DIACYLGLYERCOL Kinase Regulatory Compound

Abstract

The present application relates to diacylglycerol kinase modulating quinazolin-2-one derivatives of general formula (I) and pharmaceutical compositions thereof for the treatment of cancer, including solid tumors, and viral infections, such as HIV or Hepatitis B virus infections. The compounds can be used alone or in combination with other drugs. JPEG2024520593000438.jpg30128

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 213,893, filed Jun. 23, 2021, the entire disclosure of which is incorporated herein by reference for all purposes.

[0002] The present disclosure relates to compounds that modulate diacylglycerol kinase. The present 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 Art

[0003] Diacylglycerol (DAG) is known as a secondary messenger of signaling molecules and plays an important role in cell growth, 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 control them. DGK is an enzyme that synthesizes phosphatidic acid (PA) by transferring a phosphoryl group to DAG. Ten human isozymes (α, β, γ, δ, ε, ζ, η, θ, ι, κ) are known (Joshi, R.P., Koretzky, G.A. Int. J. Mol. Sci., 2013, 14, 6649 - 6673). Each isozyme is localized and is thought to be associated with different proteins and / or different cell types. DGK has been reported to be involved in the etiology of multiple diseases including cancer, immune diseases, neurodegenerative diseases, and diabetes (Sakane, F., et al. Front. Cell Dev. Biol., 2016, 4, 82).

[0004] DGKα has been the subject of research including studies on the potential of cancer treatment. For example, the inhibitory activity against the proliferation of glioblastoma cells was reported as a result of knockdown caused by RNA interference targeting DGKα (Dominguez, C. L., et al. Cancer Discov., 2013, 782 - 797). Also, the inhibitory effect in a three - dimensional cell culture of human colon cancer cell lines was reported, and it was further reported that knockdown of DGKα inhibits tumor growth in a mouse model (Torres - Ayuso, P., et al. Oncotarget, 2014, 5, 9710 - 9726). Inhibition of DGKα is disclosed in International Publication No. 2007 / 114239. Therefore, a compound having inhibitory activity against DGKα may be useful as a therapeutic agent such as for the treatment of cancer in which DGKα is involved in its proliferation.

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

[0006] DGKα is expressed in T cells and is thought to mediate signaling of the T-cell receptor (TCR) and play a role in T-cell activation (Joshi et al. (supra) and Merida, I. et al., Adv. Biol. Regul., 2017, 63, 22 - 31). When T cells are in an immunologically unresponsive state such as anergy, the expression of DGKα may increase, and overexpression of DGKα has been reported to induce an anergic state (Zha, Y. et al., Nat. Immunol., 2006, 7, 1166 - 1173). Furthermore, activation of T cells has been reported as a result of knockdown of DGKα in T cells by RNA interference (Avila-Flores, A., et al. Immunol. Cell. Biol., 2017, 95, 549 - 563). Therefore, a compound having an activity to control DGKα may be useful for preventing and / or treating T cell-related diseases such as immune diseases or inflammatory diseases.

[0007] 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 effects against solid tumors (Riese, M. J. et al. Cancer Res., 2013, 73, 3566 - 3577, Jung, I. Y., et al. Cancer Res., 2018, 78, 4692 - 4703). Therefore, the use of a compound having an inhibitory effect on DGKα may complement CAR T cell therapy. However, for example, there is still a need for a DGKα inhibitor having desirable pharmaceutical and therapeutic properties.

Prior Art Documents

Non-Patent Documents

[0008]

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Summary of the Invention

Means for Solving the Problems

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

[0010] [Chemical formula] [wherein, R 1 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, or -CN, R 2 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 1~6 alkoxy, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 2a , -C(O)OR 2a , -OC(O)R 2a , -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -C(=NR 2a )N(R 2b )(R 2c ), -N(R 2a )(R 2b ), -N(R 2a )(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 )(NR2b )(R 2c )、 -S(O) 2 R 2a 、 -S(O) 2 N(R 2a )(R 2b )、 -N(R 2a )S(O) 2 (R 2b )、 -P(R 2a )(R 2b )、 -P(O)(R 2a )(R 2b )、 -P(O)(OR 2a )(R 2b )、 -P(O)(OR 2a )(OR 2b )、 C 3~10 cycloalkyl, C 1~6 alkyl - C 3~10 cycloalkyl, C 6~12 aryl, C 1~6 alkyl - C 6~12 aryl, heterocycloalkyl, C 1~6 alkyl - (heterocycloalkyl), heteroaryl, or C 1~6 alkyl - (heteroaryl), wherein each alkyl, alkenyl, or alkynyl is independently optionally substituted with 1 to 3 R 2d groups, each cycloalkyl is optionally substituted with 1 to 3 R 2e groups, each aryl is optionally substituted with 1 to 3 R 2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R 2g groups, each heteroaryl is optionally substituted with 1 to 3 R 2h groups, 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, C1~6 Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12 Aryl, heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 Alkyl-(heteroaryl), and aryl or heteroaryl may be optionally substituted with 1 to 3 Rs 2j and, alternatively, when R 2a , R 2b , and R 2c are attached to the same atom, they may combine with the atom to which they are attached to form heterocycloalkyl each R 2d is independently -CN, -C(O)R 2d1 , -C(O)OR 2d1 , -OC(O)R 2d1 , -C(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)R 2d2 , -OC(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)OR 2d2 , -N(R 2d1 )(R 2d2 ), =O, -OR 2d1 , -SR 2d1 , -S(O)R 2d1 , -S(O)(NR 2d1 )(R 2d2 ), -S(O) 2 R 2d1 , -S(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )S(O) 2 R 2d2 、C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10Cycloalkyl, 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), and each R 2d1 and R 2d2 is independently hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 2~6 alkoxyalkyl, or C 1~6 haloalkyl, and each R 2e , R 2f , R 2g , and R 2h is 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, and each R 2j is 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, and 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 1~6Haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)OR 3b , -C(=NR 3a )N(R 3b )(R 3c ), -N(R 3a )(R 3b ), -N(R 3a )N(R 3b )(R 3c ), -N(R 3a )N=C(R 3b )(OR 3c ), -OR 3a , -SR 3a , -S(O)R 3a , -S(O)(NR 3a )(R 3b ), -S(NR 3a )(NR 3b )(R 3c ), -S(O) 2 R 3a ), -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 (R 3b ), -P(R 3a )(R 3b ), -P(O)(R 3a )(R 3b ), -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~12 Aryl, C 1~6 Alkyl-C 6~12Aryl, heterocycloalkyl, C 1~6 alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), and each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R 3d groups, each cycloalkyl is optionally substituted with 1 to 3 R 3e groups, each aryl is optionally substituted with 1 to 3 R 3f groups which may be the same or different, each heterocycloalkyl is optionally substituted with 1 to 3 R 3g groups which may be the same or different, each heteroaryl is optionally substituted with 1 to 3 R 3h groups which may be the same or different, and each R 3a , R 3b , and R 3c is 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, and alternatively, when R 3a , R 3b , and R 3c are attached to the same atom, they can combine with the atom to which they are attached to form a heterocycloalkyl, each R 3d is 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 6~12is aryl, heterocycloalkyl, or heteroaryl, each R 3d1 and R 3d2 is independently hydrogen, C 1~6 alkyl, or -C(O)O-(C 1~6 alkyl); each R 3e , R 3f , R 3g , and R 3h is independently hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, or C 1~6 haloalkoxy; R 4 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, or -CN; R 5 is 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 optionally substituted with R 5a ; R 5a is -OSi(R 5a1 )(R 5a2 )(R 5a3 ); R 5a1 , R5a2 and R 5a3 each independently is C 1~6 alkyl, R 6 may be the same or different and is C substituted with 1 to 3 R 6a alkenyl, C 2~6 alkynyl, C 2~6 haloalkyl, C 1~6 aryl, or heteroaryl optionally substituted with 1 to 3 R that may be the same or different, 6~12 each R 6a is independently C alkyl, C 6a alkenyl, C 1~6 alkynyl, C 2~6 hydroxyalkyl, C 2~8 aminoalkyl, C 1~6 alkoxy, C 1~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 2~6 haloalkoxy, -CN, -NO 1~6 -C(O)R 1~6 -OC(O)R 2 -C(O)N(R 6b )(R 6b )、-N(R 6b )(R 6c )、-N(R 6b )C(O)R 6c 、-C(=NR 6b )N(R 6c )(R 6d )、-N(R 6b )(R 6c )、-OR 6b 、-SR 6b 、-S(O)R 6b 、-S(O) 2 R 6b 、-S(NR 6b )(NR 6c )R 6d 、-S(O)(NR 6b )(R 6c )、-S(O) 2 N(R 6b )(R 6c )、-N(R 6b )S(O) 2 (R6c ), -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), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and each is optionally substituted with 1 to 3 R 6e 's, the alkyl is optionally substituted with R 6f 's, the alkynyl is optionally substituted with 1 to 4 R 6j 's which may be the same or different, each R 6b , R 6c , and R 6d is 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), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and each is optionally substituted with 1 to 3 R6k is optionally replaced by each R 6k is 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 is 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, -NO 2 ,-C(O)R 6e1 ,-C(O)OR 6e1 ,-OC(O)R 6e1 ,-C(O)N(R 6e1 )(R 6e2 )、-N(R 6e1 )C(O)R 6e2 、-OC(O)N(R 6e1 )(R 6e2 )、-N(R 6e1 )C(O)OR 6e2 、-C(=NR 6e1 )N(R 6e2 )(R 6e3 )、-N(R 6e1 )(R 6e2 )、=O、-OR 6e1 、-SR 6e1 、-S(O)R 6e1 、-S(NR 6e1 )(NR 6e2 )、-S(O)(NR 6e1)(R 6e2 )、 -S(O) 2 R 6e1 、 -S(O) 2 N(R 6e1 )(R 6e2 )、 -SF 5 、 -N(R 6e1 )S(O) 2 (R 6e2 )、 -P(R 6e1 )(R 6e2 )、 -P(O)(R 6e1 )(R 6e2 )、 -P(O)(OR 6e1 )(R 6e2 )、 -P(O)(OR 6e1 )(OR 6e2 )、 -Si(R 6e1 )(R 6e2 )(R 6e3 )、 C 3~10 cycloalkyl, C 1~6 alkyl - C 3~10 cycloalkyl, C 6~12 aryl, C 1~6 alkyl - C 6~12 aryl, heterocycloalkyl, C 1~6 alkyl - heterocycloalkyl, heteroaryl, or C 1~6 alkyl - heteroaryl, where the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may each be optionally substituted with 1 - 3 identical or different R 6h groups, and the alkyl may be optionally substituted with 1 - 3 identical or different R 6m groups, 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 1~6Alkyl-C 6~10 aryl, heterocycloalkyl, C 1~6 alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), and cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and are optionally substituted with 1 to 3 R 6n ; each R 6n is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 1~6 alkoxy, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -C(O)R 6n1 , -C(O)OR 6n1 , -OC(O)R 6n1 , -C(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)R 6n2 , -OC(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)OR 6n2 , -C(=NR 6n1 )N(R 6n2 )(R 6n3 ), -N(R 6n1 )(R 6n2 ), =O, -OH, -SR 6n1 , -S(O)R 6n1 , -S(NR 6n1 )(NR 6n2 )R 6n3 , -S(O)(NR 6n1 )(R 6n2 ), -S(O) 2 R 6n1 , -S(O) 2 N(R 6n1 )(R 6n2 ), or -N(R 6n1 )S(O) 2 (R 6n2) and each R 6n1 、R 6n2 and R 6n3 is 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), and each R 6h is 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 )(R 6h2 )、=O、-OH、-SR 6h1 、-S(O)R 6h1 、-S(NR 6h1 )(NR6h2 )R 6h3 、 -S(O)(NR 6h1 )(R 6h2 )、 -S(O) 2 R 6h1 、 -S(O) 2 N(R 6h1 )(R 6h2 )、 -N(R 6h1 )S(O) 2 (R 6h2 )、 C 3~10 cycloalkyl, C 1~6 alkyl - C 3~10 cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl), where each R 6h1 、 R 6h2 、 and R 6h3 is 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), where each R 6m is independently halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -C(O)R 6m1 、 -C(O)OR 6m1 、 -OC(O)R 6m1 、 -C(O)N(R 6m1 )(R 6m2 )、 -N(R 6m3 )C(O)R 6m2 、 -OC(O)N(R 6m1 )(R 6m2 )、 -N(R 6m1 )C(O)OR 6m2, -C(=NR 6m3 )N(R 6m1 )(R 6m2 )、-N(R 6m1 )(R 6m2 )、=O、-OH、-SR 6m1 、-S(O)R 6m1 、-S(NR 6m1 )(NR 6m2 )R 6m3 、-S(O)(NR 6m1 )(R 6m2 )、-S(O) 2 R 6m1 、-S(O) 2 N(R 6m1 )(R 6m2 )、 or -N(R 6m3 )S(O) 2 (R 6m2 ) and each R 6m1 , R 6m2 , and R 6m3 is 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) and R 6f is -OSi(R 6f1 )(R 6f2 )(R 6f3 ) and R 6f1 , R 6f2 , and R 6f3 are each independently C 1~6 alkyl and each R 6j is independently C 2~6 alkoxyalkyl, halogen, C1~6 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 6j1 )(C(O)R 6j2 , -OC(O)N(R 6j1 )(R 6j2 ), -N(R 6j1 )(C(O)OR 6j2 , -C(=NR 6j3 )(N(R 6j1 )(R 6j2 ), -N(R 6j1 )(R 6j2 ), =O, -OR 6j1 , -SR 6j1 , -S(O)R 6j1 , -S(NR 6j1 )(NR 6j2 ), -S(NR 6j1 )(NR 6j2 )R 6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O) 2 R 6j1 , -S(O) 2 N(R 6j1 )(R 6j2 ), -N(R 6j1 )(S(O) 2 (R 6j2 ), -Si(R 6j1 )(R 6j2 )(R 6j3 ), C 3~10 cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be optionally substituted with 1 to 3 identical or different R 6p ; and each R 6j1 , R 6j2 , and R 6j3 is independently hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6Aminoalkyl, C 2~6 Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 C optionally substituted with haloalkyl 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 Alkyl-(heteroaryl), and each R 6p is 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) 2 R 6p1 , -S(O) 2 N(R 6p1 )(R6p2 ) or -N(R 6p1 )S(O) 2 (R 6p2 ) and each R 6p1 , R 6p2 , and R 6p3 is 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), and or, R 5 and one R 6a together with the atom to which they are attached optionally form a heterocycloalkyl optionally substituted with 1 to 3 R 6g which are the same or different, and each R 6g is 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, and R 7 is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, C 1~6 alkyl-C3~10 Cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl), and each heterocycloalkyl is a 3- to 20-membered ring having 1 to 4 heteroatoms each independently being N, O, or S, each heteroaryl is a 5- to 18-membered ring having 1 to 4 heteroatoms each independently being N, O, or S], or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the present disclosure provides a method for treating it in a subject in need of treating cancer, 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 for treating it in a subject in need of treating an HIV or hepatitis B virus infection, 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.

BEST MODE FOR CARRYING OUT THE INVENTION

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

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

[0015] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least 1 double bond. Alkenyl can contain any number of carbons such as C 2 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C 3 , C 3~4 , C 3~5 , C 3~6 , C 4 , C 4~5 , C 4~6 , C 5 , C 5~6 , and C 6 etc. The alkenyl group 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-hexatriene. The alkenyl group can be substituted or unsubstituted.

[0016] "Alkynyl" refers to either a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least 1 triple bond. Alkynyl can contain C 2 , C 2~3 , C2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C 3 , C 3~4 , C 3~5 , C 3~6 , C 4 , C 4~5 , C 4~6 , C 5 , C 5~6 , and C 6 may contain any number of carbons such as C. Examples of the alkynyl group include, but are not limited to, ethynyl, 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-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatriynyl. The alkynyl group may be substituted or unsubstituted.

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

[0018] "Alkoxyalkyl" refers to an alkoxy group linked to an alkyl group that is linked to the remainder of the compound, such that the alkyl group is divalent. The alkoxyalkyl has 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C 2~5 alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C2~3 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, C 6 alkoxyalkyl refers to ethoxy (C 4 alkoxy) linked to butyl (C 2 alkyl), and n-propoxy (C 3 alkoxy) linked to isopropyl (C 3 alkyl). Alkoxy and alkyl are as defined above, and alkyl is divalent and, without limitation, includes methoxymethyl (CH 3 OCH 2 -), methoxyethyl (CH 3 OCH 2 CH 2 -), etc.

[0019] "Aminoalkyl" refers to an amino group linked to an alkyl group that is in turn linked to the rest of the compound, such that the alkyl group is divalent. The amino group may be unsubstituted amino (-NH 2 ), or may be substituted with an alkyl group, for example, monosubstituted amino (e.g., -NHCH 3 ), or disubstituted amino (e.g., -N(CH 3 ) 2 ). Aminoalkyl may have any suitable number of carbons, such as 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 aminoalkyl). The number of carbons refers to the total number of carbons in the amino and alkyl groups. For example, C 6 aminoalkyl refers to -N(CH 4 ) 3 (C 2 amino) linked to butyl (C 2 alkyl), and -NHCH 3 linked to isopropyl (C 2 CH 2 CH 3 (C3 refers to "(amino)". Alkyl is as defined above, and alkyl is divalent. Examples of aminoalkyl include, but are not limited to, aminomethyl (H 2 NCH 2 -), methylaminomethyl (CH 3 NHCH 2 -), dimethylaminomethyl ((CH 3 ) 2 NCH 2 -), dimethylethylamino ((CH 3 ) 2 NCH 2 CH 2 -), etc.

[0020] "Alkoxy-alkoxy" refers to an alkoxy group that is linked to a second alkoxy group which is in turn linked to the remainder of the compound. Alkoxy is as defined above, and examples include, but are not limited to, methoxy-methoxy (CH 3 OCH 2 O-), methoxy-ethoxy (CH 3 OCH 2 CH 2 O-), etc.

[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, wherein 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, and C 1~4One or more of the hydrogen atoms of the alkyl are replaced by a halo substituent. 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. The haloalkoxy group can have any suitable number of carbon atoms, such as C 1~6 etc. The alkoxy group may be substituted with one, two, three, or more halogens. When all the hydrogens are replaced by a halogen, such as fluorine, the compound is oversubstituted, for example, perfluorinated. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0024] "Cycloalkyl" refers to a cyclic group having 3 to 20 carbon atoms (i.e., C 3~20"(Cycloalkyl)", for example, refers to a saturated or partially unsaturated all-carbon monocyclic ring having 3 to 12 ring atoms, for example, 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also includes saturated and partially unsaturated all-carbon polycondensed ring systems (for example, ring systems containing 2, 3, or 4 carbon rings). Thus, cycloalkyl includes bicyclic carbon rings (for example, bicyclic carbon rings having 6 to 12 ring carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbon rings (for example, tricyclic and tetracyclic carbon rings having up to 20 ring carbon atoms). The rings of the polycondensed ring system may be linked to each other by fused bonds, spiro bonds, and bridging bonds when permitted by the valence requirements. Non-limiting examples of monocyclic cycloalkyl 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, and the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene for the alkyl component to link to the cycloalkyl component and the point of attachment. Optionally, the alkyl component may not be present. The alkyl component is 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 、C 4~6 、and C 5~6It may contain any number of carbons such as. The cycloalkyl component 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 "heterocyclic" or "heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic ring system having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur) within the ring, and the polycyclic ring system includes at least one non-aromatic ring containing at least one heteroatom. The polycyclic ring system may also include other aromatic and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has 3 to 20 ring atoms, for example, 3 to 12 ring atoms, for example, 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a saturated or partially unsaturated monocyclic ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) having 1 to 6 cyclic carbon atoms within the ring and 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatom is optionally oxidized to -N(-OH)-, =N(-O) - )-, -S(=O)-, or -S(=O) 2- may be formed. When permitted by the valence requirements, the rings of a polycondensed ring (e.g., bicyclic heterocyclyl) system may be linked to each other by a fused bond, a spiro bond, or a crosslinking bond. Examples of the heterocycle include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 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] Examples of the heterocycloalkyl ring also include 9- to 15-membered fused-ring heterocycloalkyl having two, three, or more rings, at least one of which is an aryl ring and at least one of which is a non-aromatic ring containing at least one heteroatom. Representative bicyclic fused-ring heterocycloalkyl includes, but is not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazole (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenz[b]dioxin, dihydrobenz[d]oxazole, dihydrobenz[b]thiophene, dihydroisobenz[c]thiophene, dihydrobenz[d]thiazole, dihydrobenz[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the following structures:

[0028] [Chemistry]

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

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

[0031] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, and 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 for connecting the heterocycloalkyl component and the point of attachment. The alkyl component is 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 5~6It may contain any number of carbons such as. In some cases, the alkyl component may not be present. 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 or all-carbon polycondensed ring system in which at least one of the rings is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of aryl include phenyl radicals. Aryl also includes polycondensed ring systems having 9 to 20 carbon atoms, for example, 9 to 16 carbon atoms (e.g., a ring system containing 2, 3, or 4 rings), with at least one ring being aromatic and the other ring being either aromatic or non-aromatic (i.e., a carbocyclic ring). Any carbocyclic moiety of such a polycondensed ring system is optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups. The rings of the polycondensed ring system may be linked to each other by fused bonds, spiro bonds, and bridging bonds, if permitted by valence requirements. It should also be understood that when referring to aryl of a particular range of atomic members (e.g., 6- to 10-membered aryl), the atomic range is for the total ring atoms of the aryl. For example, 6-membered aryl includes phenyl, and 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0033] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene for linking the aryl component and the point of attachment. The alkyl component is 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 may contain any number of carbons such as, etc. In some cases, the alkyl component may not be present. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethylbenzene. The alkyl-aryl group may be substituted or unsubstituted.

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

[0035] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, and the alkyl component links the heteroaryl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene for linking the heteroaryl component and the point of attachment. The alkyl component may contain any number of carbons such as 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 etc. In some cases, the alkyl component may not be present. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0036] "The compounds of the present disclosure" include the compounds disclosed herein. For example, the compounds of the present disclosure include compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), such as the compounds of the examples.

[0037] As used herein, "composition" is intended to encompass a product containing specific components in specific amounts and any product directly or indirectly resulting from the combination of specific amounts of specific components. "Pharmaceutically acceptable" means that a carrier, diluent, or excipient must be compatible with the other components of the formulation and not harmful to its recipient.

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

[0039] Examples of "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the United States Food and Drug Administration for use in humans or livestock.

[0040] As used herein, "treatment" or "treating" or "treatment" refers to an approach for obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms, and / or reduction in the degree of symptoms, and / or prevention of worsening of symptoms associated with a disease or condition. In some embodiments, "treatment" or "treatment" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the degree 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, delaying the worsening or progression of the disease or condition), and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the pathological condition, delaying the progression of the disease, improving the quality of life, and / or extending the survival period.

[0041] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response, including an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment of the disease. The effective amount can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated. The effective amount can include a range of amounts. As is understood in the art, the effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The 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 used in combination with one or more other agents, whether or not a desirable or beneficial result is achieved, or when such result is achieved. The preferred dosage of any concurrently administered compound can optionally be reduced due to the combined action (e.g., additive or synergistic effect) of the compounds.

[0042] "Administering" refers to oral administration to a subject, 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. Administration can be carried out according to a schedule specifying the frequency of administration, the dosage administered, and other factors.

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

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

[0045] "Disease" or "condition" refers to the physical state or health condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. Diseases can be autoimmune, inflammatory, cancer, infectious (e.g., viral infections), metabolic, developmental, cardiovascular, hepatic, intestinal, endocrine, neurological, or other diseases. 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, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colorectal 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), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, 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 esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0047] As further examples, there are cancer of the thyroid, endocrine system, brain, breast, cervix, large intestine, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, Waldenström's macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical cancer, neoplasm of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular cancer, Paget's disease of the breast, phyllodes tumor, lobular cancer, ductal cancer, cancer of pancreatic stellate cells, cancer of hepatic stellate cells, or prostate cancer.

[0048] "Leukemia" generally refers to a progressive malignant disease of the hematopoietic organs, and is generally characterized by abnormal proliferation and generation of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease - acute or chronic, (2) the type of cells involved: bone marrow (myeloid), lymphocytes (lymphocytic), or monocytes, and (3) the increase or non-increase in the number of abnormal cells in the blood - leukemic or non-leukemic (sub-leukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, embryonal cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastocytic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micro-myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Nägeli type leukemia, plasmacytic leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, sub-leukemic leukemia, or undifferentiated cell leukemia.

[0049] "Sarcoma" generally refers to a tumor composed of substances such as embryonic connective tissue, generally composed of densely packed cells embedded in fibrous or homogeneous substances. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphoma, melanoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, lipoma, alveolar soft part sarcoma, ameloblastic epithelioma, sarcoma botryoides, chloroma, 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, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer stellate cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, juxtaosteal sarcoma, reticulosarcoma, Rous sarcoma, serous cystadenosarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0050] "Melanoma" is considered to mean a tumor arising from the melanocyte system of the skin and other organs. Melanomas that can 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, malignant lentigo-derived melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0051] "Cancer tumor" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and metastasize. Exemplary cancer tumors that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, lobular carcinoma, alveolar cancer, adenocystic tumor, adenoid cystic cancer, adenoid cancer, adrenal cortical cancer tumor, alveolar cancer, alveolar epithelial cancer, basal cell cancer, basal cell cancer tumor, basaloid cancer, basal squamous cell cancer tumor, bronchioloalveolar epithelial cancer, bronchiolar cancer, bronchogenic lung cancer, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, acneiform cancer, endometrial cancer, cribriform cancer, scirrhous cancer, skin cancer, cylindrical carcinoma, columnar cell cancer, ductal cancer, mammary duct cancer, carcinoma durum, embryonal cancer tumor, medullary cancer, epidermoid cancer, adenocarcinoma, exophytic cancer, ulcerative cancer, fibrosarcoma, colloid cancer, colloid adenocarcinoma, giant cell cancer, giant cell carcinoma, adenocarcinoma, granular cell cancer, trichoblastoma, hematoid cancer, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline cancer, hypernephroid carcinoma, pediatric embryonal cancer tumor, intraepithelial cancer, intraepidermal cancer, intraepithelial cancer tumor, chromophobe cancer, Kultschitzky cell carcinoma, large cell cancer, lenticular carcinoma, carcinoma lenticulare, lipomatous cancer, lobular cancer, lymphoepithelial cancer, carcinoma medullare, medullary carcinoma, melanoma, soft cancer tumor, mucinous carcinoma, mucinous cancer tumor, mucinous cell cancer, mucoepidermoid cancer, carcinoma mucosum, mucousCarcinoma), myxoid carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, spinous cell carcinoma, medullary carcinoma, renal cell carcinoma, precursor cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, solid carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, carcinoid tumor, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous epithelial cell carcinoma, cord carcinoma, angiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, tuberosum carcinoma, tubulocystic carcinoma, nodular carcinoma, verrucous carcinoma, or villous carcinoma.

[0052] The terms "metastasis," "metastatic," and "metastatic cancer" may be used interchangeably and refer to the spread of a proliferative disease or disorder, such as cancer, from one organ to another non-adjacent organ or body part. Cancer develops at a site, for example, in the breast, and that site is referred to as the primary tumor, for example, primary breast cancer. Some cancer cells within the primary tumor or site of origin acquire the ability to invade and infiltrate the surrounding normal tissue in the local area and / or to invade the walls of the lymphatic or vascular system and spread through that system to other sites and tissues within the body. A second clinically detectable tumor formed from the cancer cells of the primary tumor is referred to as a metastatic tumor or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be the same as those of the original tumor. Thus, when lung cancer metastasizes to the breast, the secondary tumor at the breast site consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to as metastatic lung cancer. Thus, the term "metastatic cancer" refers to a disease in a subject who has or has had a primary tumor and has one or more secondary tumors. The phrase "subject with non-metastatic cancer, or cancer that is not metastatic" refers to a disease in a subject who 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" or "relating to" means that 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) is (wholly or partially) caused by the substance or the activity or function of the substance, or that the symptoms of the disease are (wholly or partially) caused.

[0054] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary use 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 forms of the compounds having the desired pharmacological activity. These salts can be derived from inorganic or organic acids or inorganic or organic bases. Examples of pharmaceutically acceptable salts of the compounds of formula (I) of the present disclosure include, for example, inorganic acid salts such as hydrochloride, sulfate, carbonate, and phosphate, and organic acid salts such as fumarate, maleate, methanesulfonate, and p-toluenesulfonate. Further salts including those containing alkaline earth metals such as magnesium or calcium, organic amines such as lower alkylamines or lower alcoholamines, basic amino acids such as lysine, arginine, ornithine, or ammonium salts including alkali metals such as sodium, potassium, etc. are also included. For example, a compound containing basic nitrogen can be prepared as a pharmaceutically acceptable salt 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, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is Remington: The Science and Practice of Pharmacy, 21 stIt can be found in Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

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

[0057] Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 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, thus, may 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 are replaced by deuterium.

[0058] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, each 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I are also included. 11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotope-labeled compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) can generally be prepared by using appropriate isotope-labeled reagents instead of the unlabeled reagents used heretofore, by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below.

[0059] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and, thus, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent 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 a racemic compound (or a racemic compound of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When the compounds are represented in their chiral forms, it is understood that the embodiments include, but are not limited to, specifically diastereomerically or enantiomerically enriched forms. When chirality is not specified but is present, it is understood that the embodiments are directed to either a specifically diastereomerically or enantiomerically enriched form or a racemic or scaemic mixture of such compounds. As used herein, a "scaemic 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. A compound may exist in stereoisomeric forms if it has one or more asymmetric centers or double bonds with asymmetric substitution and can thus be produced as individual stereoisomers or as mixtures. Unless otherwise specified, the 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] "Tautomers" refer to alternative forms of compounds in which the position of a proton is different, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N-.

[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 at the front or end of a chemical group are for convenience, and chemical groups can be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. A dashed line indicates an optional bond. Unless required chemically or structurally, the order in which a chemical group is written or the point at which it is attached to the rest of the molecule indicates neither directionality nor implies it. For example, the group "-SO 2 CH 2 -" is equivalent to "-CH 2 SO 2 -", and both can be linked in either direction. Similarly, for example, an "arylalkyl" group may be attached to the rest of the molecule by either the aryl or alkyl portion of the group. "C u~v」 or (C u ~C v ) prefixes such as indicate that the group that follows has u to v carbon atoms. For example, "C 1~6 alkyl" and "C 1 ~C 6 alkyl" both indicate that the alkyl group has 1 to 6 carbon atoms.

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

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

[0066] II. Compounds The present disclosure provides compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), and (Ia-12), and pharmaceutically acceptable salts thereof.

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

[0068]

Chemical formula

[0069] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 1 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, C 1~6is haloalkoxy or -CN, R 2 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 1~6 alkoxy, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -NO, -NO 2 、-C(O)R 2a 、-C(O)OR 2a 、-OC(O)R 2a 、-C(O)N(R 2a )(R 2b )、-N(R 2a )C(O)R 2b 、-OC(O)N(R 2a )(R 2b )、-N(R 2a )C(O)OR 2b 、-C(=NR 2a )N(R 2b )(R 2c 、-N(R 2a )(R 2b 、-N(R 2a )N(R 2b )(R 2c 、-N(R 2a )N=C(R 2b )(OR 2c )、-OR 2a 、-SR 2a 、-S(O)R 2a 、-S(O)(NR 2a )(R 2b 、-S(NR 2a )(NR 2b )(R 2c 、-S(O) 2 R 2a 、-S(O) 2 N(R 2a )(R 2b 、-N(R 2a )S(O) 2 (R 2b 、-P(R 2a )(R 2b)、 -P(O)(R 2a )(R 2b )、 -P(O)(OR 2a )(R 2b )、 -P(O)(OR 2a )(OR 2b )、 C 3~10 cycloalkyl, C 1~6 alkyl-C 3~10 cycloalkyl, C 6~12 aryl, C 1~6 alkyl-C 6~12 aryl, heterocycloalkyl, C 1~6 alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), wherein each alkyl, alkenyl, or alkynyl is independently optionally substituted with 1 to 3 R 2d groups, each cycloalkyl is optionally substituted with 1 to 3 R 2e groups, each aryl is optionally substituted with 1 to 3 R 2f groups, each heterocycloalkyl is optionally substituted with 1 to 3 R 2g groups, each heteroaryl is optionally substituted with 1 to 3 R 2h groups, and each R 2a 、 R 2b 、 and R 2c is 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, C1~6 alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), wherein aryl or heteroaryl is optionally substituted with 1 to 3 R 2j groups, alternatively, when R 2a , R 2b , and R 2c are attached to the same atom, they can combine with the atom to which they are attached to form heterocycloalkyl, each R 2d is independently -CN, -C(O)R 2d1 , -C(O)OR 2d1 , -OC(O)R 2d1 , -C(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)R 2d2 , -OC(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(O)OR 2d2 , -N(R 2d1 )(R 2d2 ), =O, -OR 2d1 , -SR 2d1 , -S(O)R 2d1 , -S(O)(NR 2d1 )(R 2d2 ), -S(O) 2 R 2d1 , -S(O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )S(O) 2 R 2d2 , C 3~10 cycloalkyl, C 1~6 alkyl-C 3~10 cycloalkyl, C 6~12 aryl, C 1~6 alkyl-C 6~12 aryl, heterocycloalkyl, C 1~6 alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), each R 2d1 and R 2d2is, independently, hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 2~6 alkoxyalkyl, or C 1~6 haloalkyl, and each R 2e , R 2f , R 2g , and R 2h is, 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, and each R 2j is, 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, and R 3 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 1~6 alkoxy, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -NO, -NO 2 , -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -OC(O)N(R 3a )(R3b )、 -N(R 3a )C(O)OR 3b 、 -C(=NR 3a )N(R 3b )(R 3c )、 -N(R 3a )(R 3b )、 -N(R 3a )N(R 3b )(R 3c )、 -N(R 3a )N=C(R 3b )(OR 3c )、 -OR 3a 、 -SR 3a 、 -S(O)R 3a 、 -S(O)(NR 3a )(R 3b )、 -S(NR 3a )(NR 3b )(R 3c )、 -S(O) 2 R 3a 、 -S(O) 2 N(R 3a )(R 3b )、 -N(R 3a )S(O) 2 (R 3b )、 -P(R 3a )(R 3b )、 -P(O)(R 3a )(R 3b )、 -P(O)(OR 3a )(R 3b )、 -P(O)(OR 3a )(OR 3b )、 C 3~10 cycloalkyl, C 1~6 alkyl-C 3~10 cycloalkyl, C 6~12 aryl, C 1~6 alkyl-C 6~12 aryl, heterocycloalkyl, C 1~6 alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 alkyl-(heteroaryl), and each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R 3d groups, and each cycloalkyl is optionally substituted with 1 to 3 R 3eoptionally substituted with a radical, each aryl may be the same or different and is 1 to 3 R 3f optionally substituted with a radical, each heterocycloalkyl may be the same or different and is 1 to 3 R 3g optionally substituted with a radical, each heteroaryl may be the same or different and is 1 to 3 R 3h optionally substituted with a radical, each R 3a , R 3b and R 3c is 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, when R 3a , R 3b and R 3c are attached to the same atom, they can combine with the atom to which they are attached to form heterocycloalkyl, each R 3d is 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 is independently hydrogen, C 1~6 alkyl, or -C(O)O-(C 1~6 alkyl), each R 3e , R 3f, R 3g , and R 3h is, independently, hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, or C 1~6 haloalkoxy, 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 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 optionally substituted with R 5a , and R 5a is -OSi(R 5a1 )(R 5a2 )(R 5a3 ), and R 5a1 , R 5a2 , and R 5a3 are each independently C 1~6 alkyl, and R 6 is C alkenyl, C alkynyl, C 6a which may be the same or different and is substituted with 1 to 3 R 2~6 alkenyl, C 2~6 alkynyl, C 1~6Haloalkyl, C 6~12 Aryl, or one to three Rs which may be the same or different 6a Optionally substituted heteroaryl, Each R 6a Independently is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~8 Alkynyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -NO 2 , -C(O)R 6b , -OC(O)R 6b , -C(O)N(R 6b )(R 6c ), -N(R 6b )C(O)R 6c , -C(=NR 6b )N(R 6c )(R 6d ), -N(R 6b )(R 6c ), -OR 6b , -SR 6b , -S(O)R 6b , -S(O) 2 R 6b , -S(NR 6b )(NR 6c )R 6d , -S(O)(NR 6b )(R 6c ), -S(O) 2 N(R 6b )(R 6c ), -N(R 6b )S(O) 2 (R 6c ), -P(R 6b )(R 6c ), -P(O)(R 6b )(R 6c ), -P(O)(OR 6b )(R 6c ), -P(O)(OR 6b )(OR 6c ), C 3~10Cycloalkyl, 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), and cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and each is optionally substituted with 1 to 3 R 6e and alkyl is optionally substituted with R 6f and alkynyl is optionally substituted with 1 to 4 R which may be the same or different 6j Each R 6b R 6c and R 6d is 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), and cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and each is optionally substituted with 1 to 3 R 6k Each R 6k is 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), and each R 6e is 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, -NO 2 , -C(O)R 6e1 , -C(O)OR 6e1 , -OC(O)R 6e1 , -C(O)N(R 6e1 )(R 6e2 ), -N(R 6e1 )C(O)R 6e2 , -OC(O)N(R 6e1 )(R 6e2 ), -N(R 6e1 )C(O)OR 6e2 , -C(=NR 6e1 )N(R 6e2 )(R 6e3 ), -N(R 6e1 )(R 6e2 ), =O, -OR 6e1 , -SR 6e1 , -S(O)R 6e1 , -S(NR 6e1 )(NR 6e2 ), -S(O)(NR 6e1 )(R 6e2 ), -S(O) 2 R 6e1 , -S(O) 2 N(R 6e1 )(R 6e2 ), -SF 5 , -N(R 6e1 )S(O) 2 (R 6e2 ), -P(R 6e1)(R 6e2 )、 -P(O)(R 6e1 )(R 6e2 )、 -P(O)(OR 6e1 )(R 6e2 )、 -P(O)(OR 6e1 )(OR 6e2 )、 -Si(R 6e1 )(R 6e2 )(R 6e3 )、 C 3~10 cycloalkyl, C 1~6 alkyl - C 3~10 cycloalkyl, C 6~12 aryl, C 1~6 alkyl - C 6~12 aryl, heterocycloalkyl, C 1~6 alkyl - heterocycloalkyl, heteroaryl, or C 1~6 alkyl - heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and each is optionally substituted with 1 - 3 R 6h groups, and the alkyl is optionally substituted with 1 - 3 R 6m groups, each R 6e1 , R 6e2 , and R 6e3 is 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), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and each is optionally substituted with 1 - 3 R 6nis optionally replaced with, each R 6n is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 1~6 alkoxy, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -C(O)R 6n1 , -C(O)OR 6n1 , -OC(O)R 6n1 , -C(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)R 6n2 , -OC(O)N(R 6n1 )(R 6n2 ), -N(R 6n1 )C(O)OR 6n2 , -C(=NR 6n1 )N(R 6n2 )(R 6n3 ), -N(R 6n1 )(R 6n2 ), =O, -OH, -SR 6n1 , -S(O)R 6n1 , -S(NR 6n1 )(NR 6n2 )R 6n3 , -S(O)(NR 6n1 )(R 6n2 ), -S(O) 2 R 6n1 , -S(O) 2 N(R 6n1 )(R 6n2 ), or -N(R 6n1 )S(O) 2 (R 6n2 ) and each R 6n1 , R 6n2 and R 6n3 are independently hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 2~6 alkoxyalkyl, C 1~6Haloalkyl, 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), and each R 6h is 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 )(R 6h2 ), =O, -OH, -SR 6h1 , -S(O)R 6h1 , -S(NR 6h1 )(NR 6h2 )R 6h3 , -S(O)(NR 6h1 )(R 6h2 ), -S(O) 2 R 6h1 , -S(O) 2 N(R 6h1 )(R 6h2 ), -N(R 6h1 )S(O)2 (R 6h2 )、C 3~10 cycloalkyl, C 1~6 alkyl-C 3~10 cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl), and each R 6h1 、R 6h2 、and R 6h3 is 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), and each R 6m is 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 )R6m3 、 -S(O)(NR 6m1 )(R 6m2 )、 -S(O) 2 R 6m1 、 -S(O) 2 N(R 6m1 )(R 6m2 )、 or -N(R 6m3 )S(O) 2 (R 6m2 ) and each R 6m1 、 R 6m2 、 and R 6m3 is 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) and R 6f is -OSi(R 6f1 )(R 6f2 )(R 6f3 ) and R 6f1 、 R 6f2 、 and R 6f3 are each independently C 1~6 alkyl and each R 6j is 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 6j1 )C(O)R 6j2, -OC(O)N(R 6j1 )(R 6j2 ), -N(R 6j1 )C(O)OR 6j2 , -C(=NR 6j3 )N(R 6j1 )(R 6j2 ), -N(R 6j1 )(R 6j2 ), =O, -OR 6j1 , -SR 6j1 , -S(O)R 6j1 , -S(NR 6j1 )(NR 6j2 ), -S(NR 6j1 )(NR 6j2 )R 6j3 , -S(O)(NR 6j1 )(R 6j2 ), -S(O) 2 R 6j1 , -S(O) 2 N(R 6j1 )(R 6j2 ), -N(R 6j1 )S(O) 2 (R 6j2 ), -Si(R 6j1 )(R 6j2 )(R 6j3 ), C 3~10 cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be optionally substituted with 1 to 3 identical or different R 6p ; each R 6j1 , R 6j2 , and R 6j3 is independently hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 1~6 cycloalkyl optionally substituted with haloalkyl, C 3~10 cycloalkyl, C 1~6 alkyl-C 3~10 cycloalkyl, C 6~10 aryl, C 1~6Alkyl-C 6~10 Aryl, heterocycloalkyl, C 1~6 Alkyl-(heterocycloalkyl), heteroaryl, or C 1~6 Alkyl-(heteroaryl), and each R 6p is, 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) 2 R 6p1 , -S(O) 2 N(R 6p1 )(R 6p2 ), or -N(R 6p1 )S(O) 2 (R 6p2 ), and each R 6p1 , R 6p2 , and R 6p3 is, 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), and or, R 5 and one R 6a are, together with the atoms to which they are attached, the same or different 1-3 R 6g optionally substituted with to form a heterocycloalkyl, each R 6g is, 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, and R 7 is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, C 1~6 alkyl-C 3~10 cycloalkyl, heterocycloalkyl, or C 1~6 alkyl-(heterocycloalkyl), and each heterocycloalkyl is a 3-20 membered ring having 1-4 heteroatoms each independently N, O, or S, The compound is one in which each heteroaryl is a 5- to 18-membered ring having 1 to 4 heteroatoms each independently being N, O, or S.

[0070] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound in which R 1 is hydrogen, C 1~6 alkyl, or halogen, R 2 is hydrogen, C 1~6 alkyl, or halogen, R 3 is hydrogen, C 1~6 alkyl, or halogen, R 4 is hydrogen, C 1~6 alkyl, or halogen, R 7 is C 1~6 alkyl optionally substituted with hydrogen or -OH, R 5 is C 1~6 alkyl or C 1~6 haloalkyl, R 6 is phenyl substituted with 1 to 3 R 6a which may be the same or different, or heteroaryl optionally substituted with 1 to 3 R 6a which may be the same or different, wherein the heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently being N, O, or S, or

[0071]

Chemical formula

[0072]

Chemical formula

[0073] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein 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), wherein heterocycloalkyl is a 5- to 8-membered ring having 1 to 2 heteroatoms each independently N, O, or S, and heteroaryl is a 5- to 6-membered ring having 1 to 2 heteroatoms each independently N, O, or S, and R 6 is phenyl substituted with 1 to 3 R 6a which may be the same or different, or heteroaryl optionally substituted with 1 to 3 R 6a which may be the same or different, and heteroaryl is a 5- to 6-membered ring having 1 to 2 heteroatoms each independently N, O, or S.

[0074] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 5 is C 1~6 alkyl. In some embodiments, R 5 is methyl, ethyl, or propyl. In some embodiments, R 5 is C 1~6 haloalkyl. In some embodiments, R 5 is -CH 2 CHF 2 ,-CH 2 CF 3、or -CF 3 is. In some embodiments, R 5 is -CH 2 CHF 2 .

[0075] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 6 is phenyl substituted with one or two R 6a which may be the same or different, or heteroaryl optionally substituted with one or two R 6a , the heteroaryl being a 5- to 6-membered ring having 1 to 2 heteroatoms each independently being N, O, or S, and R 6 is phenyl substituted with one R 6a . In some embodiments, R 6 is phenyl substituted with two R 6a .

[0076] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 6 is heteroaryl optionally substituted with one or two R 6a . In some embodiments, R 6 is heteroaryl substituted with one R 6a . In some embodiments, R 6 is heteroaryl substituted with two R 6a . In some embodiments, R 6 is thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with one or two R 6a . In some embodiments, R 6 is thienyl, thiazolyl, pyridyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with one or two R 6a . In some embodiments, R6 is pyridyl optionally substituted with one or two R 6a s. In some embodiments, R 6 is C 2~8 alkynyl-substituted pyridyl, and the alkynyl is optionally substituted with one or two R 6j s that may be the same or different. In some embodiments, R 6 is pyrazinyl optionally substituted with one or two R 6a s. In some embodiments, R 6 is C 2~8 alkynyl-substituted pyrazinyl, and the alkynyl is substituted with one or two R 6j s. In some embodiments, R 6 is

[0077]

Chemical formula

[0078]

Chemical formula

[0079] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound in which R 6 is phenyl substituted with C 2~8 alkynyl, and the alkynyl is optionally substituted with one or two R 6j s that may be the same or different, and the phenyl is optionally substituted with one additional R 6a s. In some embodiments, R 6 is phenyl substituted with C 2~8 alkynyl, and the alkynyl is substituted with one R 6j s. In some embodiments, R 6 is phenyl substituted with C 2~8 alkynyl, and the alkynyl is substituted with two R6j is replaced. In some embodiments, R 6 is phenyl substituted with F and C 2~8 alkynyl, where the alkynyl may be the same or different and is substituted with 1 or 2 R 6j In some embodiments, R 6 is phenyl substituted with 1 or 2 substituents selected from the group consisting of F, phenyl, pyridyl, or pyrazinyl, where the phenyl, pyridyl, or pyrazinyl may be the same or different and each is optionally substituted with 1 or 2 R 6e In some embodiments, R 6 is phenyl substituted with F and one additional substituent selected from the group consisting of phenyl, pyridyl, or pyrazinyl, where the phenyl, pyridyl, or pyrazinyl is optionally substituted with 1 or 2 R 6e In some embodiments, each of the phenyl, pyridyl, or pyrazinyl is substituted with 1 or 2 R 6e In some embodiments, R 6 is

[0080]

Chemical formula

[0081]

Chemical formula

[0082]

Chemical formula

[0083] In some embodiments, R R 6 is

[0084]

Chem.

[0085] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 6 is

[0086]

Chem.

[0087] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 6 is

[0088]

Chem.

[0089] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 6 is

[0090]

Chem.

[0091] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 6 is R 5 and one R 6a together with the atom to which they are attached forms a heterocycloalkyl optionally substituted with 1 to 3 R 6g which may be the same or different, is a compound.

[0092] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein

[0093]

Chem.

[0094]

Chem.

[0095]

Chem.

[0096]

Chem.

[0097]

Chem.

[0098]

Chem.

[0099]

Chem.

[0100]

Chem.

[0101] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-1), wherein

[0102]

Chem.

[0103] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-2),

[0104]

Chemical formula

[0105] In some embodiments, ring A is a 6-membered heterocycloalkyl optionally having one additional heteroatom N, O, or S. In some embodiments, ring A is a 6-membered heterocycloalkyl having no additional heteroatoms. In some embodiments, ring A is a 6-membered heterocycloalkyl having one additional heteroatom O. In some embodiments, ring A is a 6-membered heterocycloalkyl having one additional heteroatom N. In some embodiments, ring A is a 7-membered heterocycloalkyl optionally having one additional heteroatom N, O, and S. In some embodiments, ring A is a 7-membered heterocycloalkyl having one additional heteroatom O. In some embodiments, ring A is a 7-membered heterocycloalkyl having one additional heteroatom N. In some embodiments, ring A is a 7-membered heterocycloalkyl having no additional heteroatoms. In some embodiments, ring A is an 8-membered heterocycloalkyl optionally having one additional heteroatom N, O, or S. In some embodiments, ring A is an 8-membered heterocycloalkyl having one additional heteroatom O. In some embodiments, ring A is an 8-membered heterocycloalkyl having one additional heteroatom N. In some embodiments, ring A is an 8-membered heterocycloalkyl having no additional heteroatoms.

[0106] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound

[0107]

Chemical formula

[0108]

Chemical formula

[0109]

Chemical formula

[0110]

Chem.

[0111]

Chem.

[0112]

Chem.

[0113]

Chem.

[0114]

Chem.

[0115]

Chem.

[0116]

Chem.

[0117] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-3), wherein

[0118]

Chem.

[0119] In some embodiments, the compound of formula (Ia-3), (Ia-6), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein X 6 is C-R 6a , and X 3 , X 4 , and X 5 are CH. In some embodiments, X 6 is C-R 6a , and X 3 is N, and X 4 and X 5 are CH. In some embodiments, X 6 is C-R 6a , and X 4 is N, and X 3 and X 5 are CH. In some embodiments, X 6 is C-R 6a , and X 5 is N, and X 3 and X 4 are CH.

[0120] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-4), wherein

[0121] [Chemical formula] In the formula, n is 0, 1, or 2, and it is a compound. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0122] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-5).

[0123]

Chemical Structure

[0124] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-6),

[0125]

Chemical Structure

[0126] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-7),

[0127]

Chemical Structure

[0128] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-8).

[0129]

Chemical formula

[0130] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-9).

[0131]

Chemical formula

[0132] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-10).

[0133]

Chemical formula

[0134] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-11),

[0135]

Chemical formula

[0136] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-12), wherein

[0137]

Chemical formula

[0138] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein Each R 6a is independently C 1~6 alkyl, C 2~8 alkynyl, C 1~6 hydroxyalkyl, C 1~6 alkoxy, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, —CN, —NO 2 , —C(O)R6b ,-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 may be the same or different and each is optionally substituted with 1 to 3 R 6e and the alkynyl is optionally substituted with 1 to 3 R 6j which may be the same or different, each R 6b and R 6c is independently hydrogen,C 1~6 alkyl,C 1~6 haloalkyl,or C 3~10 cycloalkyl, each R 6j is 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 6j1 )(C(O)R 6j2 ),-OC(O)N(R 6j1 )(R 6j2 ),-N(R 6j1 )(C(O)OR 6j2 ),-C(=NR 6j3 )(N(R 6j1 )(R 6j2 ),-N(R 6j1 )(R 6j2 ),=O,-OR 6j1 ),-SR 6j1 ),-S(O)R 6j1 ),-S(NR 6j1 )(NR 6j2 ),-S(NR 6j1 )(NR 6j2 )(R 6j3, -S(O)(NR 6j1 )(R 6j2 ), -S(O) 2 R 6j1 ), -S(O) 2 N(R 6j1 )(R 6j2 ), -N(R 6j1 )S(O) 2 (R 6j2 ), -Si(R 6j1 )(R 6j2 )(R 6j3 ), C 3~10 cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may be the same or different and are optionally substituted with 1 to 3 R 6p ; each R 6j1 , R 6j2 , and R 6j3 are independently hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 cycloalkyl optionally substituted with C 3~10 haloalkyl; 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, -OH, or heterocycloalkyl; each R 6p1 and R 6p2 are independently hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, or C 3~10 cycloalkyl; Each R 6e 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) 2 N(R 6e1 )(R 6e2 ), -N(R 6e1 )(S(O) 2 (R 6e2 ), heterocycloalkyl, C 1~6 alkyl - heterocycloalkyl, heteroaryl, or C 1~6 alkyl - heteroaryl, wherein cycloalkyl, aryl, heterocycloalkyl, or heteroaryl may each be optionally substituted with 1 to 3 identical or different R 6h groups, and alkyl may be optionally substituted with 1 to 3 identical or different R 6m groups, each R 6e1 and R 6e2 are, independently, hydrogen or C 1~6 alkyl, each R 6m is, independently, halogen, -CN, or -OH, each R 6h is, independently, halogen, C 1~6 alkyl, =O, or C 1~6 haloalkyl, a compound.

[0139] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein, each R 6a is independently C 2~8 alkynyl, halogen, C 1~6 haloalkyl, C 3~10 cycloalkyl, C 6~12 aryl, heterocycloalkyl, or heteroaryl, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R 6e each of which is the same or different, and the alkynyl is optionally substituted with 1 to 3 R 6j each of which is the same or different, each R 6j is independently halogen, -OR 6j1 , -CN, -N(R 6j1 )(R 6j2 ), -N(R 6j1 )C(O)R 6j2 , C 3~10 cycloalkyl, heteroaryl, heterocycloalkyl, and the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1 to 3 R 6p each of which is the same or different, each R 6j1 and R 6j2 are independently hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, or C 1~3 cycloalkyl optionally substituted with haloalkyl, 3~6 wherein, each R 6p is independently C 1~6 alkyl, halogen, C 1~6 haloalkyl, =O, -CN, -OH, C(O)R 6p1 , or heterocycloalkyl, R 6p1 is C1~6 alkyl, or C 3~6 is cycloalkyl, each R 6e is independently C 1~6 alkyl, halogen, C 1~6 haloalkyl, C 3~6 cycloalkyl, or heterocycloalkyl, and the cycloalkyl or heterocycloalkyl may be the same or different and is optionally substituted with 1 to 3 R 6h ; each R 6h is independently halogen, C 1~6 alkyl, =O, or C 1~6 haloalkyl, and is a compound.

[0140] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently C 2~8 alkynyl, halogen, C 6~12 aryl, a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms each independently N or O, or a 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms each independently N, O, or S, and the aryl, heterocycloalkyl, or heteroaryl may be the same or different and is optionally substituted with 1 to 3 R 6e ; alkynyl is optionally substituted with 1 to 3 R 6j ; each R 6j is independently halogen, -OR 6j1 -, -CN, C 3~10 cycloalkyl, heterocycloalkyl, and the cycloalkyl or heterocycloalkyl may be the same or different and is optionally substituted with 1 to 3 R 6p ; R6j1 is hydrogen or C 1~6 alkyl, each R 6p is independently C 1~6 alkyl, halogen, =O, -OH, or C 1~6 haloalkyl, each R 6e is independently C 1~6 alkyl, halogen, C 1~6 haloalkyl, cyclopropyl, a heterocycloalkyl ring having 1 to 2 heteroatoms each independently N, O, or S, and the cyclopropyl or heterocycloalkyl may be the same or different and is optionally substituted with 1 to 3 R 6h groups, each R 6h is independently halogen, C 1~6 alkyl, =O, or C 1~6 haloalkyl, a compound.

[0141] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently C 2~8 alkynyl or halogen, and the alkynyl is optionally substituted with 1 to 3 R 6j groups. In some embodiments, each R 6a is independently C 2~6 alkynyl or F, and the alkynyl is optionally substituted with 1 to 3 R 6j groups.

[0142] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently 1 to 3 Rs which may be the same or different 6j substituted C 2~8 alkynyl. In some embodiments, each R 6a is independently C 6j alkynyl substituted with 1 to 3 Rs 2~6 . In some embodiments, each R 6a is independently C 6j alkynyl substituted with 1 R 2~6 . In some embodiments, each R 6a is independently C 6j alkynyl substituted with 2 Rs 2~6 . In some embodiments, each R 6a is independently C 6j alkynyl substituted with 3 Rs 2~6 .

[0143] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is

[0144]

Chemical formula

[0145] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6j is, independently, halogen, C 1~6 haloalkyl, -OR 6j1 , -CN, -N(R 6j1 )(R 6j2 ), -N(R 6j1 )C(O)R 6j2 , C 3~6 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1 to 3 identical or different R 6p , and each R 6j1 and R 6j2is, independently, hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 cycloalkyl optionally substituted with haloalkyl, and each R 3~10 is, independently, halogen, C 6p alkyl, C 1~6 haloalkyl, -C(O)R 1~6 , or heterocycloalkyl, where heterocycloalkyl is a 3- to 10-membered ring having 1 to 2 heteroatoms each independently being N, O, or S, and R 6p1 is C 6p1 alkyl, or C 1~6 cycloalkyl, and is a compound. In some embodiments, cycloalkyl, heteroaryl, or heterocycloalkyl is substituted with one R 3~6 . In some embodiments, cycloalkyl, heteroaryl, or heterocycloalkyl is substituted with two R 6p s. In some embodiments, cycloalkyl, heteroaryl, or heterocycloalkyl is substituted with three R 6p s. 6p In some embodiments, a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R

[0146] is, independently, Me, -CF 6p , -CH 3 F, -CF 2 CH 2 , or -CHF 3, , and is a compound. In some embodiments, R 2 is -CF 6p . In some embodiments, R 3 is Me. 6p

[0147] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6j is independently halogen, C 1~6 haloalkyl, -OH, -OMe, or -CN.

[0148] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6j is independently -OH, -CN, -F, -OMe, -CHF 2 , or -CF 3 . In some embodiments, R 6j is C 1~3 haloalkyl. In some embodiments, R 6j is -OH or -OMe. In some embodiments, R 6j is -N(R 6j1 )C(O)R 6j2 , wherein R 6j1 is hydrogen or C 1~6 alkyl, and R 6j2 is C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 cycloalkyl optionally substituted with C 3~10 haloalkyl. In some embodiments, R 6j is -NHC(O)R 6j2 , and R 6j2 is cyclopropyl substituted with C 1~3 haloalkyl.

[0149] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6j is independently C 3~6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, and the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1 to 3 identical or different R 6p wherein each R 6p is independently C 1~3 alkyl, C 1~3 haloalkyl, -C(O)R 6p1 or heterocycloalkyl, the heterocycloalkyl being a 3- to 6-membered ring having 1 to 2 heteroatoms each independently being N, O, or S, and R 6p1 is C 1~3 alkyl, or C 3~6 cycloalkyl, a compound.

[0150] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6j is independently cyclopropyl,

[0151]

Chemical formula

[0152] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently phenyl or a 5- or 6-membered heteroaryl ring having 1 to 2 heteroatoms each independently being N, O, or S, and the phenyl or heteroaryl is optionally substituted with 1 to 3 R 6e . In some embodiments, R 6a is phenyl optionally substituted with 1 to 3 R 6e . In some embodiments, R 6a is a 5- or 6-membered heteroaryl ring having 1 to 2 heteroatoms each independently being N, O, or S, and the heteroaryl is optionally substituted with 1 to 3 R 6e . In some embodiments, R 6a is an optionally substituted 5- or 6-membered heteroaryl ring having 1 to 2 heteroatoms each independently being N or O. In some embodiments, R 6a is a 5- or 6-membered heteroaryl ring having 1 or 2 N's optionally substituted with 1 or 2 R 6e . In some embodiments, R 6a is a 6-membered heteroaryl ring having 1 or 2 N's substituted with 1 R 6e .

[0153] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6e is independently C 1~6 haloalkyl, cyclopropyl, or =O or C 1~6A compound that is a 4- to 6-membered heterocycloalkyl optionally substituted with alkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered ring having 1 to 3 heteroatoms each independently being N, O, or S. In some embodiments, each R 6e is independently C 1~3 haloalkyl, cyclopropyl, or =O or C 1~3 a 5- to 6-membered heterocycloalkyl optionally substituted with alkyl. In some embodiments, each R 6e is independently -CHF 2 , cyclopropyl,

[0154]

Chemical formula

[0155] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently F, Br,

[0156]

Chemical formula

[0157] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein at least one R 6a is

[0158]

Chemical formula

[0159] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently F, Br,

[0160]

Chemical formula

[0161] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein at least one R 6a is

[0162]

Chemical formula

[0163] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6a is independently F, Br,

[0164]

Chem.

[0165] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein at least one R 6a is

[0166]

Chem.

[0167] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein

[0168]

Chem.

[0169]

Chem.

[0170] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein

[0171]

Chem.

[0172] [Chemical formula] is a compound.

[0173] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein

[0174] [Chemical formula] is

[0175] [Chemical formula] is a compound.

[0176] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein

[0177] [Chemical formula] is a compound.

[0178] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein

[0179] [Chemical formula] is

[0180] [Chemical formula] is a compound. In some embodiments,

[0181] [Chemical formula] is

[0182] [Chemical formula] It is. In some embodiments,

[0183]

Chemical formula

[0184]

Chemical formula

[0185] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein R 1 is hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, or -CN. In some embodiments, R 1 is hydrogen, C 1~3 alkyl, C 1~3 alkoxy, or halogen. In some embodiments, R 1 is hydrogen, F, or Cl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl.

[0186] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein R 2 is hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6It is a compound that is haloalkyl or -CN. In some embodiments, R 2 is hydrogen, C 1~3 alkyl, halogen, C 1~3 haloalkyl, or -CN. In some embodiments, R 2 is hydrogen, F, or Cl. In some embodiments, R 2 is Cl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is F.

[0187] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein R 3 is hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, or -CN. 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.

[0188] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein R 4 is hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, or -CN. In some embodiments, R 4 is hydrogen, C 1~3Alkyl, halogen, C 1~3 haloalkyl, or -CN. In some embodiments, R 4 is hydrogen, C 1~3 alkyl, or halogen. In some embodiments, R 4 is F. In some embodiments, R 4 is hydrogen.

[0189] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound wherein R 7 is hydrogen or C 1~6 alkyl. In some embodiments, R 7 is hydrogen, Me, or Et. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is Me (-CH 3 ). In some embodiments, R 7 is Et (-CH 2 CH 3 ).

[0190] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is a compound having the structure of the compound of Table 1.

[0191] Those skilled in the art will appreciate that when a group is substituted with two or more substituents, the two or more substituents may be the same or different unless otherwise specified.

[0192] Those skilled in the art will appreciate that each and every embodiment of the groups disclosed herein (e.g., R 1 ) and all the remaining groups (e.g., R 2, R 3 , R 4 , R 5 , R 6 , R 7 It is understood that each of the above (e.g., , R 3 , R 4 , R 5 , R 6 , R 7 etc.) can be combined with any other embodiments of the present disclosure to produce the compounds of formula (I) or any formula described herein, or pharmaceutically acceptable salts thereof, each of which is considered to be within the scope of the present disclosure.

[0193] [Table 1-1]

[0194] [Table 1-2]

[0195] [Table 1-3]

[0196] [Table 1-4]

[0197] [Table 1-5]

[0198] [Table 1-6]

[0199] [Table 1-7]

[0200] [Table 1-8]

[0201]

Table 1-9

[0202]

Table 1-10

[0203]

Table 1-11

[0204]

Table 1-12

[0205]

Table 1-13

[0206]

Table 1-14

[0207]

Table 1-15

[0208]

Table 1-16

[0209]

Table 1-17

[0210]

Table 1-18

[0211]

Table 1-19

[0212]

Table 1-20

[0213]

Table 1-21

[0214]

Table 1-22

[0215]

Table 1-23

[0216]

Table 1-24

[0217]

Table 1-25

[0218]

Table 1-26

[0219]

Table 1-27

[0220]

Table 1-28

[0221]

Table 1-29

[0222]

Table 1-30

[0223]

Table 1-31

[0224]

Table 1-32

[0225]

Table 1-33

[0226]

Table 1-34

[0227]

Table 1-35

[0228]

Table 1-36

[0229]

Table 1-37

[0230]

Table 1-38

[0231]

Table 1-39

[0232]

Table 1-40

[0233]

Table 1-41

[0234]

Table 1-42

[0235]

Table 1-43

[0236]

Table 1-44

[0237]

Table 1-45

[0238]

Table 1-46

[0239]

Table 1-47

[0240]

Table 1-48

[0241]

Table 1-49

[0242]

Table 1-50

[0243]

Table 1-51

[0244]

Table 1-52

[0245]

Table 1-53

[0246]

Table 1-54

[0247]

Table 1-55

[0248]

Table 1-56

[0249]

Table 1-57

[0250]

Table 1-58

[0251]

Table 1-59

[0252]

Table 1-60

[0253]

Table 1-61

[0254]

Table 1-62

[0255]

Table 1-63

[0256]

Table 1-64

[0257]

Table 1-65

[0258]

Table 1-66

[0259]

Table 1-67

[0260]

Table 1-68

[0261]

Table 1-69

[0262]

Table 1-70

[0263]

Table 1-71

[0264]

Table 1-72

[0265]

Table 1-73

[0266]

Table 1-74

[0267]

Table 1-75

[0268]

Table 1-76

[0269]

Table 1-77

[0270]

Table 1-78

[0271]

Table 1-79

[0272]

Table 1-80

[0273]

Table 1-81

[0274] In vivo metabolites of the compounds described in this specification are also within the scope of this specification, provided that such products are novel and non-obvious compared to the prior art. Such products can be produced, for example, mainly by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound by an enzymatic process. Thus, it includes novel and non-obvious compounds produced by a process that includes contacting the compound with a mammal for a time sufficient to obtain metabolites. Such products are typically prepared from a radiolabeled (e.g., 14 C or 3 H) compound, which is administered parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), ensuring a time sufficient for metabolism to occur (typically about 30 seconds to about 30 hours), and isolating the conversion product from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to epitopes remaining in the metabolite). The structure of the metabolite is determined by conventional methods, such as MS or NMR analysis. Generally, the analysis of metabolites is carried out in the same manner as conventional drug metabolism studies known to those skilled in the art.

[0275] In some embodiments, the compounds of the present disclosure have selectivity for DGKα over one or more of the other DGK isoforms, such as β, γ, δ, ε, ζ, η, θ, ι, and / or κ. The selectivity can be measured by relative values in the corresponding biochemical assay, such as the inhibitory activity of the DGK isoforms. In some embodiments, the compound has activity against DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKι, and / or DGKκ, and the IC 50 is greater than about 30 μM in a biochemical assay.

[0276] In some embodiments, the compounds of the present disclosure have a selectivity for DGKα 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-fold or more greater than 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 a selectivity for DGKα 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-fold or more greater than DGKβ and / or DGKγ. In some embodiments, the compound has a selectivity for DGKα 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-fold or more greater than DGKβ. In some embodiments, the compound has a selectivity for DGKα 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-fold or more greater than DGKγ.In some embodiments, the compound has a selectivity for DGKα 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-fold greater than for DGKδ. In some embodiments, the compound has a selectivity for DGKα 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-fold greater than for DGKε. In some embodiments, the compound has a selectivity for DGKα 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-fold greater than for DGKζ. In some embodiments, the compound has a selectivity for DGKα 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-fold greater than for DGKη. In some embodiments, the compound has a selectivity for DGKα 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-fold greater than for DGKθ.In some embodiments, the compound has selectivity for DGKα 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-fold greater than for DGKι. In some embodiments, the compound has selectivity for DGKα 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-fold greater than for DGKκ.

[0277] III. Pharmaceutical Formulations In some embodiments, the disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the 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), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and a pharmaceutically acceptable carrier or excipient.

[0278] 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 in combination with a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, such as the agents and therapies described herein.

[0279] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) and an additional therapeutic agent, and 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 anti-neoplastic agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, or resection 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.

[0280] In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent comprises one or more populations of immune cells such as natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocyte (TIL), and dendritic cell (DC).

[0281] In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent comprises one or more chimeric antigen receptors (CAR).

[0282] In some embodiments, the pharmaceutical composition is a pharmaceutical composition wherein the additional therapeutic agent comprises immunotherapy, immunostimulation therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, or a combination thereof.

[0283] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) and an additional therapeutic agent, wherein the additional therapeutic agent is a drug 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, the pharmaceutical composition comprises a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) and an additional therapeutic agent, wherein the additional therapeutic agent comprises a vaccine.

[0284] In some embodiments, the pharmaceutical composition is for use in the treatment of cancer.

[0285] In some embodiments, the pharmaceutical composition is for use in the treatment of HIV or hepatitis B infection.

[0286] In some embodiments, the compounds disclosed herein are formulated with conventional carriers and excipients that can be selected according to ordinary practice. Tablets may contain excipients, glidants, fillers, binders, etc. Aqueous formulations can be prepared in a sterile form and can be isotonic, for example, if delivery other than oral administration is intended. In some embodiments, the formulation may optionally contain excipients such as those described in "Handbook of Pharmaceutical Excipients" (1986). Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH of the formulation ranges from about 3 to about 11, for example, from about 7 to about 10.

[0287] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in a pharmaceutical formulation. In some embodiments, the formulations for animals and / or humans comprise at least one compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt, solvate, and / or ester thereof, together with one or more acceptable carriers and optionally other therapeutic ingredients such as additional therapeutic ingredients discussed herein. In some embodiments, a carrier is "acceptable" in that it is compatible with the other ingredients of the formulation and physiologically innocuous to its recipient.

[0288] In some embodiments, the formulations of the disclosure include those suitable for the aforementioned routes of administration. In some embodiments, the formulations are provided in unit dosage form. The formulations can be prepared by methods known in the art of pharmacy. Techniques and formulations can be found, for example, in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include, for example, the step of associating an active ingredient with a carrier that includes one or more accessory ingredients. In some embodiments, the formulations are prepared by associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, in some embodiments, shaping the product.

[0289] Formulations suitable for oral administration can be presented as individual units, such as capsules, cachets, or tablets, each containing a predetermined amount of an active ingredient, such as a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), 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, lozenge, or paste.

[0290] Tablets can be produced, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared, for example, by compressing, in a suitable machine, a free-flowing form of the active ingredient, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets can be produced, for example, by molding, in a suitable machine, a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can be optionally coated or scored. In some embodiments, the tablets are formulated to provide for slow or controlled release of the active ingredient therefrom.

[0291] For the treatment of infections of the eye or other external tissues, such as the mouth and skin, the formulation may contain a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) in an amount, for example, of about 0.075 to about 20% w / w (including active ingredients in units of about 0.1% w / w in the range of about 0.1% to about 20%, such as about 0.6% w / w, about 0.7% w / w, etc.), for example, about 0.2 to about 15% w / w, and for example, about 0.5 to about 10% w / w, and can be applied as a topical ointment or cream. When formulated as an ointment, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) can be used with either a paraffinic or water-miscible ointment base. Alternatively, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) can be formulated into a cream using an oil-in-water cream base.

[0292] 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 PEG400), and mixtures thereof. In some embodiments, the topical formulation may contain a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0293] The oily phase of the emulsion can be composed of known components in a known manner. The phase can contain only an emulsifier (also known as an emulgent), but can also contain, for example, a mixture of at least one emulsifier and a fat or an oil, or a mixture of both a fat and an oil. In some embodiments, the 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, and the wax, together with the oil and the fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0294] Examples of emulsifiers (emulgent) and emulsion stabilizers suitable for use in the formulation include, for example, Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0295] The selection of an oil or a fat suitable for the formulation is based on achieving the desired properties. The cream can be a non-oily, non-staining, and washable product having a suitable consistency to avoid leakage from a tube or other container. Straight-chain or branched-chain, mono- or dibasic alkyl esters, for example, 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-chain 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.

[0296] In some embodiments, the pharmaceutical formulations herein include one or more pharmaceutically acceptable carriers or excipients, and optionally in combination with other therapeutic agents. The pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs can be prepared. Compositions for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preservatives to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin, or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. For example, time-delay substances such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0297] Formulations for oral use can 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 an oil medium such as water or peanut oil, liquid paraffin or olive oil.

[0298] The aqueous suspension contains the active substance in a mixture with excipients suitable for the manufacture of the aqueous suspension. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, and dispersing agents or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol), condensation products of ethylene oxide and partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0299] The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents as described above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

[0300] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in a mixture with a dispersing agent or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing agents or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients such as sweetening agents, flavoring agents, and colorants may also be present.

[0301] 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 acacia gum and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavoring agents, or coloring agents.

[0302] The pharmaceutical composition may be in the form of a sterile injectable or intravenous preparation such as a sterile injectable aqueous or oily suspension. Such suspensions may be formulated according to known techniques using the suitable dispersing or wetting agents and suspending agents described above. Sterile injectable preparations or intravenous administration preparations include, for example, sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils have conventionally been used as solvents or suspending media. For this purpose, any solvent-free fixed oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used in the preparation of injections.

[0303] The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form can vary depending on the host being treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans can contain from about 1 to about 1000 mg of active substance combined with a suitable and convenient amount of carrier substance that can vary from about 5 to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to about 500 μg of active ingredient per milliliter of solution so that a suitable volume of infusion can occur at a rate of about 30 mL / hour.

[0304] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous vehicle for the active ingredient. The active ingredient can be present in such formulations at a concentration of from about 0.5 to about 20%, for example from about 0.5 to about 10%, for example about 1.5% w / w.

[0305] Formulations suitable for topical administration to the mouth include, for example, lozenges containing the active ingredient in a flavored base such as sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0306] Formulations for rectal administration can be provided, for example, as suppositories containing a suitable base such as cocoa butter or a salicylate.

[0307] Formulations suitable for administration by inhalation to the lungs or nasally are, for example, in the range of from about 0.1 to about 500 micrometers, for example having a particle size such as about 0.5, about 1, about 30, or about 35, and are administered by rapid inhalation through the nose or by inhalation through the mouth such that the alveolar sacs are reached. 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 together with other therapeutic agents such as compounds previously used for the treatment of cancer as described below.

[0308] In some embodiments, the inhalable composition comprises a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), 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 comprising hydrochloride, hydrobromide, sulfate, or phosphate. For example, such salts may be less likely to cause lung inflammation compared to other salts. In some embodiments, the inhalable composition is delivered into the intratracheal space as an aerosol comprising particles having an aerodynamic mass median diameter (MMAD) of about 1 to about 5 μm. In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) is formulated for aerosol delivery using a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0309] Non-limiting examples of nebulizers include atomizers, jet nebulizers, ultrasonic nebulizers, pressurized nebulizers, vibrating porous plate nebulizers, or equivalent nebulizers that utilize adaptable aerosol delivery technologies (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10). Jet nebulizers utilize air pressure to break up a liquid solution into aerosol droplets. Ultrasonic nebulizers function by means of a piezoelectric crystal that shears the liquid into small aerosol droplets. Pressurized spray systems generate aerosol droplets by applying pressure to force the solution through small pores. Vibrating porous plate devices utilize rapid vibration to shear the liquid stream into appropriate droplet sizes.

[0310] In some embodiments, the aerosol formulation is delivered into the bronchial space as an aerosol containing particles having a MMAD of from 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), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) into particles of the required MMAD. To optimize therapeutic efficacy and to avoid upper airway and systemic side effects, most of the aerosolized particles should not have a MMAD greater than about 5 μm. If the aerosol contains a large number of particles having a MMAD greater than about 5 μm, the particles will be deposited in the upper airway, reducing the amount of drug delivered to the sites of inflammation and bronchoconstriction in the lower airway. If the MMAD of the aerosol is less than about 1 μm, the particles may remain suspended in the inhaled air and may then be exhaled.

[0311] When formulated and delivered according to the methods of this specification, aerosol formulations for spraying deliver a therapeutically effective dose of a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) to a therapeutic target such as the 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), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12). In some embodiments, the combination of an aqueous aerosol formulation and a spray, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer enables delivery into the airways of from about 20% to about 90%, such as 70%, of the administered dose of a compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), depending on the nebulizer. In some embodiments, from about 30% to about 50% of the active compound is delivered. For example, from about 70% to about 90% of the active compound can be delivered.

[0312] In some embodiments, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The compound is administered intratracheally as a dry powder formulation using a dry powder inhaler or a metered-dose inhaler to effectively deliver the microparticles of the compound into the intratracheal space. For delivery by DPI, the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) is processed mainly into particles having an MMAD of about 1 μm to about 5 μm by milling, spray drying, supercritical fluid processing, or precipitation from solution. Media milling, jet milling, and spray drying devices and procedures capable of providing a particle size with an MMAD of about 1 μm to about 5 μm are well known in the art. In some embodiments, the excipient is added to the compound of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) before being processed into particles of the required size. In some embodiments, the excipient is blended with particles of the desired size, for example, by using lactose as an excipient to aid in the dispersion of the drug particles.

[0313] Determination of particle size is performed using devices well known in the art. For example, as a characteristic device for metered doses and aerosols in a dry powder inhaler, a multi-stage Andersen cascade impactor or other suitable method, such as those specifically cited in US Pharmacopoeia Chapter 601.

[0314] In some embodiments, the compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) can be delivered as dry powder using a device such as a dry powder inhaler or other dry powder dispersion device. Non-limiting examples of dry powder inhalers and devices include those disclosed in U.S. Patent No. 5,458,135, U.S. Patent No. 5,740,794, U.S. Patent No. 5,775,320, 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 main designs for dry powder inhalers. One design is a metering device in which a reservoir for the drug is located within the device and the patient adds a dose of the drug to the inhalation chamber. The second design is a device in which each individual dose is pre-metered at the factory and manufactured in a separate container. Both systems rely on the formulation of the drug into small particles with a MMAD of about 1 μm to about 5 μm and often require co-formulation with larger excipient particles such as lactose, although not limited to this. The drug powder is placed in the inhalation chamber (either by metering in the device or by breaking open a pre-metered dose from the factory) and the patient's inspiratory flow accelerates the powder exiting the device and entering the oral cavity. The non-laminar flow characteristics of the powder path break up the excipient-drug aggregates and large agglomerates of excipient particles adhere to the back of the throat while smaller drug particles deposit deep in the lungs. In some embodiments, the compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, are delivered as dry powder using any type of dry powder inhaler described herein, and the MMAD of the dry powder excluding all excipients is primarily in the range of about 1 μm to about 5 μm.

[0315] In some embodiments, the compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) are delivered as 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, the compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12), or a pharmaceutically acceptable salt thereof, are delivered as dry powder using a metered dose inhaler, and the MMAD of the dry powder excluding all excipients is mainly in the range of about 1 to about 5 μm.

[0316] 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, a carrier as known to be appropriate in the art.

[0317] Formulations suitable for parenteral administration may include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to 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.

[0318] The preparation is presented in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried state that requires only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Immediate injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Unit dose preparations include those containing the active ingredient in a daily dose or unit daily sub-dose as listed above herein, or appropriate proportions thereof.

[0319] In addition to the aforementioned components in particular, it should be understood that the preparation may include other agents that are standard in the art with respect to the type of preparation in question. For example, those suitable for oral administration may include flavoring agents.

[0320] There is further provided a veterinary composition comprising at least one active ingredient as defined above, together with a veterinary carrier therefor.

[0321] A veterinary carrier is a substance useful for the purpose of administering the composition and is otherwise inert or acceptable in veterinary technology and compatible with the active ingredient, and can be a solid, liquid, or gaseous substance. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0322] The compounds herein are used to provide a controlled release pharmaceutical formulation (a "controlled release formulation") containing one or more of such compounds as active ingredients, and the release of the active ingredient is controlled and regulated to allow for less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0323] The effective dosage of the active ingredient depends at least on the nature of the condition being treated, its toxicity, the method of delivery, and the pharmaceutical formulation, and can be determined by a clinician using conventional dose escalation testing. This can be expected to be in the range of 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 daily dose candidate for an adult human of about 70 kg body weight can be in the range of about 1 mg to about 1000 mg, for example, about 5 mg to about 500 mg, and can take the form of a single dose or multiple doses.

[0324] IV. Route of Administration One or more of the compounds of formula (I), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10), (Ia-11), or (Ia-12) (referred to herein as the active ingredient) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), intravaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the route may vary, for example, depending on the condition of the recipient. An advantage of the compounds of the present specification is that they are orally bioavailable and can be administered orally.

[0325] The compounds of the present disclosure (also referred to herein as the active ingredient) can be administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, intravaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the route may vary, for example, depending on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0326] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen over a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In some embodiments, the compound is administered daily or on an intermittent schedule over the lifespan of the individual.

[0327] The dosage or dosing frequency of the compounds of the present disclosure can be adjusted over the course of treatment based on the judgment of the administering physician.

[0328] 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.

[0329] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can be from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example, from about 0.3 mg per day to about 30 mg, or for example, from about 30 mg per day to about 300 mg.

[0330] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure (e.g., from about 1 mg to about 1000 mg of the compound). Therapeutically effective amounts can range from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or for example from about 100 mg per dose to about 400 mg per dose, or for example from about 150 mg per dose to about 350 mg per dose, or for example from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure can be 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 can be 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. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every about 1, about 2, about 3, about 4, about 6, about 8, about 12, about 16 hours, or once every about 24 hours. Also, a single dose can be administered once every about 1, about 2, about 3, about 4, about 5, about 6 days, or once every about 7 days. Also, a single dose can be administered once every about 1, about 2, about 3 weeks, or once every about 4 weeks. In some embodiments, a single dose can be administered approximately once a week. Also, a single dose can be administered approximately once a month.

[0331] Other therapeutically effective amounts of the compounds of the present disclosure can be 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.

[0332] The dosing frequency of the compounds of the present disclosure can be determined according to the needs of the individual patient and can be, for example, once a day, or twice a day, or more times a day. The 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 having cancer for a period of about 20 days to about 180 days, or for example, for a period of about 20 days to about 90 days, or for example, for a period of about 30 days to about 60 days.

[0333] Administration can be intermittent, involving a period of several days or more during which the patient receives a daily dose of the compound of the present disclosure, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, a patient can receive a dose of the compound every other day or three times a week. As a further example, a 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 is not administered a dose of the compound, followed by a subsequent period (e.g., about 1 to about 14 days) during which the patient is again administered a daily dose of the compound. The alternating periods of administration of the compound, followed by non - administration of the compound, can be repeated as clinically necessary to treat the patient.

[0334] In some embodiments, there is provided a pharmaceutical composition comprising the 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 - 3, or 1 - 4) additional therapeutic agents, and a pharmaceutically acceptable excipient.

[0335] In some embodiments, there is provided a kit comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, 1 - 3, or 1 - 4) additional therapeutic agents.

[0336] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents. In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are 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.

[0337] In some embodiments, when the compounds of the present disclosure are combined with one or more of the 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 more than one dose.

[0338] In some embodiments, the 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.

[0339] In some embodiments, the compounds of the present disclosure are co-administered with one or more additional therapeutic agents.

[0340] To extend the effect of the compounds of the present disclosure, it is often desirable to slow the absorption of the compounds by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. In that case, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, the delay in absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oily medium. Injectable depot forms are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactic acid - polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0341] V. Combination Therapy The compounds of the present disclosure and the compositions provided herein are also used in combination with other active therapeutic agents. The other active therapeutic agents can be, where appropriate, anti - cancer agents or anti - viral agents, for example, anti - HIV or anti - hepatitis B virus agents.

[0342] A. Combination Therapy 1. Cancer In various embodiments, the compounds described herein are combined with one or more additional therapeutic agents, such as inhibitory immune checkpoint blockers or inhibitors, stimulatory immune checkpoint agonists, activators, or enhancers, chemotherapeutic agents, anti-cancer agents, radiation therapy agents, anti-tumor agents, anti-proliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapeutic agents, therapeutic antigen-binding molecules (single- 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, adnectin, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins (ARMs), atrimers, avimers, designed ankyrin repeat proteins (DARPins®), finomers, knottins, knotted domain peptides, monobodies, and nanoclamps), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editors, cells comprising a chimeric antigen receptor (CAR) (e.g., T cell immunotherapeutic agents, NK cell immunotherapeutic agents, or macrophage immunotherapeutic agents, cells comprising a genetically engineered T cell receptor (TCR-T)), or any combination thereof.

[0343] 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), and these therapeutic agents include, but are not limited to, Abelson murine leukemia viral oncogene homolog 1 gene (ABL, e.g., ABL1), acetyl-CoA carboxylase (e.g., ACC1 / 2), activated CDC kinase (ACK, e.g., ACK1), adenosine deaminase, adenosine receptor (e.g., A2BR, A2aR, A3aR), adenylate cyclase, ADP ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aerolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, α1 adrenergic receptor, α2 adrenergic receptor, α-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, e.g., ALK1), androgen receptor, angiopoietin (e.g., ligand-1, ligand-2), angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (e.g., AKT1, AKT2, AKT3), apolipoprotein A-I (APOA1) gene, apoptosis-inducing factor, apoptosis protein (e.g., 1, 2), apoptosis signal-regulating kinase (ASK, e.g., ASK1), arginase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad3-related (ATR) serine / threonine protein kinase, aurora protein kinase (e.g., 1, 2), Axl tyrosine kinase receptor, 4-1BB ligand (CD137L), baculoviral 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, β adrenergic receptor, β-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesion molecule,B lymphocyte stimulator ligand, bone morphogenetic protein-10 ligand, bone morphogenetic protein-9 ligand modifier, brachyurin protein, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and extra-terminal domain (BET) bromodomain-containing proteins (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 (CTAG1) gene, cannabinoid receptor (e.g., CB1, CB2), carbonic anhydrase, casein kinase (CK, e.g., CKI, CKII), caspase (e.g., caspase-3, caspase-7, caspase-9), caspase 8 apoptosis-related cysteine peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK-activating kinase (CAK), checkpoint kinase (e.g., CHK1, CHK2), chemokine (C-C motif) receptor (e.g., CCR2, CCR4, CCR5, CCR8), chemokine (C-X-C motif) receptor (e.g., CXCR1, CXCR2, CXCR3, and CXCR4), chemokine CC21 ligand, cholecystokinin CCK2 receptor, human chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), CISH (cytokine-inducible SH2-containing protein), claudin (e.g., 6, 18), cluster of differentiation (CD), e.g., 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 growth factor, COP9 signalosome subunit 5, CSF-1 (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), cyclin D1, cyclin G1, cyclin-dependent kinase (CDK, e.g., CDK1, CDK12, CDK1B, CDK2-9), cyclooxygenase (COX1, COX2, etc.), CYP2B1 gene, cysteine palmitoyltransferase porcupine, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling 1, cytokine signaling 3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T-lymphocyte protein-4, DDR2 gene, DEAD-box helicase (DEAD-box helicase 6, DDX6), death receptor 5 (DR5, TRAILR2), death receptor 4 (DR4, TRAILR1), delta-like protein ligand (3, 4, etc.), deoxyribonuclease, deubiquitinating enzyme (DUB), Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoidin domain receptor (DDR, e.g., DDR1, etc.), diacylglycerol kinase ζ (DGKZ), DNA-binding protein (HU-β, etc.), DNA-dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (α, etc.), DNA primase, dUTP pyrophosphatase,L-DOPA chromotropism tautomerase, E3 ubiquitin-protein ligase (such as RNF128, CBL-B, etc.), echinoderm microtubule-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulum aminopeptidase (ERAP, such as ERAP1, ERAP2, etc.), endoplasmin, endosialin, endostatin, endothelin (ET-A, ET-B, etc.), Enhancer of zeste homolog 2 (EZH2), Ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4, etc.), Ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epigen, Epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β dehydrogenase, estrogen receptor (α, β, etc.), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (1, 2, etc.), Extracellular signal-regulated kinase (ERK), Hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factor (such as Xa, VIIa, etc.), farnesoid x receptor (FXR), Fas ligand, Fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4, etc.), fibronectin,Focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (such as α), folic acid, folate transporter 1, FYN tyrosine kinase, basic amino acid cleavage enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, such as 3-β), glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte colony-stimulating factor (GCSF) ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein) calcium-binding protein, molecular chaperone groEL2 gene, heme oxygenase 1 (HO1), heme oxygenase 2 (HO2), heat shock protein (27, 70, 90α, β, etc.), heat shock protein gene, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-HLTR associated protein 2, hexokinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (HDAC, such as 1, 2, 3, 6, 10, 11, etc.), histone H1, histone H3, HLA class I antigen (A-2α),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 (such as E6, E7) protein, hyaluronic acid, hyaluronidase, Hypoxia inducible factor-1 alpha (HIF1α), imprinted maternally expressed transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine protein kinase HCK, I-Kappa-B kinase (IKK, such as IKKβ), IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (G, G1, G2, K, M, etc.), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (I, III, IIIA, etc.), indoleamine 2,3-dioxygenase (IDO, such as IDO1, IDO2, etc.), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor 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 (α, α2, β, γ, etc.), absent in melanoma 2 interferon-induced protein (AIM2), type I interferon receptor, interleukin 1 ligand, interleukin 13 receptor α2, interleukin 2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, interleukin 35 (IL-35), isocitrate dehydrogenase (IDH1, IDH2, etc.), Janus kinase (JAK, e.g., JAK1, JAK2, etc.), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-related protein-1, leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor, lyase, lymphocyte activation gene 3 protein (lymphocyte activation gene3. LAG-3), lymphocyte antigen 75, lymphocyte function-associated antigen 3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphotactin, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylase (KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D, etc.), lysophosphatidic acid-1 receptor, lysosomal-associated membrane protein family (LAMP) gene, lysyl oxidase homolog 2, lysyl oxidase (LOX) protein, 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, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (MK2, etc.), Mas-related G protein-coupled receptor, matrix metalloprotease (MMP, e.g., MMP2, MMP9, etc.), MCL1 differentiation protein, Mdm2 p53-binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel17, melanocyte-stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigen (1, 2, 3, 6, etc.), copper membrane amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (prostate six-transmembrane epithelial antigen 1), metastasin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl-CoA thiolase, mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase (mitogen-activated proteinkinase, MEK, such as MEK1, MEK2, etc.), mTOR (the mechanistic target of rapamycin (serine / threonine kinase)), mTOR complex (1, 2, etc.), mucin (1, 5A, 16, etc.), mutT homolog (MTH, such as MTH1, etc.), Myc oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, sodium natriuretic peptide receptor C, neural cell adhesion molecule 1, Neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NFκB activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A B activating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) modulator, norepinephrine transporter, Notch (Notch-2 receptor, Notch-3 receptor, Notch-4 receptor, etc.), nuclear erythroid 2-related factor 2, nuclear factor (NF)κB, nucleolin, nucleophosmin, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptor (δ, etc.), 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, p38MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (peroxisomeProliferator-activated receptor, PPAR, e.g., α, β, γ, etc.), P-glycoprotein (such as 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, e.g., α, β, γ, etc.), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, e.g., α, β, etc.), platelet-derived growth factor (PDGF, α, β, etc.), multidrug 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), melanoma antigen preferentially expressed (PRAME) gene, Prenyl-binding protein (PrPB), transcriptional coactivator PML, progesterone receptor, Programmed cell death 1 (PD-1), Programmed cell death ligand 1 (PD-L1) inhibitor, Prosaposin (PSAP) gene, prostaglandin receptor (EP4), prostaglandin E2 synthase, prostate-specific antigen, prostate acid phosphatase, proteasome, protein E7, protein farnesyltransferase, protein kinase (proteinkinase, PK, such as A, B, C, etc.), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine / threonine-protein kinase (PIM-1, PIM-2, PIM-3, etc. PIM), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5α-reductase, Raf protein kinase (1, B, etc.), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (γ, etc.), retinoid X receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras homolog)-associated protein kinase 2, ribonuclease, ribonucleotide reductase (M2 subunit, etc.), ribosomal protein S6 kinase, RNA polymerase (I, II, etc.), Ron (Recepteur d'Origine Nantais) tyrosine kinase, ROS1 (ROS oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, γ-secretase, S100 calcium-binding protein A9, sarcoplasmic reticulum calcium ATPase, second mitochondria-derived activator of caspases (SMAC) protein, secreted frizzled-related protein-2, secreted phospholipase A2, semaphorin-4D, serine protease, serine / threonine kinase (STK), serine / threonine protein kinase (TBK, such as TBK1, etc.), signal transduction and transcription (STAT, such as STAT-1, STAT-3, STAT-5, etc.), signaling lymphocytic activationmolecule, SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptor (1, 2, 3, 4, 5, etc.), sonic hedgehog protein, Son of sevenless (SOS), Specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (1, 2, etc.), 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 modulators (SOCS), survivin protein, synapsin 3, syndecan-1, synuclein α, 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 ζ chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing-3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, Telomerase reverse transcriptase (TERT) gene, tenascin, Three prime repair exonuclease 11. TREX1), three prime repair exonuclease 2 ase 2, TREX2), thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (such as α1), thyroid hormone receptor, thyroid-stimulating hormone 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, such as 1 to 13, etc.), topoisomerase (I, II, III, etc.), transcription factor, transferase, transferrin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFB) and its isoforms, TGFβ2 ligand, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-related protein, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptor (TrkA, TrkB, TrkC, etc.), tryptophan 2,3-dioxygenase (TDO), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, such as α, β, etc.), 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 (TIE) receptor containing immunoglobulin-like domain and EGF-like domain, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxylase 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 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig suppressor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, oncogene tyrosine-protein kinase, Mer (Mer tyrosine kinase receptor modulator), YAP (Yes-associated protein modulator), Wee-1 protein kinase, Werner Syndrome RecQ Like Helicase (WRN), Wilms tumor antigen 1, Wilms tumor protein, WW domain-containing transcriptional regulator 1 (TAZ), X-linked apoptosis inhibitor protein, zinc finger protein transcription factor, or any combination thereof may be mentioned.,

[0344] Exemplary mechanism of action In some embodiments, one or more additional therapeutic agents may be classified, by their mechanism of action, for example, 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 / α2-adrenergic antagonists, such as phenoxybenzamine hydrochloride (injectable, pheochromocytoma); Androgen receptor antagonists, such as nilutamide; Anti-cadherin antibodies, such as HKT-288; Anti-leucine-rich repeat containing 15 (LRRC15) antibodies, such as 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 (plexigebersen), IONIS-STAT3-2.5Rx; Anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617 and LY3127804; Anti-ANG-1 / ANG-2 antibodies, such as AMG-780; Anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab); Anti-endoglin antibodies, such as TRC105 (carotuximab); Anti-ERBB antibodies, such as CDX-3379, HLX-02, seribantumab; Anti-HER2 antibodies, for example, HERCEPTIN® (trastuzumab), trastuzumab biosimilars, 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, for example, IMMU-114; Anti-IL-3 antibodies, for example, JNJ-56022473; Anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI Gene ID: 8784) antibodies, for example, MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and for example, those described in International Patent Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628; Anti-EphA3 antibodies, for example, KB-004; Anti-CD37 antibodies, for example, otrexup (TRU-016); Anti-FGFR-3 antibodies, for example, LY3076226, B-701; Anti-FGFR-2 antibodies, for example, GAL-F2; Anti-C5 antibodies, for example, ALXN-1210; Anti-EpCAM antibodies, for example, VB4-845; Anti-CEA antibodies, for example, RG-7813; CD66C) antibodies such as BAY-1834942, NEO-201 (CEACAM5 / 6); Anti-GD2 antibodies, for example, APN-301; Anti-interleukin-17 (IL-17) antibodies, for example, CJM-112; Anti-interleukin-1β antibodies, for example, canakinumab (ACZ885), VPM087; Anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, for example, TX-250; Anti-CD38 antibodies, such as isatuximab, MOR-202, TAK-079; Anti-CD38-Attenukine, such as TAK573; Anti-mucin 1 (MUC1) antibodies, such as gacipotsuzumab, Mab-AR-20.5; Anti-CD33 antibodies, such as IMGN-779; Anti-KMA antibodies, such as MDX-1097; Anti-CD55 antibodies, such as PAT-SC1; Anti-c-Met antibodies, such as ABBV-399; Anti-PSMA antibodies, such as ATL-101; Anti-CD100 antibodies, such as VX-15; Anti-EPHA3 antibodies, such as fibatuzumab; Anti-APRIL antibodies, such as BION-1301; Anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461; Anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386; Anti-fucosyl-GM1 antibodies, such as BMS-986012; Anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam; Anti-myostatin inhibitors, such as landogrozumab; Anti-delta-like protein ligand 3 (DDL3) antibodies, such as robatupizumab tesirine; Anti-DLL4 (delta-like ligand 4) antibodies, such as demcizumab; Anti-clusterin antibodies, such as AB-16B5; Anti-ephrin-A4 (EFNA4) antibodies, such as PF-06647263; Anti-RANKL antibodies, such as denosumab; Anti-mesothelin antibodies, such as BMS-986148, anti-MSLN-MMAE; Anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as lifastuzumab; Anti-TGFβ antibodies, e.g., SAR439459; Anti-transforming growth factor-beta (TGF-β) antibodies, e.g., ABBV-151, LY3022859, NIS793, XOMA089; Purine analogs, folic acid antagonists (e.g., pralatrexate), cladribine, pentostatin, fludarabine, and related inhibitors; Natural products, e.g., vinca alkaloids (vinblastine, vincristine), and microtubule-disrupting agents, e.g., taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilone, vinorelbine (NAVELBINE (registered trademark)), and epipodophyllotoxins (etoposide, teniposide), anti-proliferative / anti-mitotic agents; DNA-damaging agents, e.g., actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN (registered trademark)), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin C, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophosphoramide; DNA hypomethylating agents, e.g., guadecitabine (SGI-110), ASTX727; Antibiotics, e.g., dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin); Enzymes, e.g., L-asparaginase, which metabolizes L-asparagine systemically and removes cells that do not have the ability to synthesize asparagine by themselves; DNAi oligonucleotides targeting Bcl-2, e.g., PNT2258; agents that activate or reactivate latent human immunodeficiency virus (HIV), e.g., panobinostat and romidepsin; Asparaginase stimulators, such as, Crisantaspase (Erwinase (registered trademark)) and GRASPA (ERY-001, ERY-ASP), Caraspase Pegol, Pegaspargase; pan-Trk, ROS1, and ALK inhibitors, such as, Entrectinib, TPX-0005; Anaplastic lymphoma kinase (ALK) inhibitors, such as, Alectinib, Ceritinib, Alecensa (RG7853), ALUNBRIG (registered trademark) (brigatinib); Antiproliferative / antimitotic alkylating agents, such as, Nitrogen mustard cyclophosphamide and analogs (e.g., Melphalan, Chlorambucil, Hexamethylmelamine, Thiotepa), Alkylnitrosourea (e.g., Carmustine) and analogs, Streptozocin, and Triazene (e.g., Dacarbazine); Antiproliferative / antimitotic antimetabolites, such as, Folic acid analogs (Methotrexate); Platinum coordination complexes (e.g., Cisplatin, Oxaliplatinum, and Carboplatin), Procarbazine, Hydroxyurea, Mitotane, and Aminoglutethimide; Hormones, Hormone analogs (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; Fibrinolytics, such as, Tissue plasminogen activator, Streptokinase, Urokinase, Aspirin, Dipyridamole, Ticlopidine, and Clopidogrel; Antimigratory agents; Antisecretory agents (e.g., Breveldin); Immunosuppressive agents, such as, Tacrolimus, Sirolimus, Azathioprine, and Mycophenolate; Growth factor inhibitors and Vascular endothelial growth factor inhibitors; Fibroblast growth factor inhibitors, such as, 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, such as mifamurtide (liposome); CCR5 chemokine antagonists, such as MK-7690 (vicriviroc); CDC7 protein kinase inhibitors, such as TAK-931; Cholesterol side-chain cleavage enzyme inhibitors, such as ODM-209; Dihydropyrimidine dehydrogenase / orotate phosphoribosyltransferase inhibitors, such as celecoxib (tegafur + gimeracil + oteracil potassium); DNA polymerase / ribonucleotide reductase inhibitors, such as clofarabine; DNA interfering oligonucleotides, such as PNT2258, AZD-9150; Estrogen receptor modulators, such as bazedoxifene; Estrogen receptor agonists / progesterone receptor antagonists, such as 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, such as PBMC engineered by MART-1 F5 TCR; Human granulocyte colony-stimulating factor, such as PF-06881894; GnRH receptor agonists, such as leuprolide acetate, leuprolide acetate sustained release depot (ATRIGEL), tryptorelin pamoate, goserelin acetate; GnRH receptor antagonists, such as elagolix, relugolix, degarelix; Endoplasmin modulators, such as anlotinib; H+ K+ ATPase inhibitors, such as omeprazole, esomeprazole; ICAM-1 / CD55 modulators, such as cavatak (V-937); IL-15 / IL-12 modulators, such as SAR441000; Interleukin 23A inhibitors, such as guselkumab; Lysine-specific histone demethylase 1 inhibitors, such as CC-90011; IL-12 Mrna, such as MEDI1191; RIG-I modulators, such as 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 modulator / DNA-binding protein Ikaros inhibitor / zinc finger-binding protein Aiolos inhibitor, such as lenalidomide; Retinoid X receptor modulators, such as alitretinoin, bexarotene (oral formulation); RIP-1 kinase inhibitors, such as GSK-3145095; Selective estrogen receptor degrader, such as AZD9833; SUMO inhibitors, such as TAK-981; Thrombopoietin receptor agonists, such as eltrombopag; Thyroid hormone receptor agonists, such as levothyroxine sodium; TNF agonists, such as tasnemermin; Tyrosine phosphatase substrate 1 inhibitors, such as CC-95251; HER2 inhibitors, such as neratinib, tucatinib (ONT-380); EGFR / ErbB2 / Ephb4 inhibitors, such as tesevatinib; EGFR / HER2 inhibitors, such as TAK-788; EGFR family tyrosine kinase receptor inhibitors, such as DZD-9008; EGFR / ErbB-2 inhibitors, such as baricitinib; Mutant-selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694; epha2 inhibitors, such as MM-310; Polycomb protein (EED) inhibitors, such as MAK683; DHFR inhibitor / folate transporter 1 modulator / folate receptor antagonist, such as pralatrexate; DHFR / GAR transformylase / thymidylate synthase / transferase inhibitor, such as pemetrexed disodium; p38 MAP kinase inhibitors, such as larimetinib; PRMT inhibitors, such as MS203, PF-06939999, GSK3368715, GSK3326595; Sphingosine kinase 2 (SK2) inhibitors, such as opaganib; Nuclear erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408); Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579; Mucin 1 inhibitors, such as GO-203-2C; MARCKS protein inhibitors, such as BIO-11006; Folate antagonists, such as alfoleucovorin; Galectin-3 inhibitors, such as GR-MD-02; Phosphorylated P68 inhibitors, such as RX-5902; CD95 / TNF modulators, such as ofranergene obadenovec; pan-PIM kinase inhibitors, such as INCB-053914; IL-12 gene stimulators, such as EGEN-001, tabokinogene telseplasmid; Heat shock protein HSP90 inhibitors, such as TAS-116, PEN-866; VEGF / HGF antagonists, such as MP-0250; VEGF ligand inhibitors, such as bevacizumab biosimilar; VEGF receptor antagonist / VEGF ligand inhibitor, such as 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 vaccine; Placenta growth factor ligand inhibitor / VEGF-A ligand inhibitor, such as aflibercept; SYK tyrosine kinase / JAK tyrosine kinase inhibitors, such as ASN-002; Trk tyrosine kinase receptor inhibitors, such as larotrectinib sulfate; JAK3 / JAK1 / TBK1 kinase inhibitors, such as CS-12912; IL-24 antagonists, such as AD-IL24; NLRP3 (NACHT LRR PYD domain protein 3) modulators, such as BMS-986299; RIG-I agonists, such as RGT-100; Aerolysin stimulators, such as topsalysin; P-glycoprotein 1 inhibitors, such as HM-30181A; CSF-1 antagonists, such as ARRY-382, BLZ-945; CCR8 inhibitors, such as I-309, SB-649701, HG-1013, RAP-310; Anti-methotrexate antibodies, such as SEL-403; Thymidine kinase stimulators, such as aglatimagene besadenovec; Polo-like kinase 1 inhibitors, such as PCM-075, onvansertib; NAE inhibitors, such as pevonedistat (MLN-4924), TAS-4464; Multi-faceted pathway modulators, such as abedomid (CC-122); Amyloid protein binding protein-1 inhibitors / ubiquitin ligase modulators, such as pevonedistat; FoxM1 inhibitors, such as thiostrepton; UBA1 inhibitors, such as TAK-243; Src tyrosine kinase inhibitors, such as VAL-201; VDAC / HK inhibitors, such as VDA-1102; Elf4a inhibitors, such as rohitinib, eFT226; TP53 gene stimulators, such as 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, such as olaptesed pegol (NOX-A12); IL-4 receptor modulators, such as MDNA-55; Arginase I stimulators, such as pegargiminase; Topoisomerase I inhibitors, such as irinotecan hydrochloride, onivyde; Topoisomerase I inhibitor / hypoxia-inducible factor-1α inhibitor, such as PEG-SN38 (filtecanpegol); Hypoxia-inducible factor-1α inhibitors, such as 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, such as NKTR-262; TLR7 agonists, such as DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod); p53 tumor suppressor protein stimulators, such as kevetrin; Mdm4 / Mdm2 p53 binding protein inhibitors, such as ALRN-6924; Kinesin spindle protein (KSP) inhibitors, such as 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, such as RGX-104; IL-10 agonists, such as pegilodecakin (AM-0010); VEGFR / PDGFR inhibitors, such as sorafenib; IRAK4 inhibitors, such as CA-4948; Anti-TLR-2 antibodies, such as OPN-305; Calmodulin modulators, such as CBP-501; Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134); Second mitochondria-derived activator of caspases (SMAC) protein inhibitors, such as BI-891065; Lactoferrin modulators, such as LTX-315; KIT proto-oncogene, receptor tyrosine kinase (KIT) inhibitors, such as 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, such as eltanexor; CHST15 gene inhibitors, such as 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, e.g., MSC2363318A; Methionine aminopeptidase 2 (MetAP2) inhibitors, e.g., M8891, APL-1202; Arginine N-methyltransferase 5 inhibitors, e.g., GSK-3326595; CD71 modulators, e.g., CX-2029 (ABBV-2029); ATM (ataxia telangiectasia) inhibitors, e.g., AZD0156, AZD1390; CHK1 inhibitors, e.g., GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2); CXCR4 antagonists, e.g., BL-8040, LY2510924, brixafol (TG-0054), X4P-002, X4P-001-IO, prexasafol; EXH2 inhibitors, e.g., GSK2816126; KDM1 inhibitors, e.g., ORY-1001, IMG-7289, INCB-59872, GSK-2879552; CXCR2 antagonists, e.g., AZD-5069; GM-CSF antibodies, e.g., lenzilumab; DNA-dependent protein kinase inhibitors, e.g., MSC2490484A (neddiceltyb), VX-984, AsiDNA (DT-01); protein kinase C (PKC) inhibitors, e.g., LXS-196, sotrastaurin; Selective estrogen receptor downregulators (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 receptor modulators (SARMs), such as GTX-024, darolutamide; Transforming growth factor-β (TGF-β) kinase antagonists, such as galunisertib, LY3200882; TGF-β inhibitors described in International Publication No. 2019 / 103203; TGFβ receptor 1 inhibitors, such as PF-06952229; Bispecific antibodies, for example, 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), bevacizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD3), 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), MEDI-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), BI-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), Navicixizumab (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, such as selinexor (KPT-330); Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221); IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032; IDH1 gene inhibitors, such as ivosidenib; Interleukin-3 receptor (IL-3R) modulators, such as SL-401; Arginine deiminase stimulators, such as pegargiminase (ADI-PEG-20); Claudin-18 inhibitors, such as claudiximab; β-catenin inhibitors, such as CWP-291; Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2 / CCR5); Thymidylate synthase inhibitors, such as ONX-0801; ALK / ROS1 inhibitors, such as lorlatinib; Tankyrase inhibitors, such as 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, such as eribulin mesylate; c-MET inhibitors, such as AMG-337, savolitinib, crizotinib (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361; c-Met / VEGFR inhibitors, such as BMS-817378, TAS-115; c-Met / RON inhibitors, such as BMS-777607; BCR / ABL inhibitors, such as lestaurtinib, asimicinib, ponatinib (ICLUSIG®); MNK1 / MNK2 inhibitors, such as eFT-508; Cytochrome P450 11B2 / Cytochrome P450 17 / AKT protein kinase inhibitors, such as LAE-201; Cytochrome P450 3A4 stimulators, such as mitotane; Lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011; CSF1R / KIT and FLT3 inhibitors, such as pexidartinib (PLX3397); Flt3 tyrosine kinase / Kit tyrosine kinase inhibitors, and PDGF receptor antagonists, such as quizartinib dihydrochloride; Kinase inhibitors, such as vandetanib; E-selectin antagonists, such as GMI-1271; Differentiation inducers, such as tretinoin; Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291), cetuximab; Topoisomerase inhibitors, such as adriamycin, doxorubicin, daunorubicin, dactinomycin, DaunoXome, Caelyx, etoposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), bosaroxime and GPX-150, aldoxorubicin, AR-67, maravertinib, AST-2818, abitinib (ACEA-0010), irofulven (MGI-114); Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone; Growth factor signaling kinase inhibitors; Nucleoside analogs, such as DFP-10917; Axl inhibitors, such as BGB-324 (bemcentinib), SLC-0211; Axl / Flt3 inhibitors, such as gilteritinib; Inhibitors of bromodomain and extra-terminal 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), such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mibresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829; PARP inhibitors, such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, BGB-290, furzoleparib (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, Simtuzumab; Proteasome inhibitors, e.g., Ixazomib (NINLARO®), Carfilzomib (Kyprolis®), Marizomib, Bortezomib; Glutaminase inhibitors, e.g., CB-839 (Telaglenastat), bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Mitochondrial complex I inhibitors, e.g., Metformin, Phenformin; Vaccines, for example, peptide vaccines TG-01(RAS), GALE-301, GALE-302, nelipeptimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpeptimut-S, SVN53-67 / M57-KLH, IMU-131, peptide subunit vaccine (acute lymphoblastic leukemia, University Children’s Hospital Tuebingen); bacterial vector vaccines, for example, CRS-207 / GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines, for example, nadofaragene firadenovec; autologous Gp96 vaccine; dendritic cell vaccines, for example, CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, ADXS31-142, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal / intravenous, Universitatsklinikum Erlangen); oncolytic vaccines, for example, talimogene laherparepvec,pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, for example, CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax (trademark); tumor cell vaccines, for example, Vigil® (IND-14205), Oncoquest-L vaccine; live attenuated recombinant serotype 1 poliovirus vaccine, for example, PVS-RIPO; adagroxad simolenin; MEDI-0457; DPV-001, a tumor-derived autophagosome-enriched cancer vaccine; RNA vaccines, for example, CV-9209, LV-305; DNA vaccines, for example, MEDI-0457, MVI-816, INO-5401;Modified vaccinia virus Ankara vaccines expressing p53, such as MVA-p53; DPX-Survivac; BriaVax™; GI-6301; GI-6207; GI-4000; IO-103; neoantigen peptide vaccines, such as AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; peptide vaccines targeting heat shock proteins such as PhosphoSynVax™; Vitespen (HSPPC-96-C), NANT colorectal cancer vaccine containing aldoxorubicin, autologous tumor cell vaccine + systemic CpG-B + IFN-α (cancer), IO-120 + IO-103 (PD-L1 / PD-L2 vaccine), HB-201, HB-202, HB-301, TheraT®-based vaccines; TLR-3 agonists / interferon inducers, such as poly ICLC (NSC-301463); STAT-3 inhibitors, such as napabucasin (BBI-608); ATPase p97 inhibitors, such as 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), ropeginterferon α-2b (AOP-2014, P-1101, PEG IFNα-2b), multiferon (alphana tibev, Viragen), interferon α1b, roferon-A (canferon, Ro-25-3036), interferon α-2a follow-on biologic (Biosidus) (Inmutag, Inter 2A), interferon α-2b follow-on biologic (Biosidus-Bioferon, sitferon, Ganapar, Beijing Kawin Technology-Kaferon), alphapheron, pegylated interferon α-1b, pegylated interferon α-2b follow-on biologic (Amega), recombinant human interferon α-1b, recombinant human interferon α-2a, recombinant human interferon α-2b, belzutifan-IFNα2b conjugate, Dynavax (SD-101), and interferon α-n1 (Humoferon, SM-10500, sumiferon); Interferon γ ligand modulators, such as interferon γ (OH-6000, Ogamma100); IL-6 receptor modulators, such as tocilizumab, AS-101 (CB-06-02, IVX-Q-101); Heat shock protein inhibitor / IL-6 receptor antagonist, such as 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 inhibitor / topoisomerase II inhibitor, such as amrubicin; Inhibitors of Bcl-2 family proteins, such as ABT-263, Venetoclax (ABT-199), ABT-737, RG7601, and AT-101; Bcl-2 / Bcl-XL inhibitors, such as Novitoclax; Notch inhibitors, such as LY3039478 (Krenigacestat), Taletrectinib (anti-Notch2 / 3), BMS-906024; Hyaluronidase stimulators, such as PEGPH-20; Erbb2 tyrosine kinase receptor inhibitors / hyaluronidase stimulators, such as Herceptin Hylecta; Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974; γ-secretase inhibitors, such as PF-03084014, MK-0752, RO-4929097; Grb-2 (Growth factor receptor-bound protein-2) inhibitors, such as BP1001; TRAIL pathway-inducing compounds, such as ONC201, ABBV-621; TRAIL modulators, such as SCB-313; Focal adhesion kinase inhibitors, such as VS-4718, Defactinib, GSK2256098; Hedgehog inhibitors, such as Saridegib, 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), such as Bryostatin, Apatorin; ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (Berzosertib), and VX-970; Hsp90 inhibitors, such as AUY922, Onalespib (AT13387), SNX-2112, SNX5422; Murine double minute (mdm2) gene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388); CD137 agonists, such as 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, GSK3745417; FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347; Fatty acid synthase (FASN) inhibitors, such as TVB-2640; Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, inebilizumab; CD44 binders, such as A6; Protein phosphatase 2A (PP2A) inhibitors, such as LB-100; CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate; RXR agonists, such as IRX4204; Hedgehog / smoothened (hh / Smo) antagonists, such as taladegib, pactidegib, vismodegib; Complement C3 modulators, such as 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, such as 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), bosimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301, IMLYGIC (registered trademark); DOT1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676); Toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, adenylate cyclase toxin of Bordetella pertussis, diphtheria toxin, and caspase activator; DNA plasmids, such as mBC-819; PLK inhibitors of PLK1, 2, and 3, such as volasertib (PLK1); WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase (ROCK) inhibitors, such as AT13148, KD025; Inhibition of Apoptosis Protein (IAP) inhibitors, such as ASTX660, debio-1143, birinapant, APG-1387, LCL-161; RNA polymerase inhibitors, such as lurbinectedin (PM-1183), CX-5461; Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin), and OXI-4503, fluorapacin (AC-0001), purvalanol, vinflunine; Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091, and PEPA-10; Elongation factor 1α2 inhibitors, such as plitidepsin; Elongation factor 2 inhibitor / interleukin-2 ligand / NAD ADP-ribosyltransferase stimulator, such as denileukin diftitox; CD95 inhibitors, such as APG-101, APO-010, aselizumab; WT1 inhibitor, for example, DSP-7888; Splicing factor 3B subunit 1 (SF3B1) inhibitor, for example, H3B-8800; Retinoid Z receptor γ (RORγ) agonist, for example, LYC-55716; and Microbiome modulator, for example, SER-401, EDP-1503, MRx-0518.

[0345] In some embodiments, the compounds described herein are co-administered with one or more additional therapeutic agents including the following inhibitors or antagonists: 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); erb-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 anaplastic lymphoma kinase 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-inducible poly(ADP-ribose) 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 (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 apoptosis inhibitor (XIAP, BIRC4, IAP-3; NCBI Gene ID: 331); baculoviral IAP repeat-containing 2 (BIRC2, cIAP1; NCBI Gene ID: 329); baculoviral IAP repeat-containing 3 (BIRC3, cIAP2; NCBI Gene ID: 330); baculoviral IAP repeat-containing 5 (BIRC5, survivin; NCBI Gene ID: 332); C-C motif chemokine receptor 2 (CCR2, CD192; NCBI Gene ID: 729230); C-C 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 (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 (prostaglandin-endoperoxide synthase 1, PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2;NCBI Gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), and / or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053); secreted phospholipase A2 (e.g., PLA2G1B (NCBI Gene ID: 5319); PLA2G7 (NCBI Gene ID: 7941), PLA2G3 (NCBI Gene ID: 50487), PLA2G2A (NCBI Gene ID: 5320); PLA2G4A (NCBI Gene ID: 5321); PLA2G12A (NCBI Gene ID: 81579); PLA2G12B (NCBI Gene ID: 84647); PLA2G10 (NCBI Gene ID: 8399); PLA2G5 (NCBI Gene ID: 5322); PLA2G2D (NCBI Gene ID: 26279); PLA2G15 (NCBI Gene ID: 23659)); indoleamine-2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620); indoleamine-2,3-dioxygenase 2 (IDO2; NCBI Gene ID: 169355); hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091); angiopoietin 1 (ANGPT1; NCBI Gene ID: 284); endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI Gene ID: 7010); Janus kinase 1 (JAK1; NCBI Gene ID: 3716); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734), and / or 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464).;

[0346] TCR signaling modulator In some embodiments, the compounds described herein are combined with one or more agonists or antagonists of T cell receptor (TCR) signaling modulators. Activation of T cells via the TCR is essential for thymocyte development and effector T cell function. TCR activation promotes a signaling cascade that ultimately determines 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-b, CISH, HPK1.

[0347] Examples of agonists of cluster of differentiation 3 (CD3) that can be co-administered include, but are not limited to, MGD015.

[0348] In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of an inhibitory immune checkpoint protein or receptor, 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 microenvironment. Activation or stimulation of stimulatory immune checkpoints can enhance the effect of immune checkpoint inhibitors in cancer treatment. In some embodiments, the immune checkpoint protein or receptor regulates the T cell response (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, the immune checkpoint protein or receptor regulates the NK cell response (e.g., as reviewed in Davis, et al., Semin Immunol (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0349] Examples of immune checkpoint proteins or receptors include, but are not limited to, the following: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set Domain-containing T cell Activation Inhibitor 1 (VTCN1, B7H4); V-set Immunoregulatory Receptor (VSIR, B7H5, VISTA); Immunoglobulin Superfamily Member 11 (IGSF11, VSIG3); Natural Killer Cell Cytotoxicity Receptor 3 Ligand 1 (NCR3LG1, B7H6); HERV-H LTR-Associating 2 (HHLA2, B7H7); Inducible T cell Co-stimulator (ICOS, CD278); Inducible T cell Co-stimulator 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 lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor (KIR); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A);Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1).;

[0350] 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 T cell activation inhibitor 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-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG-3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor (KIR); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (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-stimulating immune checkpoint proteins or receptors include, but are not limited to, the following: CD27, CD70; CD40, CD40LG; inducible T cell co-stimulatory molecule (ICOS, CD278); inducible T cell co-stimulatory 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, for example, Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0351] In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory 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, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In some embodiments, the compounds described herein are combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include, but are not limited to: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75, Fang, et al., Semin Immunol. (2017) 31:37-54, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0352] 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 mAb (Vx-1004), anti-human CD47 mAb (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, but are not limited to, IBI-188, TJC-4, SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015.

[0353] In some embodiments, the inhibitor of CD47 is a bispecific antibody that targets CD47. Examples of bispecific antibodies that target CD47 include, but are not limited to, IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), and HMBD-004A (CD47 / CD33).

[0354] In some embodiments, the anti-CD47 targeting agent is as described in International Publication Nos. WO 1997 / 27873, WO 1999 / 40940, WO 2002 / 092784, WO 2005 / 044857, WO 2009 / 046541, WO 2010 / 070047, WO 2011 / 143624, WO 2012 / 170250, WO 2013 / 109752, WO 2013 / 119714, WO 2014 / 087248, WO 2015 / 191861, WO 2016 / 022971, WO 2016 / 023040, WO 2016 / 024021, WO 2016 / 081423, WO 2016 / 109415, WO 2016 / 141328, WO 2016 / 188449, WO 2017 / 027422, WO 2017 / 049251, WO 2017 / 053423, WO 2017 / 121771, WO 2017 / 194634, WO 2017 / 196793, WO 2017 / 215585, WO 2018 / 075857, WO 2018 / 075960, WO 2018 / 089508, WO 2018 / 095428, WO 2018 / 137705, WO 2018 / 233575, WO 2019 / 027903, WO 2019 / 034895, WO 2019 / 042119, WO 2019 / 042285, WO 2019 / 042470, WO 2019 / 086573, WO 2019 / 108733, WO 2019 / 138367, WO 2019 / 144895, WO 2019 / 157843, WO 2019 / 179366, WO 2019 / 184912, WO 2019 / 185717, WO 2019 / 201236, WO 2019 / 238012, WO 2019 / 241732, WO 2020 / 019135, WO 2020 / 036977, WO 2020 / 043188, or WO 2020 / 009725.

[0355] In some embodiments, the one or more immune checkpoint inhibitors include proteinaceous inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4 (e.g., an antibody or fragment thereof, or an antibody mimetic). In some embodiments, the one or more immune checkpoint inhibitors include small molecule organic inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

[0356] Examples of CTLA4 inhibitors that can 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).

[0357] Examples of inhibitors / antibodies of PD-L1 (CD274) or PD-1 (PDCD1) 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-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 (dostarlimab), 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 bispecific inhibitor FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (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-7121661 (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 registration 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 (semiplimab), 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, 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-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, and MDX1105-01, and, for example, those described in International Publication Nos. 2018 / 195321, 2020 / 014643, 2019 / 160882, and 2018 / 195321, but not limited thereto.,

[0358] Examples of inhibitors of PVRIG that can be co-administered include, but are not limited to, COM-701.

[0359] Examples of inhibitors of TIGIT that can be co-administered include, but are not limited to, BMS-986207, RG-6058, AGEN-1307, COM-902.

[0360] Examples of inhibitors of TIM-3 that can be co-administered include, but are not limited to, TSR-022, LY-3321367, MBG-453, INCAGN-2390, RO-7121661 (PD-1 / TIM-3), LY-3415244 (TIM-3 / PDL1), RG7769 (PD-1 / TIM-3).

[0361] Examples of inhibitors of LAG-3 that can be co-administered include, but are not limited to, relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1).

[0362] Examples of monoclonal antibodies against killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811), for example, lirilumab (IPH-2102), IPH-4102.

[0363] Examples of anti-NKG2a antibodies that can be co-administered include, but are not limited to, monalizumab.

[0364] Examples of anti-VISTA antibodies that can be co-administered include, but are not limited to, HMBD-002, CA-170 (PD-L1 / VISTA).

[0365] Examples of anti-CD70 antibodies that can be co-administered include, but are not limited to, AMG-172.

[0366] Examples of anti-CD20 antibodies that can be co-administered include, but are not limited to, obinutuzumab, IGN-002, PF-05280586.

[0367] Examples of anti-ICOS antibodies that can be co-administered include, but are not limited to, JTX-2011, GSK3359609.

[0368] 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).

[0369] Agonists or activators of TNF Receptor Superfamily (TNFRSF) members In some embodiments, the compounds described herein are combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), 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 (CD27, 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), TNFRSF10D (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 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0370] Exemplary anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabalixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in International Publication Nos. 2016 / 179517, 2017 / 096179, 2017 / 096182, 2017 / 096281, and 2018 / 089628.

[0371] Exemplary anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2) antibodies that can be co-administered include, but are not limited to, DS-8273, CTB-006, INBRX-109, GEN-1029, and the like.

[0372] Exemplary anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, ABBV-428, ABBV-927, JNJ-64457107.

[0373] In some embodiments, the anti-TNFRSF7 (CD27) antibody balilumab (CDX-1127) is co-administered.

[0374] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0375] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0376] Exemplary anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in International Publication Nos. 2017 / 096179 and 2018 / 089628.

[0377] Exemplary anti-TRAILR1, anti-TRAILR2, anti-TRAILR3, anti-TRAILR4 antibodies that can be co-administered include, but are not limited to, ABBV-621.

[0378] Bispecific antibodies that can be co-administered and target TNFRSF family members 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).

[0379] Adenosine generation and signaling In some embodiments, the compounds described herein are combined with an agonist or antagonist of A1R, A2AR, A2BR, A3R, CD73, CD39, CD26.

[0380] Examples of adenosine A3 receptor (A3R) agonists such as Namodenoson (CF102).

[0381] Examples of A2aR / A2bR antagonists such as AB928.

[0382] Examples of anti-CD73 antibodies such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006.

[0383] Examples of CD73 inhibitors such as AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, and those described in International Publication No. 19173692.

[0384] Examples of CD39 / CD73 inhibitors such as PBF-1662.

[0385] Examples of anti-CD39 antibodies such as TTX-030.

[0386] Examples of adenosine A2A receptor antagonists such as CPI-444, AZD-4635, Preladenant, PBF-509.

[0387] Examples of adenosine deaminase inhibitors such as Pentostatin, Cladribine.

[0388] c-kit targeting agent In various embodiments, the compounds described herein are combined with inhibitors of c-kit (PBT, SCFR, CD117, MASTC; NCBI Gene ID: 3815; Uniprot - P10721).

[0389] Examples of c-kit inhibitors include imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229 (c-kit / PDGFR inhibitor), teratinib (c-kit / PDGF / VEGF2 inhibitor), quizartinib dihydrochloride (FLT3 / c-kit), pexidartinib hydrochloride (CSF1R / FLT3 / c-kit), avapritinib (PDGFR / c-Kit inhibitor), brolanib (multi-kinase VEGF / PDGFR / c-kit inhibitor), and ripretinib (c-kit / PDGFRα inhibitor).

[0390] Examples of multi-kinase inhibitors of c-kit include dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, levastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, citravatinib, tiboxanib, masitinib, regorafenib, HQP-1351, cabozantinib, ponatinib, and famitinib L-malate. Examples of anti-c-kit antibodies include CDX-0158, CDX-0159, and FSI-174.

[0391] In some embodiments, the anti-c-kit targeting agent is as described in International Publication Nos. WO 1992 / 03459, WO 1992 / 21766, WO 2004 / 080462, WO 2005 / 020921, WO 2006 / 009755, WO 2007 / 078034, WO 2007 / 092403, WO 2007 / 127317, WO 2008 / 005877, WO 2012 / 154480, WO 2014 / 100620, WO 2014 / 039714, WO 2015 / 134536, WO 2017 / 167182, WO 2018 / 112136, WO 2018 / 112140, WO 2019 / 155067, WO 2020 / 076105, and International Application PCT / US2019 / 063091.

[0392] SIRPα targeting agent In various embodiments, the compounds described herein are combined with an inhibitor of SIRPα (NCBI Gene ID: 140885; UniProt P78324).

[0393] Examples of SIRPα inhibitors such as AL-008, RRx-001, and CTX-5861.

[0394] Examples of anti-SIRPα antibodies such as FSI-189, ES-004, BI765063, ADU1805, and CC-95251.

[0395] In some embodiments, the SIRPα targeting agent is one described in International Publication Nos. WO 2001 / 40307, WO 2002 / 092784, WO 2007 / 133811, WO 2009 / 046541, WO 2010 / 083253, WO 2011 / 076781, WO 2013 / 056352, WO 2015 / 138600, WO 2016 / 179399, WO 2016 / 205042, WO 2017 / 178653, WO 2018 / 026600, WO 2018 / 057669, WO 2018 / 107058, WO 2018 / 190719, WO 2018 / 210793, WO 2019 / 023347, WO 2019 / 042470, WO 2019 / 175218, WO 2019 / 183266, WO 2020 / 013170, or WO 2020 / 068752.

[0396] Bispecific T cell engager In some embodiments, the compounds of this specification are combined with a bi-specific T-cell engager (e.g., without an Fc) or an anti-CD3 bispecific antibody (e.g., with an Fc).Exemplary anti-CD3 bispecific antibodies or BiTEs that can 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-64052781 (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 / heme), JNJ-63709178 (CD123 / CD3), MGD-007 (CD3 / gpA33), MGD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), XmAb-18087 (SSTR2 / CD3), 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), SAR440234 (CD3 / CDw123). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc.Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens described herein (e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG 330); 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).

[0397] Bispecific and trispecific Natural Killer (NK) cell engagers In some embodiments, the compounds described herein are bispecific NK cell engagers (BiKEs) or trispecific NK cell engagers (TriKEs) (e.g., without an Fc), or bispecific antibodies against NK cell activating receptors (e.g., with an Fc), e.g., 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 receptor FcγR (mediating antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs 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. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., including CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKEs and TriKEs are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346, Fang, et al., Semin Immunol. (2017) 31:37-54.

[0398] Inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1) 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 International Publication Nos. 2018 / 183418, 2016 / 033486, and 2017 / 147410.

[0399] Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) 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 International Publication Nos. 2018 / 183956, 2018 / 183964, 2018 / 167147, 2018 / 183964, 2016 / 205942, 2018 / 049214, 2018 / 049200, 2018 / 049191, 2018 / 102366, 2018 / 049152, 2020 / 092528, 2020 / 092621, and 2016 / 090300.

[0400] Inhibitor of Apoptosis Signal-Regulating Kinase (ASK) In some embodiments, the compounds described herein are combined with an ASK inhibitor, e.g., 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 International Publication No. WO 2011 / 008709 (Gilead Sciences) and International Publication No. WO 2013 / 112741 (Gilead Sciences).

[0401] Bruton Tyrosine Kinase (BTK) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of Bruton 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, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence + AZD6738, Calquence + danvatirsen.

[0402] Cyclin-dependent kinase (CDK) inhibitor In some embodiments, the compounds described herein are combined with inhibitors 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); 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); 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, milciclib, trilaciclib, PF-06873600, AZD4573, and TG-02.

[0403] Discoidin Domain Receptor (DDR) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor 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 International Publication No. WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. US 2009 / 0142345 (Takeda Pharmaceutical), US 2011 / 0287011 (Oncomed Pharmaceuticals), International Publication No. WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0404] Histone deacetylase (HDAC) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of histone deacetylase, such as 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, givinostat, mocetinostat, panobinostat, pracinostat, xenoSTAT (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat, romidepsin, tucidinostat.

[0405] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0406] Janus kinase (JAK) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor 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), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0407] Matrix metalloprotease (MMP) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of matrix metallopeptidase (MMP), 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), MMP19 (NCBI Gene ID: 4327), MMP20 (NCBI Gene ID: 9313), MMP21 (NCBI Gene ID: 118856), MMP24 (NCBI Gene ID: 10893), MMP25 (NCBI Gene ID: 64386), MMP26 (NCBI Gene ID: 56547), MMP27 (NCBI Gene ID: 64066), and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), sipematastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics).

[0408] RAS and RAS pathway inhibitors In some embodiments, the compounds described herein are combined with inhibitors of the KRAS oncogene, GTPase (KRAS; aliases, NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-Ras; C-K-Ras; K-Ras2A; K-Ras2B; K-Ras4A; K-Ras4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS oncogene, GTPase (NRAS; aliases, NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893); HRas oncogene, GTPase (HRAS; aliases, CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; C-H-RAS; c-K-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). The Ras inhibitor can inhibit Ras either at the polynucleotide level (e.g., a transcriptional inhibitor) or at the polypeptide (e.g., a GTPase enzyme inhibitor). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway and inhibits, for example, one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.

[0409] In some embodiments, the compounds described herein are combined with an inhibitor of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and KRpep-2 (Ac-RRCPLYISYDPVCRR-NH 2 )(SEQ ID NO: 108) and KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH 2 )(SEQ ID NO: 109), including K-RAS (G12D) selective inhibitory peptides.

[0410] In some embodiments, the compounds described herein are combined with an inhibitor of KRAS mRNA. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adapter, AZD-4785, siG12D-LODER™, and siG12D exosomes.

[0411] In some embodiments, the compounds described herein are combined with an inhibitor of MEK. Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and serimetinib.

[0412] In some embodiments, the compounds described herein are combined with an inhibitor of AKT. Exemplary AKT inhibitors that can be co-administered include RG7440, MK-2206, ipatasertib, afuresertib, AZD5363, and ARQ-092, capivasertib, triciribine, ABTL-0812 (PI3K / Akt / mTOR).

[0413] In some embodiments, the compounds described herein are combined with an inhibitor of Raf. 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), PLX8394. RAF-265 (Raf / VEGFR), ASN-003 (Raf / PI3K).

[0414] 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, labracetib, GDC-0994, and ulixertinib.

[0415] In some embodiments, the compounds described herein are combined with an inhibitor of PI3K. Exemplary PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pictilisib. Exemplary PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, bosteralisib, gedatolisib, GSK2141795, RG6114.

[0416] In some embodiments, the compounds described herein are combined with an inhibitor of mTOR. Exemplary mTOR inhibitors that can be co-administered include sapitinib, bistethracetib (AZD2014), ME-344, sirolimus (oral nanoamorphous formulation, cancer), TYME-88 (mTOR / cytochrome P450 3A4).

[0417] In some embodiments, Ras-driven cancers having a CDKN2A mutation (e.g., NSCLC) 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 the irreversible inhibitor neratinib of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0418] In some embodiments, the compounds described herein are combined with an inhibitor of RAS. Examples of RAS inhibitors include NEO-100, rigosertib.

[0419] 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), tolmotuzumab, ABT-806, bevacizumab, modotuzumab, RM-1929.

[0420] 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 International Publication No. 2018 / 172984 and International Publication No. 2017 / 211303.

[0421] In some embodiments, the compounds described herein are combined with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include anthroquinonol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, RG7421.

[0422] Phosphatidylinositol 3-kinase (PI3K) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, 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, 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, Buparlisib (BKM120), BYL719 (Alpelisib), CH5132799, Copanlisib (BAY 80-6946), Duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Idelalisib (Zydelig (registered trademark)), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, Ligosertib, RP5090, RP6530, SRX3177, Taselisib, TG100115, TGR-1202 (Umbrelisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Wortmannin, ZSTK474, and compounds described in International Publication Nos. 2005 / 113556 (ICOS), 2013 / 052699 (Gilead Calistoga), 2013 / 116562 (Gilead Calistoga), 2014 / 100765 (Gilead Calistoga), 2014 / 100767 (Gilead Calistoga), and 2014 / 201409 (Gilead Sciences).

[0423] Mitogen-activated Protein Kinase (MEK) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include, but are not limited to, anthroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib.

[0424] Spleen Tyrosine Kinase (SYK) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of spleen 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]pyrazine-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in U.S. Patent No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 2015 / 0175616.

[0425] Toll-like receptor (TLR) agonist In some embodiments, the compounds described herein are combined with an agonist of a toll-like receptor (TLR), for example, 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 can 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 compounds disclosed in U.S. Patent Application Publication Nos. 2010 / 0143301 (Gilead Sciences), 2011 / 0098248 (Gilead Sciences), 2009 / 0047249 (Gilead Sciences), 2014 / 0045849 (Janssen), 2014 / 0073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), 2014 / 076221 (Janssen), 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Application Publication Nos. 2008 / 0234251 (Array Biopharma), 2008 / 0306050 (Array Biopharma), 2010 / 0029585 (Ventirx Pharma), 2011 / 0092485 (Ventirx Pharma), 2011 / 0118235 (Ventirx Pharma), 2012 / 0082658 (Ventirx Pharma), 2012 / 0219615 (Ventirx Pharma), 2014 / 0066432 (Ventirx Pharma), 2014 / 0088085 (Ventirx Pharma), 2014 / 0275167 (Novira Therapeutics), and 2013 / 0251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that can be co-administered is NKTR-262.Examples of TLR8 agonists that can 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 the compounds disclosed in U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), International Publication No. 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 Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics).Exemplary TLR9 agonists that can be co-administered include, but are not limited to, AST-008, CMP-001, IMO-2055, IMO-2125, lenitimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, refitrimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0426] Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763.

[0427] Examples of TLR8 agonists include, but are not limited to, MCT-465, motrimod, GS-9688, and VTX-1463.

[0428] Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, refitrimod, lenitimod, MGN-1601, and PUL-042.

[0429] Examples of TLR7 / TLR8 agonists such as NKTR-262, IMO-4200, MEDI-9197 (teltrimod), resiquimod.

[0430] Examples of TLR agonists include, but are not limited to, refitrimod, chiltrimod, lintrimod, DSP-0509, AL-034, G-100, cobitrimod, AST-008, motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, teltrimod.

[0431] 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.

[0432] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitor In some embodiments, the compounds described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0433] 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.

[0434] Tyrosine-kinase Inhibitor (TKI) In some embodiments, the compounds described herein are combined with a tyrosine-kinase inhibitor (TKI). The TKI can target the epidermal growth factor receptor (EGFR), as well as the 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, bosutinib, brigatinib, cabozantinib, cediranib, clenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tivozanib, TH-4000, tivozanib, and MEDI-575 (anti-PDGFR antibody), TAK-659, cabozantinib.

[0435] Chemotherapeutic agent (standard treatment) In some embodiments, the compounds described herein are combined with a chemotherapeutic agent or an anti-neoplastic agent.

[0436] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic drug" (or "chemotherapy" when treating with a chemotherapeutic agent) means 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; ethylene imines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemilolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecin including the synthetic analog topotecan; bryostatin, calicheamicin; CC-1065 including the adozelesin, carzelesin, and bizelesin synthetic analogs; cryptophycins, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin including the synthetic analogs KW-2189 and CBI-TMI; ellipticine; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, cyclophosphamide, glufosfamide, ifosfamide, melphalan, novembicin, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γII and calicheamicin φI1), dynemicin including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rhodomycin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as demopterin, methotrexate, pteropterin, and trimethoprexate; purine analogs, such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiampurine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, drostanolone propionate, epitioestanol, mepitiostane, and testolactone; antiadrenal drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; radiotherapy agents such as radium-223; trichothecenes, particularly T-2 toxin, verracurin A, roridin A, and anguidine; taxoids, such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel;Platinum analogs, such as cisplatin and carboplatin, NC-6004 nanoplatins; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine, hestrubucil; bisantrene; edatrexate; defofamine; demeclocycline; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rizoxin; schizophyllan; spirogermanium; tenuazonic acid; trabectedin, triaziquone; 2,2’,2’’-trichlorotriethylamine; 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; vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folic acid, 5-fluorouracil, irinotecan);FOLFOXIRI (folic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folic acid, 5-fluorouracil, irinotecan, oxaliplatin), and any pharmaceutically acceptable salts, acids, or derivatives thereof are included. Such agents can be conjugated to an antibody or any targeting agent described herein for making an antibody-drug conjugate (ADC) or a targeted drug conjugate.;

[0437] Anti-hormonal agent The definition of "chemotherapeutic agent" also includes anti-hormonal agents such as anti-estrogen agents and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgen agents, and any pharmaceutically acceptable salts, acids, or derivatives thereof that act to regulate or inhibit the hormonal action on tumors.

[0438] Examples of anti-estrogen agents and SERMs include, for example, tamoxifen (including NOLVADEX (trademark)), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON (registered trademark)).

[0439] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE (registered trademark)), exemestane, formestane, fadrozole, vorozole (RIVISOR (registered trademark)), letrozole (FEMARA (registered trademark)), and anastrozole (ARIMIDEX (registered trademark)).

[0440] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprorelin, goserelin, ODM-201, APC-100, and ODM-204.

[0441] An example of a progesterone receptor antagonist is onapristone.

[0442] Anti-angiogenic agent In some embodiments, the compounds described herein are combined with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necitumumab, 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 (curpain), sulfated chitin derivative (prepared from the shell of the Japanese spider crab), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, proline analogs such as l-azetidine-2-carboxylic acid (LACA) and modulators of matrix metabolism including cis-hydroxyproline, d,I-3,4-dehydroproline, 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, epothilone, fumagillin, sodium aurothiomalate, d-penicillamine, β-1-anticollagenase serum, α-2-antiplasmin, bisantrene, robenazyrlit disodium, disodium n-2-carboxyphenyl-4-chloroanthranyl ate or "CCA", thalidomide, angiogenesis-inhibiting steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod.Other anti-angiogenic agents include antibodies, for example, monoclonal antibodies against these angiogenic growth factors such as β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF and Ang-1 / Ang-2.

[0443] Anti-fibrotic agent In some embodiments, the compounds described herein are combined with an anti-fibrotic agent. Exemplary anti-fibrotic agents that can be co-administered include, but are not limited to, compounds such as beta-aminoproprionitrile (BAPN), and U.S. Patent No. 4,965,288 regarding the use of inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with abnormal deposition of collagen, and U.S. Patent No. 4,997,854 regarding compounds that inhibit LOX for the treatment of various pathological fibrotic conditions (these are incorporated herein by reference). Further exemplary inhibitors are described in U.S. Patent No. 4,943,593, U.S. Patent No. 5,021,456, U.S. Patent No. 5,059,714, U.S. Patent No. 5,120,764, U.S. Patent No. 5,182,297 regarding compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Patent No. 5,252,608 regarding 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication No. 2004 / 0248871, which are incorporated herein by reference.

[0444] Exemplary anti-fibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that produce a product stabilized by resonance after binding to the carbonyl, such as the following primary amines: emirenmamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine lactone.

[0445] Other antifibrotic agents are copper chelators that either penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that block aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamine, in particular 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)butanesulfate, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0446] Anti-inflammatory agent In some embodiments, the compounds described herein are combined with an anti-inflammatory agent. Exemplary anti-inflammatory agents include, but are not limited to, arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene: 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), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or an inhibitor of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, e.g., a dual inhibitor of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX.

[0447] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742) that can be co-administered include, but are not limited to, mofezolac, GLY-230, and TRK-700.

[0448] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that can be co-administered include, but are not limited to, diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maysosulide, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, simicoxib, deracoxib, flumizole, firocoxib, mabacoxib, NS-398, prasugrel, parecoxib, robenacoxib, rofecoxib, luteolin, tilmacoxib, and zaltoprofen. Examples of COX1 / COX2 dual inhibitors that can be co-administered include, but are not limited to, HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of COX-2 / carbonic anhydrase (CA) dual inhibitors that can be co-administered include, but are not limited to, pormacoxib and imrecoxib.

[0449] Examples of inhibitors of secreted phospholipase A2 and prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include, but are not limited to, LY3023703, GRC 27864, and those 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 2012 / 076673, WO 2012 / 076672, WO 2010 / 034798, WO 2010 / 034799, WO 2012 / 022792, WO 2009 / 103778, WO 2011 / 048004, WO 2012 / 087771, WO 2012 / 161965, WO 2013 / 118071, 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 2015 / 059618, WO 2016 / 069376, WO 2016 / 069374, WO 2009 / 117985, WO 2009 / 064250, WO 2009 / 064251, WO 2009 / 082347, WO 2009 / 117987, and WO 2008 / 071173. Furthermore, metformin has been found to suppress 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.

[0450] Examples of inhibitors of carbonic anhydrase (e.g., one or more of 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)) that can be co-administered include, but are not limited to, acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and dichlorphenamide. An example of a COX-2 / CA1 / CA2 dual inhibitor that can be co-administered is CG100649.

[0451] Examples of inhibitors of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that can be co-administered include, but are not limited to, meclofenamic acid sodium, zileuton.

[0452] Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that can be co-administered include, but are not limited to, the compounds described in International Publication No. WO 2015 / 148954. Examples of COX-2 / SEH dual inhibitors that can be co-administered include the compounds described in International Publication No. WO 2012 / 082647. Examples of dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that can be co-administered include the compounds described in International Publication No. WO 2017 / 160861.

[0453] Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) that can be co-administered include, but are not limited to, GS-4875, GS-5290, BHM-078, and those described, for example, in International Publication No. WO 2006 / 124944, International Publication No. WO 2006 / 124692, International Publication No. WO 2014 / 064215, International Publication No. 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.

[0454] Tumor oxygenating agent In some embodiments, the compounds described herein are combined with an agent that promotes or increases tumor oxygenation or reoxygenation, or prevents or reduces tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors such as PT-2977, PT-2385; VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and / or oxygen carrier proteins such as OMX-302 and HNOX proteins (e.g., heme-nitric oxide and / or oxygen binding protein (HNOX)) described in, for example, International Publication No. WO 2007 / 137767, International Publication No. WO 2007 / 139791, International Publication No. WO 2014 / 107171, and International Publication No. WO 2016 / 149562.

[0455] Immunotherapeutic agent In some embodiments, the compounds described herein are combined with an immunotherapeutic agent. Exemplary immunotherapeutic agents that can be co-administered include, but are not limited to, abagovomab, ABP-980, adecatumumab, afucosylated antibody, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, canertinib, catumaxomab, CC49, cetuximab, cixutumumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, daratumumab, daratumumab, detumomab, dinutuximab, dorzigomab, duligotumab, dusigitumab, eculizumab, erlotinib, emibetuzumab, enzastaurin, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, fucosylated antibody, ganitumab, gemtuzumab, glembatumumab, ibritumomab, igovomab, imiglucerase, indatuximab, inotuzumab, inteumomab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), irinotecan, labesfamide, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, mirvetuximab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naplitamab, nalatumomab, nesitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatumumab, pasotuxizumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab, samuraciclib, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, takatumumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, vedotin, volociximab, voratumumab, zalutumumab, and 3F8.Rituximab can be used to treat slow-progressing B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapeutic agents is particularly effective.

[0456] The exemplified therapeutic antibodies can further be labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y ibritumomab), or iodine 131.

[0457] In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Exemplary ADCs that can 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 can be co-administered include gemtuzumab, brentuximab, trastuzumab, inotuzumab, glenvacumab, anetumab, mirvetuximab, depatuxizumab, lobaplizumab, batatuximab, labesimab, sacituzumab, rifatuximab, indatuximab, polatuzumab, pinatuzumab, coltuximab, indatuximab, miratuximab, lobaplizumab, 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.

[0458] Exemplary therapeutic agents that can be conjugated to a drug conjugate antibody, a fragment thereof, or an antibody mimetic (e.g., an anti-cancer agent or an anti-tumor agent) include, but are not limited to, monomethyl auristatin E, monomethyl auristatin F, calicheamicin, ansamitocin, maytansine or an analog thereof (e.g., mertansine / DM1, ladostatin / sorladostatin (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA cross-linking agent SC-DR002 (D6.5), duocarmycin, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or a dimer thereof, duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065) and other anti-cancer agents or anti-tumor agents described herein.

[0459] Cancer gene therapy and cell therapy In some embodiments, the compounds described herein are combined with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include the insertion of a normal gene into cancer cells to replace a mutated or altered gene; gene modification to silence a mutated gene; genetic approaches to directly kill cancer cells, e.g., to enhance the immune response against cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to replace most of the patient's own immune system with immune cells designed to find and kill cancer cells; genetic approaches to modify cell activity to further alter the endogenous immunoreactivity against cancer.

[0460] 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, one or more co - administrations of a population of immune cells. In some embodiments, the immune cells are natural killer (NK) cells, NK - T cells, T cells, gamma - delta T cells, B cells, cytokine - induced killer (CIK) cells, macrophage (MAC) cells, tumor - infiltrating lymphocytes (TIL), granulocytes, innate lymphocytes, megakaryocytes, monocytes, macrophages, platelets, thymocytes, bone marrow cells, and / or dendritic cells (DC). In some embodiments, the cell therapy involves co - administration of a population of T - cell therapies, such as alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves co - administration of NK - cell therapy, such as NK - 92 cells. Optionally, the cell therapy may involve co - administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0461] In some embodiments, the 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, and the CAR comprises a tumor antigen - binding domain. In other embodiments, the population of immune cells is engineered to express a T - cell receptor (TCR) engineered to target a tumor - derived peptide presented 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.

[0462] 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 co-stimulatory domain, or both a primary signaling domain and a co-stimulatory domain. In some embodiments, the primary signaling domain is CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc epsilon, Rlb), CD79a, CD79b, Fc gamma RIIa, DAP10, and DAP12, 4-1BB / CD137, activating NK cell receptor, immunoglobulin protein, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 delta, CD3 epsilon, CD3 gamma, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8 alpha, CD8 beta, CD96 (Tactile), CD11a, CD11b, CD11c, CD11d, CDS, CEACAM1, CRT AM, cytokine receptor, DAP-10, DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, Ig alpha (CD79a), IL-2R beta, IL-2R gamma, IL-7R alpha, inducible T cell co-stimulator (ICOS), integrin, ITGA4, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, LFA-1, ligand binding to CD83, LIGHT, LIGHT, LTBR, Ly9 (CD229), Ly108), lymphocyte function-associated antigen-1 (LFA-1;comprises a functional signaling domain of one or more proteins selected from the group consisting of CD1-1a / CD18), MHC class 1 molecules, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG / Cbp, programmed death-1 (PD-1), PSGL1, SELPLG (CD162), signaling lymphocyte activation molecule (SLAM protein), SLAM (SLAMF1; CD150; IPO-3), SLAMF4 (CD244; 2B4), SLAMF6 (NTB-A, SLAMF7, SLP-76, TNF receptor protein, TNFR2, TNFSF14, Toll ligand receptor, TRANCE / RANKL, VLA1, or VLA-6, or fragments, cleavage, or combinations thereof.;

[0463] In some embodiments, the co-stimulatory domain specifically binds to a ligand 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, CD5, 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), CD1D (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 (BY55), 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, and comprises a functional domain of one or more proteins selected from the group consisting of.

[0464] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from a protein 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), GITR, 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), ITGB7, 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 activating NK cell receptor, immunoglobulin protein, BTLA, CD247, CD276 (B7-H3), CD30, CD84, CDS, cytokine receptor, Fc gamma receptor, GADS, ICAM-1, Ig alpha (CD79a), integrin, LAT, a ligand that binds to CD83, LIGHT, MHC class 1 molecule, PAG / Cbp, TNFSF14, Toll ligand receptor, TRANCE / RANKL, or a fragment, cleavage, or combination thereof.

[0465] In some embodiments, the CAR comprises a hinge domain. The hinge domain may be 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), CD150 (SLAMF1), CD158A (KIR2DL1), CD158B1 (KIR2DL2), CD158B2 (KIR2DL3), CD158C (KIR3DP1), CD158D (KIRDL4), CD158F1 (KIR2DL5A), CD158F2 (KIR2DL5B), CD158K (KIR3DL2), CD160 (BY55), CD162 (SELPLG), CD226 (DNAM1), CD229 (SLAMF3), CD244 (SLAMF4), CD247 (CD3-zeta), CD258 (LIGHT), CD268 (BAFFR), CD270 (TNFSF14), CD272 (BTLA), CD276 (B7-H3), CD279 (PD-1), CD314 (NKG...

Claims

Claim 1 Formula (I): 【Chemical 300】 [wherein, R １ is hydrogen, C １～６ alkyl, or halogen, and R ２ is hydrogen, C １～６ alkyl, or halogen, and R ３ is hydrogen, C １～６ alkyl, or halogen, and R ４ is hydrogen, C １～６ alkyl, or halogen, and R ７ is C １～６ alkyl optionally substituted with hydrogen or -OH, R ５ is C １～６ alkyl or C １～６ haloalkyl, and R ６ is phenyl which may be the same or different and is substituted with 1 to 3 Rs ６ａ or heteroaryl which may be the same or different and is optionally substituted with 1 to 3 Rs ６ａ wherein the heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently being N, O, or S 【Chemical 301】 is, 【Chemical 302】 and is, X ３ 、 X ４ 、 X ５ 、 and X ６ are each independently CH, N, or C—R ６ａ wherein, however, up to two of X ３ 、 X ４ 、 X ５ 、 and X ６ are N, and up to two of X ３ 、 X ４ 、 X ５ 、 and X ６ are C—R ６ａ wherein 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 optionally substituted with Each R ６ａ is independently halogen, C ２～８ alkynyl, phenyl, heterocycloalkyl, or heteroaryl, wherein the phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R ６ｅ each, and the alkynyl is optionally substituted with 1 to 4 R ６ｊ which may be the same or different, the heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently N, O, or S, and the heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently N, O, or S. Each R ６ｊ is, independently, halogen, C １～６ haloalkyl, -OR ６ｊ１ , -CN, -N(R ６ｊ１ )(R ６ｊ２ ), -N(R ６ｊ１ )(C(O)R ６ｊ２ , C ３～１０ cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1 to 3 R ６ｐ which may be the same or different, and said heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently being N, O, or S, and said heteroaryl is a 5- or 6-membered ring having 1 to 3 heteroatoms each independently being N, O, or S, Each R ６ｊ１ and R ６ｊ２ are, independently, hydrogen, C １～６ alkyl, C １～６ haloalkyl, or C １～６ cycloalkyl optionally substituted with C ３～１０ haloalkyl, Each R ６ｐ is independently halogen, C １～６ alkyl, C １～６ haloalkyl, -C(O)R ６ｐ１ , or heterocycloalkyl, wherein the heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently being N, O, or S, R ６ｐ１ is C １～６ alkyl, or C ３～１０ cycloalkyl, and Each R ６ｅ is independently C １～６ alkyl, C ３～６ cycloalkyl, heterocycloalkyl, halogen, C １～６ haloalkyl, or -CN, wherein said cycloalkyl and heterocycloalkyl are each optionally substituted with 1 to 3 R ６ｈ which may be the same or different, and said heterocycloalkyl is a 3- to 10-membered ring having 1 to 3 heteroatoms each independently selected from N, O, or S, Each R ６ｈ is independently C １～６ alkyl, C １～６ haloalkyl, =O, or -OH, and Each R ６ｇ is independently a C １～６ alkyl, halogen, C １～６ haloalkyl], or a pharmaceutically acceptable salt thereof. Claim 2 R ５ is -CH ２ CHF ２ ,-CH ２ CF ３ or Me, R ６ is phenyl substituted with C ２～８ alkynyl, wherein the alkynyl may be the same or different and is substituted with one or two R ６ｊ and The phenyl is optionally substituted with one additional R ６ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with ６ａ .

3. 【Fig. 309】 is, 【Chemical 310】 and is, n is 0, 1, or 2, 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 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with ６ｇ . Claim 4 Formula (Ia-2) 【Chemical 312】 [wherein, 【Chemical 313】 is, 【Chemical 314】 and is, n is 0, 1, or 2] The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Claim 5 Formula (Ia-4): 【Chemical 316】 [wherein n is 0, 1, or 2] The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Claim 6 Each R ６ａ is, independently, C ２～８ alkynyl or halogen, and the alkynyl is 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. Claim 7 Each R ６ｐ is independently Me, -CF ３ , -CH ２ F, -CF ２ CH ３ , or -CHF ２ , or a pharmaceutically acceptable salt thereof, of the compound according to claim 1. Claim 8 Each R ６ｊ is independently, -OH, -CN, -F, -OMe, -CHF ２ , or -CF ３ and is the compound according to claim 1, or a pharmaceutically acceptable salt thereof. Claim 9 Each R ６ｊ is, independently, C ３～６ cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, and the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1 to 3 R ６ｐ which may be the same or different, Each R ６ｐ is independently C １～３ alkyl, C １～３ haloalkyl, -C(O)R ６ｐ１ , or heterocycloalkyl, wherein the heterocycloalkyl is a 3- to 6-membered ring having 1 to 2 heteroatoms each independently being N, O, or S, R ６ｐ１ is C １～３ alkyl, or C ３～６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. Claim 10 Each R ６ａ is, independently, F, Br, 【Chemical 326】 【Chemical 327】 【Chemical 328】 is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. 【Chemical Formula 347】 is, 【Chemical 330】 is, The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

12. 【Fig. 331】 is, 【Chemical 348】 is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. 【Fig. 337】 is, 【Chemical 338】 and is, The compound according to claim 4, or a pharmaceutically acceptable salt thereof. Claim 14 R １ is hydrogen, F, or Cl, and R ２ is hydrogen, F, or Cl, and R ３ is hydrogen or F, and R ４ is hydrogen or F, and R ７ is hydrogen or C １～６ alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Claim 15 The following: 【Table 15-1】 【Table 15-2】 【Table 15-3】 【Table 15-4】 【Table 15-5】 【Table 15-6】 【Table 15-7】 【Table 15-8】 【Table 15-9】 【Table 15-10】 【Table 15-11】 【Table 15-12】 【Table 15-13】 【Table 15-14】 【Table 15-15】 【Table 15-16】 【Table 15-17】 【Table 15-18】 【Table 15-19】 【Table 15-20】 【Table 15-21】 【Table 15-22】 【Table 15-23】 【Table 15-24】 【Table 15-25】 【Table 15-26】 【Table 15-27】 【Table 15-28】 【Table 15-29】 【Table 15-30】 【Table 15-31】 【Table 15-32】 【Table 15-33】 【Table 15-34】 【Table 15-35】 【Table 15-36】 【Table 15-37】 【Table 15-38】 【Table 15-39】 【Table 15-40】 【Table 15-41】 【Table 15-42】 【Table 15-43】 【Table 15-44】 【Table 15-45】 【Table 15-46】 【Table 15-47】 【Table 15-48】 【Table 15-49】 【Table 15-50】 【Table 15-51】 【Table 15-52】 【Table 15-53】 【Table 15-54】 【Table 15-55】 【Table 15-56】 【Table 15-57】 【Table 15-58】 【Table 15-59】 【Table 15-60】 The compound shown in, or a pharmaceutically acceptable salt thereof. Claim 16 A compound having the following structure, 【Chemical 339】 or a pharmaceutically acceptable salt thereof. Claim 17 A compound having the following structure, 【Chemical 340】 or a pharmaceutically acceptable salt thereof. Claim 18 A compound having the following structure, 【Chemical 341】 or a pharmaceutically acceptable salt thereof. Claim 19 A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 and 15 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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