Diacylglycerol kinase regulatory compound

Abstract

JPEG2024522594000352.jpg55128This application relates to diacylglycerol kinase modulating compounds of general formula (I) and pharmaceutical compositions thereof for treating cancer, including solid tumors, and viral infections, such as HIV or Hepatitis B virus infection.The compounds may be used alone or in combination with other drugs.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 213,880, 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 signaling molecule and a second messenger, playing 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 regulated, and diacylglycerol kinase (DGK) is one of the enzymes that regulates them. DGK synthesizes phosphatidic acid (PA) by transferring a phosphoryl group to DAG. Ten human isozymes (α, β, γ, δ, ε, ζ, η, θ, ι, and κ) are known (Joshi, RP, Koretzky, GAINt. J. Mol. Sci. 2013, 14, 6649-6673). Each isozyme is localized and thought to associate with different proteins and / or different cell types. DGK has been reported to be involved in the pathogenesis of multiple diseases, including cancer, immune disorders, 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 into its potential therapeutic potential for cancer. 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 have also been reported in human colon cancer cell lines in three-dimensional cell culture, and knockdown of DGKα was further reported to inhibit tumor growth in a mouse model (Torres-Ayuso, P., et al. Oncotarget, 2014, 5, 9710-9726). Inhibition of DGKα has been disclosed in International Publication No. 2007 / 114239. Therefore, compounds with inhibitory activity against DGKα may be useful as therapeutic agents for the treatment of cancers in which DGKα is involved in their proliferation.

[0005] In recent years, cancer immunotherapy has attracted attention as a potential treatment for cancer. 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. Several immune checkpoint inhibitors have already been approved as drugs for antitumor therapy. However, the antitumor effect is often limited to a small number of patients. Furthermore, some patients develop resistance to the inhibitors (Spranger, S., Gajewski, T. F., Nat. Rev. Cancer., 2018, 18, 139-147).

[0006] DGKα is expressed in T cells, mediates T cell receptor (TCR) signaling, and is thought to play a role in T cell activation (Joshi et al. (supra) and Merida, I. et al., Adv. Biol. Regul., 2017, 63, 22-31). DGKα expression may increase when T cells are in an immunologically unresponsive state, such as anergy, and overexpression of DGKα has been reported to induce an anergic state (Zha, Y. et al., Nat. Immunol., 2006, 7, 1166-1173). Furthermore, knockdown of DGKα in T cells by RNA interference has been reported to result in T cell activation (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, chimeric antigen receptor (CAR) T cell therapy has attracted attention as a promising immunotherapy for cancer. DGKα-deficient CAR T cells have been reported to have high effector function and antitumor efficacy against solid tumors (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, for example, 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​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ In one embodiment, the present disclosure provides a compound of formula (I):

[0010] [ka] [In the formula, Z 1 is N or CR 1 and Z 2 is N or CR 2 and Z 4 is N or CR 4 and Z 7 is N or CR 7 and Z 8 is N or CR 8 and Z 9 is N or CR 9 and Each R 1 and 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, and each R 1 and R 4 may be the same or different, 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, -NO2, -C(O)R 2a , -C(O)OR 2a , -OC(O)R 2a , -C(O)N(R 2a )(R2b ), -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)R 2a , -S(O)2N(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 2dEach cycloalkyl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 2e Each aryl may be optionally substituted with 1 to 3 R 2f and each heterocycloalkyl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 2g Each heteroaryl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 2h optionally substituted with a 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 the aryl or heteroaryl is selected from 1 to 3 R 2j and optionally substituted with Alternatively, R 2a , R 2b , and R 2c when attached to the same atom, can combine 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 )(R2d2 ), -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)R 2d1 , -S(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )S(O)2R 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 R2j independently, 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, or C 1~6 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, -NO2, -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)R 3a, -S(O)2N(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 independently is selected from 1 to 3 R 3d groups, and each cycloalkyl may be optionally substituted with 1 to 3 R 3e Each aryl may be optionally substituted with 1 to 3 R 3f and each heterocycloalkyl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 3g Each heteroaryl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 3h optionally substituted with a 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-C6~12 aryl, heterocycloalkyl, or heteroaryl; Alternatively, R 3a , R 3b , and R 3c when attached to the same atom, can combine 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 haloalkoxy, 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 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 C 1~6 is alkyl, R 6 is C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, 1 to 3 R 6a C replaced with 6-12 Aryl or 1 to 3 R 6a and each R is a heteroaryl substituted with 6a independently, 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, -NO2, -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)2R 6b , -S(NR 6b )(NR6c )R 6d , -S(O)(NR 6b )(R 6c ), -S(O)2N(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 have 1 to 3 R 6e and the alkyl is optionally substituted with R 6f and the 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 6~12Aryl, 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 independently, C 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 independently, 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, -NO2, -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(R6e1 )(R 6e2 ), =O, -OR 6e1 , -SR 6e1 , -S(O)R 6e1 , -S(NR 6e1 )(NR 6e2 ), -S(O)(NR 6e1 )(R 6e2 ), -S(O)R 6e1 , -S(O)2N(R 6e1 )(R 6e2 ), -SF5, -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 optionally substituted, and alkyl is 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 1~6Haloalkyl, 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)R 6n1, -S(O)2N(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 independently, 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 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 )(R6h2 ), =O, -OH, -SR 6h1 , -S(O)R 6h1 , -S(NR 6h1 )(NR 6h2 )R 6h3 , -S(O)(NR 6h1 )(R 6h2 ), -S(O)R 6h1 , -S(O)2N(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 )(R6m2 ), -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)R 6m1 , -S(O)2N(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 C 1~6 is alkyl, Each R 6j independently, C 2~6Alkoxyalkyl, 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)R 6j1 , -S(O)2N(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, C2~6 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 6p independently, 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, -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)R 6p1 , -S(O)2N(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 one 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 independently, C 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; Each R 7 , R 8 , and R 9 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~6 Alkylthio, halogen, C 1~6 Haloalkyl, -CN, -OH, -NH2, C 3~10 Cycloalkyl, C1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl), and R 7 , R 8 and R 9 may be the same or different, each heterocycloalkyl is a 3- to 20-membered ring having 1-4 heteroatoms, each independently N, O, or S; each heteroaryl is a 5- to 18-membered ring having 1-4 heteroatoms, each independently N, O, or S; However, Z 7 , Z 8 and Z 9 At least one of is N and Z 7 is CR 7 and Z 8 and Z 9 If both are N, then Z 1 , Z 2 and Z 4 wherein at least one of is N], or a pharmaceutically acceptable salt thereof.

[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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0012] In another embodiment, the present disclosure provides a method of treating HIV or Hepatitis B virus infection 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0013] I. Definition "Alkyl" refers to a straight- or branched-chain saturated monovalent hydrocarbon. For example, an alkyl group may contain 1 to 18 carbon atoms (i.e., C 1~18 alkyl) or 1 to 8 carbon atoms (i.e., C1~8 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 methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)CHCH), 2-methyl-2- Propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH 3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl ( Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0014] "Alkylene" refers to a straight-chain or branched 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 -(CH2) 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. Alkylene groups 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, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 , and C6. Alkenyl groups can 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. Alkenyl groups can be substituted or unsubstituted.

[0016] "Alkynyl" refers to either a straight or branched chain hydrocarbon containing at least two carbon atoms and at least one triple bond. Alkynyl includes C, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 and C6. 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 alkyl groups, alkoxy groups include C 1~6 Alkoxy groups can have any suitable number of carbon atoms, such as , ...

[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. Alkoxyalkyls are those having 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C2~5 alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3 The alkoxy and alkyl groups may have any suitable number of carbons, such as alkoxyalkyl. The number of carbons refers to the total number of carbons in the alkoxy and alkyl groups. For example, Calkoxyalkyl refers to ethoxy (Calkoxy) linked to butyl (Calkyl), and n-propoxy (Calkoxy) linked to isopropyl (Calkyl). Alkoxy and alkyl are as defined above, where the alkyl is divalent and may include, but are not limited to, methoxymethyl (CHOCH-), methoxyethyl (CHOCHCH-), and the like.

[0019] "Aminoalkyl" refers to an amino group linked to an alkyl group which is linked to the remainder of the compound, making the alkyl group divalent. The amino group can be unsubstituted amino (-NH2) or substituted with an alkyl group, e.g., monosubstituted amino (e.g., -NHCH3), or disubstituted amino (e.g., -N(CH3)2). An aminoalkyl can have 1 to 8 (C 1~8 aminoalkyl), 1 to 6 (C 1~6 aminoalkyl), 2 to 6 (C 2~6 aminoalkyl), 2 to 4 (C 2~4 aminoalkyl), or 2 to 3 (C 2~3 The amino alkyl may have any suitable number of carbons, such as -N(CH)(Camino) (aminoalkyl). The number of carbons refers to the total number of carbons in the amino and alkyl groups. For example, a C amino alkyl refers to -N(CH)(Camino) linked to butyl (C alkyl) and -NHCHCHCH(Camino) linked to isopropyl (C alkyl). Alkyl is as defined above, where alkyl is divalent. Amino alkyls may include, but are not limited to, aminomethyl (HNCH-), methylaminomethyl (CHNHCH-), dimethylaminomethyl ((CH)NCH-), dimethylaminoethyl ((CH)NCHCH-), and the like.

[0020] "Alkoxy-alkoxy" refers to an alkoxy group linked to a second alkoxy group that is linked to the remainder of the compound. Alkoxy is as defined above and can include, but is not limited to, methoxy-methoxy (CH3OCH2O-), methoxy-ethoxy (CHOCH2CHO-), 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 wherein one or more of the alkyl hydrogen atoms are replaced by halo substituents. 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. The alkoxy group may be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is persubstituted, e.g., perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0024] "Cycloalkyl" refers to a group of 3 to 20 cyclic carbon atoms (i.e., C 3~20 Cycloalkyl) refers to a saturated or partially unsaturated all-carbon monocyclic ring, e.g., having 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 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 multiple condensed ring systems may be connected to each other by fused, spiro, 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 connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the cycloalkyl component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any of C 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 , C4~6 , and C 5~6 The 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 ring carbon atoms and 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatoms are optionally oxidized to form -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 via fused, spiro, and bridged bonds, where 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 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]dioxin, 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—, —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 connects the heterocycloalkyl 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 connect 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 5~6The alkyl-heterocycloalkyl group may contain any number of carbons, such as . In 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 condensed 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 condensed 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 condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the multiple condensed ring system. The rings of a multiple condensed ring system may be connected to each other by fused, spiro, and bridged bonds, where permitted by valency requirements. When referring to an aryl having a particular range of atom numbers (e.g., a 6- to 10-membered aryl), it is also understood that the atom range refers to the total ring atoms of the aryl. For example, a 6-membered aryl includes phenyl, and a 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 connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the aryl 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 The alkyl group may contain any number of carbon atoms, such as , ...

[0034] As used herein, "heteroaryl" refers to a monocyclic aromatic ring having at least one atom other than carbon in the ring, where that atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also encompasses multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" encompasses a monocyclic aromatic ring of 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized form, provided 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 fused polycyclic ring 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 a multiple condensed ring system may be connected to each other through fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. It is understood that the individual rings of a multiple condensed ring system may be connected to each other in any order. It is understood that the point of attachment of a heteroaryl or heteroaryl to a 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 having a particular range of atom member numbers (e.g., a 5- to 10-membered heteroaryl) is referred to, it is also understood that the atom range is for the total ring atoms of the heteroaryl and includes 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 connects the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect 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 present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), including the compounds of the Examples.

[0037] As used herein, "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 produces the desired therapeutic or pharmaceutical result.

[0039] "Pharmaceutically acceptable excipients" include, but are 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 "treating" or "treating" refers to an approach for obtaining a beneficial or desired result. For purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing worsening of symptoms associated with a disease or condition. In some embodiments, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the severity of the disease or condition); b) delaying or suppressing the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, slowing the worsening or progression of the disease or condition); and c) alleviating the 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, a "therapeutically effective amount" or "effective amount" refers to an amount that, when administered to a subject to treat a disease, is effective to elicit a desired biological or medical response, including an amount of 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 being treated. An effective amount may include a range of amounts. As 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 or is achieved in combination with one or more other agents. The suitable dose of any co-administered compound may, in some cases, be reduced due to the combined effects (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 can be carried out according to a schedule that dictates the frequency of administration, the dosage administered, 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 the 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 several 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 several 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 bodily condition or health state 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, liver, 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, kidney 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 can 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, kidney 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 cancers that may be present 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 cancer, 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, and 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 tumor, cancer, malignant pancreatic insulinoma, malignant leukemia, and malignant leukemia. thyroid cancer, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, 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 blood-forming organs and is 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) whether or not there is 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 myelogenous leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hematoblastic leukemia, hematoblast Cytic cell leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia leukemia), lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0049] "Sarcoma" generally refers to a tumor composed of a substance like embryonic connective tissue 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 cells, lymphoma, immunoblastic sarcoma of T cells, 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 understood 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 neoplasm composed of epithelial cells that tend to infiltrate 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, adenoid carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous 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, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, childhood embryonal carcinoma, carcinoma in situ, carcinoma in situ in epidermis, carcinoma in situ, Krompecher 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, mucinous carcinoma, mucocytic carcinoma, mucoepidermoid carcinoma, mucinous carcinoma mucosum, mucous carcinoma, myxomatous 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, cord-like carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or choriocarcinoma.

[0052] The terms "metastasis," "metastatic," and "metastatic cancer" can 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, and that site is called a primary tumor, e.g., primary breast cancer. Some cancer cells within the primary tumor or site of origin acquire the ability to invade and infiltrate surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system and spread through that system to other sites and tissues in the body. A second, clinically detectable tumor formed from cancer cells of the primary tumor is called 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, if lung cancer metastasizes to the breast, the secondary tumor in the breast site will consist of abnormal lung cells, not abnormal breast cells. A secondary tumor in the breast is called metastatic lung cancer. Therefore, the term metastatic cancer refers to a disease in which a subject has or has previously had a primary tumor and has one or more secondary tumors.The term non-metastatic cancer or a subject with non-metastatic cancer refers to a disease in which a 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 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 related to a disease (e.g., diabetes, cancer (e.g., prostate cancer, kidney cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)), "related to" or "related to" 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, kidney 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 can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possess the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts of 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 and 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 can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically 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-dioate, hexyl phosphate ... Examples of suitable pharmaceutically acceptable salts include 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 pharmaceutically 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 NX4 salts. + Also included are salts derived from appropriate bases, such as: (wherein X is C1-C4 alkyl). Also included are base addition salts, such as sodium or potassium salts.

[0057] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may have enhanced resistance to metabolism and may therefore be useful for increasing the half-life of the compounds described herein, or pharmaceutically 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 with 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, such as 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 for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous 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 pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, with respect to 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, such as 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 racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When 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 embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that 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] A "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 possess one or more asymmetric centers or double bonds with asymmetric substitution and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, a description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the 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 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 one of ordinary skill in the art. Dashes before or after chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn across lines in structures indicate points of attachment of groups. 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 their point of attachment to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and both can be linked in either direction. Similarly, for example, an "arylalkyl" group may be attached to the rest of the molecule at either the aryl or alkyl portion of the group. "C u~v " or "(C u ~C vA prefix such as "C" indicates that the following group has u to v carbon atoms. 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 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 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), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), and (Ia-6), and pharmaceutically acceptable salts thereof.

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

[0068] [ka] [In the formula, Z 1 is N or CR 1 and Z 2 is N or CR 2 and Z 4 is N or CR 4 and Z 7 is N or CR 7 and Z 8 is N or CR 8 and Z 9 is N or CR 9 and Each R 1 and R 4 is hydrogen, C 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or -CN, and each R 1 and R 4 may be the same or different, 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, -NO2, -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)R 2a, -S(O)2N(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 2d Each cycloalkyl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 2e Each aryl may be optionally substituted with 1 to 3 R 2f and each heterocycloalkyl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 2g Each heteroaryl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 2h optionally substituted with a 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, C3~10 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 the aryl or heteroaryl is selected from 1 to 3 R 2j and optionally substituted with Alternatively, R 2a , R 2b , and R 2c when attached to the same atom, can combine 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)R 2d1 , -S(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )S(O)2R 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, C1~6 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 independently, 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, or C 1~6 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, -NO2, -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)R 3a , -S(O)2N(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 independently is selected from 1 to 3 R 3dgroups, and each cycloalkyl may be optionally substituted with 1 to 3 R 3e Each aryl may be optionally substituted with 1 to 3 R 3f and each heterocycloalkyl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 3g Each heteroaryl may be optionally substituted with 1 to 3 R groups, which may be the same or different. 3h optionally substituted with a 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; Alternatively, R 3a , R 3b , and R 3c when attached to the same atom, can combine 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-(C1~6 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 haloalkoxy, 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 1~6 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 C 1~6 is alkyl, R 6 is C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, 1 to 3 R 6a C replaced with 6~12 Aryl or 1 to 3 R 6a and each R is a heteroaryl substituted with 6a independently, C 1~6 Alkyl, C 2~6Alkenyl, 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, -NO2, -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)2R 6b , -S(NR 6b )(NR 6c )R 6d , -S(O)(NR 6b )(R 6c ), -S(O)2N(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 1~6alkyl-(heteroaryl), where cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each have 1 to 3 R 6e and the alkyl is optionally substituted with R 6f and the 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 independently, C 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 independently, 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, -NO2, -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)R 6e1 , -S(O)2N(R 6e1 )(R 6e2 ), -SF5, -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 3~10Cycloalkyl, 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 optionally substituted, and alkyl is 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, C1~6 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)R 6n1 , -S(O)2N(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 6hindependently, 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 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)(NR 6h1 )(R 6h2 ), -S(O)R 6h1 , -S(O)2N(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, C2~6 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)R 6m1 , -S(O)2N(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, C1~6 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 C 1~6 is alkyl, Each R 6j independently, C 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 )R6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O)R 6j1 , -S(O)2N(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 2~6 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 6p independently, 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, -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)R 6p1 , -S(O)2N(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 one R 6a together with the atom to which they are attached form a heterocycloalkyl, and 1 to 3 R 6gand optionally substituted with Each R 6g independently, C 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; Each R 7 , R 8 , and R 9 are independently hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~6 Alkylthio, halogen, C 1~6 Haloalkyl, -CN, -OH, -NH2, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl), and R 7 , R 8 and R 9 may be the same or different, each heterocycloalkyl is a 3- to 20-membered ring having 1-4 heteroatoms, each independently N, O, or S; each heteroaryl is a 5- to 18-membered ring having 1-4 heteroatoms, each independently N, O, or S; However, Z 7 , Z 8 and Z 9 At least one of is N and Z 7 is CR 7 and Z 8 and Z 9 If both are N, then Z 1 , Z 2 and Z 4at least one of which is N], or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 1 is N or CR 1 and R 1 is hydrogen, Z 2 is N or CR 2 and R 2 is hydrogen, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, -OR 2a , -N(R 2a )(R 2b ) and R 2a and R 2b are each independently hydrogen or C 1~6 alkyl, which may be the same or different; Z 4 is N or CR 4 and R 4 is hydrogen, C 1~6 alkyl, or halogen; Z 7 is N or CR 7 and R 7 is hydrogen or C 1~6 is alkyl, Z 8 is N or CR 8 and R 8 is hydrogen or C 1~6 is alkyl, Z 9 is N or CR 9 and R 9 is hydrogen or C 1~6 is alkyl, R 3 is hydrogen, C 1~6 alkyl, or halogen; R 5 But C 1~6 Alkyl or C 1~6 is haloalkyl, R 6is phenyl or heteroaryl, and the phenyl or heteroaryl is a group consisting of 1 to 3 R 6a wherein heteroaryl is a 5- or 6-membered ring having 1-3 heteroatoms, each independently being N, O, or S; or

[0070] [ka] and X 1 , X 2 , X 3 and X 4 are each independently CH, N, or CR 6a where there are no more than two X 1 , X 2 , X 3 and X 4 is N and there are two or fewer X 1 , X 2 , X 3 and X 4 is CR 6a and Ring A is a 5-8 membered heterocycloalkyl optionally having 1-2 additional heteroatoms, each independently N, O, or S, and optionally ring A is a 5-8 membered heterocycloalkyl optionally having 1-2 additional heteroatoms, each independently N, O, or S, and optionally having 1 or 2 R 6g is replaced by Each R 6a are independently halogen, C 2~8 alkynyl, phenyl, heterocycloalkyl, or heteroaryl, each of which is selected from the group consisting of 1 to 3 R 6e and alkynyl is optionally substituted with 1 to 4 R 6j wherein heterocycloalkyl is a 3- to 10-membered ring having 1-3 heteroatoms, each independently N, O, or S; and heteroaryl is a 5- or 6-membered ring having 1-3 heteroatoms, each independently N, O, or S; Each R 6j are independently halogen, C1~6 Haloalkyl, -OR 6j1 , -CN, C 3~10 cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is a cycloalkyl, heterocycloalkyl, or heteroaryl group consisting of 1 to 3 R 6p wherein heterocycloalkyl is a 3- to 10-membered ring having 1-3 heteroatoms, each independently N, O, or S; and heteroaryl is a 5- or 6-membered ring having 1-3 heteroatoms, each independently 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 6e independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, heterocycloalkyl, halogen, C 1~6 Haloalkyl, -CN, -OR 6e1 or —SF5, wherein cycloalkyl and heterocycloalkyl are each selected from 1 to 3 R 6h and heterocycloalkyl is a 3- to 10-membered ring having 1-3 heteroatoms, each independently N, O, or S; R 6e1 is hydrogen or C 1~6 is alkyl, Each R 6h independently, C 1~6 Alkyl, C 1~6 haloalkyl, ═O, or —OH; Each R 6g independently, C 1~6 Alkyl, halogen, or C 1~6 is haloalkyl, However, Z 7 , Z 8 and Z9 At least one of is N and Z 7 is CR 7 and Z 8 and Z 9 If both are N, then Z 1 , Z 2 and Z 4 At least one of is N.

[0071] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula (Ia-1):

[0072] [ka]

[0073] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula (Ia-2):

[0074] [ka]

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

[0076] [ka]

[0077] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula (Ia-4):

[0078] [ka]

[0079] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula (Ia-5):

[0080] [ka]

[0081] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula (Ia-6):

[0082] [ka]

[0083] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 5 But 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 A compound that is alkyl-(heteroaryl), where heterocycloalkyl is a 5-8 membered ring having 1-2 heteroatoms, each independently N, O, or S, and heteroaryl is a 5-6 membered ring having 1-2 heteroatoms, each independently N, O, or S.

[0084] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is 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 —CH2CHF2, —CH2CF3, or CH3(Me). In some embodiments, R 5 is -CH2CHF2.

[0085] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 6 is 1 to 3 R, which may be the same or different 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 three R 6a In some embodiments, R 6 is C 2~8 phenyl substituted with alkynyl, wherein the alkynyl is substituted with one or two R 6j and the phenyl is substituted with one additional R 6a In some embodiments, the phenyl is optionally substituted with one additional R 6a In some embodiments, one additional R 6a is F. In some embodiments, R 6 F and C 2~8phenyl substituted with alkynyl, wherein the alkynyl is selected from one or two R 6j In some embodiments, R 6 is phenyl substituted with one or two substituents selected from the group consisting of F, phenyl, pyridyl, or pyrazinyl, each of which is substituted with one or two R 6e may be optionally substituted with

[0086] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 6 where R 6 but

[0087] [ka] In some embodiments, R 6 teeth

[0088] [ka] In some embodiments, R 6 is the following equation:

[0089] [ka] In the formula, X 5 and X 6 are each independently N or CH, and X 7 is CH or CF. In some embodiments, X 5 and X 6 Both are CH.

[0090] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R6 but,

[0091] [ka] It is a compound in which

[0092] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 6 is a compound having the formula:

[0093] [ka]

[0094] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 6 is 1 to 3 R, which may be the same or different 6a In some embodiments, R is a heteroaryl substituted with R, wherein the heteroaryl is a 5- to 6-membered ring having 1-2 heteroatoms, each independently being N, O, or S. 6 is one R 6a In some embodiments, R is heteroaryl substituted with 6 is two R 6a In some embodiments, R is heteroaryl substituted with 6 is three R 6a In some embodiments, heteroaryl is thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, or pyrimidinyl, each of which is substituted with one or two R, which may be the same or different. 6aIn some embodiments, heteroaryl is thienyl, thiazolyl, pyridyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or two R 6a is replaced by .

[0095] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 6 One or two R 6a In some embodiments, R 6 is pyrazinyl substituted with one or two substituents selected from the group consisting of F, phenyl, pyridyl, or pyrazinyl, each of which is substituted with one or two R 6e In some embodiments, R 6 is one or two R 6a In some embodiments, R 6 is pyridyl substituted by one or two substituents selected from the group consisting of F, phenyl, pyridyl, or pyrazinyl, each of which is substituted by one or two R 6e In some embodiments, R 6 is C 2~8 and pyridyl substituted with alkynyl, wherein the alkynyl is one or two R 6j In some embodiments, R 6 teeth

[0096] [ka] In some embodiments, R 6 teeth

[0097] [ka] is.

[0098] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 6 is a compound having the formula:

[0099] [ka] In some embodiments, R 6 teeth

[0100] [ka] is.

[0101] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 5 and one R 6a together with the atoms to which they are attached, form 1 to 3 R 6g and forming an optionally substituted heterocycloalkyl group.

[0102] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0103] [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 N, O, or S; and optionally ring A contains 1 or 2 R 6gIn some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments,

[0104] [ka] In some embodiments,

[0105] [ka] In some embodiments,

[0106] [ka] In 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- to 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.

[0107] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0108] [ka] and X 1 , X 2 , and X 3 are each independently CH, N, or CR 6a where X 1 , X 2 , and X 3At most two of the 1 , X 2 , and X 3 One or less of the following is CR 6a In some embodiments, X 1 , X 2 and X 3 is CH. In some embodiments, X 1 is N and X 2 and X 3 is CH. In some embodiments, X 2 is N and X 1 , X 1 and X 3 is CH. In some embodiments, X 3 is N and X 1 and X 2 is CH.

[0109] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0110] [ka] and n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments,

[0111] [ka] In some embodiments,

[0112] [ka] In some embodiments,

[0113] [ka] In some embodiments,

[0114] [ka] is.

[0115] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0116] [ka] In some embodiments, the compound is

[0117] [ka] In some embodiments,

[0118] [ka] In some embodiments,

[0119] [ka] In some embodiments,

[0120] [ka] In some embodiments,

[0121] [ka] is.

[0122] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0123] [ka] but,

[0124] [ka] and X 1 , X 2 , X 3 and X 4 are each independently CH, N or CR 6a where X 1 , X 2 , X 3 , and X 4 At most two of them are N, and X 1 , X 2 , X 3 , and X 4 Two or fewer of these are CR 6a is a compound.

[0125] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0126] [ka] and n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments,

[0127] [ka] is.

[0128] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0129] [ka] but,

[0130] [ka] and X 1 , X 2 , X 3 and X 4 are each independently CH, N or CR 6a where X 1 , X 2 , X 3 , and X 4 At most two of them are N, and X 1 , X 2 , X 3 , and X 4 Two or fewer of these are CR 6a In some embodiments, the compound is

[0131] [ka] and n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments,

[0132] [ka] be.

[0133] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0134] [ka] It is a compound in which

[0135] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0136] [ka] It is a compound in which

[0137] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0138] [ka] It is a compound in which

[0139] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0140] [ka] It is a compound in which

[0141] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is Each R 6a is independently C 1~6 Alkyl, C 2~8 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO2, -C(O)R 6b , -C(O)N(R 6b (R 6c -N(R 6b (R 6c ), -OR 6b , C 3~10 Cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each has 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, C 3~10 is cycloalkyl, Each R 6j independently, C 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 )(NR6j2 ), -S(NR 6j1 )(NR 6j2 )R 6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O)R 6j1 , -S(O)2N(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 or 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 R6e is independently C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 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)2N(R 6e1 (R 6e2 ), -N(R 6e1 )S(O)2(R 6e2 ), -CN, SF5, heterocycloalkyl, C 1~6 Alkyl-heterocycloalkyl, heteroaryl, or C 1~6 alkyl-heteroaryl, and each of the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups is 1 to 3 R 6h and the alkyl may be the same or different, and may be 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.

[0142] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is Each R 6a is independently C 2~8Alkynyl, halogen, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from the group consisting of 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, wherein the cycloalkyl or heterocycloalkyl is a group consisting of 1 to 3 R 6p and optionally substituted with Each R 6j1 are independently hydrogen or C 1~6 is alkyl, Each R 6p independently, C 1~6 Alkyl, halogen, C 1~6 haloalkyl, ═O, —CN, or —OH; Each R 6e independently, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, -CN, SF5, -OR 6e1 , C 3~6 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is a group consisting of 1 to 3 R 6h and optionally substituted with R 6e1 are independently hydrogen or C 1~6 is alkyl, Each R 6h are independently halogen, C 1~6 Alkyl, =O or C 1~6 A compound that is a haloalkyl.

[0143] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is Each R 6a independently, C 2~8 Alkynyl, halogen, C 6~12 aryl, 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 the aryl, heterocycloalkyl, or heteroaryl each independently being 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, wherein the cycloalkyl or heterocycloalkyl is a group consisting of 1 to 3 R 6p and optionally substituted with R 6j1 is hydrogen or C 1~6 is alkyl, Each R 6p independently, C 1~6 Alkyl, halogen, =O, -OH or C 1~6 is haloalkyl, Each R 6e independently, C 1~6 Alkyl, halogen, C 1~6 haloalkyl, cyclopropyl, heterocycloalkyl ring having 1 to 2 heteroatoms, each independently N, O, or S, and cyclopropyl or heterocycloalkyl may have 1 to 3 R 6h and optionally substituted with Each R 6h are independently halogen, C 1~6 Alkyl, =O or C1~6 A compound that is a haloalkyl.

[0144] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), wherein each R 6a independently C 2~8 alkynyl or halogen, and the alkynyls are the same or different, and each R 6j and optionally substituted with

[0145] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 6a are independently 1 to 3 R which may be the same or different 6j C replaced with 2~8 The compound is an alkynyl.

[0146] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), wherein each R 6a but

[0147] [ka] and R 6j is C 1~6 Haloalkyl, C 3~6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is selected from the group consisting of one R 6p and each R 6p independently, C 1~6 Alkyl or C 1~6 A compound that is a haloalkyl.

[0148] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6j are independently halogens, C 1~6 Haloalkyl, -OR 6j1 , -CN, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may be the same or different, and 1 to 3 R 6p and R 6j1 is hydrogen or C 1~6 alkyl, and each R 6p independently, C 1~3 Alkyl or C 1~3 A compound that is a haloalkyl.

[0149] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6p are independently Me, —CF3, —CH2F, —CF2CH3, or —CHF2.

[0150] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), wherein each R 6j are independently halogen, C 1~6 In some embodiments, each R 6j is independently —OH, —CN, —F, —CHF, or —CF. In some embodiments, R 6j is —OH. In some embodiments, R 6j In some embodiments, R 6j is -CF3.

[0151] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6j But independently, C 3~6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is a cycloalkyl, a 5- to 6-membered heteroaryl, or a 4- to 6-membered heterocycloalkyl, and ... 6p and each R 6p independently, C 1~3 Haloalkyl and C 1~3 It is a compound that is alkyl.

[0152] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6j are independently cyclopropyl,

[0153] [ka] In some embodiments, R 6j teeth,

[0154] [ka] is.

[0155] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6a is independently phenyl or a 5- or 6-membered heteroaryl ring having 1-2 heteroatoms, each independently N, O, or S, wherein the phenyl or heteroaryl is followed by 1-3 R 6e is a compound optionally substituted with

[0156] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is 6e independently, C 1~6 Haloalkyl, cyclopropyl, -SF5, -OC 1~6 Alkyl, =O or C 1~6 The compound is a 4- to 6-membered heterocycloalkyl optionally substituted with alkyl.

[0157] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), wherein each R 6e are independently cyclopropyl, -CHF2, -SF5, -OMe,

[0158] [ka] is a compound.

[0159] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6a However, independently, F, Br, Cl,

[0160] [ka] In some embodiments, at least one R 6a teeth,

[0161] [ka] In some embodiments, the compound has an additional R 6a In some embodiments, the additional R 6a is F.

[0162] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6a However, independently, F, Br, Cl,

[0163] [ka] In some embodiments, at least one R 6a teeth,

[0164] [ka] In some embodiments, the compound has an additional R 6a In some embodiments, the additional R 6a is F.

[0165] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, comprises each R 6a However, independently, F, Br, Cl,

[0166] [ka] In some embodiments, at least one R 6a teeth,

[0167] [ka] In some embodiments, the compound is selected from the group consisting of: 6a In some embodiments, another R 6a is F.

[0168] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0169] [ka] It is a compound in which

[0170] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0171] [ka] is a compound having the formula:

[0172] [ka]

[0173] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0174] [ka] is a compound having the formula:

[0175] [ka]

[0176] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0177] [ka] is a compound having the formula:

[0178] [ka]

[0179] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0180] [ka] is a compound having the formula:

[0181] [ka]

[0182] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0183] [ka] is a compound having the formula:

[0184] [ka]

[0185] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is

[0186] [ka] It is a compound in which

[0187] In some embodiments, the compound of Formula (I), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 In some embodiments, R 1 is hydrogen.

[0188] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is R 2 is hydrogen, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl-OR 2a , -N(R 2a )(R 2b ) and R 2a and R 2b are each independently hydrogen or C which may be the same or different. 1~6 In some embodiments, R 2 is hydrogen, C 1~3 Alkyl, halogen, C 1~6 Haloalkyl-OR 2a ,-N(R 2a )(R 2b ) and R 2a and R 2b are each independently hydrogen or C which may be the same or different. 1~3 In some embodiments, R 2 is hydrogen, —CF, —N(CH), —NH(CH), —NH, —OCH, —OCH, or —CH. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is hydrogen.

[0189] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is 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.

[0190] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, is 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 Alkyl, halogen, C 1~3 haloalkyl or -CN. In some embodiments, R 4 is hydrogen, C 1~3 In some embodiments, R 4 is F. In some embodiments, R 4 is hydrogen.

[0191] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), or (Ia-5), or a pharmaceutically acceptable salt thereof, is R 7 is hydrogen or C 1~6 In some embodiments, R 7 is hydrogen, Me, or Et. In some embodiments, R7 is hydrogen. In some embodiments, R 7 is Me.

[0192] In some embodiments, the compound of Formula (I) or (Ia-4) or a pharmaceutically acceptable salt thereof is R 8 is a compound where

[0193] In some embodiments, the compound of Formula (I) or (Ia-5) or a pharmaceutically acceptable salt thereof is R 9 is hydrogen.

[0194] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5) or (Ia-6) or a pharmaceutically acceptable salt thereof is a compound having the structure of a compound in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E or Table 1F.

[0195] In some embodiments, the disclosure provides a compound or a pharmaceutically acceptable salt thereof shown in Table 1. In some embodiments, the disclosure provides a compound shown in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.

[0196] One of ordinary skill in the art will recognize that when a group is substituted with more than one substituent, the two or more substituents may be the same or different, unless otherwise specified.

[0197] Those skilled in the art will recognize the groups disclosed herein (e.g., R 1 ) may be used in combination with any and all embodiments 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 compounds (e.g., phenyl ...

[0198] Table 1A

[0199] Table 1B

[0200]

Table 1C-1

[0201]

Table 1C-2

[0202]

Table 1C-3

[0203]

Table 1D-1

[0204]

Table 1D-2

[0205]

Table 1D-3

[0206]

Table 1E-1

[0207]

Table 1E-2

[0208]

Table 1E-3

[0209]

Table 1E-4

[0210]

Table 1E-5

[0211]

Table 1E-6

[0212]

Table 1E-7

[0213]

Table 1E-8

[0214]

Table 1E-9

[0215]

Table 1E-10

[0216]

Table 1E-11

[0217]

Table 1E-12

[0218]

Table 1E-13

[0219]

Table 1E-14

[0220]

Table 1E-15

[0221]

Table 1E-16

[0222]

Table 1E-17

[0223]

Table 1F-1

[0224]

Table 1F-2

[0225]

Table 1F-3

[0226]

Table 1F-4

[0227]

Table 1F-5

[0228]

Table 1F-6

[0229] [Table 1F-7]

[0230] [Table 1F-8]

[0231] [Table 1F-9]

[0232] [Table 1F-10]

[0233] [Table 1F-11]

[0234] [Table 1F-12]

[0235] 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 the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Thus, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield metabolic products. Such products are typically radiolabeled (e.g., 14 C or 3H) Compounds are prepared and identified by parenteral administration to animals such as rats, mice, guinea pigs, monkeys, or humans at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes remaining in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. Metabolite analysis is generally performed similarly to conventional drug metabolism studies known to those skilled in the art.

[0236] In some embodiments, compounds of the present disclosure have selectivity for DGKα over one or more of 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, compounds have activity against DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKι, and / or DGKκ, and exhibit IC 50 is greater than about 30 μM in biochemical assays.

[0237] In some embodiments, compounds of the present 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 10,000 times 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 that is 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 10,000 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 10,000 times or more selectivity for DGKα over DGKβ. 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 10,000 times or more selectivity for DGKα over DGKγ.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 10,000 times or more selectivity for DGKα over DGKδ. 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 10,000 times or more selectivity for DGKα over DGKε. 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 10,000 times or more selectivity for DGKα over DGKζ. 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 10,000 times or more selectivity for DGKα over DGKη. 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 10,000 times or more selectivity for DGKα over DGKθ.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 10,000 times or more selectivity for DGKα over DGKι. 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 10,000 times or more selectivity for DGKα over DGKκ.

[0238] III. Pharmaceutical Preparations In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein are pharmaceutical formulations comprising a pharmaceutically effective amount of a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and a pharmaceutically acceptable carrier or excipient.

[0239] 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), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically acceptable salt thereof, such as the agents and therapies described herein.

[0240] In some embodiments, a pharmaceutical composition comprises a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) 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 wherein the additional therapeutic agent is independently an antineoplastic agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, or ablation therapy. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein 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 wherein the additional therapeutic agent is a PD-1 / PD-L1 inhibitor. In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent is a vaccine.

[0241] In some embodiments, the pharmaceutical composition is one 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, macrophages (MAC) cells, tumor infiltrating lymphocytes (TIL), and dendritic cells (DC).

[0242] In some embodiments, the pharmaceutical composition is one in which the additional therapeutic agent comprises one or more chimeric antigen receptors (CARs).

[0243] 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.

[0244] In some embodiments, a pharmaceutical composition comprises a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) 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), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) and an additional therapeutic agent, wherein the additional therapeutic agent comprises a vaccine.

[0245] In some embodiments, the pharmaceutical composition is for use in treating cancer.

[0246] In some embodiments, the pharmaceutical composition is for use in treating an HIV or Hepatitis B infection.

[0247] 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, etc. Aqueous formulations may be prepared in sterile form and may be isotonic, for example, if intended for delivery by a route other than oral administration. In some embodiments, 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, and stearic acid. The pH of the formulation ranges from about 3 to about 11, e.g., from about 7 to about 10.

[0248] In some embodiments, a compound disclosed herein is administered alone. In some embodiments, a compound disclosed herein is administered in a pharmaceutical formulation. In some embodiments, a formulation for veterinary and / or human use comprises at least one compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) or a pharmaceutically acceptable salt, solvate, and / or ester thereof, 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) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0249] 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(s) which may include one or more accessory ingredients. In some embodiments, the formulations are prepared by bringing into association the active ingredient(s) with liquid carriers or finely divided solid carriers, or both, and then, in some embodiments, shaping the product.

[0250] 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), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) or a pharmaceutically 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.

[0251] Tablets can be made, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent, 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 optionally be coated or scored. In some embodiments, tablets are formulated to provide sustained or controlled release of the active ingredient therefrom.

[0252] For infections of the eye or other external tissues, e.g., mouth and skin, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5) or (Ia-6) may be applied as a topical ointment or cream in an amount of, for example, about 0.075 to about 20% w / w (including about 0.1% to about 20% in increments of about 0.1% w / w, such as about 0.6% w / w, about 0.7% w / w, or the like, of active ingredient(s)), for example, about 0.2 to about 15% w / w, and for example, about 0.5 to about 10% w / w. When formulated in an ointment, the compounds of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) may be used with either a paraffinic or a water-miscible ointment base. Alternatively, the compounds of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) may be formulated in a cream with an oil-in-water cream base.

[0253] 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 include 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 dimethyl sulfoxide and related analogues.

[0254] The oily phase of the emulsion can be composed of known ingredients in a known manner. The phase can contain only an emulsifier (also known as an emulsifier (emulgent)), but can also contain, for example, a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that functions as a stabilizer. In some embodiments, the emulsion contains both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of a cream formulation.

[0255] 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.

[0256] The selection of suitable oils or fats for the formulation is based on achieving the desired properties. The cream can be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, 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, can be used. These can be used alone or in combination depending on the required properties. Alternatively, high-melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0257] In some embodiments, the pharmaceutical formulations herein comprise one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents in combination. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. 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 pharmaceutically 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; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. 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.

[0258] 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.

[0259] 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-hydroxybenzoates, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0260] Oil suspensions can be prepared 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 adding antioxidants such as ascorbic acid.

[0261] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of 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 sweeteners, flavoring agents, and coloring agents, may also be present.

[0262] 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. Emulsions 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 demulcents, preservatives, flavorings, or coloring agents.

[0263] Pharmaceutical compositions may be in the form of sterile injectable or intravenous preparations, such as sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described 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. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic monoglycerides or diglycerides, may be used. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0264] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 to about 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may 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 may contain from about 3 to about 500 μg of active ingredient per milliliter of solution, such that infusion of a suitable volume at a rate of about 30 mL / hour can occur.

[0265] Formulations suitable for topical administration to the eye also include eye drops wherein 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%, e.g., about 0.5 to about 10%, e.g., about 1.5% w / w.

[0266] 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.

[0267] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0268] Formulations suitable for pulmonary or nasal administration have particle sizes ranging from about 0.1 to about 500 micrometers, e.g., about 0.5, about 1, about 30, or about 35 micrometers, 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 can be prepared according to conventional methods and can be delivered with other therapeutic agents, such as compounds previously used to treat cancer, as described below.

[0269] In some embodiments, the inhalable composition comprises a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable composition is suitable for treating cancer. In some embodiments, the pharmaceutically 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), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) is formulated for aerosol delivery using a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0270] Non-limiting examples of nebulizers include atomizers, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers, including nebulizers that utilize adaptive aerosol delivery technologies (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10). Jet nebulizers utilize air pressure to break up liquid solutions into aerosol droplets. Ultrasonic nebulizers work by using piezoelectric crystals to shear liquids into small aerosol droplets. Pressurized nebulizer systems create aerosol droplets by applying pressure to force a solution through small pores. Vibrating porous plate devices use rapid vibrations to shear a liquid stream into the appropriate droplet size.

[0271] In some embodiments, the nebulized formulation is delivered to the endobronchial space in an aerosol containing primarily particles having an MMAD of about 1 μm to about 5 μm using a nebulizer capable of aerosolizing a formulation of a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) into particles of the required MMAD. To optimize therapeutic efficacy and avoid upper respiratory tract and systemic side effects, the majority of 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 and may subsequently be exhaled.

[0272] When formulated and delivered according to the methods herein, the nebulized aerosol formulation delivers a therapeutically effective dose of a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) 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 a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6). In some embodiments, the combination of an aqueous aerosol formulation with a spray, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer allows delivery of about 20 to about 90%, e.g., 70%, of an administered dose of a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) to the respiratory tract, 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 may be delivered.

[0273] In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) or a pharmaceutically 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 metered-dose inhaler to effectively deliver fine particles of the compound to the endobronchial space. For delivery via a DPI, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) is processed by milling, spray drying, critical fluid processing, or precipitation from solution to particles having a MMAD primarily of about 1 μm to about 5 μm. Media milling, jet milling, and spray drying devices and procedures capable of producing particle sizes with a MMAD of about 1 μm to about 5 μm are well known in the art. In some embodiments, an excipient is added to a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) prior to processing into particles of the required size. In some embodiments, an excipient is blended with the particles of the desired size to aid in the dispersion of the drug particles, for example, by using lactose as an excipient.

[0274] Particle size determination is performed using devices well known in the art, such as a multistage Anderson cascade impactor or other suitable method, such as those specifically cited in U.S. Pharmacopeia Chapter 601 as characteristic devices for aerosols in metered dose and dry powder inhalers.

[0275] In some embodiments, a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) can be delivered as a 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. 5,775,320, 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 primary designs of dry powder inhalers. One design is a metered device, in which 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-metered device, in which each individual dose is manufactured in a separate container. Both systems rely on the formulation of the drug into small particles of approximately 1 μm to approximately 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 into the device or by dividing a factory-metered dose), and the patient's inspiratory flow accelerates the powder as it exits the device and enters the oral cavity. The non-laminar flow characteristics of the powder pathway break down excipient-drug agglomerates, allowing clumps of large excipient particles to 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), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically 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.

[0276] In some embodiments, the compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) 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. Patent No. 5,261,538, U.S. Patent No. 5,544,647, U.S. Patent No. 5,622,163, U.S. Patent No. 4,955,371, U.S. Patent No. 3,565,070, U.S. Patent No. 3,361,306, and U.S. Patent No. 6,116,234. In some embodiments, a compound of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or a pharmaceutically 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.

[0277] 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.

[0278] 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.

[0279] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, 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, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0280] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents standard in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0281] There is further provided a veterinary composition comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

[0282] A veterinary carrier is a substance useful for the purpose of administering the composition and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0283] The compounds herein are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more of the compounds as active ingredients, wherein 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.

[0284] The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, delivery method, and pharmaceutical formulation, and can be determined by a 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 an adult human weighing about 70 kg can range from about 1 mg to about 1000 mg, e.g., about 5 mg to about 500 mg, and can take the form of a single dose or multiple doses.

[0285] IV. Route of Administration One or more compounds of Formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6) (referred to herein as the active ingredient) 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 depending, for example, on the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be administered orally.

[0286] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to 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 depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0287] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for any 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.

[0288] 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.

[0289] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0290] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound can 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.

[0291] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., from about 1 mg to about 1000 mg of compound). Therapeutically effective amounts can 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. 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, or 16 hours, or about once every 24 hours. A dose may also be administered about once every 1, 2, 3, 4, 5, or 6 days, or about once every 7 days. A dose may also be administered about once every 1, 2, 3, or 4 weeks, or about once every 4 weeks. In some embodiments, a dose may be administered about once every week. A dose may also be administered about once every month.

[0292] 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.

[0293] 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, twice a day, or more frequently. Administration of the compound continues as long as necessary to treat the disease or condition. For example, the compound can be administered to a human with cancer for a period of about 20 to about 180 days, or for example, for a period of about 20 to about 90 days, or for example, for a period of about 30 to about 60 days.

[0294] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, 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 compound administration followed by non-administration of the compound can be repeated as clinically needed to treat the patient.

[0295] In some embodiments, a pharmaceutical composition is provided that includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, and a pharmaceutically acceptable excipient.

[0296] In some embodiments, kits are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0297] In some embodiments, a compound of the present disclosure, or a pharmaceutically 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 pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically 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.

[0298] In some embodiments, when a compound of the present disclosure is 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 doses.

[0299] 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.

[0300] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0301] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be 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 used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0302] 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, where appropriate, be anti-cancer or anti-viral agents, such as anti-HIV or anti-hepatitis B virus agents.

[0303] 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, etc.), or other therapeutic agents. and / or any combination thereof.

[0304] Exemplary Targets In some embodiments, the one or more additional therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or suppressors of a target (e.g., a polypeptide or polynucleotide), including, but not limited to: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (e.g., ACC1 / 2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine 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, unactivated ATP, unactivated ATP, unactivated ATP-activated protein kinase ... Differential lymphoma kinase (ALK, e.g., ALK1), androgen receptor, angiopoietin (e.g., ligand-1, ligand-2), angiotentinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (e.g., AKT1, AKT2, AKT3), apolipoprotein AI (APOA1) gene, apoptosis-inducing factor, apoptosis protein (e.g., 1, 2), apoptosis signal-regulating kinase (ASK, such as 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-β 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 NY-ESO-1, cancer / testis antigen 1B (CTAG) 1) Genes, cannabinoid receptors (CB1, CB2, etc.), carbonic anhydrase, casein kinase (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 kinase (CHK1, CHK2, etc.), chemokine (CC motif) receptor receptors (e.g., CCR2, CCR4, CCR5, CCR8, etc.), chemokine (C-X-C motif) receptors (e.g., CXCR1, CXCR2, CXCR3, and CXCR4), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine protein kinase Kit or CD117), CISH (cytokinin-inducible SH2-containing protein), claudins (e.g., 6, 18), CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG 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; clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue antigen Growth factors, 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 CDK1, CDK12, CDK1B, and CDK2-9), cyclooxygenases (e.g., COX1 and COX2), CYP2B1 gene, cysteine ​​palmitoyltransferase porcupine, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, and cytochrome P4502D6, cytochrome P4503A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytoplasmic isocitrate deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein-4, DDR2 gene, DEAD-box helicase 6 (DDX6), death receptor 5 (DR5, TRAILR2), death receptor 4 (DR4, TRAILR1), Delta-like protein ligands (e.g., 3, 4), deoxyribonucleases, deubiquitinating enzymes (DUBs), Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase tidase IV, discoidin domain receptor (DDR, e.g., DDR1), diacylglycerol kinase zeta (DGKZ), DNA-binding proteins (e.g., HU-beta), DNA-dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (e.g., alpha), 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, endonucleases, endoplasmic reticulum aminopeptidase (ERAP) ERAP (e.g., ERAP 1, ERAP 2), endoplasmin, endosialin, endostatin, endothelin (e.g., ET-A, ET-B), enhancer of zest 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, epidermal cell adhesion molecule (EpCAM), Erb-b 2 (v-erb-b 2 avian erythroblastic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b 3 tyrosine kinase receptor, Erb-b 4 tyrosine kinase receptor, E-selectin, estradiol 17β dehydrogenase, estrogen receptor (e.g., α, β), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (e.g., 1, 2), extracellular signal-regulated kinase (ERK), hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factor (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., FAK 2), folate hydrolase, prostate-specific membrane antigen 1 (FOLH 1), folate receptor (e.g., alpha), folate, folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD 2, glucocorticoid, glucocorticoid-inducible TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione-S-transferase P, glycogen synthase kinase (GSK, e.g., 3-beta), 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, 90 alpha, beta), heat shock protein genes, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-HLTR-associated protein 2, hexokinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (HDACs such as 1, 2, 3, 6, 10, and 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-inducing factor-1 alpha (HIF1α), imprinted material expressed transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-κB kinase (IKK, e.g., IKKbe), IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor α subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (e.g., G, G1, G2, K, M), immunoglobulins Fc receptors, immunoglobulin gamma Fc receptors (e.g., I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1 and IDO2), indoleamine pyrrole 2,3-dioxygenase 1 inhibitors, insulin receptor, insulin-like growth factors (e.g., 1, 2), integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / β-5, integrin α-V / β-6, intercellular adhesion molecule 1 (ICAM-1), interferons (e.g., , alpha, alpha2, beta, gamma), interferon-inducible protein absent in melanoma 2 (AIM2), interferon type I receptor, interleukin-1 ligand, interleukin-13 receptor alpha2, interleukin-2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, interleukin-35 (IL-35), isocitrate dehydrogenases (e.g., IDH1, IDH2), Janus kinases (JAKs, e.g., JAK1, JAK2), JunN-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF 11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, K IT 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 (ILT 2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT 4), leukotriene A4 hydrolase, ristriolysin, 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., KDM 1, KDM 2, KDM 4, KDM 5, KDM 6, A / B / C / D), lysophosphatide-1 receptor, lysosome-associated membrane protein family (LAMP) gene, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5-lipoxygenase (5-LOX), hematopoietic progenitor kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony-stimulating factor (MCSF) ligand, macrophage migration inhibitory factor, MAGEC 1 gene, MAGEC 2 gene, major vault protein, MAPK-activated protein kinase (MK 2, etc.), Mass-related G protein-coupled receptor, matrix metalloproteinases (MMPs such as MMP2 and MMP9), Mcl-1 differentiation protein, Mdm 2 p53-binding protein, Mdm4 proteins, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel17, 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 STEAP1 (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, 5A, 16), mut T homolog (MTH, e.g., MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) 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 activating NK receptor, NLRP3 (NLRP4), NK cell receptor activating NK receptor, NKG2 AB, NLRP3 (NLRP4), NK cell receptor activating NK receptor, ... PYD domain protein 3 modulators, 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, p 53 tumor suppressor proteins, parathyroid hormone ligands, 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, e.g., alpha, beta), platelet-derived growth factor (PDGF, e.g., alpha, beta), pleiotropic drug resistance transporter, plexin B1, PLK1 gene, polo-like kinase (PLK), polo-like kinase 1, poly(ADP-ribose) polymerase (PARP, e.g., PARP1, PARP2, and PARP3, PARP7, and mono-PARP), preferentially expressed antigen in melanoma (PRAME) gene, prenyl-binding protein (PrPB), putative transcription factor PML, progenitor protein kinase C (PGK), progenitor protein kinase C (PGK), progenitor protein kinase B ... C (PGK), progenitor protein kinase C (PGK), progenitor protein kinase C (PGK), Steroid 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 kinase (PK, e.g., A, B, C), protein tyrosine kinase, protein tyrosine phosphatase beta, proto-oncogene serine / threonine-protein kinase (PIM, e.g., PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-alpha-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 inbrain) 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 (Recepteur 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 caspase activator (SMAC) protein, secreted frizzled-associated protein-2, secreted phospholipase A2, semaphorin-4D, serine proteases, serine / threonine kinase (ST) K), serine / threonine protein kinase (TBK, e.g., TBK1), signal transduction and transcription (STATs such as STAT-1, STAT-3, and STAT-5), signaling lymphocyte activation molecule (SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide symporter, sodium phosphate symporter 2B, somatostatin receptors (e.g., 1, 2, 3, 4, and 5), sonic hedgehog protein, Son of sevenless (SOS), specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (e.g., 1 and 2), sphingosine-1-phosphate receptor 1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, stabilin-1 (STAB1), STAT3 gene, steroid sulfatase, stimulator of interferon genes (STING) receptor, 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 CD3 glycoprotein zeta chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing 3 (TIM-3), T cell surface glycoprotein CD8, Tec protein kinase, Tek tyrosine kinase receptor, telomerase, telomerase reverse transcriptase (TERT) gene, tenascin, 3 prime repair exonuclease 1 (TREX 1), 3 prime 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-associated death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptor (TLR, e.g., 1-13), topoisomerase (e.g., I, II, III), transcription factor, transferase, transferrin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFβ), TGF-β receptor kinase (TGFB) and its isoforms, TGF-β ligand, transforming growth factor receptor kinase (TGF-β receptor kinase), transglutaminase, translocation-associated protein, transmembrane glycoprotein NMB, Trop-2 calcium signaling agent, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptors (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 receptor with immunoglobulin-like and EGF-like domains (TIE), 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, uteroglobin, vanilloid VR1, vascular cell adhesion protein and VEGF-1, VEGF-2, VEGF-3, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, oncogenic tyrosine protein kinase, Mer (Mer tyrosinase 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.

[0305] Exemplary Mechanisms of Action In some embodiments, the one or more additional therapeutic agents may be categorized by 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, for example, 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., emactuzumab, 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. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628; anti-EphA3 antibodies, e.g., KB-004; anti-CD37 antibodies, e.g., otlertuzumab (TRU-016); anti-FGFR-3 antibodies, e.g., 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, e.g., 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, e.g., 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 antibody, BMS-986012, etc.; anti-IL-8 (interleukin-8) antibodies, e.g., HuMax-Inflam; Anti-myostatin inhibitors, e.g., landgrozumab; anti-delta-like protein ligand 3 (DDL3) antibodies, e.g., rovalpituzumab tesirin; anti-DLL4 (delta-like ligand 4) antibodies, e.g., 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; drugs 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 analogs (methotrexate); Platinum coordination complexes (e.g., cisplatin, oxiloplatin, 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 (liposomal); CCR5 chemokine antagonists, e.g., MK-7690 (Vicriviroc); CDC7 protein kinase inhibitors, e.g., TAK-931; cholesterol side chain cleavage enzyme inhibitors, for example, ODM-209; Dihydropyrimidine dehydrogenase / orotate phosphoribosyltransferase inhibitors, for example, cefezone (tegafur + gimeracil + oteracil potassium); DNA polymerase / ribonucleotide reductase inhibitors, such as clofarabine; DNA interference oligonucleotides, such as 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, such as 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, for example, anlotinib; H+K+ATPase inhibitors, for example, 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 mRNAs, 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 modulators such as CC-92480, CC-90009; Protein cereblon modulators / DNA binding protein Ikaros inhibitors / zinc finger binding protein Aiolos inhibitors, for example, iverdomide; Retinoid X receptor modulators, e.g., alitretinoin, bexarotene (oral formulations); RIP-1 kinase inhibitors, e.g., GSK-3145095; Selective estrogen receptor degraders, such as 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; Mutant-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, e.g., 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, for example, BIO-11006; Folate antagonists such as arfolitixoline, e.g.; Galectin-3 inhibitors, e.g., GR-MD-02; phosphorylated P68 inhibitors, such as 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, such as 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, e.g., 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, such as ARRY-382, BLZ-945; CCR8 inhibitors, such as 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, e.g., pevonedistat; FoxM1 inhibitors, for example, thiostrepton; 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, such as MDNA-55; Arginase I stimulators, e.g., pegzylariginase; 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, e.g., 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., pegylodecaquin (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, such as 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, such as GSK-3326595; CD71 modulators, e.g., CX-2029 (ABBV-2029); ATM (ataxia telangiectasia) inhibitors, such as 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, such as 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-regulators (SERDs), such as fulvestrant (Faslodex®), RG6046, RG6047, RG6171, elacestrant (RAD-1901), SAR439859, and AZD9496; Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545; Selective androgen modulators (SARMs), e.g., GTX-024, darolutamide; Transforming growth factor-β (TGF-β) kinase antagonists such as galunisertib and 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-ciquizumab (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, such as 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, for example, ivosidenib; Interleukin-3 receptor (IL-3R) modulators, such as SL-401; arginine deiminase stimulators, e.g., 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, such as CMG-097, HDM-201; c-PIM inhibitors, such as 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, and 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., rebastinib, asciminib, ponatinib (ICLUSIG®); MNK1 / MNK2 inhibitors, e.g., eFT-508; cytochrome P450 11B2 / cytochrome P450 17 / AKT protein kinase inhibitors, e.g., 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, e.g., 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 (telaglenast), bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Mitochondrial complex I inhibitors, e.g., metformin, phenformin; Vaccines, such as 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, such as CRS-207 / GVAX, Axalimodin phyllosvac (ADXS11-001); adenovirus vector vaccines, such as nadofaragene firadenovec; autologous Gp96 vaccine; dendritic cell vaccine, e.g., CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, rocapuldencel-T (AGS-003), DCVAC, CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, 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, enadenocilib, 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, such as Vigil® (IND-14205), Oncoquest-L vaccine; attenuated recombinant serotype 1 poliovirus vaccines, such as PVS-RIPO; adagloxadrimorenin; MEDI-0457; tumor-derived autophagosome-enriched cancer vaccine DPV-001; RNA vaccines, such as CV-9209, LV-305; DNA vaccines, such as MEDI-0457, MVI-816, INO-5401;p53-expressing modified vaccinia virus Ankara vaccines, 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), a NANT colorectal cancer vaccine containing aldoxorubicin, an 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 agonist / interferon inducer, e.g., PolyICLC (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 α ligand modulators, such as interferon α-2b, interferon α-2a biosimilar (Biogenomics), PEG interferon α-2b (AOP-2014, P-1101, PEG IFNα-2b), multiferon (Alpha Native, Viragen), interferon α 1b, Roferon-A (Camferon, Ro-25-3036), interferon α-2a post-development (Biosidus) (Inmutag, Inter 2A), interferon α-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-IFN alpha 2b 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, e.g., 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, such as 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 chromosome (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, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347; fatty acid synthase (FASN) inhibitors, e.g., TVB-2640; Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab; CD44 binding agents, e.g., A6; Protein phosphatase 2A (PP2A) inhibitors, e.g., LB-100; CYP17 inhibitors, such as ceviteroner (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 protein, 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), bosimazine amiretrolepvec, 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; inhibitors of apoptosis protein (IAP) inhibitors, such as ASTX660, debio-1143, birinapant, APG-1387, and LCL-161; RNA polymerase inhibitors, e.g., lurbinectedin (PM-1183), CX-5461; tubulin inhibitors such as PM-184, BAL-101553 (risabumbulin), and OXI-4503, fluolapacin (AC-0001), plinabulin, and vinflunine; Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091, and PEPA-10; Elongation factor 1α2 inhibitors, for example, 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, e.g., SER-401, EDP-1503, MRx-0518.

[0306] 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 known 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 cerebrospinal fluid) polymerase (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); C-C 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: 779), CA23 (NCBI Gene ID: 771), CA24 (NCBI Gene ID: 772), CA25 (NCBI Gene ID: 773), CA26 (NCBI Gene ID: 774), CA27 (NCBI Gene ID: 775), CA28 (NCBI Gene ID: 776), CA29 (NCBI Gene ID: 777), CA30 (NCBI Gene ID: 56934), CA31 (NCBI Gene ID: 778), CA32 (NCBI Gene ID: 779), CA33 (NCBI Gene ID: 779), CA34 (NCBI Gene ID: 779), CA35 (NCBI Gene ID: 779), 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 β1 (CTNNB1; NCBI Gene ID: 1499); Histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734), and / or 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464).

[0307] 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 modulators. T cell activation via the 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 activation of T cells, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src, Zap-70, SLP-76, DGKα, CBL-β, CISH, and HPK1.

[0308] Examples of cluster of differentiation 3 (CD3) agonists that may be co-administered include, but are not limited to, MGD015.

[0309] 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. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor environment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate 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).

[0310] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain 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 inhibitory factor 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-activating receptor 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);

[0311] 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 T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG-3, CD223); hepatitis A virus 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.

[0312] 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-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating 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, e.g., 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.

[0313] In some embodiments, the compounds described herein are combined with an inhibitor 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 antibody (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, and KD-015.

[0314] 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), and 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).

[0315] In some embodiments, the anti-CD47 targeting agent is selected from the group consisting of compounds of the present invention, such as compounds of the present invention, ... , 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.

[0316] 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.

[0317] 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).

[0318] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors / antibodies that can 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-104 (AK-104 ... -105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), 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 the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), and 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 (toripalimab), 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 those described in, for example, WO 2018 / 195321, WO 2020 / 014643, WO 2019 / 160882, and WO 2018 / 195321, but are not limited to these.

[0319] An example of an inhibitor of PVRIG that may be co-administered includes, but is not limited to, COM-701.

[0320] Examples of inhibitors of TIGIT that can be co-administered include, but are not limited to, BMS-986207, RG-6058, AGEN-1307, COM-902.

[0321] 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), and RG7769 (PD-1 / TIM-3).

[0322] 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), and FS-118 (LAG-3 / PD-L1).

[0323] 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.

[0324] Examples of anti-NKG2a antibodies that may be co-administered include, but are not limited to, monalizumab.

[0325] Examples of anti-VISTA antibodies that may be co-administered include, but are not limited to, HMBD-002, CA-170 (PD-L1 / VISTA).

[0326] Examples of anti-CD70 antibodies that may be co-administered include, but are not limited to, AMG-172.

[0327] Examples of anti-CD20 antibodies that may be co-administered include, but are not limited to, obinutuzumab, IGN-002, and PF-05280586.

[0328] Examples of anti-ICOS antibodies that may be co-administered include, but are not limited to, JTX-2011, GSK3359609.

[0329] Examples of ICOS agonists that can 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).

[0330] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In some embodiments, the compounds described herein are directed 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 TNFRSF25 (DR3, NCBI Gene ID: 8718), TNFRSF16 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF17 (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).

[0331] 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 WO 2016179517, WO 2017096179, WO 2017096182, WO 2017096281, and WO 2018089628.

[0332] 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.

[0333] 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.

[0334] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0335] 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.

[0336] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0337] 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 International Publication Nos. 2017096179, 2017096276, 2017096189, and 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0338] Exemplary anti-TRAILR1, anti-TRAILR2, anti-TRAILR3, anti-TRAILR4 antibodies that may be co-administered include, but are not limited to, ABBV-621.

[0339] Bispecific antibodies targeting TNFRSF family members that can 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).

[0340] Adenosine production and signal transduction In some embodiments, the compounds described herein are combined with an agonist or antagonist of A1R, A2AR, A2BR, A3R, CD73, CD39, or CD26.

[0341] Examples of adenosine A3 receptor (A3R) agonists include namodenoson (CF102).

[0342] Examples of A2aR / A2bR antagonists include AB928.

[0343] Examples of anti-CD73 antibodies include MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, and CPI-006.

[0344] Examples of CD73 inhibitors include AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, and those described in WO19173692.

[0345] Examples of CD39 / CD73 inhibitors include PBF-1662.

[0346] Examples of anti-CD39 antibodies include TTX-030.

[0347] Examples of adenosine A2A receptor antagonists include CPI-444, AZD-4635, preladenant, and PBF-509.

[0348] Examples of adenosine deaminase inhibitors include pentostatin and cladribine.

[0349] 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).

[0350] 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).

[0351] 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.

[0352] 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 2154480, 2014100620, 2014039714, 2015134536, 2017167182, 2018112136, 2018112140, 2019155067, 2020076105, and International Application No. PCT / US2019 / 063091.

[0353] SIRPα targeting agent In various embodiments, the compounds described herein are combined with an inhibitor of SIRPα (NCBI Gene ID: 140885. UniProt P78324) which is an antibody or antigen-binding fragment thereof that binds to SIRPα.

[0354] Examples of SIRPα inhibitors include AL-008, RRx-001, and CTX-5861.

[0355] Examples of anti-SIRPα antibodies include FSI-189, ES-004, BI765063, ADU1805, and CC-95251.

[0356] 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.

[0357] Bispecific T cell engager 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 suitable anti-CD3 binding bispecific molecules 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 domain.Exemplary bispecific T cell engagers that can be co-administered target CD3 and a tumor-associated antigen 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).

[0358] Bispecific and trispecific natural killer (NK) cell engagers In some embodiments, the compounds described herein are combined with bispecific NK cell engagers (BiKEs) or tri-specific NK-cell engagers (TriKEs) (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 (KIRs) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE that can 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 domain. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., 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.

[0359] 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, a 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.

[0360] 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.

[0361] 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).

[0362] 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 and AZD6738, and Calquence and danvatirsen.

[0363] 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); :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.

[0364] 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).

[0365] 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, licorinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, entinostat, romidepsin, and tucidinostat.

[0366] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, a compound described herein is 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, and LY-3381916.

[0367] 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.

[0368] 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), MMP29 (NCBI Gene ID: 4341), MMP20 (NCBI Gene ID: 4342), MMP21 (NCBI Gene ID: 4343), MMP22 (NCBI Gene ID: 4344), MMP23 (NCBI Gene ID: 4 and / or 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).

[0369] RAS and RAS pathway inhibitors In some embodiments, the compounds described herein are directed to a compound selected from the group consisting of 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 a 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 at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.

[0370] In some embodiments, the compounds described herein are combined with KRAS inhibitors. 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 K-RAS (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2) (SEQ ID NO: 108) and KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2) (SEQ ID NO: 109).

[0371] 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.

[0372] In some embodiments, the compounds described herein are combined with MEK inhibitors. Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and selumetinib.

[0373] 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).

[0374] In some embodiments, the compounds described herein are combined with a Raf inhibitor. Exemplary Raf inhibitors that can be co-administered include BGB-283 (Raf / EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, encorafenib (LGX818), and PLX8394. RAF-265 (Raf / VEGFR), and ASN-003 (Raf / PI3K).

[0375] In some embodiments, the compounds described herein are combined with an inhibitor of ERK. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, lavoxertinib, GDC-0994, and ulixertinib.

[0376] In some embodiments, the compounds described herein are combined with a PI3K inhibitor. 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.

[0377] 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), and TYME-88 (mTOR / cytochrome P450 3A4).

[0378] In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and 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 neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0379] In some embodiments, the compounds described herein are combined with inhibitors of the RAS. Examples of RAS inhibitors include NEO-100 and rigosertib.

[0380] 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, or RM-1929.

[0381] 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.

[0382] In some embodiments, a compound described herein is 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 plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, and RG7421.

[0383] 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-α, p110-α; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, The compound may be 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) and WO 2013 / 052699 (Gilead Sciences, Inc.). Calistoga), 2013 / 116562 (Gilead Calistoga), 2014 / 100765 (Gilead Calistoga), 2014 / 100767 (Gilead Calistoga), and 2014 / 201409 (Gilead Sciences).

[0384] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, a compound described herein is 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 plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib.

[0385] Spleen Tyrosine Kinase (SYK) inhibitor 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, celdulatinib (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.

[0386] Toll-like receptor (TLR) agonists In some embodiments, a compound described herein is 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), WO 2014 / 0045849 (Janssen), WO 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

[0013] Examples of compounds that may be co-administered include those disclosed in Patent Applications Nos. 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), ... 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 Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication 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 Patent Application Publication No. 20130251673 (Novira Therapeutics) include compounds 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 lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0387] Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763.

[0388] Examples of TLR8 agonists include, but are not limited to, MCT-465, motolimod, GS-9688, and VTX-1463.

[0389] Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, ritenimod, MGN-1601, and PUL-042.

[0390] Examples of TLR7 / TLR8 agonists include NKTR-262, IMO-4200, MEDI-9197 (tellatolimod), and resiquimod.

[0391] 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, and tellulatorimod.

[0392] 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.

[0393] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, a compound described herein is 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, and LY-3381916.

[0394] 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.

[0395] Tyrosine kinase inhibitors (TKIs) In some embodiments, the compounds described herein are combined with a tyrosine kinase inhibitor (TKI), which may 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), tivoanib, TH-4000, tivoanib, and MEDI-575 (anti-PDGFR antibody), TAK-659, and cabozantinib.

[0396] Chemotherapy (standard treatment) In some embodiments, the compounds described herein are combined with a chemotherapeutic or anti-neoplastic agent.

[0397] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are 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; ethyleneimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptoxanthin; ficins, 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, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi II), dynemycins, including dynemycin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin leucine, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodorubicin, 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 furoic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, veracrine A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Platinum analogues, such as cisplatin and carboplatin, NC-6004 Nanoplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine, hestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformutine; 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 inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan);Examples include FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated to antibodies or any of the targeting agents described herein to create antibody drug conjugates (ADCs) or targeted drug conjugates.

[0398] Antihormonal drugs Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0399] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0400] 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®).

[0401] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

[0402] An example of a progesterone receptor antagonist is onapristone.

[0403] Antiangiogenic agents In some embodiments, the compounds described herein are combined with an anti-angiogenic agent. Anti-angiogenic agents that may be co-administered include, but are not limited to, retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuranib, 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, proline analogs such as l-azetidine-2-carboxylic acid (LACA), modulators of matrix metabolism, cis-hydroxyproline, d,l-3,4-deoxyglucan, and the like. Hydroproline, thiaproline, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, β-1-anticollagenase serum, α-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.

[0404] antifibrotic agents In some embodiments, the compounds described herein are combined with antifibrotic agents. Antifibrotic agents that may be co-administered include, but are not limited to, compounds such as β-aminopropionitrile (BAPN) and the 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 collagen deposition, and U.S. Patent No. 4,997,854, which relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, both of which 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 No. 2004 / 0248871, which are incorporated herein by reference.

[0405] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate resonance-stabilized products after binding to the carbonyl, such as the following primary amines: ethylenamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactone.

[0406] Other antifibrotic agents are copper chelators, which may or may not be cell-permeable. 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.

[0407] 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.

[0408] 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.

[0409] 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, and 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.

[0410] 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, WO 2013 / 024898 ...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 / 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 2 Examples of compounds that may 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. Furthermore, 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.

[0411] Carbonic anhydrases 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 the following: 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.

[0412] 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.

[0413] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) inhibitors that may be co-administered include, but are not limited to, the compounds described in WO 2015 / 148954. Dual COX-2 / SEH inhibitors that may be co-administered include the 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 the compounds described in WO 2017 / 160861.

[0414] 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 other compounds 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.

[0415] 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 (for example, heme-nitric oxide and / or oxygen-binding protein (HNOX)), as described in, for example, WO2007 / 137767, WO2007 / 139791, WO2014 / 107171, and WO2016 / 149562.

[0416] immunotherapy 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, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumumab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratuzumab, detumomab, dinutuximab, drozitumab, dutuximab, and daviduzumab. Rigotumab, dusigizumab, 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, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotumab, 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.

[0417] The exemplary therapeutic antibodies may further be labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0418] 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, coltuximab, 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.

[0419] 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), calicheamicin, ansamitocin, 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 anticancer or antineoplastic agents described herein.

[0420] 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, for example, injecting immune cells designed to enhance the immune response to cancer cells or 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 detect and kill cancer cells; genetic approaches to modify cell activity to further change the endogenous immune responsiveness to cancer.

[0421] 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, 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 (TILs), granulocytes, innate lymphoid cells, megakaryocytes, monocytes, macrophages, platelets, thymocytes, myeloid cells, and / or dendritic cells (DCs). In some embodiments, the cell therapy involves 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 co-administration of an NK cell therapy, e.g., NK-92 cells. Optionally, the cell therapy can involve co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0422] In some embodiments, cell therapy involves 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, wherein 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 tumor cells. 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.

[0423] Regarding 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 selected from the group consisting of 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 proteins, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D), and the like. ), 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, LTBR, ​​Ly9 (CD229), Ly108), lymphocyte function-associated antigen-1 (LFA-1;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 a fragment, truncation, or combination thereof;

[0424] 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 to 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.

[0425] 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 invention 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 to CD83, LIGHT, an MHC class 1 molecule, PAG / Cbp, TNFSF14, a Toll ligand receptor, TRANCE / RANKL, or a fragment, truncation, or combination thereof.

[0426] In some embodiments, the CAR comprises a hinge domain, which may be any of the following: 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 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 a fragment or combination thereof.

[0427] In some embodiments, the one or more additional therapeutic agents comprise 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).

[0428] 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 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 known 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 (EGFRvIII); 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 α; 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); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropaque). subunit, beta type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of the 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 cellular 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 (MAGEA1); melanoma-associated antigen 3 (MAGE-A3); melanoma-associated antigen 4 (MAGE-A4);T cell receptor β2 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 MARTI); rat Sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; 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 binder (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 anchor 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 papillomavirus E6 (HPV E6); human papillomavirus 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 an MHC-presented tumor-associated antigen.

[0429] 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, and 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 receptor, folate-binding protein, gp100, hepatitis B surface antigen, Epstein-Barr nuclear antigen The antigen is selected from the group consisting of ribonucleic acid phosphate dehydrogenase (RID) receptor 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).

[0430] Examples of cell therapy include AMG-119, Algenpantucel-L, ALOFISEL (registered trademark), Sipuleucel-T, (BPX-501) rivogenlecleucel, U.S. Patent Application Publication No. 9089520, International Publication No. 2016 / 100236, AU-105, ACTR-087, activated allogeneic neoplastic cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and I Milecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treatment of bone marrow stem cell therapy, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, 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 anti-tumor T cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T cell therapy + PD-1 anti-tumor T cell therapy (esophageal c...

Claims

1. A compound of formula (I): 【Chemical 248】 [wherein, Z １ is N or CR １ wherein R １ is hydrogen, Z ２ is N or CR ２ where R ２ is hydrogen, C １～６ alkyl, halogen, C １～６ haloalkyl, -OR ２ａ , -N(R ２ａ )(R ２ｂ ), and R ２ａ and R ２ｂ are each independently hydrogen or C １～６ alkyl, and these may be the same or different; Z ４ is N or CR ４ where R ４ is hydrogen, C １～６ alkyl, or halogen, Z ７ is N or CR ７ wherein R ７ is hydrogen or C １～６ alkyl Z ８ is N or CR ８ where R ８ is hydrogen or C １～６ alkyl, Z ９ is N or CR ９ where R ９ is hydrogen or C １～６ alkyl R ３ is hydrogen, C １～６ alkyl, or halogen, and R ５ is C １～６ alkyl or C １～６ haloalkyl, and R ６ is phenyl or heteroaryl, and the phenyl or heteroaryl may be the same or different and is optionally substituted with 1 to 3 R ６ａ and the heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently being N, O or S, or 【Chemical 249】 is, 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 6- to 8-membered heterocycloalkyl optionally having 1 to 2 additional heteroatoms each independently being N, O, or S, and optionally, Ring A is substituted with 1 or 2 Rs which may be the same or different ６ｇ and is substituted with Each R ６ａ is independently halogen, C ２～８ alkynyl, phenyl, heterocycloalkyl, or heteroaryl, and the phenyl, heterocycloalkyl, or heteroaryl may each be optionally substituted with 1 to 3 R ６ｅ groups, the alkynyl may be optionally substituted with 1 to 4 R ６ｊ groups which may be the same or different, the heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently selected from N, O, or S, and the heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently selected from N, O, or S. Each R ６ｊ is, independently, halogen, C １～６ haloalkyl, -OR ６ｊ１ , -CN, C ３～１０ cycloalkyl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl may optionally be substituted with 1 to 3 R ６ｐ which may be the same or different, and the heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently selected from N, O, or S, and the heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently selected from N, O, or S, Each R ６ｊ１ is, independently, hydrogen, C １～６ alkyl, or C １～６ haloalkyl, and Each R ６ｐ is, independently, halogen, C １～６ alkyl, or C １～６ haloalkyl, and Each R ６ｅ is independently C １～６ alkyl, C ３～６ cycloalkyl, heterocycloalkyl, halogen, C １～６ haloalkyl, -CN, -OR ６ｅ１ , or -SF ５ wherein said cycloalkyl and heterocycloalkyl may each independently be optionally substituted with 1 to 3 R ６ｈ and said heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently being N, O or S, R ６ｅ１ is hydrogen or C １～６ alkyl, and Each R ６ｈ is independently C １～６ alkyl, C １～６ haloalkyl, =O, or -OH, and Each R ６ｇ is, independently, C １～６ alkyl, halogen, or C １～６ haloalkyl, However, Z ７ , Z ８ and Z ９ at least one of which is N, and Z ７ is CR ７ , and when Z ８ and Z ９ are both N, at least one of Z １ , Z ２ and Z ４ is N], or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5) or (Ia-6): 【Chemical 250】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ５ is -CH ２ CHF ２ ,-CH ２ CF ３ or Me, R ６ is phenyl or heteroaryl, and the phenyl or heteroaryl may be the same or different and is optionally substituted with one or two R ６ａ and the heteroaryl is a 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms each independently being N, O or S The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is represented by the following formula 【Chemical 299】 【Chemical 300】

5. 【Fig. 261】 is, n is 0, 1, or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. Each R ６ａ is independently C ２～８ alkynyl or halogen, where the alkynyl may be optionally substituted with 1 to 3 R ６ｊ which may be the same or different, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. Each R ６ｊ is independently halogen, C １～６ haloalkyl, -OR ６ｊ１ , -CN, C ３～６ cycloalkyl, 4- to 6-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 3 R ６ｐ which may be the same or different, R ６ｊ１ is hydrogen or C １～６ alkyl, and Each R ６ｐ is independently C １～３ alkyl, C １～３ haloalkyl The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. Each R ６ａ is independently F, Br, Cl, 【Chemical 299】 is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

10. R ２ is hydrogen, C １～３ alkyl, halogen, C １～６ haloalkyl - OR ２ａ , - N(R ２ａ )(R ２ｂ ), and R ２ａ and R ２ｂ each independently is hydrogen or C １～３ alkyl, and these may be the same or different The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R ３ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is hydrogen.

12. R ４ is hydrogen, C １～３ alkyl or halogen, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, Me or Et.

14. R ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

15. R ９ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

16. and below: 【Chemical Formula 16-1】 【Chemical Formula 16-2】 【Chemical Formula 16-3】 【Chemical 16-4】 [Chemical 16-5] 【Chemical Formula 16-6】 【Chemical Formula 16-7】 【Chemical Formula 16-8】 [Chemical 16-9] 【Chemical Formula 16-10】 【Chemical 16-11】 【Chemical 16-12】 【Chemical Formula 16-13】 【Chemical 16-14】 【Chemical 16-15】 【Chemical 16-16】 【Chemical Formula 16-17】 【Chemical Formula 16-18】 ​ 【Chemical 16-20】 ​ ​ 【Chemical 16-23】 【Chemical Formula 16-24】 【Chemical 16-25】 【Chemical 16-26】 【Chemical 16-27】 【Chemical 16-28】 【Chemical Formula 16-29】 【Chemical 16-30】 ​ 【Chemical 16-32】 【Chemical 16-33】 【Chemical Formula 16-34】 ​ 【Chemical 16-36】 【Chemical 16-37】 【Chemical 16-38】 【Chemical 16-39】 The compound shown in, or a pharmaceutically acceptable salt thereof.

17. A compound having the following structure, 【Chemical 300】 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1, 16 and 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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