ceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be de?ned in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as Well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, e.g., chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. When no chirality is specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0060] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0061] "Stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms if they have one or more asymmetric centers or double bonds with asymmetric substitutions and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0062] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- rings, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0063] 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. Dashes before or after chemical groups are for convenience, and chemical groups may be shown with or without one or more dashes without losing their normal meaning. Wavy lines drawn across lines in structures indicate the point of attachment of a group. Dashed lines indicate optional bonds. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or the point at which they are attached to the rest of the molecule. For example, the group "-SO 2 CH 2 -" is "-CH 2 SO 2 -" and both may be linked in either orientation. Similarly, for example, an "arylalkyl" group may be attached to the remainder of the molecule at either the aryl or alkyl portion of the group. u~v" or "(C u ~C v A prefix such as "C" indicates that the following group has u to v carbon atoms. For example, "C 1-6 Alkyl" and "C 1 ~C 6 Both the terms "alkyl" and "alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0064] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0065] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug through some chemical or enzymatic pathway.

[0066] II. Compounds The present disclosure provides compounds of formula (I) as well as pharma- ceutically acceptable salts thereof.

[0067] In some embodiments, the compound has the structure of formula (I):

[0068] [ka] or a pharma- ceutically acceptable salt thereof.

[0069] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is represented by the formula: Z 1 is N or CR 1 and Z 2 is N or CR 2 and R 1 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, C 1~6haloalkoxy, or -CN; R 2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 2a , -C(O)OR 2a , -OC(O)R 2a , -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -C(=NR 2a )N(R 2b )(R 2c ), -N(R 2a )(R 2b ), -N(R 2a )N(R 2b )(R 2c ), -N(R 2a )N=C(R 2b )(OR 2c ), -OR 2a , -SR 2a , -S(O)R 2a , -S(O)(NR 2a )(R 2b ), -S(NR 2a )(NR 2b )(R 2c ), -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ), -N(R 2a )S(O) 2 (R 2b ), -P(R 2a )(R 2b), -P(O)(R 2a )(R 2b ), -P(O)(OR 2a )(R 2b ), -P(O)(OR 2a )(OR 2b ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where each alkyl, alkenyl, or alkynyl is independently the same or different, and 1 to 3 R 2d Each cycloalkyl may be optionally substituted with 1 to 3 R 2e Each aryl may be optionally substituted with 1 to 3 R 2f Each heterocycloalkyl may be optionally substituted with 1 to 3 R 2g Each heteroaryl may be optionally substituted with 1 to 3 R 2h group, Each R 2a , R 2b , and R 2c are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where aryl or heteroaryl, which may be the same or different, are each selected from 1 to 3 R 2j and optionally substituted with Or, R 2a , R 2b , and R 2c when attached to the same atom, can be combined with the atom to which they are attached to form a heterocycloalkyl, Each R 2d are independently -CN, -C(O)R 2d1 , -C(O)OR 2d1 , -OC(O)R 2d1 , -C(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)R 2d2 , -OC(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)OR 2d2 , -N(R 2d1 )(R 2d2 ), =O, -OR 2d1 , -SR 2d1 , -S(O)R 2d1 , -S(O)(NR 2d1 )(R 2d2 ), -S(O) 2 R 2d1 , -S(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )S(O) 2 R 2d2 , C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 2d1 and R 2d2 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, or C 1~6 is haloalkyl, Each R 2e , R 2f , R 2g , and R 2h are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, -CN, or -OH; Each R 2j is independently 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, or C 1~6 is haloalkoxy; R 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R3b , -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)OR 3b , -C(=NR 3a )N(R 3b )(R 3c ), -N(R 3a )(R 3b ), -N(R 3a )N(R 3b )(R 3c ), -N(R 3a )N=C(R 3b )(OR 3c ), -OR 3a , -SR 3a , -S(O)R 3a , -S(O)(NR 3a )(R 3b ), -S(NR 3a )(NR 3b )(R 3c ), -S(O) 2 R 3a , -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 (R 3b ), -P(R 3a )(R 3b ), -P(O)(R 3a )(R 3b ), -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where each alkenyl or alkynyl is independently selected from 1 to 3 R 3dEach cycloalkyl may be optionally substituted with 1 to 3 R 3e Each aryl may be optionally substituted with 1 to 3 R 3f Each heterocycloalkyl may be optionally substituted with 1 to 3 R 3g Each heteroaryl may be optionally substituted with 1 to 3 R 3h group, Each R 3a , R 3b , and R 3c are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 aryl, heterocycloalkyl, or heteroaryl; Or, R 3a , R 3b , and R 3c when attached to the same atom, can be combined with the atom to which they are attached to form a heterocycloalkyl, Each R 3d are independently -N(R 3d1 )(R 3d2 ), -OR 3d1 , C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 aryl, heterocycloalkyl, or heteroaryl; Each R 3d1 and R 3d2 are independently hydrogen, C 1~6Alkyl, or -C(O)O-(C 1~6 alkyl), Each R 3e , R 3f , R 3g , and R 3h are independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl or C 1~6 is haloalkoxy; R 4 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or -CN; R 5 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where alkyl is R 5a and optionally substituted with R 5a is -OSi(R 5a1 )(R 5a2 )(R 5a3 ) and R 5a1 , R 5a2 , and R 5a3 are each independently 1~6 is alkyl, R 6 is C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 6~12 aryl, or heteroaryl, where the aryl or heteroaryl may be the same or different; 1 to 3 R 6a each of which is optionally substituted; Each R 6a is independent, C 1~6 Alkyl, C 2~6 Alkenyl, C 2-8 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO 2 , -C(O)R 6b , -C(O)OR 6b , -OC(O)R 6b , -C(O)N(R 6b )(R 6c ), -N(R 6b )C(O)R 6c , -C(=NR 6b )N(R 6c )(R 6d ), -N(R 6b )(R 6c ), -OR 6b , -SR 6b , -S(O)R 6b , -S(O) 2 R 6b , -S(NR 6b )(NR 6c )R 6d , -S(O)(NR 6b )(R 6c ), -S(O) 2 N(R 6b )(R 6c ), -N(R 6b )S(O) 2 (R 6c ), -P(R 6b )(R 6c ), -P(O)(R 6b)(R 6c ), -P(O)(OR 6b )(R 6c ), -P(O)(OR 6b )(OR 6c ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each represent 1 to 3 R 6e and alkyl is optionally substituted with R 6f and alkynyl is optionally substituted with 1 to 4 R 6j and optionally substituted with Each R 6b , R 6c and R 6d are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6k and optionally substituted by Each R 6k is independently1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl); Each R 6e is independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO 2 , -C(O)R 6e1 , -C(O)OR 6e1 , -OC(O)R 6e1 , -C(O)N(R 6e1 )(R 6e2 ), -N(R 6e1 )C(O)R 6e2 , -OC(O)N(R 6e1 )(R 6e2 ), -N(R 6e1 )C(O)OR 6e2 , -C(=NR 6e1 )N(R 6e2 )(R 6e3 ), -N(R 6e1 )(R 6e2 ), =O, -OR 6e1 , -SR 6e1 , -S(O)R 6e1 , -S(NR 6e1 )(NR 6e2 ), -S(O)(NR 6e1 )(R 6e2 ), -S(O) 2 R 6e1 , -S(O) 2N(R 6e1 )(R 6e2 ),-SCIENCE FICTION 5 , -N(R 6e1 )S(O) 2 (R 6e2 ), -P(R 6e1 )(R 6e2 ), -P(O)(R 6e1 )(R 6e2 ), -P(O)(OR 6e1 )(R 6e2 ), -P(O)(OR 6e1 )(OR 6e2 ), -Si(R 6e1 )(R 6e2 )(R 6e3 ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6 Alkyl-heterocycloalkyl, heteroaryl, or C 1~6 alkyl-heteroaryl, where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6h each of which is optionally substituted, and alkyl is the same or different, 1 to 3 R 6m and optionally substituted with Each R 6e1 , R 6e2 , and R 6e3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6n and optionally substituted with Each R 6n is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6n1 , -C(O)OR 6n1 , -OC(O)R 6n1 , -C(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)R 6n2 , -OC(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)OR 6n2 , -C(=NR 6n1 )N(R 6n2 )(R 6n3 ), -N(R 6n1 )(R 6n2 ), =O, -OH, -SR 6n1 , -S(O)R 6n1 , -S(NR 6n1 )(NR 6n2 )R 6n3 , -S(O)(NR 6n1 )(R 6n2 ), -S(O) 2 R 6n1 , -S(O) 2 N(R 6n1 )(R 6n2 ), or -N(R 6n1 )S(O) 2 (R 6n2 ) and Each R 6n1 , R6n2 and R 6n3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 6h is independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6h1 , -C(O)OR 6h1 , -OC(O)R 6h1 , -C(O)N(R 6h1 )(R 6h2 ), -N(R 6h1 )C(O)R 6h2 , -OC(O)N(R 6h1 )(R 6h2 ), -N(R 6h1 )C(O)OR 6h2 , -C(=NR 6h1 )N(R 6h2 )(R 6h3 ), -N(R 6h1 )(R 6h2 ), =O, -OH, -SR 6h1 , -S(O)R 6h1 , -S(NR 6h1 )(NR 6h2 )R 6h3 , -S(O)(NR6h1 )(R 6h2 ), -S(O) 2 R 6h1 , -S(O) 2 N(R 6h1 )(R 6h2 ), -N(R 6h1 )S(O) 2 (R 6h2 ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl); Each R 6h1 , R 6h2 , and R 6h3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 6m are independently halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6m1 , -C(O)OR 6m1 , -OC(O)R 6m1 , -C(O)N(R 6m1 )(R 6m2 ), -N(R 6m3 )C(O)R 6m2 , -OC(O)N(R 6m1 )(R 6m2 ), -N(R 6m1 )C(O)OR 6m2 , -C(=NR 6m3 )N(R 6m1)(R 6m2 ), -N(R 6m1 )(R 6m2 ), =O, -OH, -SR 6m1 , -S(O)R 6m1 , -S(NR 6m1 )(NR 6m2 )R 6m3 , -S(O)(NR 6m1 )(R 6m2 ), -S(O) 2 R 6m1 , -S(O) 2 N(R 6m1 )(R 6m2 ), or -N(R 6m3 )S(O) 2 (R 6m2 ) and Each R 6m1 , R 6m2 , and R 6m3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), R 6f is -OSi(R 6f1 )(R 6f2 )(R 6f3 ) and R 6f1 , R 6f2 , and R 6f3 are each independently 1~6 is alkyl, Each R 6j is independently 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6Haloalkoxy, -CN, -C(O)R 6j1 , -C(O)OR 6j1 , -OC(O)R 6j1 , -C(O)N(R 6j1 )(R 6j2 ), -N(R 6j3 )C(O)R 6j2 , -OC(O)N(R 6j1 )(R 6j2 ), -N(R 6j1 )C(O)OR 6j2 , -C(=NR 6j3 )N(R 6j1 )(R 6j2 ), -N(R 6j1 )(R 6j2 ), =O, -OR 6j1 , -SR 6j1 , -S(O)R 6j1 , -S(NR 6j1 )(NR 6j2 ), -S(NR 6j1 )(NR 6j2 )R 6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O) 2 R 6j1 , -S(O) 2 N(R 6j1 )(R 6j2 ), -N(R 6j1 )S(O) 2 (R 6j2 ), -Si(R 6j1 )(R 6j2 )(R 6j3 ), C 3~10 Cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, where the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6p and optionally substituted with Each R 6j1 , R 6j2 , and R 6j3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 C optionally substituted with haloalkyl 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Each R 6p is independently 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6p1 , -C(O)OR 6p1 , -OC(O)R 6p1 , -C(O)N(R 6p1 )(R 6p2 ), -N(R 6p1 )C(O)R 6p2 , -OC(O)N(R 6p1 )(R 6p2 ), -N(R 6p1 )C(O)OR 6p2 , -C(=NR 6p3 )N(R 6p1 )(R 6p2 ), -N(R 6p1 )(R 6p2 ), =O, -OH, -SR 6p1 , -S(O)R 6p1 , -S(NR 6p1 )(NR 6p2 )R 6p3 , -S(O)(NR 6p1 )(R 6p2 ), -S(O) 2 R 6p1 , -S(O) 2 N(R 6p1 )(R 6p2 ), or -N(R6p1 )S(O) 2 (R 6p2 ) and Each R 6p1 , R 6p2 , and R 6p3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, Heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), Or R 5 and 1 R 6a together with the atom to which they are attached form a heterocycloalkyl, and 1 to 3 R 6g and optionally substituted with Each R 6g is independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or -CN; R 7 is hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10Cycloalkyl, heterocycloalkyl or C 1~6 alkyl-(heterocycloalkyl); each heterocycloalkyl is a 3- to 20-membered ring having 1-4 heteroatoms which are each independently N, O, or S; Each heteroaryl is a compound that is a 5-18 membered ring having 1-4 heteroatoms, each independently being N, O, or S.

[0070] In some embodiments, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein: Z 1 is N or CR 1 and R 1 is hydrogen, C 1~6 alkyl or halogen; Z 2 is N or CR 2 and R 2 is hydrogen, C 1~6 alkyl or halogen; R 3 is hydrogen, C 1~6 alkyl or halogen; R 4 is hydrogen, C 1~6 alkyl or halogen; R 7 is hydrogen or C 1~6 is alkyl, R 5 is C 1~6 Alkyl or C 1~6 is haloalkyl, R 6 is phenyl or heteroaryl, and the phenyl or heteroaryl is selected from 1 to 3 R 6a and heteroaryl is a 5- or 6-membered ring having 1-3 heteroatoms, each independently being N, O, or S; or

[0071] [ka] and X 1 , X 2 , X 3 and X 4 are each independently CH, N, or CR 6a with no more than two Xs 1 , X 2 , X 3 and X 4 is N with no more than two Xs 1 , X 2 , X 3 and X 4 CR 6a and Ring A is a 5-8 membered heterocycloalkyl optionally having 1-2 additional heteroatoms, each independently being N, O, or S; and optionally, ... 6g is replaced by Each R 6a are independently halogen or C 2~6 alkynyl, where alkynyl is a 1 to 4 R 6j and optionally substituted with Each R 6j are independently halogen, C 1~6 Haloalkyl, -OR 6j1 , -CN,C 3~10 cycloalkyl or heterocycloalkyl, each of which may be the same or different, and may be one to three R 6p and heterocycloalkyl is a 3-10 membered ring having 1-3 heteroatoms, each independently being N, O, or S; Each R 6j1 are independently hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl, Each R 6p are independently halogen, C 1~6 Alkyl or C 1~6 is haloalkyl, Each R 6g is independently 1~6Alkyl, halogen, or C 1~6 It is haloalkyl.

[0072] In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound having the structure of Formula (Ia-1):

[0073] [ka]

[0074] In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound having the structure of Formula (Ia-2):

[0075] [ka] In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound having the structure of Formula (Ia-3):

[0076] [ka]

[0077] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is R 5 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, Heterocycloalkyl, C 1~6Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), where heterocycloalkyl is a 5-8 membered ring having 1-2 heteroatoms, each independently being N, O, or S, and heteroaryl is a 5-6 membered ring having 1-2 heteroatoms, each independently being N, O, or S; R 6 is phenyl or heteroaryl, and the phenyl or heteroaryl is selected from 1 to 3 R 6a wherein heteroaryl is a 5-6 membered ring having 1-2 heteroatoms, each of which is independently N, O, or S.

[0078] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 5 C 1~6 Alkyl or C 1~6 In some embodiments, R 5 is C 1~3 Alkyl or C 1~3 In some embodiments, R 5 is -CH 2 CHF 2 It is.

[0079] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 6 is one or two R 6a In some embodiments, R 6 is one R 6a In some embodiments, R 6 is two R 6a In some embodiments, R 6 is C 2~6Phenyl substituted with alkynyl, the alkynyl being one or two R 6j and the phenyl is substituted with one additional R 6a In some embodiments, the additional R 6a is F. In some embodiments, R 6 F and C 2-6 Phenyl substituted with alkynyl, the alkynyl being one or two R 6j has been replaced with.

[0080] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 6 is one or two R 6a and R is a heteroaryl optionally substituted with R, wherein the heteroaryl is a 5-6 membered ring having 1-2 heteroatoms, each independently being N, O, or S. In some embodiments, the heteroaryl is a 5-6 membered ring having 1 N. In some embodiments, the heteroaryl is a 5-6 membered ring having 2 N. In some embodiments, R 6 But one or two R 6a In some embodiments, R is pyridyl optionally substituted with 6 is one R 6a In some embodiments, R is a pyridyl substituted with 6 is two R 6a In some embodiments, R is a pyridyl substituted with 6 is C 2~6 Pyridyl substituted with alkynyl, wherein the alkynyl is selected from one or two R 6j Pyridyl is optionally substituted with one additional R 6a In some embodiments, the additional R 6a is F. In some embodiments, R 6 F and C 2~6Pyridyl substituted with alkynyl, wherein the alkynyl is one or two R 6j has been replaced with.

[0081] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 6 but

[0082] [ka] In some embodiments, R 6 teeth

[0083] [ka] It is.

[0084] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 6 but,

[0085] [ka] It is a compound wherein

[0086] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 6 but,

[0087] [ka] It is a compound wherein

[0088] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, comprises R 5 and one R 6atogether with the atoms to which they are attached, 1 to 3 R 6g In some embodiments, the heterocycloalkyl contains one additional heteroatom selected from the group consisting of N, O, and S. In some embodiments, the heterocycloalkyl contains one additional heteroatom of N. In some embodiments, the heterocycloalkyl contains one additional heteroatom of O. In some embodiments, the heterocycloalkyl does not contain any additional heteroatoms. In some embodiments, the heterocycloalkyl is a 5-9 membered ring. In some embodiments, the heterocycloalkyl is a 6 membered ring. In some embodiments, the heterocycloalkyl is a 7 membered ring. In some embodiments, the heterocycloalkyl is an 8 membered ring. In some embodiments, the heterocycloalkyl is unsubstituted.

[0089] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0090] [ka] and n is 0, 1, or 2; ring A is a 5-8 membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms, each independently being N, O, or S; and optionally ring A is a 5-8 membered heterocycloalkyl optionally having 1 or 2 R 6gIn some embodiments, ring A contains one additional heteroatom of N. In some embodiments, ring A contains one additional heteroatom of O. In some embodiments, ring A contains no additional heteroatoms. In some embodiments, ring A is a 6-8 membered ring. In some embodiments, ring A is a 6 membered ring. In some embodiments, ring A is a 7 membered ring. In some embodiments, ring A is an 8 membered ring. In some embodiments, ring A is unsubstituted.

[0091] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, is

[0092] [ka] and Ring A is a compound that is a 5-8 membered heterocycloalkyl, optionally with 1 or 2 additional heteroatoms, each independently being N or O. In some embodiments,

[0093] [ka] In some embodiments,

[0094] [ka] In some embodiments,

[0095] [ka] It is.

[0096] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0097] [ka] is a compound.

[0098] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, is

[0099] [ka] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0100] [ka] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0101] [ka] It is a compound wherein

[0102] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is Each R 6a is independently C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO 2 , -C(O)R 6b , -C(O)N(R 6b (R 6c -N(R 6b (R6c ), -OR 6b , C 3~10 Cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each have 1 to 3 R 6e and alkynyl is optionally substituted with 1 to 3 R 6j and optionally substituted with Each R 6b and R 6c are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~10 is cycloalkyl, Each R 6j is independently 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -C(O)R 6j1 , -C(O)OR 6j1 , -OC(O)R 6j1 , -C(O)N(R 6j1 )(R 6j2 ), -N(R 6j3 )C(O)R 6j2 , -OC(O)N(R 6j1 )(R 6j2 ), -N(R 6j1 )C(O)OR 6j2 , -C(=NR 6j3 )N(R 6j1 )(R 6j2 ), -N(R 6j1 )(R 6j2 ), =O, -OR 6j1 , -SR 6j1 , -S(O)R 6j1 , -S(NR 6j1 )(NR 6j2 ), -S(NR 6j1 )(NR 6j2 )R 6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O) 2 R 6j1, -S(O) 2 N(R 6j1 )(R 6j2 ), -N(R 6j1 )S(O) 2 (R 6j2 ), -Si(R 6j1 )(R 6j2 )(R 6j3 ), C 3~10 Cycloalkyl, C 6-12 aryl, heterocycloalkyl, or heteroaryl, where the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different, and 1 to 3 R 6p and optionally substituted with Each R 6j1 , R 6j2 , and R 6j3 are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~10 is cycloalkyl, Each R 6p is independently C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, -CN, -C(O)R 6p1 , -C(O)OR 6p1 , -OC(O)R 6p1 , -C(O)N(R 6p1 (R 6p2 -N(R 6p1 )C(O)R 6p2 , -OC(O)N(R 6p1 (R 6p2 ), -N(R 6p1 )C(O)OR 6p2 , ═O, or —OH; Each R 6p1 and R 6p2 are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~10 is cycloalkyl, Each R 6e is independently C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, -C(O)OR 6e1 , -OC(O)R 6e1 , -C(O)N(R 6e1 (R 6e2 -N(R 6e1 )C(O)R 6e2 , -OR 6e1 , -S(O) 2 N(R 6e1 (R 6e2 ), -N(R 6e1 )S(O) 2 (R 6e2 ), heterocycloalkyl, C 1~6 Alkyl-heterocycloalkyl, heteroaryl, or C 1~6 alkyl-heteroaryl, wherein cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each have 1 to 3 R 6h and the alkyl is optionally substituted with 1 to 3 R 6m and optionally substituted with Each R 6e1 and R 6e2 are independently hydrogen or C 1~6 is alkyl, Each R 6m are independently halogen, -CN or -OH; Each R 6h are independently halogen, C 1~6 Alkyl, =O or C 1~6 A compound that is a haloalkyl.

[0103] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is Each R 6a is independently C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~12aryl, heterocycloalkyl, or heteroaryl, where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each have 1 to 3 R 6e and alkynyl is optionally substituted with 1 to 3 R 6j and optionally substituted with Each R 6j are independently halogen, -OR 6j1 , -CN,C 3~10 cycloalkyl, heterocycloalkyl, where cycloalkyl or heterocycloalkyl is selected from 1 to 3 R 6p and optionally substituted with Each R 6j1 are independently hydrogen or C 1~6 is alkyl, Each R 6p is independently 1~6 Alkyl, halogen, C 1~6 haloalkyl, =O, -CN or -OH; Each R 6e is independently 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 3~6 cycloalkyl, or heterocycloalkyl, where cycloalkyl or heterocycloalkyl is selected from 1 to 3 R 6h and optionally substituted with Each R 6h are independently halogen, C 1~6 Alkyl, =O or C 1~6 A compound that is a haloalkyl.

[0104] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is Each R 6a is independently 2~6 Alkynyl, halogen, C 6~12aryl, a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms each independently being N or O, or a 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms each independently being N, O, or S, and each of the aryl, heterocycloalkyl, and heteroaryl is selected from 1 to 3 R 6e and alkynyl is optionally substituted with 1 to 3 R 6j and optionally substituted with Each R 6j are independently halogen, -OR 6j1 , -CN,C 3~10 cycloalkyl, heterocycloalkyl, where cycloalkyl or heterocycloalkyl is selected from 1 to 3 R 6p and optionally substituted with R 6j1 is hydrogen or C 1~6 is alkyl, Each R 6p is independently 1~6 Alkyl, halogen, =O, -OH or C 1~6 is haloalkyl, Each R 6e is independently 1~6 Alkyl, halogen, C 1~6 haloalkyl, cyclopropyl, heterocycloalkyl ring having 1 to 2 heteroatoms, each independently being N, O, or S, and cyclopropyl or heterocycloalkyl may each be represented by 1 to 3 R 6h and optionally substituted with Each R 6h are independently halogen, C 1~6 Alkyl, =O or C 1~6 A compound that is a haloalkyl.

[0105] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, comprises each R 6a C 2~6alkynyl or halogen, where alkynyl is the same or different and is selected from 1 to 3 R 6j is a compound optionally substituted with

[0106] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, comprises each R 6a are independently 1 to 3 R which may be the same or different; 6j C replaced with 2~6 The compound is an alkynyl.

[0107] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, comprises each R 6a but,

[0108] [ka] and R 6j is substituted with -OH or -CN 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 Cycloalkyl, or C 1~6 Alkyl or C 1~6 The compound is a 4-6 membered heterocycloalkyl optionally substituted with haloalkyl.

[0109] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is Each R 6j are independently halogen, C 1~6 Haloalkyl, -OR 6j1 , -CN,C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is selected from 1 to 3 R 6pand optionally substituted with R 6j1 is hydrogen or C 1~6 is alkyl, Each R 6p is independently 1~3 Alkyl, C 1~3 A compound that is a haloalkyl.

[0110] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, comprises each R 6p Independently, Me, -CF 3 , -CH 2 F, -CF 2 CH 3 , or -CHF 2 It is a compound wherein

[0111] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, comprises each R 6j are independently halogen, C 1~6 Compounds that are haloalkyl, -OH, -OMe, or -CN.

[0112] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises each R 6j are independently -OH, -CN, -F, -CF 3 ,

[0113] [ka] It is a compound wherein

[0114] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises each R 6j became independent, C 3~6cycloalkyl or 4- to 6-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be the same or different. 1~3 Haloalkyl and C 1~3 The compound is optionally substituted with 1 to 3 substituents selected from alkyl.

[0115] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises each R 6a became independent and became F,

[0116] [ka] In some embodiments, at least one R 6a teeth,

[0117] [ka] In some embodiments, the compound has an additional R 6a In some embodiments, additional R 6a is F.

[0118] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0119] [ka] It is a compound wherein

[0120] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0121] [ka] In some embodiments,

[0122] [ka] In some embodiments,

[0123] [ka] It is.

[0124] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0125] [ka] It is a compound wherein

[0126] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0127] [ka] It is a compound wherein

[0128] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof is

[0129] [ka] It is a compound wherein

[0130] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6haloalkyl or -CN. In some embodiments, R 1 is hydrogen.

[0131] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 haloalkyl or -CN. In some embodiments, R 2 is Cl. In some embodiments, R 2 is hydrogen.

[0132] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 3 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 In some embodiments, R 3 is hydrogen, C 1~3 Alkyl, halogen, C 1~3 haloalkyl or -CN. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is F.

[0133] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 In some embodiments, R 4 is hydrogen, C 1~3 In some embodiments, R 4 is F. In some embodiments, R 4is hydrogen.

[0134] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3) or a pharma- ceutically acceptable salt thereof comprises R 7 is hydrogen or C 1~6 In some embodiments, R 7 is Et(-CH 2 CH 3 In some embodiments, R 7 is Me(-CH 3 ).

[0135] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2) or (Ia-3), or a pharma- ceutically acceptable salt thereof, is a compound having the structure of a compound in Table 1.

[0136] In some embodiments, the disclosure provides a compound having a structure as shown in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound having a structure as shown in Table 1.

[0137] One of skill in the art will recognize that when a group is substituted with more than one substituent, the two or more substituents can be the same or different, unless otherwise specified.

[0138] Those of skill in the art will recognize the groups disclosed herein (e.g., R 1 Each and every embodiment of the remaining groups (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 It is recognized that each of the above-mentioned embodiments (e.g., each of the above-mentioned formulas) can be combined with any other embodiment to produce a complete compound of formula (I), or any formula described herein, or a pharma- ceutically acceptable salt, each of which is considered to be within the scope of this disclosure.

[0139] [Table 1-1]

[0140]

Table 1-2

[0141]

Table 1-3

[0142]

Table 1-4

[0143]

Table 1-5

[0144]

Table 1-6

[0145]

Table 1-7

[0146]

Table 1-8

[0147]

Table 1-9

[0148]

Table 1-10

[0149]

Table 1-11

[0150] [Table 1-12]

[0151] In vivo metabolic products of the compounds described herein are also within the scope of the present invention, so long as such products are novel and unobvious over the prior art. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Thus, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a time sufficient to yield metabolic products. Such products are typically radiolabeled (e.g., 14 C or 3 H) The compound is prepared and identified by parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing time sufficient for metabolism to occur (typically about 30 seconds to about 30 hours), and isolating its conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to epitopes remaining in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. In general, analysis of metabolites is performed similarly to conventional drug metabolism studies known to those skilled in the art.

[0152] In some embodiments, the compounds of the present disclosure have selectivity for DGKα over one or more of the other DGK isoforms, e.g., β, γ, δ, ε, ζ, η, θ, ι, and / or κ. Selectivity can be measured by relative values ​​in corresponding biochemical assays, e.g., inhibitory activity of DGK isoforms. In some embodiments, the compounds have selectivity for DGKα over one or more of the other DGK isoforms, e.g., β, γ, δ, ε, ζ, η, θ, ι, and / or κ, including activity against DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKι, and / or DGKκ, and have selectivity for DGKα over one or more of the other DGK isoforms, e.g., β, γ, δ, ε, ζ, η, DGKθ, DGKι, and / or DGKκ, including activity against DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGK ... and have selectivity for DGKα over one or more of the other DGK isoforms, e.g., selectivity for DGKα over one or more of the other DGK isoforms, e.g., selectivity for DGKα over one or more of the other D 50is greater than about 30 μM in biochemical assays.

[0153] In some embodiments, compounds of the disclosure have at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000-fold or more selectivity for DGKα over one or more, e.g., 2, 3, 4, 5, 6, 7, 8, or 9 or more, other DGK isoforms, including DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKι, and / or DGKκ. In some embodiments, the compound has selectivity for DGKα over DGKβ and / or DGKγ at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more. In some embodiments, the compound has selectivity for DGKα over DGKβ at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more. In some embodiments, the compound has selectivity for DGKα over DGKγ at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more.In some embodiments, the compound has selectivity for DGKα over DGKδ by at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more. In some embodiments, the compound has at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more selectivity for DGKα over DGKε. In some embodiments, the compound has selectivity for DGKα over DGKζ by at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more. In some embodiments, the compounds have selectivity for DGKα over DGKη by at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more. In some embodiments, the compound has at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more selectivity for DGKα over DGKθ.In some embodiments, the compounds have selectivity for DGKα over DGKι by at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more. In some embodiments, the compound has selectivity for DGKα over DGKκ by at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000, or about 10000 times or more.

[0154] III. Pharmaceutical Preparations In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a pharma- ceutical effective amount of a compound of the present disclosure or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier or excipient. Also provided herein is a pharmaceutical formulation comprising a pharma- ceutical effective amount of a compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) or a pharma- ceutical acceptable salt, solvate, and / or ester thereof, and a pharma- ceutical acceptable carrier or excipient.

[0155] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination therapy can be used with a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3) or a pharma- ceutically acceptable salt thereof, such as the agents and therapies described herein.

[0156] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3) and an additional therapeutic agent, wherein the additional therapeutic agent is an anti-cancer agent. In some embodiments, the pharmaceutical composition is a pharmaceutical composition where the additional therapeutic agent is independently an anti-neoplastic agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, or ablation therapy. In some embodiments, the pharmaceutical composition is a pharmaceutical composition where the additional therapeutic agent is independently Rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, atezolizumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab. In some embodiments, the pharmaceutical composition is a pharmaceutical composition where the additional therapeutic agent is a PD-1 / PD-L1 inhibitor. In some embodiments, the pharmaceutical composition is a pharmaceutical composition where the additional therapeutic agent is a vaccine.

[0157] In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the additional therapeutic agent comprises one or more immune cell populations, such as natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TIL), and dendritic cells (DC).

[0158] In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the additional therapeutic agent comprises one or more chimeric antigen receptors (CARs).

[0159] In some embodiments, the pharmaceutical composition is one in which the additional therapeutic agent comprises immunotherapy, immunostimulatory therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, or a combination thereof.

[0160] In some embodiments, a pharmaceutical composition comprises a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3) and an additional therapeutic agent, wherein the additional therapeutic agent is an agent effective against a viral infection. In some embodiments, the viral infection is HIV. In some embodiments, the viral infection is Hepatitis B virus. In some embodiments, a pharmaceutical composition comprises a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3) and an additional therapeutic agent, wherein the additional therapeutic agent comprises a vaccine.

[0161] In some embodiments, the pharmaceutical composition is for use in the treatment of cancer.

[0162] In some embodiments, the pharmaceutical composition is for use in treating an HIV or Hepatitis B infection.

[0163] In some embodiments, the compounds disclosed herein are formulated with conventional carriers and excipients, which may be selected according to ordinary practice. Tablets may contain excipients, glidants, fillers, binders, and the like. Aqueous formulations may be prepared in sterile form and may be isotonic, for example, if intended for delivery other than by oral administration. In some embodiments, the formulations may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, for example, from about 7 to about 10.

[0164] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in a pharmaceutical formulation. In some embodiments, the formulation for veterinary and / or human use comprises at least one compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) or its pharma- ceutically acceptable salt, solvate, and / or ester, together with one or more acceptable carriers and optionally other therapeutic components, such as additional therapeutic components discussed herein. In some embodiments, the carrier(s) is "acceptable" in the sense of being compatible with the other components of the formulation and physiologically harmless to the recipient thereof.

[0165] In some embodiments, formulations of the present disclosure include those suitable for the aforementioned routes of administration. In some embodiments, the formulations are provided in unit dosage form. The formulations may be prepared by methods known in the art of pharmacy. Techniques and formulations may be found, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include, for example, the step of bringing into association the active ingredient with the carrier which may include one or more accessory ingredients. In some embodiments, the formulations are prepared by bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, in some embodiments, shaping the product.

[0166] Formulations suitable for oral administration may be presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, e.g., a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt, solvate, and / or ester thereof; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; In some embodiments, the active ingredient is administered as a bolus, electuary, or paste.

[0167] Tablets can be prepared, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared, for example, by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be produced, for example, by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored. In some embodiments, the tablets are formulated to provide a slow or controlled release of the active ingredient therefrom.

[0168] For infections of the eye or other external tissues, such as the mouth and skin, a compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) may be applied in a topical ointment or cream containing, for example, about 0.075 to about 20% w / w (including active ingredient(s) in increments of about 0.1% w / w ranging from about 0.1% to about 20%, such as about 0.6% w / w, about 0.7% w / w, etc.), for example, about 0.2 to about 15% w / w, and for example, about 0.5 to about 10% w / w. When formulated into an ointment, the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) may be used with either a paraffinic or water-miscible ointment base. Alternatively, the compounds of Formula (I), (Ia-1), (Ia-2) or (Ia-3) may be formulated in a cream containing an oil-in-water cream base.

[0169] Optionally, the aqueous phase of the cream base may contain, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. In some embodiments, the topical formulation may contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.

[0170] The oily phase of the emulsion can be composed of known ingredients in a known manner. The phase can comprise only an emulsifier (also known as emulgent), but can also comprise, for example, a mixture of at least one emulsifier with a fat or oil, or with both a fat and an oil. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. In some embodiments, the emulsion comprises both an oil and a fat. Together, the emulsifier with or without a stabilizer constitutes the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0171] Suitable emulsifiers and emulsion stabilizers for use in the formulation include, for example, Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0172] The selection of suitable oils or fats for the formulation is based on achieving the desired properties. The cream can be a non-oily, non-staining, and washable product with the appropriate consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP. These can be used alone or in combination, depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0173] In some embodiments, the pharmaceutical formulation herein comprises one or more pharma- ceutically acceptable carriers or excipients, and optionally in combination with other therapeutic agents. Pharmaceutical formulations containing active ingredients may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0174] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0175] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxy-benzoates, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0176] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin. Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0177] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweetening, flavoring, and coloring agents, may also be present.

[0178] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners, such as glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring, or a coloring agent.

[0179] The pharmaceutical compositions may be in the form of a sterile injectable or intravenous preparation, such as a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. Sterile injectable or intravenous preparations may also include sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or may be prepared as lyophilized powders. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be used as a solvent or suspending medium. For this purpose, any solventless fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0180] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending on the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans can contain about 1 to about 1000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which can vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain about 3 to about 500 μg of active ingredient per milliliter of solution, such that infusion of a suitable volume can occur at a rate of about 30 mL / hour.

[0181] Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient may be present in such formulations in a concentration of about 0.5 to about 20%, for example, about 0.5 to about 10%, e.g., about 1.5% w / w.

[0182] Formulations suitable for topical administration to the mouth include, for example, lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0183] Formulations for rectal administration may be presented as a suppository containing a suitable base comprising, for example, cocoa butter or a salicylate.

[0184] Formulations suitable for pulmonary or nasal administration have particle sizes ranging from about 0.1 to about 500 micrometers, such as about 0.5, about 1, about 30, or about 35, and are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds previously used to treat cancer, as described below.

[0185] In some embodiments, the inhalable composition comprises a compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhalable composition is suitable for treating cancer. In some embodiments, the pharma- ceutically acceptable salt is an inorganic acid salt, including hydrochloride, hydrobromide, sulfate, or phosphate. For example, such salts may be less likely to cause pulmonary inflammation compared to other salts. In some embodiments, the inhalable composition is delivered to the endobronchial space in an aerosol comprising particles having a mass median aerodynamic diameter (MMAD) of about 1 to about 5 μm. In some embodiments, the compound of (I), (Ia-1), (Ia-2), or (Ia-3) is formulated for aerosol delivery using a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0186] Non-limiting examples of nebulizers include atomizers, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers, including nebulizers that utilize adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010,23 Supp 1,S1-S10). Jet nebulizers use air pressure to break up liquid solutions into aerosol droplets. Ultrasonic nebulizers work by piezoelectric crystals that shear liquid into small aerosol droplets. Pressurized nebulizer systems create aerosol droplets by applying pressure to force the solution through small pores. Vibrating porous plate devices use rapid vibration to shear the liquid stream into the appropriate droplet size.

[0187] In some embodiments, the formulation for nebulization is delivered to the endobronchial space in an aerosol containing particles with a MMAD of about 1 μm to about 5 μm, using a nebulizer capable of aerosolizing the formulation of the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) into particles of the required MMAD. To optimize therapeutic efficacy and to avoid upper respiratory tract and systemic side effects, the majority of the aerosolized particles should not have an MMAD greater than about 5 μm. If the aerosol contains a large number of particles with an MMAD greater than about 5 μm, the particles will be deposited in the upper respiratory tract, reducing the amount of drug delivered to sites of inflammation and bronchial narrowing in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 μm, the particles may remain suspended in the inhaled air, in some cases, and then be exhaled during expiration.

[0188] When formulated and delivered according to the methods herein, the nebulized aerosol formulation delivers a therapeutically effective dose of the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) to a therapeutic target, such as a site of cancer. The amount of drug administered can be adjusted to reflect the efficiency of delivery of a therapeutically effective dose of the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3). In some embodiments, the combination of an aqueous aerosol formulation with a nebulizer, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer allows delivery of about 20 to about 90%, e.g., about 70%, of the administered dose of the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) into the airways, depending on the nebulizer. In some embodiments, about 30 to about 50% of the active compound is delivered. For example, about 70 to about 90% of the active compound can be delivered.

[0189] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) or a pharma- ceutically acceptable salt thereof is delivered as a dry inhalable powder. The compound is administered intrabronchially as a dry powder formulation using a dry powder inhaler or a metered dose inhaler to effectively deliver fine particles of the compound to the endobronchial space. For delivery by DPI, the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) is processed by milling, spray drying, critical fluid processing, or precipitation from solution into particles having a MMAD of primarily about 1 μm to about 5 μm. Media milling, jet milling, and spray drying devices and procedures that can result in particle sizes with a MMAD of about 1 μm to about 5 μm are well known in the art. In some embodiments, excipients are added to the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) before processing into particles of the required size. In some embodiments, an excipient is blended with the particles of a desired size to aid in the dispersion of the drug particles, for example, by using lactose as an excipient.

[0190] Particle size determination is performed using devices well known in the art, such as a multi-stage Anderson cascade impactor or other suitable methods, such as those specifically cited in the United States Pharmacopeia Chapter 601 as characteristic devices for aerosols in metered dose and dry powder inhalers.

[0191] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2) or (Ia-3) can be delivered as dry powder using a device such as a dry powder inhaler or other dry powder dispersion device.Non-limiting examples of dry powder inhalers and devices include those disclosed in U.S. Patent No. 5,458,135, U.S. Patent No. 5,740,794, U.S. Patent No. 5,775320, U.S. Patent No. 5,785,049, U.S. Patent No. 3,906,950, U.S. Patent No. 4,013,075, U.S. Patent No. 4,069,819, U.S. Patent No. 4,995,385, U.S. Patent No. 5,522,385, U.S. Patent No. 4,668,218, U.S. Patent No. 4,667,668, U.S. Patent No. 4,805,811 and U.S. Patent No. 5,388,572.There are two main designs of dry powder inhalers. One design is a metered device where a reservoir for the drug is placed within the device and the patient adds a dose of drug to the inhalation chamber. The second design is a factory-premetered device where each individual dose is manufactured in a separate container. Both systems rely on the formulation of the drug into small particles of about 1 μm to about 5 μm MMAD, often requiring co-formulation with larger excipient particles such as, but not limited to, lactose. The drug powder is placed in the inhalation chamber (either by metering in the device or by dividing a factory-premetered dose) and the patient's inspiratory flow accelerates the powder as it exits the device and into the oral cavity. The non-laminar flow characteristics of the powder pathway break up excipient-drug agglomerates and clumps of large excipient particles stick to the back of the throat while smaller drug particles are deposited deep in the lungs. In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, is delivered as a dry powder using any type of dry powder inhaler described herein, wherein the MMAD of the dry powder, excluding any excipients, is primarily in the range of about 1 μm to about 5 μm.

[0192] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3) is delivered as a dry powder using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in U.S. Pat. No. 5,261,538, U.S. Pat. No. 5,544,647, U.S. Pat. No. 5,622,163, U.S. Pat. No. 4,955,371, U.S. Pat. No. 3,565,070, U.S. Pat. No. 3,361,306, and U.S. Pat. No. 6,116,234. In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof, is delivered as a dry powder using a metered dose inhaler, and the MMAD of the dry powder, excluding any excipients, is primarily in the range of about 1 to about 5 μm.

[0193] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0194] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0195] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Unit-dose formulations include those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient, as hereinbefore recited.

[0196] It should be understood that in addition to the ingredients specifically mentioned above, the formulations may include other agents standard in the art for the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0197] There is further provided veterinary compositions comprising at least one active ingredient as above defined, together with a veterinary carrier therefor.

[0198] Veterinary carriers can be solid, liquid, or gaseous substances that are useful for the purpose of administering the compositions and are otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0199] The compounds herein are used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more of said compounds as active ingredients, where the release of the active ingredient is controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0200] The effective dose of the active ingredient depends at least on the nature of the condition to be treated, the toxicity, the delivery method, and the pharmaceutical formulation, and can be determined by the clinician using conventional dose escalation studies. This can be expected to be about 0.0001 to about 100 mg / kg body weight per day, typically about 0.01 to about 10 mg / kg body weight per day, more typically about 0.01 to about 5 mg / kg body weight per day, and most typically about 0.05 to about 0.5 mg / kg body weight per day. For example, the candidate daily dose for a human adult weighing about 70 kg can range from about 1 mg to about 1000 mg, for example, about 5 mg to about 500 mg, and can take the form of a single dose or multiple doses.

[0201] IV. Route of Administration One or more of the compounds of formula (I), (Ia-1), (Ia-2) or (Ia-3) (referred to herein as active ingredients) are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the route may vary, for example, depending on the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be administered orally.

[0202] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). It will be understood that the route may vary, for example, depending on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0203] The compounds of the present disclosure may be administered to an individual according to an effective dosing regimen for a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, in some embodiments, the compounds are administered on a daily or intermittent schedule for the duration of the individual's life.

[0204] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0205] The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once a day.

[0206] The compound may be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound may include about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example, about 0.3 mg to about 30 mg per day, or for example, about 30 mg to about 300 mg per day.

[0207] The compounds of the present disclosure may be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure (e.g., from about 1 mg to about 1000 mg of compound). Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, e.g., from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg per dose, or about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 mg per dose. The dose can be administered hourly, daily, or weekly. For example, a dose may be administered about once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or about once every 24 hours. A dose may be administered about once every 1, 2, 3, 4, 5, 6 days, or about once every 7 days. A dose may be administered about once every 1, 2, 3 weeks, or about once every 4 weeks. In some embodiments, a dose may be administered about once every week. A dose may be administered about once every month.

[0208] Other therapeutically effective amounts of the compounds of the present disclosure are about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mg per dose.

[0209] The frequency of administration of the compounds of the present disclosure can be determined by the needs of an individual patient, and can be, for example, once a day, or twice a day, or more. Administration of the compounds continues as long as necessary to treat the disease or condition. For example, the compounds can be administered to a human with cancer for a period of about 20 days to about 180 days, or for example, for a period of about 20 days to about 90 days, or for example, for a period of about 30 days to about 60 days.

[0210] Administration can be intermittent, with a period of several days or more during which the patient receives a daily dose of the disclosed compound, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day, or three times per week. As a further example, the patient can be administered a dose of the compound daily for a period of about 1 to about 14 days, followed by a period of about 7 to about 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., about 1 to about 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of administration of the compound followed by non-administration of the compound can be repeated as clinically required to treat the patient.

[0211] In some embodiments, a pharmaceutical composition is provided that includes a compound of the present disclosure or a pharma- ceutical acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents, and a pharma- ceutical acceptable excipient.

[0212] In some embodiments, kits are provided that include a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents.

[0213] In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents.

[0214] In some embodiments, when the compounds of the present disclosure are combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or as a sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0215] In some embodiments, compounds of the present disclosure are combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0216] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0217] In order to prolong the effect of the compounds of the present disclosure, it is often desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0218] V. Combination Therapy The compounds of the present disclosure and compositions provided herein may also be used in combination with other active therapeutic agents, which may be, where appropriate, anti-cancer or anti-viral agents, such as anti-HIV or anti-hepatitis B virus agents.

[0219] A. Combination Therapy 1. Cancer In some embodiments, the compounds described herein may be administered in combination with one or more additional therapeutic agents, such as inhibitory immune checkpoint blockers or inhibitors, stimulatory immune checkpoint stimulators, agonists, or activators, chemotherapeutic agents, anti-cancer agents, radiotherapeutic agents, anti-neoplastic agents, anti-proliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapeutic agents, therapeutic antigen binding molecules (mono- and multispecific antibodies and fragments thereof in any format (e.g., but not limited to, DARTs®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimetics (e.g., but not limited to, adnectins, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins, and the like). and / or nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editors, cells comprising a chimeric antigen receptor (CAR), including, for example, T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics, cells comprising a genetically engineered T cell receptor (TCR-T), or any combination thereof.

[0220] Exemplary Targets In some embodiments, the one or more additional therapeutic agents include, but are not limited to, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator or suppressor of a target (e.g., a polypeptide or polynucleotide), including, but not limited to, an Abelson murine leukemia viral oncogene homolog 1 gene (ABL, e.g., ABL1), acetyl-CoA carboxylase (e.g., ACC1 / 2), activated CDC kinase (ACK, e.g., ACK1), adenosine deaminase, adenosine triphosphate (ATP), or adenosine triphosphate (ATP). Synth receptors (e.g., A2BR, A2aR, A3aR), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aerolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha 1 adrenergic receptor, alpha 2 adrenergic receptor, alpha-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, e.g., ALK1), androgen receptor, angiopoietin (e.g., ligand-1, ligand -2), angiotensinogen (AGT) gene, mouse thymoma viral oncogene homolog 1 (AKT) protein kinase (e.g., AKT1, AKT2, AKT3), apolipoprotein AI (APOA1) gene, apoptosis inducer, apoptosis protein (e.g., 1, 2), apoptosis signal-regulating kinase (ASK, e.g., ASK1), arginase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad3-related (ATR) serine / threonine protein kinase, Aurora protein kinase (e.g., 1, 2), Axl tyrosine kinase receptor, 4-1BB ligand (CD137L), baculovirus IAP repeat containing 5 (BIRC5) gene, basigin, B cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta adrenergic receptor, beta catenin, B lymphocyte antigen CD19, B lymphocyte antigen CD20, B lymphocyte cell adhesion molecule, B lymphocyte stimulatory factor ligand,Bone morphogenetic protein-10 ligand, bone morphogenetic protein-9 ligand modulator, brachyury protein, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinase (CaMK, e.g., CAMKII), cancer testis antigen 2, cancer testis antigen 1B (CTAG1), cancer / testis antigen 1B (CTAG2), canine ovarian tumor suppressor (CVT) gene, ... Navinoid receptors (e.g., CB1, CB2, etc.), carbonic anhydrase, casein kinases (CK, e.g., CKI, CKII), caspases (e.g., caspase-3, caspase-7, caspase-9), caspase-8 apoptosis-associated cysteine ​​peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK-activating kinase (CAK), checkpoint kinases (e.g., CHK1, CHK2), chemokine (CC motif) receptors (e.g., CCR2, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CCR13, CCR14, CCR15, CCR16, CCR17, CCR18, CCR19, CCR20, CCR21, CCR22, CCR23, CCR24, CCR25, CCR26, CCR27, CCR28, CCR29, CCR210, CCR211, CCR222, CCR23, CCR24, CCR25, CCR26, CCR27, CCR28, CCR29, CCR211, CCR222, CCR23, CCR24, CCR25, CCR26, CCR27, CCR28, CCR29, CCR29, CCR212, CCR213, CCR222, CCR23, CCR24, CCR25, CCR26, CCR27, CCR28, CCR29, CCR29, CCR214, CCR215, CCR216, CCR217, CCR218, CCR219, CCR222, CCR23, CCR2 CR8), chemokine (CXC motif) receptors (e.g., CXCR1, CXCR2, CXCR3, and CXCR4), chemokine CC21 ligand, cholecystokinin CCK2 receptor, human chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), CISH (cytokine-inducible SH2-containing protein), claudins (e.g., 6, 18), cluster of differentiation (CD) receptors, e.g., CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue growth factor, COP9 signalosome subunit 5,CSF-1 (colony stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), cyclin D1, cyclin G1, cyclin-dependent kinases (CDKs such as CDK 1, CDK 12, CDK 1 B, CDK 2-9), cyclooxygenases (e.g., COX1, COX2), CYP2B1 gene, cysteine ​​palmitoyltransferase porcupine, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein-4, DDR2 gene, DEAD-box helicase 6 (DDX6), death receptor 5 (DR5, TRAILR2), death receptor 4 (DR 4, TRAILR 1), Delta-like protein ligands (e.g., 3, 4), deoxyribonucleases, deubiquitinating enzymes (DUBs), Dickkopf-1 ligands, dihydrofolate reductases (DHFRs), dihydropyrimidine dehydrogenases, dipeptidyl peptidase IV, discoidin domain receptors (DDRs, e.g., DDR1), diacylglycerol kinase zeta (DGKZ), DNA-binding proteins (e.g., HU-beta), DNA-dependent protein kinases, DNA gyrases, DNA methyltransferases, DNA polymerases, and the like. alpha, etc.), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, E3 ubiquitin-protein ligase (e.g., RNF128, CBL-B), echinoderm microtubule-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulum aminopeptidase (ERAP, e.g., ERAP1, ERAP2), endoplasmin, endosialin, endostatin, endothelin (e.g., ET-A, ET-B), Enhancer of zeste homolog 2 (EZH2),Ephrin (EPH) tyrosine kinase (e.g., Epha3, Ephb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, Epigen, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-Erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β Dehydrogenases, estrogen receptors (e.g., α, β), estrogen-related receptors, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinases (e.g., 1, 2), extracellular signal-regulated kinase (ERK), hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factors (e.g., Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand , FGF-5 ligand, fibroblast growth factor (FGF, e.g., FGF1, FGF2, FGF4), fibronectin, focal adhesion kinase (FAK, e.g., FAK2), folate hydrolase, prostate-specific membrane antigen 1 (FOLH1), folate receptor (α, etc.), folate, folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleavage enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoids, glucosides, Corticoid-inducible TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, e.g., 3-β), glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte-colony-stimulating factor (GCSF) ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein) calcium-binding protein, molecular chaperone groEL2 gene, heme oxygenase 1 (HO1), heme oxygenase 2 (HO2), heat shock proteins (e.g., 27, 70, 90α, β), heat shock protein genes,Heat-stable enterotoxin receptor, Hedgehog protein, Heparanase, Hepatocyte growth factor, HERV-H LTR-associated protein 2, Hexose kinase, Histamine H2 receptor, Histone methyltransferase (DOT1L), Histone deacetylase (HDAC, e.g. 1, 2, 3, 6, 10, 11), Histone H1, Histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen, HLA class I antigen alpha G (HLA-G), Non-classical HLA, Homeobox protein NANOG, HSPB1 gene, Human leukocyte antigen (HLA), Human papillomavirus (e.g. E6, E7) proteins, Hyaluronic acid, Hyaluronidase, Hypoxia-inducible factor-1 alpha (HIF 1α), imprinted material expressed transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-kappa-B kinase (IKK, e.g., IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (e.g., G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (e.g., I, III, I IIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1, IDO2), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (e.g., 1, 2), integrin alpha-4 / beta-1, integrin alpha-4 / beta-7, integrin alpha-5 / beta-1, integrin alpha-V / beta-3, integrin alpha-V / beta-5, integrin alpha-V / beta-6, intercellular adhesion molecule 1 (ICAM-1), interferons (e.g., alpha, alpha 2, beta, gamma), interferon-inducible protein absent in melanoma 2 (AIM 2), interferon I receptor, interleukin 1 ligand, interleukin 13 receptor alpha 2, interleukin 2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, interleukin 35 (IL-35),Isocitrate dehydrogenase (IDH1, IDH2, etc.), Janus kinase (JAK, e.g. JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-related protein-1, leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor lyase, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphotactin, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylase (e.g., KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D), lysophosphatide-1 receptor, lysosome-associated membrane protein family (LAMP) genes, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5-lipoxygenase (5-LOX), hematopoietic progenitor kinase 1 (HPK 1), hepatocyte growth factor receptor (MET) gene, macrophage colony-stimulating factor (MCSF) ligand, macrophage migration inhibitory fact, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (e.g., MK2), Mas-related G protein-coupled receptor, matrix metalloproteinases (MMPs such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein Pmel 17, melanocyte-stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigens (e.g., 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP 1 (six transmembrane epithelial antigen of prostate 1), metastin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl-CoA thiolase, mitogen-activated protein kinase (MAPK),Mitogen-activated protein kinases (MEKs, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine / threonine kinase), mTOR complex (e.g., 1, 2), mucins (e.g., 1, 5 A, 16), mut T homolog (MTH, e.g., MTH 1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL 1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP-ribosyltransferase, natriuretic peptide receptor C, neural cell adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NF-kappa B-activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 AB-activating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) modulator, noradrenaline transporter, Notch (e.g., Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF) kappa B, nucleolin, nucleophosmin, nucleophosmin anaplastic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptors (e.g., delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4 or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptors (PPARs such as alpha, delta, and gamma), P-glycoprotein (e.g., 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3Ks such as alpha, delta, and gamma), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF) such as alpha, delta, and gamma ... and platelet-derived growth factor (PDGF) such as alpha, delta, and gamma.PDGF such as β), pleotropic drug resistance transporters, plexin B1, PLK1 gene, polo-like kinase (PLK), polo-like kinase 1, poly(ADP-ribose) polymerase (PARPs such as PARP 1, PARP 2, and PARP 3, PARP7, and mono-PARP), melanoma (PRAME) gene, prenyl-binding protein (PrPB), transcription factor PML, progesterone receptor, programmed cell death 1 (PD-1), programmed cell death ligand 1 inhibitor (PD-L1), prosaposin (PSAP) gene, prostanoid receptor (EP4), prostaglandin E2 synthase, prostate-specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyltransferase, protein kinases (PKs, e.g., A, B, C, D, D, E, F ... , C), protein tyrosine kinase, protein tyrosine phosphatase beta, proto-oncogene serine / threonine-protein kinase (PIM such as PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-α-reductase, Raf protein kinase (e.g., 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (e.g., gamma), retinoid X receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras homolog)-related protein kinase 2, ribonuclease, ribonucleotide reductase (e.g., M2 subunit), ribosomal protein S6 kinase, RNA polymerase (e.g., I, II), Ron (receptor d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, gamma secretase, S100 calcium-binding protein A9, sarcoendoplasmic calcium ATPase, second mitochondrial-derived activator of caspases (SMAC) protein, secreted frizzled-related protein 2,secreted phospholipase A2, semaphorin-4D, serine proteases, serine / threonine kinases (STKs), serine / threonine protein kinases (TBKs, e.g., TBK 1), signal transduction and transcription (STATs, e.g., STAT-1, STAT-3, STAT-5), signaling lymphocyte activation molecule (SLAM) family member 7, genes for six transmembrane epithelial antigen of the prostate (STEAP), SL cytokine ligands, smoothened (SMO) receptor, sodium iodide symporter, sodium phosphate symporter 2B, somatostatin receptors (e.g., 1, 2, 3, 4, 5), sonic hedgehog proteins, Son of sevenless (SOS), specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinases (e.g., 1, 2), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC genes, Src tyrosine kinase, stabilin-1 (STAB 1), STAT3 gene, steroid sulfatase, receptor for interferon genes (STING), stimulator of interferon genes protein, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, suppressor of cytokine signaling regulators (SOCS), survivin protein, synapsin 3, syndecan-1, synuclein alpha, T cell surface glycoprotein CD28, TANK-binding kinase (TBK), TATA box-binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell glycoprotein zeta chain, T cell differentiation antigen CD6, T Intercellular immunoglobulin and mucin domain containing 3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek kinase receptor, telomerase, telomerase reverse transcriptase (TERT) gene, tenascin, three-phase repair exonuclease 1 (TREX1), three-phase repair exonuclease 2 (TREX2), thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (e.g. alpha 1), thyroid hormone receptor, thyrotropin receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-related death domain protein,TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptors (TLR, e.g., 1-13), topoisomerases (e.g., I, II, III), transcription factors, transferases, transferrin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFB) and its isoforms, TGF beta 2 ligand, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-related protein protein, transmembrane glycoprotein NMB, Trop-2 calcium signaling agent, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptor (e.g., TrkA, TrkB, TrkC), tryptophan 2,3-dioxygenase (TDO), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, e.g., α, β), tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate 2 (TUSC2) gene, tumor-specific Neoantigen, tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK), tyrosine kinase receptor, tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), ubiquitin-specific processing protease 7 (USP7), urease, urokinase plasminogen activator, uteroglobulin, vanilloid VR1, vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig inhibitor of T cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine-protein kinase, Mer (Mer tyrosine kinase receptor modulator), YAP (Yes-associated protein modulator), Wee-1 protein kinase, Werner syndrome RecQ-like helicase (WRN), Wilms tumor antigen 1,Wilms tumor protein, WW domain-containing transcriptional regulatory protein 1 (TAZ), X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or any combination thereof.

[0221] Exemplary Mechanisms of Action In some embodiments, the one or more additional therapeutic agents may be categorized according to their mechanism of action, e.g., into the following groups: Antimetabolites / anticancer agents, such as the pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118; α1-adrenergic receptor / α2-adrenergic receptor antagonists, such as phenoxybenzamine hydrochloride (injection, pheochromocytoma); Androgen receptor antagonists, such as nilutamide; Anti-cadherin antibodies, e.g., HKT-288; Anti-leucine-rich repeat containing 15 (LRRC15) antibodies, e.g., ABBV-085.ARGX-110; angiotensin receptor blockers, nitric oxide donors; Antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (plexigeversen), IONIS-STAT3-2.5Rx; Anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617 and LY3127804; Anti-ANG-1 / ANG-2 antibodies, e.g., AMG-780; Anti-CSF1R antibodies, e.g., emactumab, LY3022855, AMG-820, FPA-008 (caviralizumab); Anti-endoglin antibodies, e.g., TRC105 (carotuximab); Anti-ERBB antibodies, e.g., CDX-3379, HLX-02, seribantumab; Anti-HER2 antibodies, e.g., HERCEPTIN® (trastuzumab), trastuzumab biosimilar, margetuximab, MEDI4276, BAT-8001, pertuzumab (Perjeta), RG6264, ZW25 (bispecific HER2-directed antibody targeting extracellular domains 2 and 4; Cancer Discov. 2019 Jan;9(1):8; PMID:30504239); Anti-HLA-DR antibodies, e.g., IMMU-114; anti-IL-3 antibodies, e.g., JNJ-56022473; Anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI Gene ID: 8784) antibodies, such as MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those described, for example, in International Patent Publication Nos. WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628; anti-EphA3 antibodies, e.g., KB-004; Anti-CD37 antibodies, e.g., otlertuzumab (TRU-016); Anti-FGFR-3 antibodies, such as LY3076226, B-701; anti-FGFR-2 antibodies, e.g., GAL-F2; Anti-C5 antibodies, e.g., ALXN-1210; anti-EpCAM antibody, e.g. VB4-845; Anti-CEA antibodies, e.g., RG-7813; CD66C) antibodies such as BAY-1834942, NEO-201 (CEACAM5 / 6); Anti-GD2 antibodies, such as APN-301; Anti-interleukin 17 (IL-17) antibodies, e.g., CJM-112; Anti-interleukin-1β antibodies, e.g., canakinumab (ACZ885), VPM087; Anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, e.g., TX-250; Anti-CD38 antibodies, e.g., isatuximab, MOR-202, TAK-079; Anti-CD38-Attenukine, e.g., TAK573; Anti-mucin 1 (MUC1) antibodies, e.g., gatipotuzumab, Mab-AR-20.5; Anti-CD33 antibodies, e.g., IMGN-779; Anti-KMA antibodies, e.g., MDX-1097; anti-CD55 antibodies, e.g., PAT-SC1; Anti-c-Met antibodies, e.g., ABBV-399; Anti-PSMA antibodies, e.g., ATL-101; Anti-CD100 antibodies, e.g., VX-15; Anti-EPHA3 antibodies, such as fivatuzumab; Anti-APRIL antibodies, e.g., BION-1301; anti-fibroblast activation protein (FAP) / IL-2R antibodies, e.g., RG7461; Anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, e.g., RG7386; Anti-fucosyl-GM1 antibodies, such as BMS-986012; Anti-IL-8 (Interleukin-8) antibodies, e.g., HuMax-Inflam; Anti-myostatin inhibitors, e.g., randolozumab; Anti-delta-like protein ligand 3 (DDL3) antibodies, e.g., rovalpituzumab tesirin; Anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab; Anti-clusterin antibodies, e.g., AB-16B5; Anti-ephrin-A4 (EFNA4) antibodies, e.g., PF-06647263; Anti-RANKL antibodies, e.g., denosumab; Anti-mesothelin antibodies, e.g., BMS-986148, anti-MSLN-MMAE; Anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, e.g., rifastuzumab; Anti-TGFb antibodies, e.g., SAR439459; Anti-transforming growth factor-β (TGF-β) antibodies, e.g., ABBV-151, LY3022859, NIS793, XOMA089; Purine analogues, folate antagonists (e.g., pralatrexate), cladribine, pentostatin, fludarabine, and related inhibitors; Antiproliferative / antimitotic agents, including natural products such as vinca alkaloids (vinblastine, vincristine) and microtubule disruptors such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (NAVELBINE®), and epipodophyllotoxins (etoposide, teniposide); DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophosphoramide; DNA hypomethylating agents, e.g., guadecitabine (SGI-110), ASTX727; Antibiotics, such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, primycin (mithramycin); Enzymes, such as L-asparaginase, which metabolizes L-asparagine throughout the body and eliminates cells that do not have the ability to synthesize asparagine themselves; DNAi oligonucleotides that target Bcl-2, such as PNT2258; agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin; Asparaginase stimulators, such as crisantaspase (Erwinase®) and GRASPA (ERY-001, ERY-ASP), calaspargase pegol, pegaspargase; pan-Trk, ROS1, and ALK inhibitors, e.g., entrectinib, TPX-0005; Anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib, Alecensa (RG7853), ALUNBRIG® (brigatinib); Antiproliferative / antimitotic alkylating agents such as nitrogen mustard cyclophosphamide and analogs (e.g., melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkylnitrosoureas (e.g., carmustine) and analogs, streptozocin, and triazenes (e.g., dacarbazine); Antiproliferative / antimitotic antimetabolites, e.g., folic acid analogues (methotrexate); Platinum coordination complexes (e.g., cisplatin, oxicoplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide; Hormones, hormone analogues (e.g., estrogen, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (e.g., letrozole and anastrozole); Antiplatelet agents; anticoagulants, such as heparin, synthetic heparin salts, and other inhibitors of thrombin; Fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; Antimigratory agents; antisecretory agents (e.g., breveldin); Immunosuppressants, such as tacrolimus, sirolimus, azathioprine, and mycophenolate; Growth factor inhibitors and vascular endothelial growth factor inhibitors; Fibroblast growth factor inhibitors, e.g., FPA14; AMP-activated protein kinase stimulators, such as metformin hydrochloride; ADP-ribosyl cyclase-1 inhibitors, such as daratumumab (DARZALEX®); Caspase recruitment domain protein-15 stimulators, e.g., mifamurtide (liposomes); CCR5 chemokine antagonists, e.g., MK-7690 (Vicriviroc); CDC7 protein kinase inhibitors, e.g., TAK-931; Cholesterol side chain cleavage enzyme inhibitors, e.g., ODM-209; Dihydropyrimidine dehydrogenase / orotate phosphoribosyltransferase inhibitors, such as cefezone (tegafur + gimeracil + oteracil potassium); DNA polymerase / ribonucleotide reductase inhibitors, such as clofarabine; DNA interference oligonucleotides, e.g., PNT2258, AZD-9150; Estrogen receptor modulators, such as bazedoxifene; Estrogen receptor agonist / progesterone receptor antagonist, e.g., TRI-CYCLEN LO (norethindrone + ethinyl estradiol); HLA class I antigen A-2α modulators, e.g., FH-MCVA2TCR; HLA class I antigen A-2α / MART-1 melanoma antigen modulators, e.g., MART-1 F5 TCR engineered PBMCs; Human granulocyte colony-stimulating factor, e.g., PF-06881894; GNRH receptor agonists, such as leuprorelin acetate, leuprorelin acetate extended-release depot (ATRIGEL), triptorelin pamoate, goserelin acetate; GNRH receptor antagonists, e.g., elagolix, relugolix, degarelix; Endoplasmin modulators, such as anlotinib; H+ K+ ATPase inhibitors, e.g., omeprazole, esomeprazole; ICAM-1 / CD55 modulators, e.g., cavatak (V-937); IL-15 / IL-12 modulators, e.g., SAR441000; Interleukin-23A inhibitors, e.g., guselkumab; Lysine-specific histone demethylase 1 inhibitors, e.g., CC-90011; IL-12 mRNA, e.g., MEDI 1191; RIG-I modulators, e.g., RGT-100; NOD2 modulators, such as SB-9200 and IR-103. Progesterone receptor agonists, such as levonorgestrel; Protein cereblon regulators such as CC-92480, CC-90009; Protein cereblon modulators / DNA binding protein Ikaros inhibitors / Zinc finger binding protein Aiolos inhibitors, e.g., iverdomid; Retinoid X receptor modulators, e.g., alitretinoin, bexarotene (oral formulations); RIP-1 kinase inhibitors, e.g., GSK-3145095; Selective estrogen receptor degraders, e.g., AZD9833; SUMO inhibitors, e.g., TAK-981; Thrombopoietin receptor agonists, such as eltrombopag; Thyroid hormone receptor agonists, such as levothyroxine sodium; TNF agonists, for example, tasonermin; Tyrosine phosphatase substrate 1 inhibitors, e.g., CC-95251; HER2 inhibitors, e.g., neratinib, tucatinib (ONT-380); EGFR / ErbB2 / Ephb4 inhibitors, e.g., tesevatinib; EGFR / HER2 inhibitors, e.g., TAK-788; EGFR family tyrosine kinase receptor inhibitors, such as DZD-9008; EGFR / ErbB-2 inhibitors, e.g., valitinib; Mutation-selective EGFR inhibitors, e.g., PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694; epha2 inhibitors such as MM-310; Polycomb protein (EED) inhibitors, e.g., MAK683; DHFR inhibitors / folate transporter 1 modulators / folate receptor antagonists, e.g., pralatrexate; DHFR / GAR transformylase / thymidylate synthase / transferase inhibitors, e.g., pemetrexed disodium; p38 MAP kinase inhibitors, e.g., ralimetinib; PRMT inhibitors, e.g., MS203, PF-06939999, GSK3368715, GSK3326595; Sphingosine kinase 2 (SK2) inhibitors, such as opaganib; nuclear erythroid 2-related factor 2 stimulators, e.g., omaveloxolone (RTA-408); Tropomyosin receptor kinase (TRK) inhibitors, e.g., LOXO-195, ONO-7579; Mucin 1 inhibitors, e.g., GO-203-2C; MARCKS protein inhibitors, e.g., BIO-11006; Folate antagonists such as arfolitixoline, e.g.; Galectin-3 inhibitors, e.g., GR-MD-02; Phospho-P68 inhibitors, e.g., RX-5902; CD95 / TNF modulators, e.g., ofranelgene obadenovec; pan-PIM kinase inhibitors, e.g., INCB-053914; IL-12 gene stimulators, e.g., EGEN-001, taboquinogen terce plasmid; Heat shock protein HSP90 inhibitors, e.g., TAS-116, PEN-866; VEGF / HGF antagonists, e.g., MP-0250; VEGF ligand inhibitors, e.g., bevacizumab biosimilars; VEGF receptor antagonists / VEGF ligand inhibitors, e.g., ramucirumab; VEGF-1 / VEGF-2 / VEGF-3 receptor antagonists, such as fruquintinib; VEGF-1 / VEGF-2 receptor modulators, such as HLA-A2402 / HLA-A0201 restricted epitope peptide vaccines; Placental growth factor ligand inhibitors / VEGF-A ligand inhibitors, e.g., aflibercept; SYK tyrosine kinase / JAK tyrosine kinase inhibitors such as ASN-002; Trk tyrosine kinase receptor inhibitors, for example, larotrectinib sulfate; JAK3 / JAK1 / TBK1 kinase inhibitors, e.g., CS-12912; IL-24 antagonists, e.g., AD-IL24; NLRP3 (NACHT LRR PYD domain protein 3) modulators, e.g., BMS-986299; RIG-I agonists, e.g., RGT-100; Aerolysin stimulators, for example, topsalisin; P-glycoprotein 1 inhibitors, for example, HM-30181A; CSF-1 antagonists, e.g., ARRY-382, BLZ-945; CCR8 inhibitors, e.g., I-309, SB-649701, HG-1013, RAP-310; Anti-mesothelin antibodies, e.g., SEL-403; Thymidine kinase stimulators, such as agratimagenbesadenovec; Polo-like kinase 1 inhibitors, e.g., PCM-075, onvansertib; NAE inhibitors, e.g., pevonedistat (MLN-4924), TAS-4464; Pleiotropic pathway modulators, e.g., avadomide (CC-122); Amyloid protein binding protein-1 inhibitors / ubiquitin ligase modulators, such as pevonedistat; FoxM1 inhibitors, such as thiostreptomycin; UBA1 inhibitors such as TAK-243; Src tyrosine kinase inhibitors, e.g., VAL-201; VDAC / HK inhibitors, e.g., VDA-1102; Elf4a inhibitors, e.g., rohitinib, eFT226; TP53 gene stimulators, e.g., ad-p53; Retinoic acid receptor agonists, such as tretinoin; Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425; SIRT3 inhibitors such as YC8-02; Stromal cell-derived factor 1 ligand inhibitors, e.g., Oraptest pegol (NOX-A12); IL-4 receptor modulators, e.g., MDNA-55; Arginase I stimulators, such as PEGylariginase; Topoisomerase I inhibitors, such as irinotecan hydrochloride, Onivyde; Topoisomerase I inhibitors / hypoxia-inducible factor-1α inhibitors, e.g., PEG-SN38 (filtecampegol); Hypoxia-inducible factor-1α inhibitors, e.g., PT-2977, PT-2385; CD122 (IL-2 receptor) agonists, such as Proleukin (aldesleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707); TLR7 / TLR8 agonists, e.g., NKTR-262; TLR7 agonists, e.g., DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod); p53 tumor suppressor protein stimulators, such as kevetlin; Mdm4 / Mdm2 p53 binding protein inhibitors, e.g., ALRN-6924; kinesin spindle protein (KSP) inhibitors, e.g., filanesib (ARRY-520); CD80-fc fusion protein inhibitors, such as FPT-155; Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539; Liver x receptor agonists, e.g., RGX-104; IL-10 agonists, e.g., pegylidecaquine (AM-0010); VEGFR / PDGFR inhibitors, e.g., borolanib; IRAK4 inhibitors such as CA-4948; Anti-TLR-2 antibodies, e.g., OPN-305; Calmodulin modulators, e.g., CBP-501; Glucocorticoid receptor antagonists, e.g., relacorilant (CORT-125134); second mitochondria-derived activator of caspases (SMAC) protein inhibitors, such as BI-891065; Lactoferrin modulators, for example, LTX-315; KIT proto-oncogene, receptor tyrosine kinase (KIT) inhibitors, e.g., PLX-9486; Platelet-derived growth factor receptor alpha (PDGFRA) / KIT proto-oncogene, receptor tyrosine kinase (KIT) mutant-specific antagonists / inhibitors, e.g., BLU-285, DCC-2618; Exportin 1 inhibitors, e.g., ertanexor; CHST15 gene inhibitors, e.g., STNM-01; Somatostatin receptor antagonists, e.g., OPS-201; CEBPA gene stimulators, e.g., MTL-501; DKK3 gene modulators, e.g., MTG-201; Chemokine (CXCR1 / CXCR2) inhibitors, e.g., SX-682; p70s6k inhibitors such as MSC2363318A; Methionine aminopeptidase 2 (MetAP2) inhibitors, e.g., M8891, APL-1202; Arginine N-methyltransferase 5 inhibitors, e.g., GSK-3326595; CD71 modulators, e.g., CX-2029 (ABBV-2029); ATM (ataxia telangiectasia) inhibitors, e.g., AZD0156, AZD1390; CHK1 inhibitors, e.g., GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2); CXCR4 antagonists, such as BL-8040, LY2510924, blixafor (TG-0054), X4P-002, X4P-001-IO, plerixafor; EXH2 inhibitors such as GSK2816126; KDM1 inhibitors, e.g., ORY-1001, IMG-7289, INCB-59872, GSK-2879552; CXCR2 antagonists, such as AZD-5069; GM-CSF antibodies, e.g., lenzilumab; DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01); protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin; Selective estrogen receptor down-modulators (SERDs), such as fulvestrant (Faslodex®), RG6046, RG6047, RG6171, elacestrant (RAD-1901), SAR439859, and AZD9496; Selective estrogen receptor covalent antagonists (SERCAs), e.g., H3B-6545; Selective androgen modulators (SARMs), e.g., GTX-024, darolutamide; Transforming growth factor-β (TGF-β) kinase antagonists such as galunisertib, LY3200882; TGF-β inhibitors as described in WO 2019 / 103203; TGFβ receptor 1 inhibitors, e.g., PF-06952229; Bispecific antibodies, such as ABT-165 (DLL4 / VEGF), MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3), PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), JNJ-61186372 (EGFR / cMET), AMG-211 (CEA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), vancizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD 3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA-117 (CD3 / CLEC12A), MCLA-128 (HER2 / HER3), JNJ-0819, JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA-4), KN-046 (PD-1 / CTLA-4), MED I-5752 (CTLA-4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA-4), AK-104 (CTLA-4 / PD-1), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), B I-836880(VEFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), AGEN1223, IMCgp100(CD3 / gp100), AGEN-1423, ATOR -1015 (CTLA-4 / OX40), LY-3415244 (TIM-3 / PDL1), INHIBRX-105 (4-1BB / PDL1), faricimab (VEGF-A / ANG-2), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), TAK-252 (PD-1 / OX40L), TG-1801 (CD19 / CD47), XmAb-18087 (SSTR2 / CD3), catumaxomab (CD3 / EpCAM), SAR-156597 (IL4 / IL13), EMB-01 (EGFR / cMET),REGN-4018 (MUC16 / CD3), REGN-1979 (CD20 / CD3), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), nabi-cizumab (DLL4 / VEGF), GRB-1302 (CD3 / Erbb2), vanucizumab (VEGF-A / ANG-2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33), IMM-0306 (CD47 / CD20), RG6076, MEDI5752 (PD-1 / CTLA-4), LY3164530 (MET / EGFR); α-Ketoglutarate dehydrogenase (KGDH) inhibitors, e.g., CPI-613; XPO1 inhibitors, e.g., selinexor (KPT-330); isocitrate dehydrogenase 2 (IDH2) inhibitors, e.g., enasidenib (AG-221); IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032; IDH1 gene inhibitors, e.g., ivosidenib; Interleukin-3 receptor (IL-3R) modulators, such as SL-401; Arginine deiminase stimulators, such as pegalgiminase (ADI-PEG-20); Claudin-18 inhibitors, e.g., claudiximab; β-catenin inhibitors, e.g., CWP-291; chemokine receptor 2 (CCR) inhibitors such as PF-04136309, CCX-872, and BMS-813160 (CCR2 / CCR5); Thymidylate synthase inhibitors, e.g., ONX-0801; ALK / ROS1 inhibitors, e.g., lorlatinib; Tankyrase inhibitors, for example, G007-LK; Mdm2 p53 binding protein inhibitors, e.g., CMG-097, HDM-201; c-PIM inhibitors, e.g., PIM447; Sphingosine kinase-2 (SK2) inhibitors, such as Yeliva® (ABC294640); DNA polymerase inhibitors, such as sapacitabine; Cell cycle / microtubule inhibitors, e.g., eribulin mesylate; c-MET inhibitors, such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361; c-Met / VEGFR inhibitors, e.g., BMS-817378, TAS-115; c-Met / RON inhibitors, e.g., BMS-777607; BCR / ABL inhibitors, e.g., revastinib, asciminib, ponatinib (ICLUSIG®); MNK1 / MNK2 inhibitors, e.g., eFT-508; Cytochrome P450 11B2 / cytochrome P450 17 / AKT protein kinase inhibitors, such as LAE-201; Cytochrome P450 3A4 stimulators, such as mitotane; Lysine-specific demethylase-1 (LSD1) inhibitors, e.g., CC-90011; CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397); Flt3 tyrosine kinase / Kit tyrosine kinase inhibitors, such as quizartinib dihydrochloride, and PDGF receptor antagonists; Kinase inhibitors, such as vandetanib; E-selectin antagonists, e.g., GMI-1271; Differentiation inducers, such as tretinoin; Epidermal growth factor receptor (EGFR) inhibitors, e.g., osimertinib (AZD-9291), cetuximab; Topoisomerase inhibitors such as adriamycin, doxorubicin, daunorubicin, dactinomycin, DaunoXome, Caelyx, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavereltinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114); Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone; growth factor signaling kinase inhibitors; Nucleoside analogues, e.g., DFP-10917; Axl inhibitors, e.g., BGB-324 (bemcentinib), SLC-0211; Axl / Flt3 inhibitors, e.g., gilteritinib; Inhibitors of bromodomain and extraterminal motif (BET) proteins, including ABBV-744, BRD2 (NCBI Gene ID: 6046), BRD3 (NCBI Gene ID: 8019), BRD4 (NCBI Gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI Gene ID: 676), e.g., INCB-054329, INCB057643, TEN-010, AZD-5153, AB T-767, BMS-986158, CC-90010, GSK525762 (molybresive), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mibebrexit, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829; PARP inhibitors, such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, BGB-290, fluzoleparib (SHR-3162), niraparib (JNJ-64091742), bendamustine hydrochloride; PARP / tankyrase inhibitors, e.g., 2X-121 (e-7499); IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simmiparib; Proteasome inhibitors, such as ixazomib (NINLARO®), carfilzomib (Kyprolis®), marizomib, bortezomib; Glutaminase inhibitors, such as CB-839 (telagrenast), bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Mitochondrial complex I inhibitors, e.g., metformin, phenformin; Vaccines, e.g. peptide vaccines TG-01 (RAS), GALE-301, GALE-302, Neripepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, Galinpepimut-S, SVN53-67 / M57-KLH, IMU-131, peptide subunit vaccines (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines, e.g. CRS-207 / GVAX, Axalimodine phyllosvac (ADXS11-001); adenovirus vector vaccines, e.g. nadofaragene firadenovec; autologous Gp96 vaccine; dendritic cell vaccine, e.g., CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, ADXS31-142, autologous dendritic cell vaccine (metastatic melanoma, intradermal / intravenous, Universitatsklinikum Erlangen); oncolytic vaccines such as talimogene laherparepvec, pexastimodine devasilepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotsileb, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines such as CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax™; Tumor cell vaccines, e.g., Vigil® (IND-14205), Oncoquest-L vaccine; attenuated recombinant serotype 1 poliovirus vaccines, e.g., PVS-RIPO; adaggloxacin; MEDI-0457; DPV-001, a tumor-derived autophagosome-enriched cancer vaccine; RNA vaccines, e.g., CV-9209, LV-305; DNA vaccines, e.g., MEDI-0457, MVI-816, INO-5401;Modified vaccinia virus Ankara vaccines expressing p53, e.g., MVA-p53; DPX-Survivac; BriaVax™; GI-6301; GI-6207; GI-4000; IO-103; neoantigen peptide vaccines, e.g., AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; peptide vaccines targeting heat shock proteins, such as PhosphoSynVax™; Vitespen (HSPPC-96-C), NANT colorectal cancer vaccine containing aldoxorubicin, autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer), IO-120 + IO-103 (PD-L 1 / PD-L2 vaccine), HB-201, HB-202, HB-301, TheraT®*-based vaccine; TLR-3 agonists / interferon inducers, e.g., Poly ICLC (NSC-301463); STAT-3 inhibitors, e.g., napabvacacin (BBI-608); ATPase p97 inhibitors, e.g., CB-5083; Smoothened (SMO) receptor inhibitors, such as Odomzo® (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole; Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), PEG interferon alpha-2b (AOP-2014, P-1101, PEG IFNα-2b), multiferon (Alpha Nativ, Viragen), interferon alpha 1b, Roferon-A (Campheron, Ro-25-3036), interferon alpha-2a post-development (Biosidus) (Inmutag, Inter 2A), interferon alpha-2b post-development (Biosidus-Bioferon, Citoferon, Ganapar, Beijing Kawin Technology-Kaferon), Alphaferon, pegylated interferon alpha-1b, pegylated interferon alpha-2b post-development formulation (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFNα2b conjugate, Dynavax (SD-101), and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon); Interferon gamma ligand modulators, e.g., interferon gamma (OH-6000, Ogamma100); IL-6 receptor modulators, e.g., tocilizumab, AS-101 (CB-06-02, IVX-Q-101); Heat shock protein inhibitors / IL-6 receptor antagonists, e.g., siltuximab; Telomerase modulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937); DNA methyltransferase inhibitors, such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine (CC-486); DNA gyrase inhibitors such as pixantrone and sobuzoxane; DNA gyrase inhibitors / topoisomerase II inhibitors, such as amrubicin; Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, RG7601, and AT-101; Bcl-2 / Bcl-XL inhibitors, e.g., novitoclax; Notch inhibitors, e.g., LY3039478 (crenigacestat), tarexuzumab (anti-Notch2 / 3), BMS-906024; Hyaluronidase stimulating factors, e.g., PEGPH-20; Erbb2 tyrosine kinase receptor inhibitors / hyaluronidase stimulators, e.g., Herceptin Hylecta; Wnt pathway inhibitors, e.g., SM-04755, PRI-724, WNT-974; gamma-secretase inhibitors, e.g., PF-03084014, MK-0752, RO-4929097; Grb-2 (growth factor receptor-bound protein-2) inhibitors, e.g., BP1001; TRAIL pathway inducing compounds, e.g., ONC201, ABBV-621; TRAIL modulators, e.g., SCB-313; focal adhesion kinase inhibitors, e.g., VS-4718, defactinib, GSK2256098; Hedgehog inhibitors, e.g., salidegib, sonidegib (LDE225), glasdegib; Aurora kinase inhibitors, such as alisertib (MLN-8237), and AZD-2811, AMG-900, barasertib, ENMD-2076; HSPB1 modulators (heat shock protein 27, HSP27), e.g., brivudin, apatrusen; ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib), and VX-970; Hsp90 inhibitors, e.g., AUY922, onarespib (AT13387), SNX-2112, SNX5422; Mouse double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idazanutulin (RG7388); CD137 agonists, e.g., urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480; STING agonists such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, and GSK3745417; FGFR inhibitors, e.g., FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347; Fatty acid synthase (FASN) inhibitors, e.g., TVB-2640; Antigen CD19 inhibitors, e.g., MOR208, MEDI-551, AFM-11, inebilizumab; CD44 binding agents, e.g., A6; Protein phosphatase 2A (PP2A) inhibitors, e.g., LB-100; CYP17 inhibitors, e.g., seviteroner (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate; RXR agonists, e.g., IRX4204; Hedgehog / Smoothened (hh / Smo) antagonists, e.g., taladegib, pachidegib, vismodegib; Complement C3 modulators, e.g., Imprime PGG; IL-15 agonists, such as ALT-803, NKTR-255, interleukin-15 / Fc fusion proteins, AM-0015, NIZ-985, and hetIL-15; EZH2 (enhancer of zeste homolog 2) inhibitors, e.g., tazemetostat, CPI-1205, GSK-2816126, PF-06821497; Oncolytic viruses such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), bosimadine amireterorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301, IMLYGIC®; DOT1L (histone methyltransferase) inhibitors, e.g., pinometostat (EPZ-5676); Toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; DNA plasmids such as BC-819; PLK inhibitors of PLK1, 2, and 3, e.g., volasertib (PLK1); WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase (ROCK) inhibitors, such as AT13148, KD025; Inhibitor of apoptosis protein (IAP) inhibitors, e.g., ASTX660, debio-1143, birinapant, APG-1387, LCL-161; RNA polymerase inhibitors, e.g., lurbinectedin (PM-1183), CX-5461; tubulin inhibitors such as PM-184, BAL-101553 (risabumbulin), and OXI-4503, fluorapasin (AC-0001), plinabulin, and vinflunine; Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091, and PEPA-10; Elongation factor 1 alpha 2 inhibitors, such as plitidepsin; Elongation factor 2 inhibitors / interleukin-2 ligands / NAD ADP-ribosyltransferase stimulators, e.g., denileukin diftitox; CD95 inhibitors, e.g., APG-101, APO-010, asnercept; WT1 inhibitors such as DSP-7888; Splicing factor 3B subunit 1 (SF3B1) inhibitors, e.g., H3B-8800; Retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716; and Microbiome modulators, for example, SER-401, EDP-1503, MRx-0518.

[0222] In some embodiments, the compounds described herein are co-administered with one or more additional therapeutic agents, including inhibitors or antagonists of the following: myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator (NCBI Gene ID: 4170); mitogen-activated protein kinase 1 (MAP4K1) (also referred to as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); ecto-5'-nucleotidase. (NT5E or CD73; NCBI Gene ID: 4907); ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39; NCBI Gene ID: 593); transforming growth factor beta 1 (TGFB1 or TGFβ; NCBI Gene ID: 7040); heme oxygenase 1 (HMOX1, HO-1, or HO1; NCBI Gene ID: 3162); heme oxygenase 2 (HMOX2, HO-2, or HO2; NCBI Gene ID: 3163); vascular endothelial growth factor A (VEGFA or VEGF; NCBI Gene ID: 7422); er b-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu, or CD340; NCBI Gene ID: 2064), epidermal growth factor receptor (EGFR, ERBB, ERBB1, or HER1; NCBI Gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI Gene ID: 238); poly(ADP-ribose) polymerase 1 (PARP1; NCBI Gene ID: 142); poly(ADP-ribose) polymerase 2 (PARP2; NCBI Gene ID: 10038); TCDD-induced poly(ADP-ribose) polymerase β-phosphate dehydrogenase (TIPARP, PARP7; NCBI Gene ID: 25976); cyclin-dependent kinase 4 (CDK4; NCBI Gene ID: 1019); cyclin-dependent kinase 6 (CDK6; NCBI Gene ID: 1021); TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270; NCBI Gene ID: 8764); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3;NCBI Gene ID: 331); baculovirus IAP repeat-containing 2 (BIRC2, cIAP1; NCBI Gene ID: 329); baculovirus IAP repeat-containing 3 (BIRC3, cIAP2; NCBI Gene ID: 330); baculovirus IAP repeat-containing 5 (BIRC5, survivin; NCBI Gene ID: 332); CC motif chemokine receptor 2 (CCR2, CD192; NCBI Gene ID: 729230); CC motif chemokine receptor 5 (CCR5, CD195; NCBI Gene ID: 1234); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); C-X-C motif chemokine receptor 2 (CXCR2, CD182; NCBI gene ID: 3579); C-X-C motif chemokine receptor 3 (CXCR3, CD182, CD183; NCBI gene ID: 2833); C-X-C motif chemokine receptor 4 (CXCR4, CD184; NCBI gene ID: 7852); arginase (ARG1 (NCBI gene ID: 383, ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA 1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 772), CA14 (NCBI gene ID: 773), CA15 (NCBI gene ID: 774), CA16 (NCBI gene ID: 775), CA17 (NCBI gene ID: 776), CA18 (NCBI gene ID: 777), CA19 (NCBI gene ID: 778), CA20 (NCBI gene ID: 56934), CA21 (NCBI gene ID: 779), CA22 (NCBI gene ID: 780), CA23 (NCBI gene ID: 781), CA24 (NCBI gene ID: 782), CA25 (NCBI gene ID: 783), CA26 (NCBI gene ID: 784), CA27 (NCBI gene ID: 785), CA28 (NCBI gene ID: 786), CA29 (NCBI gene ID: 787), CA30 (NCBI gene ID: 56934), CA31 (NCBI gene ID: 788), CA32 (NCBI gene ID: 789), CA33 (NCBI gene ID: 790), CA34 (NCBI gene ID: 791), CA35 (NCBI gene ID: 792), CA36 (NCBI gene I gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632)), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX;NCBI Gene ID: 240), and / or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053); secreted phospholipase A2 (e.g., PLA2G1B (NCBI Gene ID: 5319); PLA2G7 (NCBI Gene ID: 7941), PLA2G3 (NCBI Gene ID: 50487), PLA2G2A (NCBI Gene ID: 5320); PLA2G4A (NCBI Gene ID: 5321); PLA2G12A (NCBI Gene ID: 81579); PLA2G12B (NCBI Gene ID: 84647); PLA2G10 (NCBI Gene ID: 8399); PLA2G5 (NCBI Gene ID: 5322); PLA2G2D (NCBI Gene ID: 26279); PLA2G15 (NCBI Gene ID: 23659)); indoleamine-2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620); indoleamine-2,3-dioxygenase 2 (IDO2; NCBI Gene ID: 169355); hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091); angiopoietin 1 (ANGPT1; NCBI Gene ID: 284); endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI Gene ID: 7010); Janus kinase 1 (JAK1; NCBI Gene ID: 3716); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734), and / or 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464).

[0223] TCR Signaling Modulators In some embodiments, the compounds described herein are combined with one or more agonists or antagonists of T cell receptor (TCR) signaling regulators. T cell activation via TCR is essential for thymocyte development and effector T cell function. TCR activation promotes signaling cascades that ultimately determine cell fate by regulating cytokine production, cell survival, proliferation, and differentiation. Examples of TCR signaling modulators include, but are not limited to, CD2 (cluster of differentiation 2, LFA-2, T11, LFA-3 receptor), CD3 (cluster of differentiation 3), CD4 (cluster of differentiation 4), CD8 (cluster of differentiation 8), CD28 (cluster of differentiation 28), CD45 (PTPRC, B220, GP180), LAT (linker for T cell activation, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src, Zap-70, SLP-76, DGKα, CBL-b, CISH, HPK1.

[0224] Examples of cluster of differentiation 3 (CD3) agonists that may be co-administered include, but are not limited to, MGD015.

[0225] In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting an inhibitory immune checkpoint can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells in the tumor environment. Activation or stimulation of a stimulatory immune checkpoint can enhance the effect of immune checkpoint inhibitors in cancer treatment. In various embodiments, an immune checkpoint protein or receptor regulates T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0226] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA));TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF);TNFRSF18 (GITR), TNFSF18 (GITRL);MHC class I polypeptide-related sequence A (MICA);MHC class I polypeptide-related sequence B (MICB);CD274 (PDL1, PD-L1);Programmed cell death 1 (PDCD1, PD-1, PD-1);Cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152);CD80 (B7-1), CD28;Nectin cell adhesion molecule 2 (NECTIN2, CD112);CD226 (DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155);PVR-related immunoglobulin domain-containing (PVRIG, CD112R);T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG-3, CD223); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAM F3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor (KIR); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell Killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); Killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); Killer cell lectin-like receptor D1 (KLRD1).

[0227] In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG-3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor (KIR); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the compounds described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0228] In some embodiments, the compounds described herein are combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In some embodiments, the compounds described herein are combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0229] In some embodiments, the compounds described herein are combined with inhibitors of CD47 (IAP, MER6, OA3; NCBI gene ID: 961; UniProt Q08722). Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, ALX-148, TTI-621, RRx-001, DSP-107, VT-1021, TTI-621, TTI-622, and IMM-02, SGN-CD47M. Examples of anti-CD47 antibodies include IBI-188, TJC-4, SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015.

[0230] In some embodiments, the inhibitor of CD47 is a bispecific antibody that targets CD47. Examples of bispecific antibodies that target CD47 include IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), and HMBD-004A (CD47 / CD33).

[0231] In some embodiments, the anti-CD47 targeting agent is selected from the group consisting of compounds disclosed in WO 199727873, WO 199940940, WO 2002092784, WO 2005044857, WO 2009046541, WO 2010070047, WO 2011143624, WO 2012170250, WO 2013109752, WO 2013119714, WO 2014087248, WO 2015191861 , No. 2016022971, No. 2016023040, No. 2016024021, No. 2016081423, No. 2016109415, No. 2016141328, No. 20161884 No. 49, No. 2017027422, No. 2017049251, No. 2017053423, No. 2017121771, No. 2017194634, No. 2017196793, No. 201721 No. 5585, No. 2018075857, No. 2018075960, No. 2018089508, No. 2018095428, No. 2018137705, No. 2018233575, No. 201 No. 9027903, No. 2019034895, No. 2019042119, No. 2019042285, No. 2019042470, No. 2019086573, No. 2019108733, No. 2 019138367, 2019144895, 2019157843, 2019179366, 2019184912, 2019185717, 2019201236, 2019238012, 2019241732, 2020019135, 2020036977, 2020043188, or 2020009725.

[0232] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

[0233] Examples of inhibitors of CTLA4 that may be co-administered include, but are not limited to, ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR- 1144, PBI-5D3H5, BPI-002, HBM-4003, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0234] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors / antibodies that may be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMG-404, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GEN-1046 (PD-L1 / 4-1BB), GLS-010 (WBP-3055), AK-103 (HX-008), AK-103 (HX-103 ... -105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (Tripaliumab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (Dostarumab), MSB-2311, JTX -4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-01 3(PD-1 / LAG-3), RO-7247669(PD-1 / LAG-3), FS-118(LAG-3 / PD-L1), MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-712 1661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1),LY-3415244 (TIM-3 / PDL1), RG7769 (PD-1 / TIM-3), and INBRX-105 (4-1BB / PDL1), GNS-1480 (PD-L1 / EGFR), RG-7446 (Tecentriq, atezolizumab), ABBV-181, nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab, CAS Registry Number 1374853-91- 4), pidilizumab, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003, HLX-10, MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034, JS-001 (toriparimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (ca mrelizumab), Sym-021, ABBV-181, AK-105, PD1-PIK, BAT-1306, BMS-936559, Atezolizumab (MPDL3280A), Durvalumab (MEDI-4736), Avelumab, CK-301, (MSB0010718C), MEDI-0680, CX-072, CBT-502, PDR-001 (Spartalizumab), PDR001 + Tafinlar® + Mekinist®, MSB-2311, JTX-4014, BGB-A3 33, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, and MDX1105-01, and, for example, those described in International Publication Nos. WO 2018 / 195321, WO 2020 / 014643, WO 2019 / 160882, and WO 2018 / 195321.

[0235] An example of an inhibitor of PVRIG that may be co-administered includes, but is not limited to, COM-701.

[0236] Examples of inhibitors of TIGIT that can be co-administered include, but are not limited to, BMS-986207, RG-6058, AGEN-1307, COM-902.

[0237] Examples of inhibitors of TIM-3 that may be co-administered include, but are not limited to, TSR-022, LY-3321367, MBG-453, INCAGN-2390, RO-7121661 (PD-1 / TIM-3), LY-3415244 (TIM-3 / PDL1), RG7769 (PD-1 / TIM-3).

[0238] Examples of inhibitors of LAG-3 that may be co-administered include, but are not limited to, leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1).

[0239] Examples of anti-killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811) monoclonal antibodies, e.g., lirilumab (IPH-2102), IPH-4102.

[0240] An example of an anti-NKG2a antibody that may be co-administered includes, but is not limited to, monalizumab.

[0241] Examples of anti-VISTA antibodies that may be co-administered include, but are not limited to, HMBD-002, CA-170 (PD-L1 / VISTA).

[0242] An example of an anti-CD70 antibody that may be co-administered includes, but is not limited to, AMG-172.

[0243] Examples of anti-CD20 antibodies that may be co-administered include, but are not limited to, obinutuzumab, IGN-002, PF-05280586.

[0244] Examples of anti-ICOS antibodies that may be co-administered include, but are not limited to, JTX-2011, GSK3359609.

[0245] Examples of ICOS agonists that may be co-administered include, but are not limited to, ICOS-L.COMP (Gariepy, J. et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego) 2019, Abst 71.5).

[0246] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In some embodiments, the compounds described herein are administered to one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD 27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 8794), TN FRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 115650), TNFRSF16 (NG and / or one or more agonists of TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0247] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0248] Exemplary anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2) antibodies that may be co-administered include, but are not limited to, DS-8273, CTB-006, INBRX-109, GEN-1029, and the like.

[0249] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, ABBV-428, ABBV-927, JNJ-64457107.

[0250] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0251] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0252] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0253] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO 2017096179 and WO 2018089628.

[0254] Exemplary anti-TRAILR1, anti-TRAILR2, anti-TRAILR3, anti-TRAILR4 antibodies that may be co-administered include, but are not limited to, ABBV-621.

[0255] Bispecific antibodies targeting TNFRSF family members that may be co-administered include, but are not limited to, PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), REGN-1979 (CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20), AMG-424 (CD38.CD3).

[0256] Adenosine Generation and Signaling In some embodiments, the compounds described herein are combined with an agonist or antagonist of A1R, A2AR, A2BR, A3R, CD73, CD39, or CD26.

[0257] Examples of adenosine A3 receptor (A3R) agonists include namodenoson (CF102).

[0258] Examples of A2aR / A2bR antagonists such as AB928.

[0259] Examples of anti-CD73 antibodies include MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, and CPI-006.

[0260] Examples of CD73 inhibitors include AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, and those described in WO19173692.

[0261] Examples of CD39 / CD73 inhibitors include PBF-1662.

[0262] Examples of anti-CD39 antibodies include TTX-030.

[0263] Examples of adenosine A2A receptor antagonists include CPI-444, AZD-4635, Preladenant, and PBF-509.

[0264] Examples of adenosine deaminase inhibitors include pentostatin and cladribine.

[0265] c-kit targeting agent In various embodiments, the compounds described herein are combined with an inhibitor of c-kit (PBT, SCFR, CD117, MASTC; NCBI Gene ID: 3815; Uniprot P10721).

[0266] Examples of c-kit inhibitors include imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229 (c-kit / PDGFR inhibitor), telatinib (c-kit / PDGF / VEGF2 inhibitor), quizartinib dihydrochloride (FLT3 / c-kit), pexidartinib hydrochloride (CSF1R / FLT3 / c-kit), avapritinib (PDGFR / c-Kit inhibitor), borolanib (multiple kinase VEGF / PDGFR / c-kit inhibitor), and ripretinib (c-kit / PDGFRα inhibitor).

[0267] Examples of c-kit multikinase inhibitors include dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, HQP-1351, cabozantinib, ponatinib, and famitinib L-malate. Examples of anti-c-kit antibodies include CDX-0158, CDX-0159, and FSI-174.

[0268] In some embodiments, the anti-c-kit targeting agent is selected from the group consisting of those disclosed in WO 199203459, WO 199221766, WO 2004080462, WO 2005020921, WO 2006009755, WO 2007078034, WO 2007092403, WO 2007127317, WO 2008005877, WO 201 Nos. 2014100620, 2014039714, 2015134536, 2017167182, 2018112136, 2018112140, 2019155067, 2020076105, and International Application PCT / US2019 / 063091.

[0269] SIRPα targeting agent In various embodiments, the compounds described herein are combined with an inhibitor of SIRPα (NCBI Gene ID: 140885. UniProt P78324) or an antigen-binding fragment thereof.

[0270] Examples of SIRPα inhibitors include AL-008, RRx-001, and CTX-5861.

[0271] Examples of anti-SIRPα antibodies include FSI-189, ES-004, BI765063, ADU1805, and CC-95251.

[0272] In some embodiments, the SIRPα targeting agent is selected from the group consisting of compounds disclosed in WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 2013056352, WO 2015138600, WO 2016179399, WO 2016205042, WO 2017178 653, 2018026600, 2018057669, 2018107058, 2018190719, 2018210793, 2019023347, 2019042470, 2019175218, 2019183266, 2020013170, or WO2020068752.

[0273] Bispecific T cell engagers In some embodiments, the compounds herein are combined with a bi-specific T-cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc).Exemplary anti-CD3 bispecific antibodies, or BiTEs, that may be co-administered include AMG-160 (PSMA / CD3), AMG-212 (PSMA / CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673 (CD33 / CD3), AMG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), JNJ-64 052781 (CD19 / CD3), AMG-211 (CEA / CD3), BLINCYTO® (CD19 / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), huGD2-BsAb (CD3 / GD2), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), ERY974, flotetuzumab (CD123 / CD3), GEM333 (CD3 / CD33), GEMoab (CD3 / PSCA), REGN-1979 ( CD20 / CD3), REGN-5678(PSMA / CD28), MCLA-117(CD3 / CLEC12A), JNJ-0819, JNJ-7564(CD3 / hem), JNJ-63709178(CD123 / CD3), MGD-007(C D3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), XmAb-18087(SSTR2 / CD3), Examples of such antibodies include catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), RG6026, RG6076, RG6194, RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33), PF-06863135 (BCMA / CD3), and SAR440234 (CD3 / CDw123). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc.Exemplary bispecific T cell engagers that may be co-administered target CD3 and tumor associated antigens described herein (e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230).

[0274] Bispecific and Trispecific Natural Killer (NK) Cell Engagers In some embodiments, the compounds described herein are combined with bispecific NK cell engagers (BiKE) or tri-specific NK-cell engagers (TriKE) (e.g., without Fc), or bispecific antibodies (e.g., with Fc) against NK cell activating receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE that may be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that may be co-administered target CD16 and one or more tumor-associated antigens described herein, including, for example, CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

[0275] MCL1 Apoptosis Regulator, BCL2 Family Member (MCL1) Inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of the MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO 2018 / 183418, WO 2016 / 033486, and WO 2017 / 147410.

[0276] Hematopoietic progenitor kinase 1 (HPK1) inhibitors In some embodiments, the compounds described herein are combined with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in WO 2018 / 183956, WO 2018 / 183964, WO 2018 / 167147, WO 2018 / 183964, WO 2016 / 205942, WO 2018 / 049214, WO 2018 / 049200, WO 2018 / 049191, WO 2018 / 102366, WO 2018 / 049152, WO 2020 / 092528, WO 2020 / 092621, and WO 2016 / 090300.

[0277] Apoptosis signal-regulating kinase (ASK) inhibitors In some embodiments, the compounds described herein are combined with an ASK inhibitor, such as an inhibitor of mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences).

[0278] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, the compounds described herein are combined with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence+AZD6738, Calquence+danvatirsen.

[0279] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the compounds described herein are selected from the group consisting of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: :1019); in combination with inhibitors of cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID:1021); cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID:1022); or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID:1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include, but are not limited to, abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, PF-06873600, AZD4573, and TG-02.

[0280] Discoidin domain receptor (DDR) inhibitors In some embodiments, the compounds described herein are combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include, but are not limited to, dasatinib, and those disclosed in WO 2014 / 047624 (Gilead Sciences), WO 2009 / 0142345 (Takeda Pharmaceutical), WO 2011 / 0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0281] Histone deacetylase (HDAC) inhibitors In some embodiments, the compounds described herein are further combined with an inhibitor of histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat, romidepsin, and tucidinostat.

[0282] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, the compounds described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0283] Janus Kinase (JAK) Inhibitors In some embodiments, the compounds described herein are combined with inhibitors of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0284] Matrix metalloproteinase (MMP) inhibitors In some embodiments, the compounds described herein are inhibitors of matrix metallopeptidases (MMPs), such as MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP18 (NCBI Gene ID: 4327), MMP19 (NCBI Gene ID: 4330), MMP20 (NCBI Gene ID: 4331), MMP21 (NCBI Gene ID: 4332), MMP22 (NCBI Gene ID: 4333), MMP23 (NCBI Gene ID: 4334), MMP24 (NCBI Gene ID: 4335), MMP25 (NCBI Gene ID: 4336), MMP26 (NCBI Gene ID: 4337), MMP27 (NCBI Gene ID: 4338), MMP28 (NCBI Gene ID: 4339), MMP29 (NCBI Gene ID: 4340), MMP30 (NCBI Gene ID: 4341), MMP31 (NCBI Gene ID: 4342), MMP32 (NCBI Gene ID: 4343), MMP33 (NCBI Gene ID: 4344), MMP34 (NCBI Gene ID: 4 and / or an inhibitor of MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics).

[0285] RAS and RAS pathway inhibitors In some embodiments, the compounds described herein are administered to a subject in need thereof, including but not limited to, KRAS proto-oncogene, GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893); HRas proto-oncogene, in combination with an inhibitor of GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). Ras inhibitors can inhibit Ras either at the polynucleotide level (e.g., transcription inhibitors) or at the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, e.g., inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.

[0286] In some embodiments, the compounds described herein are combined with inhibitors of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and KRpep-2 (Ac-RRCPLYISYDPVCRR-NH 2 ) (SEQ ID NO: 108) and KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH 2 ) (SEQ ID NO: 109).

[0287] In some embodiments, the compounds described herein are combined with inhibitors of KRAS mRNA. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adaptor-, AZD-4785, siG12D-LODER™, and siG12D-exosomes.

[0288] In some embodiments, the compounds described herein are combined with inhibitors of MEK. Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and selumetinib.

[0289] In some embodiments, the compounds described herein are combined with inhibitors of AKT. Exemplary AKT inhibitors that may be co-administered include RG7440, MK-2206, ipatasertib, afuresertib, AZD5363, and ARQ-092, capivasertib, triciribine, ABTL-0812 (PI3K / Akt / mTOR).

[0290] In some embodiments, the compounds described herein are combined with inhibitors of Raf. Exemplary Raf inhibitors that may be co-administered include BGB-283 (Raf / EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394. RAF-265 (Raf / VEGFR), ASN-003 (Raf / PI3K).

[0291] In some embodiments, the compounds described herein are combined with inhibitors of ERK. Exemplary ERK inhibitors that may be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, GDC-0994, and ulixertinib.

[0292] In some embodiments, the compounds described herein are combined with inhibitors of PI3K.Exemplary PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, and pitilisib.Exemplary PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, and RG6114.

[0293] In some embodiments, the compounds described herein are combined with inhibitors of mTOR. Exemplary mTOR inhibitors that can be co-administered include sapoanisertib, bistusertib (AZD2014), ME-344, sirolimus (oral nano amorphous formulation, cancer), TYME-88 (mTOR / cytochrome P450 3A4).

[0294] In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib with the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1; 408: 130-137. Also, K-RAS and mutant N-RAS can be reduced by the irreversible inhibitor neratinib of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1; 19(2): 132-137.

[0295] In some embodiments, the compounds described herein are combined with inhibitors of the RAS. Examples of RAS inhibitors include NEO-100 and rigosertib.

[0296] In some embodiments, the compounds described herein are combined with an antagonist of EGFR, such as AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomzotuximab, ABT-806, vectibix, modotuximab, RM-1929, etc.

[0297] In some embodiments, the compounds described herein are combined with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, SAR442720, and those described in WO 2018 / 172984 and WO 2017 / 211303.

[0298] In some embodiments, the compounds described herein are combined with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, RG7421.

[0299] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the compounds described herein are directed to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, Further combined with an inhibitor of PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, R G7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication Nos. WO 2005 / 113556 (ICOS), WO 2013 / 052699 (Gilead Sciences ... and compounds described in Gilead Sciences, Inc., 2014 / 100765 (Gilead Calistoga), 2014 / 100767 (Gilead Calistoga), and 2014 / 201409 (Gilead Sciences).

[0300] Mitogen-activated Protein Kinase (MEK) inhibitors In some embodiments, the compounds described herein are combined with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib.

[0301] Spleen Tyrosine Kinase (SYK) Inhibitors In some embodiments, the compounds described herein are combined with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, Gene ID: 6850). Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celduratinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 2015 / 0175616.

[0302] Toll-like receptor (TLR) agonists In some embodiments, the compounds described herein are combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793).Exemplary TLR7 agonists that may be co-administered include, but are not limited to, DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and the TLR7 agonists described in U.S. Patent Application Publication Nos. 2010 / 0143301 (Gilead Sciences), 2011 / 0098248 (Gilead Sciences), and 2009 / 0047249 (Gilead Sciences). Sciences), 2014 / 0045849 (Janssen), 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Examples of TLR7 / TLR8 agonists that may be co-administered include those disclosed in Ventirx Pharma, 2011 / 0118235 (Ventirx Pharma), 2012 / 0082658 (Ventirx Pharma), 2012 / 0219615 (Ventirx Pharma), 2014 / 0066432 (Ventirx Pharma), 2014 / 0088085 (Ventirx Pharma), 2014 / 0275167 (Novira Therapeutics), and 2013 / 0251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that may be co-administered is NKTR-262.Examples of TLR8 agonists that may be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and those described in U.S. Patent Application Publication No. 20140045849 (Janssen), ... No. 40073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Examples of compounds disclosed in US Pat. No. 20130251673 (Novira Therapeutics) include those disclosed in US Pat.Exemplary TLR9 agonists that may be co-administered include, but are not limited to, AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatorimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0303] Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763.

[0304] Examples of TLR8 agonists include, but are not limited to, MCT-465, motolimod, GS-9688, and VTX-1463.

[0305] Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, ritenimod, MGN-1601, and PUL-042.

[0306] Examples of TLR7 / TLR8 agonists include NKTR-262, IMO-4200, MEDI-9197 (telluratolimod), and resiquimod.

[0307] Examples of TLR agonists include, but are not limited to, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod.

[0308] In some embodiments, the therapeutic agent is a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic-di-AMP.

[0309] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, the compounds described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0310] In some embodiments, the therapeutic agent is a small organic compound. In some embodiments, the therapeutic agent is an agonist or activator of a toll-like receptor (TLR) or a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic-di-AMP.

[0311] Tyrosine kinase inhibitors (TKIs) In some embodiments, the compounds described herein are combined with a tyrosine kinase inhibitor (TKI) that can target the epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), These include lapatinib, restortinib, lenvatinib, midostaurin, nintedanib, ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tiboanib, TH-4000, tiboanib, and MEDI-575 (anti-PDGFR antibody), TAK-659, and cabozantinib.

[0312] Chemotherapy (standard treatment) In some embodiments, the compounds described herein are combined with a chemotherapeutic or anti-neoplastic agent.

[0313] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) is meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerylomelanamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizeresin; cryptoxanthin, which are useful in the treatment of cancer. phycins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremstine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi I1), dynemicins, including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenime antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; radiotherapeutic agents such as radium-223; trichothecenes, especially T-2 toxin, veracrine A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel;Platinum analogues, such as cisplatin and carboplatin, NC-6004 nanoplatin;Aceglatone;Aldophosphamide glycosides;Aminolevulinic acid;Eniluracil;Amsacrine, Hestravcil;Bisantrene;Edatrexate;Defofamine;Demecolcine;Diaziquone;Elformucine;Elliptinium acetate;Epothilone;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Leucovorin;Lonidamine;Maytansinoids, such as maytansine and ansamitocin;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Phenamet;Pirarubicin;Losoxantrone;Fluoropyrimidines;Folinic acid;Podophyllic acid;2-Ethylhydrazide;Procarbazine;Polysaccharide K (PSK);Razoxane;Rhizoxane Syn; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZAR®); 6-Thioguanine; Mercaptopurine; Methotrexate; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vancristine; Vinorelbine (NAVELBINE®); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitors RFS 2000;Difluoromethylornithine (DFMO);Retinoids, e.g., retinoic acid;Capecitabine;NUC-1031;FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin);FOLFIRI (folinic acid, 5-fluorouracil, irinotecan);These include FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), as well as pharma- ceutically acceptable salts, acids, or derivatives of any of the above. Such agents may be conjugated to an antibody or any of the targeting agents described herein to create an antibody drug conjugate (ADC) or targeted drug conjugate;

[0314] Antihormonal drugs Also included within the definition of "chemotherapeutic agent" are anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgens, and pharma- ceutically acceptable salts, acids, or derivatives of any of the above that act to modulate or inhibit hormone action on tumors.

[0315] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0316] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0317] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

[0318] An example of a progesterone receptor antagonist is onapristone.

[0319] Antiangiogenic Agents In some embodiments, the compounds described herein are combined with antiangiogenic agents. Antiangiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necupranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thiaproline, alpha, These include, but are not limited to, α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinases-3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, β-1-anticollagenase serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthonylate disodium or "CCA", thalidomide, angiogenesis-suppressing steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, such as monoclonal antibodies against these angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.

[0320] Antifibrotic Agents In some embodiments, the compounds described herein are combined with antifibrotic agents.Antifibrotic agents that can be co-administered include, but are not limited to, compounds such as β-aminopropionitrile (BAPN) and compounds disclosed in U.S. Patent No. 4,965,288, which relates to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal deposition of collagen, and U.S. Patent No. 4,997,854, which relates to compounds that inhibit LOX for treating various pathological fibrotic conditions (these are incorporated herein by reference). Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, U.S. Pat. No. 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication No. 2004 / 0248871, which are incorporated herein by reference.

[0321] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate products stabilized by resonance after binding to the carbonyl, such as the following primary amines: emilenmamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamines; and selenohomocysteine ​​lactones.

[0322] Other antifibrotic agents are copper chelators that may or may not permeate cells. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0323] Anti-inflammatory agents In some embodiments, a compound described herein is combined with an anti-inflammatory agent. Exemplary anti-inflammatory agents include arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 ( NCBI Gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0324] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that may be co-administered include, but are not limited to, mofezolac, GLY-230, and TRK-700.

[0325] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include, but are not limited to, diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of COX1 / COX2 dual inhibitors that may be co-administered include, but are not limited to, HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of COX-2 / carbonic anhydrase (CA) dual inhibitors that may be co-administered include, but are not limited to, pormacoxib and imrecoxib.

[0326] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that may be co-administered include, but are not limited to, LY3023703, GRC 27864, and the compounds described in WO 2015 / 158204, WO 2013 / 024898, WO 2006 / 063466, WO 2007 / 059610, WO 2007 / 124589, WO 2010 / 100249, WO 2010 / 034796, WO 2010 / 034797, WO 2012 / 022793 ...13 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 024898, WO 2013 / 02 Publication No. 2012 / 076673, International Publication No. 2012 / 076672, International Publication No. 2010 / 034798, International Publication No. 2010 / 034799, International Publication No. 2012 / 022792, International Publication No. 2009 / 103778, International Publication No. 2011 / 048004, International Publication No. 2012 / 087771, International Publication No. 2012 / 161965, International Publication No. 2013 / 118 071, WO 2013 / 072825, WO 2014 / 167444, WO 2009 / 138376, WO 2011 / 023812, WO 2012 / 110860, WO 2013 / 153535, WO 2009 / 130242, WO 2009 / 146696, WO 2013 / 186692, WO 2014 / 170693, WO 2014 / 186694, WO 2014 / 190695, WO 2014 / 190696, WO 2014 / 190697, WO 2014 / 190699, WO 2014 / 190698, WO 2014 / 19069 ... Examples of compounds that can be co-administered include those described in International Publication Nos. 015 / 059618, 2016 / 069376, 2016 / 069374, 2009 / 117985, 2009 / 064250, 2009 / 064251, 2009 / 082347, 2009 / 117987, and 2008 / 071173. Additionally, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, for example, Tong, et al., Cancer Lett. (2017) 389: 23-32; and Liu, et al., Oncotarget. (2016) 7(19): 28235-46.

[0327] Carbonic anhydrase enzymes that may be co-administered (e.g., CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), Examples of inhibitors of one or more of CA10 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632) include, but are not limited to, acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0328] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include, but are not limited to, meclofenamate sodium, zileuton.

[0329] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) inhibitors that may be co-administered include, but are not limited to, compounds described in WO 2015 / 148954. Dual COX-2 / SEH inhibitors that may be co-administered include compounds described in WO 2012 / 082647. Dual SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) inhibitors that may be co-administered include compounds described in WO 2017 / 160861.

[0330] Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) that may be co-administered include, but are not limited to, GS-4875, GS-5290, BHM-078, and the inhibitors described in, for example, WO 2006 / 124944, WO 2006 / 124692, WO 2014 / 064215, WO 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu, et al., Bioorg Med Chem. Lett. (2009) 19(13):3485-8; Kaila, et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0331] Tumor oxygenators In some embodiments, the compounds described herein are combined with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia.Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, such as PT-2977, PT-2385; VEGF inhibitors, such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and / or oxygen carrier proteins such as OMX-302 and HNOX proteins (e.g., heme-nitric oxide and / or oxygen-binding protein (HNOX)), as described, for example, in WO2007 / 137767, WO2007 / 139791, WO2014 / 107171, and WO2016 / 149562.

[0332] Immunotherapeutic agents In some embodiments, the compounds described herein are combined with immunotherapeutic agents. Examples of immunotherapeutic agents that may be co-administered include abagovomab, ABP-980, adecatumumab, afutumumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitunomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratuzumab, detumomab, dinutuximab, drozitumab, dutuzumab, dastin ... Rigotumab, dusigitumab, ecloneximab, elotuzumab, emibetuzumab, ensituzumab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, framvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), Tumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minletuzumab, mitumomab, mogamulitumab, moxetumomab, naptumomab, narutuzumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, These include, but are not limited to, pintumomab, pritumumab, racotumomab, radletuzumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubirituximab, veltuzumab, borsetuzumab, votumumab, zalutumumab, and 3F8.Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0333] The exemplified therapeutic antibodies may further be labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0334] In some embodiments, the immunotherapeutic agent is an antibody drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein. Examples of ADCs that may be co-administered include gemtuzumab, brentuximab, trastuzumab, inotuzumab, glenbatumumab, anetuzumab, mirvetuximab, depatuximab, rovalpituzumab, vadatuximab, labetuzumab, sacituzumab, rifastuzumab, indosatuzumab, polatuzumab, pinatuzumab, cortuximab, indatuximab, milatuzumab, robalbutuzumab, ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982 , BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN529, IMGN853, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, and SYD985. ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0335] Exemplary therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicins, ansamitocins, maytansine or analogs thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinker SC-DR002 (D6.5), duocarmycins, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or dimers thereof, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065) and other anti-cancer or anti-neoplastic agents described herein.

[0336] Cancer Gene Therapy and Cell Therapy In some embodiments, the compounds described herein are combined with cancer gene therapy treatment and cell therapy.Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; genetic approaches to directly kill cancer cells, such as injection of immune cells designed to enhance immune response to cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to replace most of the patient's own immune system to find and kill cancer cells; genetic approaches to modify cell activity to further change the endogenous immune responsiveness to cancer.

[0337] cell therapy In some embodiments, the compounds described herein are combined with one or more cell therapies. Exemplary cell therapies include, but are not limited to, the co-administration of one or more populations of immune cells. In some embodiments, the immune cells are natural killer (NK) cells, NK-T cells, T cells, gamma delta T cells, B cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TIL), granulocytes, innate lymphoid cells, megakaryocytes, monocytes, macrophages, platelets, thymocytes, myeloid cells, and / or dendritic cells (DC). In some embodiments, the cell therapy involves the co-administration of a T cell therapy, e.g., a population of α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves the co-administration of an NK cell therapy, e.g., NK-92 cells. Optionally, the cell therapy can involve the co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0338] In some embodiments, the cell therapy involves the co-administration of immune cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR). In certain embodiments, the population of immune cells is engineered to express a CAR, where the CAR comprises a cancer antigen binding domain. In other embodiments, the population of immune cells is engineered to express a T cell receptor (TCR) that is engineered to target a tumor-derived peptide displayed on the surface of a tumor cell. In one embodiment, the immune cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR) are T cells. In another embodiment, the immune cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR) are NK cells.

[0339] With regard to the structure of the CAR, in some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In certain embodiments, the primary signaling domain is CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc epsilon, Rlb), CD79a, CD79b, Fc gamma RIIa, DAP10, and DAP12, 4-1BB / CD137, activating NK cell receptor, immunoglobulin protein, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D ), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 delta, CD3 epsilon, CD3 gamma, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8 alpha, CD8 beta, CD96 (Tactile), CD11a, CD11b, CD11c, CD11d, CDS, CEACAM1, CRT AM, cytokine receptor, DAP-10, DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, Ig alpha (CD79a), IL-2R beta, IL-2R gamma, IL-7R alpha, inducible T cell costimulator (ICOS), integrin, ITGA4, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, ligand binding to CD83, LIGHT, LIGHT, LTBR, ​​Ly9 (CD229), Ly108), lymphocyte function-associated antigen-1 (LFA-1;and / or a functional domain of one or more proteins selected from the group consisting of CD1-1a / CD18), MHC class 1 molecule, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG / Cbp, programmed death-1 (PD-1), PSGL1, SELPLG (CD162), signaling lymphocyte activation molecule (SLAM protein), SLAM (SLAMF1; CD150; IPO-3), SLAMF4 (CD244; 2B4), SLAMF6 (NTB-A, SLAMF7, SLP-76, TNF receptor protein, TNFR2, TNFSF14, Toll ligand receptor, TRANCE / RANKL, VLA1, or VLA-6, or fragments, truncations, or combinations thereof;

[0340] In some embodiments, the costimulatory domain is selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, lymphocyte function-associated antigen-1 (LFA-1), MYD88, B7-H3, a ligand that specifically binds CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 ( KLRFI), CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD 1D (NCBI gene ID: 912), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY 55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0341] In some embodiments, the transmembrane domain is selected from the group consisting of the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD3 delta, CD3 gamma, CD45, CD4, CD5, CD7, CD8 alpha, CD8 beta, CD9, CD11a, CD11b, CD11c, CD11d, CD16, CD18, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), G ITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD19, CD19a, IL2R beta, IL2R gamma, IL7R alpha, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, ITGB2, ITGB7, CD29, ITGB2 (LFA-1, CD18), I TGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, NKG2C activated N The protein comprises a transmembrane domain derived from a protein selected from the group consisting of a K cell receptor, an immunoglobulin protein, BTLA, CD247, CD276 (B7-H3), CD30, CD84, CDS, a cytokine receptor, an Fc gamma receptor, GADS, ICAM-1, Ig alpha (CD79a), an integrin, LAT, a ligand that binds CD83, LIGHT, an MHC class 1 molecule, PAG / Cbp, TNFSF14, a Toll ligand receptor, TRANCE / RANKL, or a fragment, truncation or combination thereof.

[0342] In some embodiments, the CAR comprises a hinge domain. The hinge domain is selected from the group consisting of CD2, CD3 delta, CD3 epsilon, CD3 gamma, CD4, CD7, CD8 alpha, CD8 beta, CD11a (ITGAL), CD11b (ITGAM), CD11c (ITGAX), CD11d (ITGAD), CD18 (ITGB2), CD19 (B4), CD27 (TNFRSF7), CD28, CD28T, CD29 (ITGB1), CD30 (TNFRSF8), CD40 (TNFRSF5), CD48 (SLAMF2), CD49a (ITGA1), CD49d (ITGA4). , CD49f (ITGA6), CD66a (CEACAM1), CD66b (CEACAM8), CD66c (CEACAM6), CD66d (CEACAM3), CD66e (CEACAM5), CD69 (CLEC2), CD79A (B cell antigen receptor complex-associated alpha chain), CD79B (B cell antigen receptor complex-associated beta chain), CD84 (SLAMF5), CD96 (Tactile), CD100 (SEMA4D), CD103 (ITGAE), CD134 (OX40), CD137 (4-1BB), CD15 0 (SLAMF1), CD158A (KIR2DL1), CD158B1 (KIR2DL2), CD158B2 (KIR2DL3), CD158C (KIR3DP1), CD158D (KIRDL4), CD158F1 (KIR2DL5A), CD158F2 (KIR2DL5B), CD158K (KIR3DL2), CD160 (BY55), CD162 (SELPLG), CD226 (DNAM1), CD229 (SLAMF3), CD244 (SLAMF4), CD247 (CD3-zeta), CD258 (LIGH T), CD268(BAFFR), CD270(TNFSF14), CD272(BTLA), CD276(B7-H3), CD279(PD-1), CD314(NKG2D), CD319(SLAMF7), CD335(NK-p46), CD336(NK- p44), CD337 (NK-p30), CD352 (SLAMF6), CD353 (SLAMF8), CD355 (CRTAM), CD357 (TNFRSF18), inducible T cell costimulatory factor (ICOS), LFA-1 (CD11a / CD18), NKG2C,The antibody may be derived from a protein selected from the group consisting of DAP-10, ICAM-1, NKp80 (KLRF1), IL-2R beta, IL-2R gamma, IL-7R alpha, LFA-1, SLAMF9, LAT, GADS (GrpL), SLP-76 (LCP2), PAG1 / CBP, CD83 ligand, Fc gamma receptor, MHC class 1 molecule, MHC class 2 molecule, TNF receptor protein, immunoglobulin protein, cytokine receptor, integrin, activating NK cell receptor, or Toll ligand receptor, IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, or fragments or combinations thereof.

[0343] In some embodiments, the one or more additional therapeutic agents include immunotherapy, immunostimulatory therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, and combinations thereof. In some embodiments, the immunotherapy comprises co-administration of one or more antibodies or antigen-binding antibody fragments thereof, or antibody drug conjugates thereof, CD3-targeted multispecific molecules, CD16-targeted multispecific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins targeted to one or more targets or tumor-associated antigens (TAA).

[0344] In some embodiments, the TCR or CAR antigen binding domain or immunotherapeutic agent (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof or an antibody mimetic) described herein binds to a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (G D2; ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); GM-CSF receptor; TNF receptor superfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesion molecule; Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protein ase serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); HLA class I antigen A-2α; HLA antigen; Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; folate receptor beta, GDNFα4 receptor, receptor tyrosine protein kinase, ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); APRIL receptor; ADP-ribosyl cyclase-1;Ephb4 tyrosine kinase receptor, DCAMKL1 serine threonine kinase, aspartate β-hydroxylase, epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrinB2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); ephrin type A receptor 3 (EphA3), fucosyl-GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o- Acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of prostate I (STEAP1); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRCSD); IL-15 receptor (IL-15); X chromosome open reading frame 61 (CXORF61); CD97; CD179a;anaplastic lymphoma kinase (ALK);polysialic acid;placenta specific 1 (PLAC1);hexasaccharide moiety of globoH glycoceramide (GloboH);mammary differentiation antigen (NY-BR-1);uroplakin 2 (UPK2);hepatitis A virus cell receptor 1 (HAVCR1);adrenergic receptor beta 3 (ADRB3);pannexin 3 (PANX3);G protein-coupled receptor 20 (GPR20);lymphocyte antigen 6 complex, locus K9 (LY6K);olfactory receptor 51E2 (ORS IE2);TCR gamma alternative reading frame protein (TARP);Wilms tumor protein (WT1);cancer / testis antigen 1 (NY-ESO-1);cancer / testis antigen 2 (LAGE-la);melanoma-associated antigen 1 (MAGE-A1);melanoma-associated antigen 3 (MAGE-A3);melanoma-associated antigen 4 (MAGE-A4); T cell receptor beta 2 chain C; ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or M ARTI);rat sarcoma (Ras) mutant;human telomerase reverse transcriptase (hTERT);sarcoma translocation breakpoints;melanoma inhibitor of apoptosis (ML-IAP);ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene);N-acetylglucosaminyltransferase V (NA17);paired box protein Pax-3 (PAX3);androgen receptor;cyclin-A1;cyclin B1;v-myc avian myeloma viral oncogene neuroblastoma-derived homolog (MYCN);Ras homolog family member C (RhoC);tyrosinase-related protein 2 (TRP-2);cytochrome P450 1B1 (CYP IBI); CCCTC-binding agent (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchoring protein 4 (AKAP-4); peptidoglycan recognition protein, synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp70-2);CD79a;CD79b;CD72;leukocyte-associated immunoglobulin-like receptor 1 (LAIRI);Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-2 (GPC2); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen that is presented on MHC.;

[0345] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B Fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HLA class I antigen αG, HM1.24, K-Ras GTPase, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL R1, TRAIL R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WTI, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic agent, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, Epstein-Barr nuclear antigen The protein is selected from the group consisting of ribonuclease 1, latent membrane protein 1, secreted protein BARF1, P2X7 purinergic receptor, syndecan-1, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0346] Examples of cell therapies include AMG-119, Algenpantucel-L, ALOFISEL (registered trademark), Sipuleucel-T, (BPX-501) rivogenlecleucel, U.S. Patent Application Publication No. 9,089,520, International Publication No. 2016 / 100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treatment with bone marrow stem cell therapy, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, lentiviral transduction of huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005, LAAP T cell therapy, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T cell therapy + PD-1 knockout T cell therapy (esophageal cancer / NSCLC), anti-KRAS G12D mTCR PBL, anti-CD123 CAR T cell therapy, anti-mutated neoantigen TCR T cell therapy, tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccine, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal / intravenous), anti-LeY-scFv-CD28-zeta CAR T cells, PRGN-3005, iC9-GD2-CAR-IL-15T-cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG, MIDRIXNEO, FCR-001, PLX Stem Cell Therapy, MDR-101, GeniusVac-Mel4, ilixadencel, Allogeneic Mesenchymal Stem Cell Therapy, romyelocel L, CYNK-001, ProTrans, ECT-100, MSCTRAIL, dilanubicel, FT-516, ASTVAC-2, E-CEL UVEC, CK-0801, Allogeneic Alpha / Beta CD3+ T Cells and CD19+ These include, but are not limited to, B cell depleted stem cells (hematological diseases, TBX-1400, HLCN-061, umbilical cord derived Hu-PHEC cells (hematological malignancies / aplastic anemia), AP-011, apceth-201, apceth-301, SENTI-101, stem cell therapy (pancreatic cancer), ICOVIR15-cBiTE, CD33HSC / CD33 CAR-T, PLX-Immune, SUBCUVAX, CRISPR allogeneic gamma-delta T cell based gene therapy (cancer), ex vivo CRISPR allogeneic healthy donor NK cell based gene therapy (cancer), ex vivo allogeneic induced pluripotent stem cell derived NK cell based gene therapy (solid tumors), and anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma).

[0347] Additional agents for targeting tumors include, but are not limited to, the following: alpha-fetoproteins such as ET-1402 and AFP-TCR; anthrax toxin receptor 1, such as anti-TEM8 CAR T-cell therapy; TNF receptor superfamily member 17 (TNFRSF17, BCMA), e.g., bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528; Anti-CLL-1 antibodies such as KITE-796. See, e.g., International Application No. PCT / US2017 / 025573; anti-PD-L1-CAR tank cell therapies such as KD-045; anti-PD-L1 t-haNK, e.g., PD-L1 t-haNK; Anti-CD45 antibodies, e.g., 131I-BC8 (lomab-B); Anti-HER3 antibodies, e.g., LJM716, GSK2849330; Anti-CD52 antibodies, such as alemtuzumab; APRIL receptor modulators, e.g., anti-BCMA CAR T cell therapy, Descartes-011; ADP-ribosyl cyclase-1 / APRIL receptor modulators, e.g., anti-BCMA / anti-CD38 dual CAR T cell therapy; CART-ddBCMA; B7 homolog 6, such as CAR-NKp30 and CAR-B7H6; Bリンパglobulin CD19, caseえば, TBI-1501, CTL-119 huCART-19 T cells, liso-cel, JCAR-015 U.S. Patent No. 7446190, JCAR-014, JCAR-017 (International Publication No. 2016 / 196388, Same No. 2016 / 033570, Same No. 2 No. 015 / 157386), KTE-C19, Yescarta (registered trademark), KTE-X19, U.S. Patent No. 77 No. 41465, same No. 6319494, UCART-19, EBV-CTL, T-cell-T (CTL019), International Publication No. 2012 / 079000, same No. 2017049166, CD19CAR-CD28-CD3ζ-EGFRt T cells, CD19 / 4-1BBL armed CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζT cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110; anti-CD19 CAR T cell therapy (B-cell acute leukemia, Maresi University); anti-CD19 CAR T cell therapy (acute leukemia / non-hodgin leukemia, Hildebeck University Hospital), anti-CD19 CAR T cell therapy (IL-6 onset inhibition, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1(CD19 / CD20), GC-197(CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR(CD19 / APRIL), ICG-134, ICG-132(CD19 / CD20), CTA-101, WZTL-002, anti-CD19 / anti-CD20 dual CAR T cells (chronic leukemia / B cell leukemia), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3ζ-EGFRt Tn / mem; UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540; Allogeneic anti-CD19 CART cells, Example, GC-007G; allogeneic T cells expressing CD20 CAR, e.g., LB-1905; APRIL receptor modulator;SLAM family member 7 modulator, BCMA-CS1 cCAR; Autologous dendritic cell tumor antigen (ADCTA), e.g., ADCTA-SSI-G; B lymphocyte antigen CD20, e.g., ACTR707 ATTCK-20, PBCAR-20A; B lymphocyte antigen CD19 / B lymphocyte antigen 22, e.g., TC-310; B lymphocyte antigen 22 cell adhesion, e.g., UCART-22, JCAR-018 WO 2016 / 090190; NY-ESO-1 modulators, e.g., GSK-3377794, TBI-1301, GSK3537142; Carbonic anhydrase, e.g., DC-Ad-GMCAIX; Caspase 9 suicide gene, e.g., CaspaCIDe DLI, BPX-501; CCR5, e.g., SB-728; CCR5 gene inhibitor / TAT gene / TRIM5 gene stimulator, e.g., CCR5 shRNA / TRIM5α / TAR decoy lentiviral vector transduced autologous CD34-positive hematopoietic progenitor cells; CDw123, for example, MB-102, IM-23, JEZ-567, UCART-123; CD4, e.g., ICG-122; CD5 modulators, e.g., CD5.28z CART cells; anti-CD22, e.g., anti-CD22 CART; anti-CD30, e.g., TT-11; CD33, e.g., CIK-CAR.CD33, CD33CART; dual anti-CD33 / anti-CLL 1, such as LB-1910; CD38, e.g., T-007, UCART-38; CD40 ligand, e.g., BPX-201, MEDI5083; CD56, e.g., allogeneic CD56-positive CD3-negative natural killer cells (myeloid malignancies); CD19 / CD7 modulators, e.g., GC-197; T cell antigen CD7 modulators, e.g., anti-CD7 CAR T cell therapy (CD7-positive hematological malignancies); CD123 modulators, e.g., UniCAR02-T-CD123; anti-CD276, e.g., anti-CD276 CART; CEACAM protein 5 modulators, such as MG7-CART; Claudin 6, e.g., CSG-002; Claudin 18.2, e.g., LB-1904; Chlorotoxins, e.g., CLTX-CART; EBV-targeted, e.g., CMD-003; MUC16EGFR, e.g., autologous 4H11-28z / fIL-12 / EFGRt T cells; Endonucleases, e.g., PGN-514, PGN-201; Epstein-Barr virus-specific T lymphocytes, e.g., TT-10; Epstein-Barr nuclear antigen 1 / latent membrane protein 1 / secreted protein BARF1 modulators, e.g., TT-10X; Erbb2, e.g., CST-102, CIDeCAR; Gangliosides (GD2), e.g., 4SCAR-GD2; γδ T cells, e.g., ICS-200; Folate hydrolase 1 (FOLH1, glutamate carboxypeptidase II, PSMA; NCBI gene ID: 2346), e.g., CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101; Glypican-3 (GPC3), e.g., TT-16, GLYCAR; Hemoglobin, for example, PGN-236; Hepatocyte growth factor receptor, e.g., anti-cMet RNA CAR T; HLA class I antigen A-2α modulators, e.g., FH-MCVA2TCR; HLA class I antigen A-2α / melanoma-associated antigen 4 modulators, e.g., ADP-A2M4CD8; HLA antigen modulators, e.g., FIT-001, NeoTCR-P1; Topapillomavirus E7 proteins, such as KITE-439. See, e.g., International Application No. PCT / US2015 / 033129; ICAM-1 modulators, e.g., AIC-100; Immunoglobulin gamma Fc receptor III, e.g., ACTR087; IL-12, e.g. DC-RTS-IL-12; IL-12 agonist / mucin 16, e.g., JCAR-020; IL-13α2, e.g., MB-101; IL-15 receptor agonists such as PRGN-3006, ALT-803; interleukin-15 / Fc fusion proteins (e.g., XmAb24306); recombinant interleukin-15 (e.g., AM0015, NIZ-985); pegylated IL-15 (e.g., NKTR-255); IL-2, e.g., CST-101; Interferon-α ligand, e.g., autologous tumor cell vaccine + systemic CpG-B + IFN-α (cancer); K-Ras GTPase, e.g., anti-KRAS G12V mTCR cell therapy; Neural cell adhesion molecule L1 L1CAM (CD171), e.g., JCAR-023; Latent membrane protein 1 / latent membrane protein 2, e.g., Ad5f35-LMPd1-2 transduced autologous dendritic cells; MART-1 melanoma antigen modulators, e.g., MART-1 F5 TCR engineered PBMCs; Melanoma associated antigen 10, e.g., MAGE-A10C796T MAGE-A10 TCR; Melanoma associated antigen 3 / melanoma associated antigen 6 (MAGE A3 / A6), such as KITE-718 (see, e.g., PCT / US Patent Application Publication No. 2013 / 059608); Mesothelin, e.g., CSG-MESO, TC-210; Mucin 1 modulators, e.g., ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053; anti-MICA / MICB, e.g., CYAD-02; NKG2D, e.g., NKR-2; Ntrkr1 tyrosine kinase receptor, e.g., JCAR-024; PRAMET cell receptors, e.g., BPX-701; Prostate stem cell antigen modulators, e.g., MB-105; Roundabout homolog 1 modulators, e.g., ATCG-427; peptidoglycan recognition protein modulators, e.g., Tag-7 genetically modified autologous tumor cell vaccines; PSMA, such as PSMA-CAR T-cell therapy (lentiviral vector, castration-resistant prostate cancer); SLAM family member 7 modulators, e.g., IC9-Luc90-CD828Z; TGFβ receptor modulators, e.g., DNR.NPC T cells; T lymphocytes, e.g., TT-12; T lymphocyte stimulators, e.g., ATL-001; TSH receptor modulators, e.g., ICTCAR-051; Tumor infiltrating lymphocytes such as LN-144, LN-145; and / or Wilms tumor proteins such as JTCR-016 and WT1-CTL.

[0348] Agonists of fms-related receptor tyrosine kinase 3 (FLT3) In some embodiments, the compounds described herein are combined with an agonist of fms-related receptor tyrosine kinase 3 (FLT3; FLK2; STK1; CD135; FLK-2; NCBI gene ID: 2322). Examples of FLT3 agonists include CDX-301 and GS-3583.

[0349] MCL1 Apoptosis Regulator, BCL2 Family Member (MCL1) Inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of the MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO 2018 / 183418, WO 2016 / 033486, WO 2019 / 222112, and WO 2017 / 147410.

[0350] Cytokine-induced SH2-containing protein (CISH) inhibitors In some embodiments, the compounds described herein are further combined with an inhibitor of cytokine-induced SH2-containing proteins (CISH; CIS; G18; SOCS; CIS-1; BACTS2; NCBI Gene ID: 1154). Examples of CISH inhibitors include those described in WO 2017 / 100861, WO 2018 / 075664, and WO 2019 / 213610.

[0351] Gene Editor In some embodiments, the compounds described herein are combined with gene editors. Exemplary gene e...

Claims

1. Compounds of formula (I): 【Chemistry 100】 or a pharma- ceutically acceptable salt thereof, wherein: Z １ is N or CR １ and R １ is hydrogen, C １～６ alkyl or halogen; Z ２ is N or CR ２ and R ２ is hydrogen, C １～６ alkyl or halogen; R ３ is hydrogen, C １～６ alkyl or halogen; R ４ is hydrogen, C １～６ alkyl or halogen; R ７ is C １～６ is alkyl, R ５ is C １～６ Alkyl or C １～６ is haloalkyl, R ６ is phenyl or heteroaryl, and said phenyl or heteroaryl is represented by 1 to 3 R ６ａ wherein the heteroaryl is a 5- or 6-membered ring having 1-3 heteroatoms, each independently being N, O or S; or 【Chemistry 101】 and X １ , X ２ , X ３ and X ４ are each independently CH, N, or C-R ６ａ where there are two or less X １ , X ２ , X ３ and X ４ is N, and there are two or less X １ , X ２ , X ３ and X ４ is C-R ６ａ and Ring A is a 5-8 membered heterocycloalkyl optionally having 1-2 additional heteroatoms, each independently being N, O, or S; and optionally ... ６ｇ is replaced by Each R ６ａ are independently halogen or C ２～６ alkynyl, wherein the alkynyl is a 1 to 4 R ６ｊ and optionally substituted with Each R ６ｊ are independently halogen, C １～６ Haloalkyl, -OR ６ｊ１ , -C.N., C. ３～１０ cycloalkyl, or heterocycloalkyl, each of which may be the same or different and may be represented by 1 to 3 R ６ｐ wherein said heterocycloalkyl is a 3- to 10-membered ring having 1-3 heteroatoms, each independently being N, O, or S; Each R ６ｊ１ are independently hydrogen, C １～６ Alkyl, or C １～６ is haloalkyl, Each R ６ｐ are independently halogen, C １～６ Alkyl, or C １～６ is haloalkyl, Each R ６ｇ is independently １～６ Alkyl, halogen, or C １～６ haloalkyl, A compound of formula (I), or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1 having the formula (Ia-1), (Ia-2), or (Ia-3), or a pharma- ceutically acceptable salt thereof. 【Chemistry 127】

3. R ５ But -CH ２ CHF ２ 2. The compound of claim 1, wherein:

4. R ６ is phenyl or heteroaryl, said phenyl or heteroaryl being represented by one or two R ６ａ wherein said heteroaryl is a 5-6 membered ring having 1-2 heteroatoms, each independently being N, O or S; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

5. R ６ is phenyl or pyridyl, said phenyl or pyridyl being represented by one or two R ６ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

6. R ６ F and C ２～６ phenyl substituted with alkynyl, said alkynyl being one or two R ６ｊ has been replaced by 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

7. 【Chemical 109】 and n is 0, 1, or 2; Ring A is a 5-8 membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms, each independently being N, O, or S; and optionally Ring A is a 5-8 membered heterocycloalkyl optionally having 1 or 2 R ６ｇ has been replaced by 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof. 【Request 8】 【Chemical 111】 2. The compound of claim 1, wherein:

9. Each R ６ａ is independently ２～６ alkynyl or halogen, wherein the alkynyl is selected from 1 to 3 R ６ｊ and optionally substituted with 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

10. Each R ６ａ are independently 1 to 3 R ６ｊ C substituted with ２～６ is alkynyl, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

11. Each R ６ｊ are independently halogen, C １～６ Haloalkyl, -OR ６ｊ１ , -C.N., C. ３～６ cycloalkyl, 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is selected from 1 to 3 R ６ｐ and optionally substituted with R ６ｊ１ is hydrogen or C １～６ is alkyl, Each R ６ｐ is independently １～３ Alkyl or C １～３ haloalkyl, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

12. Each R ６ｊ are independently -OH, -CN, -F, -CF ３ or 【Chemistry 116】 2. The compound of claim 1, wherein:

13. Each R ６ａ became independent and became F, 【Chemistry 117】 That is, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

14. 【Catalogue 118】 That is, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

15. 【Catalogue 128】 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

16. R １ is hydrogen, R ２ is hydrogen or Cl; R ３ is hydrogen or F; R ４ is hydrogen, C １～３ alkyl, or halogen; and R ７ is hydrogen or C １～３ is alkyl, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

17. The following: 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 【Chemistry 17-4】 【Chemistry 17-5】 【Chemistry 17-6】 【Chemistry 17-7】 【Chemistry 17-8】 【Chemistry 17-9】 【Chemistry 17-10】 【Chemistry 17-11】 or a pharma- ceutically acceptable salt thereof.

18. 20. A pharmaceutical composition comprising a pharma- ceutically effective amount of a compound of claim 1 or 17, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

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