Ikaros zinc finger family degraders and uses thereof

Abstract

Providing methods of treating diseases SOLUTION: The present invention relates generally to compounds that bind to and act as degraders of IKAROS family zinc-finger (IKZF) proteins, such as IKZF2 (Helios) and / or IKZF4 (Eos). It further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and / or conditions through the binding and degradation of IKZF proteins, such as IKZF2 and / or IKZF4, including cancers. As explained in detail and demonstrated specifically herein, surprisingly, according to the invention, a significant effect is achieved, which the person skilled in the art could not have easily predicted from the prior art.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 321,030, filed March 17, 2022, and U.S. Provisional Patent Application No. 63 / 386,605, filed December 8, 2022, which are hereby incorporated by reference in their entireties for all purposes.

[0002] FIELD OF THE INVENTION The present disclosure relates to compounds that bind to and act as degraders of IKAROS family zinc finger (IKZF) proteins, such as IKZF2 (Helios) and / or IKZF4 (Eos). The disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions associated with one or more IKZF proteins, e.g., IKZF2- and / or IKZF4-associated diseases or conditions, where reducing IKZF2 and / or IKZF4 protein levels can ameliorate the disease or disorder.

[0003] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML copy created on February 21, 2023, is named 1423-WO-PCT.xml and is 2,747 bytes in size. [Background technology]

[0004] The IKAROS family of transcription factors includes five members: Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). Helios is approximately 50% identical to Ikaros, Aiolos, and Eos and binds to the same DNA consensus site. When coexpressed in cells, these four IKZF proteins can heterodimerize with each other. Ikaros, Helios, and Aiolos are primarily expressed in hematopoietic cells, whereas Eos and Pegasus are more widely expressed across different tissues.

[0005] Regulatory T cells (Tregs) are a subset of CD4+ T cells that maintain normal immune tolerance and homeostasis. Treg activity can also suppress antitumor immune responses. Helios is thought to be required for maintaining a stable Treg phenotype, particularly in the context of an inflammatory tumor microenvironment. Genetic Helios knockout in Tregs has been shown to reduce Treg immunosuppressive activity and induce an effector T cell phenotype. First-generation small molecule Helios degraders have demonstrated similar effects. Therefore, Helios has emerged as a promising immuno-oncology target. Furthermore, Helios degraders are expected to be useful in the treatment of chronic viral infections, which are also characterized by the presence of high levels of activated Tregs.

[0006] There remains a need for Helios degraders that have desirable selectivity, potency, metabolic stability, or reduced adverse effects. Summary of the Invention

[0007] The present disclosure provides compounds useful as degraders of IKAROS family zinc finger (IKZF) protein 2 (IKZF2; Helios). The present invention relates to the use of compounds for the treatment and / or prevention of diseases and / or conditions through binding and degradation of IKZF2 protein by the compounds.

[0008] In one embodiment, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H, -F, or -Cl; R 21 is -H, F, or -Cl; R 3 is -H, -F, or -Cl; R 4a and R 4b each independently represents -H, a halogen, -OH, or C 1~6 is alkyl, Ring A is C 3~10 is cycloalkyl or heterocyclyl, n is 0, 1, 2, 3, or 4; R 5 are each independently a halogen, ═O, ═CH2, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -O-(R 51 ), or -N(R 51 )(R 52 ) and R 5 ═CH2, alkyl, alkenyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, may be substituted by 1 to 4 R 5a and optionally substituted with R 5a are each independently a halogen, -CN, C 1~6 Alkyl, C 6~10 Aryl, or -O(R 51 ) and R, which can be the same or different 51 and R 52 are each independently -H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 6 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)N(R 1a )(R 1b ), -S(O)(NR 1a )(R 1b ), -C(O)R 1c , -S(O2)R 1c , or -C(O)OR 1d and R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)N(R 2a )(R 2b ), -S(O)(NR 2a )(R 2b ), -C(O)R 2c , S(O2)R 2c , or -C(O)OR 2d and R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 groups which may be the same or different Z 3and R 6 and R 7 is a 3-20 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, imino, -NO2, -N3, -CN, -OR 3a , -C(O)-R 3a , -C(O)OR 3a , -C(O)-N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )C(O)-R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -NR 3a S(O)2N(R 3b )(R 3c ), -NR 3a S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a, -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , -S(O)(NR 3a )N(R 3b )(R 3c ), -SF5, or -Si(R 3a )3, each Z 1 , Z 2 , or Z 3 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, -NO2, -CN, -N3, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )-C(O)R 3b , -N(R 3a )C(O)O(R 3b ), -N(R 3a )C(O)N(R 3b )(R 3c ),-N(R 3a )S(O)2(R 3b ), -N(R3a )S(O)2-N(R 3b )(R 3c ),-N(R 3a )S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , or -Si(R 3a )3, Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 Alkyl)(heteroaryl -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15-cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 Hello -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 optionally substituted with alkyl; R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c are each independently -H, C 1~9 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Each aryl in the compounds of formula (I) is C unless otherwise specified. 6~10 is aryl, Each heteroaryl in the compounds of Formula (I) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified; Each heterocyclyl in a compound of formula (I) is a 3-20 membered heterocyclyl having from 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified.

[0009] In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0010] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0011] In some embodiments, the present disclosure provides a method of inhibiting degradation of IKZF2 protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0012] In some embodiments, the present disclosure provides a method of treating a patient having an IKZF2 protein-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIa-9), (IIIb), (IIIb-10), (IIIb), (IIIb-11), (IIIb), (IIIb), (IIIb), (IIIc), (IIId), (IIIe), (IIIf ... (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0013] In some embodiments, the present disclosure provides a method of treating a cancer patient, the method comprising administering to the cancer patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0014] In some embodiments, the present disclosure provides use of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an IKFZ2-associated disease or condition.

[0015] In some embodiments, the disclosure provides use of a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

[0016] In some embodiments, the present disclosure provides a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein, for pharmaceutical use.

[0017] In some embodiments, the present disclosure provides a compound provided herein (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein, for the treatment of an IKFZ2-associated disease or condition.

[0018] In some embodiments, the present disclosure provides a method for the treatment of cancer comprising administering to a subject a compound provided herein. (e.g., a compound of Formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVb), (V), (Va), (VI), or (VIa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein. [Brief explanation of the drawings]

[0019] [Figure 1A] 1 shows the time course of IKZF2 (Helios) degradation in HEK293 cells. The compound of Example 46 (Compound 46; closed circles) and reference compounds A-1 (Compound A-1; closed squares) and B-4 (Compound B-4; closed triangles) were tested at a concentration of 12 nM. The percent IKZF2 remaining (normalized to the DMSO control) is plotted over time.

[0020] [Figure 1B] 1 shows the time course of IKZF2 (Helios) degradation in HEK293 cells. The compound of Example 2 (Compound 2; closed circles) and reference compounds B-3 (Compound B-3; closed squares) and C-1 (Compound C-1; closed triangles) were tested at a concentration of 111 nM. The percent IKZF2 remaining (normalized to the DMSO control) is plotted over time.

[0021] [Figure 2A] FIG. 1 shows plots of IKZF2 (Helios) degradation rate constants versus compound concentration observed in HEK293 cells for the compound of Example 46 (Compound 46; filled triangles) and reference compounds A-1 (Compound A-1; filled circles) and B-4 (Compound B-4; filled squares).

[0022] [Figure 2B] 1 shows a plot of IKZF2 (Helios) degradation rate constants versus compound concentration observed in HEK293 cells for the compound of Example 2 (Compound 2; filled triangles) and reference compounds B-3 (Compound B-3; filled circles) and C-1 (Compound C-1; filled circles).

[0023] [Figure 3A] 1 shows titration curves of IL-2 production in Jurkat cells IKZF2 (Helios) for the compounds of Example 328 (Compound 328; filled circles) and Example 84 (Compound 84; open squares), and reference compounds A-1 (Compound A-1; filled triangles) and B-4 (Compound B-4; filled squares).

[0024] [Figure 3B] 1 shows titration curves of IL-2 production in Jurkat cells IKZF2 (Helios) for the compounds of Example 287 (Compound 287; filled circles), Example 94 (Compound 94; open squares), Example 283 (Compound 283; open triangles), and Example 46 (Compound 46; filled triangles).

[0025] [Figure 3C] 1 shows a bar graph illustrating the Jurkat IL-2 production levels (compared to DMSO control) achieved at saturating compound concentrations for IKZF2 (Helios) degrader compounds of Examples 35, 46, 84, 94, 218, 283, 287, 328, and 369, and reference compounds A-1, B-2, and B-4. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present disclosure relates to degraders of IKAROS family zinc finger (IKZF) proteins, such as IKZF2 (Helios). The present disclosure also relates to compositions and methods related to IKZF2 protein degraders and the use of such compounds for the treatment and / or prevention of IKZF2-mediated diseases and conditions. The present disclosure also relates to compositions and methods for treating and / or preventing cancer or viral infections, including the combination of an IKZF2 protein degrader with one or more additional therapeutic agents.

[0027] It is generally believed that patients with certain IKZF2-mediated diseases, such as cancer and viral infections, may benefit from treatment with an IKZF2 protein degrading agent and, optionally, one or more additional therapeutic agents. Definitions and general parameters

[0028] The following description is made with the understanding that the present disclosure should be considered as an example of claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. It should be noted that as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art, etc.

[0030] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless a different meaning is suggested by the context in which they are used.

[0031] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may be depicted 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 the group. No directionality is indicated or implied by the order in which chemical groups are written or named, unless chemically or structurally required. A solid line projecting from the center of a ring indicates that the point of attachment of a substituent to that ring can be at any ring atom. For example, R in the following structure: a can be attached to any of the five carbon ring atoms, or the hydrogen attached to the nitrogen ring atom is Ra can be replaced with: [ka]

[0032] "C u~v The prefix "" indicates that the following group has carbon atoms u through v. For example, "C 1~6 The term "alkyl group" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x- to y-membered" ring, where x and y are numerical ranges (e.g., "3- to 12-membered heterocyclyl") means a ring having x to y atoms (e.g., 3 to 12), up to 80% of which may be heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon.

[0033] Also, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, or alkylyl groups, "arylene" or "arylenyl" groups, or aryl groups, respectively.

[0034] "Compounds disclosed herein" or "compounds of the present disclosure" or "provided herein" "Compound" or "compound described herein" refers to a compound of Formula (I), (Ia), (Ib), or (Ic). Also included are the specific compounds of Examples 1-339 provided herein.

[0035] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, for that term, "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0036] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), 1 to 4 carbon atoms (i.e., C 1~4 alkyl), or 1 to 3 carbon atoms (i.e., C 1~3 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0037] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0038] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0039] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0040] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment (alkyl-O-). With respect to alkyl groups, alkoxy groups include C 1~6 Any preferred It has a suitable number of carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. The alkoxy group can be further substituted with various substituents described herein. The alkoxy group can be substituted or unsubstituted.

[0041] "Alkoxyalkyl" refers to an alkoxy group linked to an alkoxy group which is linked to the rest of the compound. Alkoxyalkyl has 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C 2~5 alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3 The alkoxy and alkyl groups may have any suitable number of carbons, such as alkoxyalkyl. The number of carbons refers to the total number of carbons in the alkoxy and alkyl groups. For example, in some embodiments, Calkoxyalkyl refers to ethoxy (Calkoxy) linked to butyl (Calkyl), and in other embodiments, n-propoxy (Calkoxy) linked to isopropyl (Calkyl). Alkoxy and alkyl are as defined above, where alkyl is divalent and may include, but is not limited to, methoxymethyl (CHOCH-), methoxyethyl (CHOCHCH-), and the like.

[0042] "Amino" is -NR y R z refers to a group, wherein R y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which can be optionally substituted.

[0043] "Imino" refers to a group containing a carbon-nitrogen double bond having the structure: [ka] In the formula, R 1 , R 2, and R 3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which can be optionally substituted. 1 , R 2 , and R 3 Any one of the following can serve as the point of attachment.

[0044] As used herein, "aryl" refers to an all-carbon aromatic monocyclic ring or an all-carbon polycyclic ring system in which at least one of the rings is aromatic. For example, in some embodiments, aryl groups have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such polycyclic ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the polycyclic ring system. The rings of a polycyclic ring system can be connected to each other through fused, spiro, and bridged bonds, where valence requirements allow. When referring to an aryl having a particular range of atom numbers (e.g., a 6- to 10-membered aryl), it is also understood that the atom range refers to the total ring atoms of the aryl. For example, a 6-membered aryl includes phenyl, and a 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0045] "Cyano" or "carbonitrile" refers to the group --CN.

[0046] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to cycloalkenyl groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] "Fused" refers to a ring that is bonded to an adjacent ring. In some embodiments, the fused ring system is heterocyclyl. In some embodiments, the fused ring system is oxabicyclohexanyl. In some embodiments, the fused ring system is [ka] is.

[0048] "Bridged" refers to a ring fusion in which non-adjacent atoms on the ring are joined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems. In some embodiments, the bridged ring is bicyclopentyl (e.g., bicyclo[1.1.1]pentyl), bicycloheptyl (e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl), or bicyclooctyl (e.g., bicyclo[2.2.2]octyl). In some embodiments, the bridged ring is [ka] is.

[0049] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentanyl (spiro[ab]pentanyl), spirohexanyl, spiroheptanyl, spirooctyl (e.g., spiro[2.5]octyl), spirononanyl (e.g., spiro[3.5]nonanyl), spirodecanyl (e.g., spiro[4.5]decanyl), or spiroundecanyl (e.g., spiro[5.5]undecanyl). In some embodiments, the spiro substituent is [ka] is.

[0050] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0051] As used herein, "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by halo substituents, which may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 alkyl, 1~4 and C1-4 alkyl, in which one or more of the alkyl's hydrogen atoms are replaced by halo substituents. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0052] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to alkyl groups, haloalkoxy groups include C 1~6The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, or more. The alkoxy group may be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is persubstituted, e.g., perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0053] The term "heteroaryl," as used herein, refers to a single aromatic ring or a polycyclic ring. This term includes aromatic monocyclic rings of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The sulfur and nitrogen atoms may be present in oxidized form, provided the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. This term also includes polycyclic ring systems (e.g., ring systems containing two or three rings), and heteroaryl groups may be fused to one or more heteroaryl (e.g., naphthyridinyl), carbocycles (e.g., 5,6,7,8-tetrahydroquinolyl), or aryl (e.g., indazolyl), as defined above, to form a polycyclic ring. Such polycyclic rings may be optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the polycyclic ring. It is understood that the point of attachment of a heteroaryl polycyclic ring can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portions of the ring, as defined above. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, and thianaphthenyl.

[0054] "Heterocyclyl" or "heterocyclic ring" or "heterocycle" as used herein , refers to a single saturated or partially unsaturated ring or a polycyclic ring. The term includes saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. The term also includes polycyclic ring systems (e.g., ring systems containing two or three rings), in which a heterocyclic group (as defined above) may be connected to two adjacent atoms (fused heterocycles) with one or more heterocyclic rings (e.g., decahydronaphthyridinyl), heteroaryls (e.g., 1,2,3,4-tetrahydronaphthyridinyl), carbocyclic rings (e.g., decahydroquinolyl), or aryls. It is understood that the attachment point of the heterocyclic polycyclic ring can be at any position of the ring, including the heterocyclic, heteroaryl, aryl, or carbocyclic portion of the ring, as defined above. Exemplary heterocyclic rings include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl. Exemplary fused bicyclic heterocycles include, but are not limited to: [ka] Examples include:

[0055] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0056] "Oxo" refers to the (=O) or (O) radical.

[0057] "Sulfonyl" is -S(O)R c refers to a group, wherein R c is alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0058] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an —NH group unless otherwise indicated. Similarly, unless otherwise stated, hydrogen atoms are implied and considered to be present when necessary to complete valence or provide stability, given the knowledge of those skilled in the art.

[0059] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and if such event or circumstance occurs, The description is meant to include cases where the event or circumstance is absent, as well as cases where the event or circumstance is absent. Also, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0060] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanato, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining a substituent with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, if a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0061] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano; and "substituted sulfonyl" refers to the group -S(O)R, wherein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0062] In some embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl includes cycloalkyl, heterocyclyl, aryl, and / or heteroaryl having substituents on ring atoms, where the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the remainder of the compound. For example, in the moiety below, the cyclopropyl is substituted with a methyl group: [ka]

[0063] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, "comprising," "including," "containing," "including ... Terms such as "," "," and the like are to be read broadly and not limiting. Furthermore, the terms and expressions used herein are used as terms of description and not of limitation, and there is no intention to use such terms and expressions to exclude any equivalents of the features shown and described, or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure as claimed.

[0064] The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic and organic bases or acids. The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic and organic bases or acids. When a compound of the present disclosure contains one or more acidic or basic groups, the present disclosure also includes the corresponding pharmaceutically or toxicologically acceptable salts of the compound, particularly pharmaceutically acceptable salts of the compound. Thus, compounds of the present disclosure containing acidic groups may exist in these groups and can be used in accordance with the present disclosure, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to those skilled in the art. Compounds of the present disclosure that contain one or more basic groups, i.e., groups that can be protonated, may exist and may be used in the form of their addition salts with inorganic or organic acids in accordance with the present disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0065] When the compounds of the present disclosure simultaneously contain an acidic group and a basic group in the molecule, the present disclosure also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0066] The present disclosure also includes all salts of the compounds of the present disclosure that are not directly suitable for use in pharmaceuticals due to poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reacting with the base compounds to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the base compounds (as disclosed) are also well known. Methods are known to those skilled in the art and are disclosed, for example, in Berge, at al., Journal of Pharmaceutical Science, Jan. 1977, vol. 66, No. 1, and other sources.

[0067] Furthermore, the compounds disclosed herein may be subject to tautomerism. Where tautomerism, e.g., keto-enol tautomerism, of the compounds or their prodrugs may occur, the individual forms, e.g., keto and enol forms, are each within the scope of the present disclosure, as are mixtures thereof in any ratio. The same applies to stereoisomers, e.g., enantiomers, cis / trans isomers, diastereomers, conformers, etc.

[0068] The term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, 1999. & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions, e.g., to create and break chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0069] Those skilled in the art will understand that if the list of alternative substituents includes members that cannot be used to replace a particular group due to the valence requirements of the members or for other reasons, the list is intended to be read with the knowledge of one skilled in the art to include only those members of the list that are suitable to replace the particular group.

[0070] Additionally, compounds of the present disclosure may exist in the form of solvates, such as solvates that include pharmaceutically acceptable solvates such as water of solvation or alcohols, particularly ethanol. A "solvate" is formed by the interaction of a solvent and a compound.

[0071] In certain embodiments, optical isomers, racemates, or other mixtures thereof (e.g., scalenic mixtures) of the compounds described herein or pharmaceutically acceptable salts or mixtures thereof are provided. If desired, isomers can be separated by methods well known in the art, for example, liquid chromatography. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved, for example, by crystallization in the presence of a resolving agent, or by techniques such as chiral high-pressure liquid chromatography (HPLC). C) It can be achieved by conventional methods such as column chromatography.

[0072] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different, non-interchangeable three-dimensional structures. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. 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).

[0073] The compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, contain asymmetric centers and therefore may be (R)- or (S)- with respect to absolute stereochemistry. )-, or for amino acids, as (D)- or (L)-. Some embodiments include all such possible isomers, as well as their racemic, scalenic, and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or the isolation of the racemate (or salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). This includes resolution of E and Z geometric isomers (racemic compounds). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched form, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1. For example, in some embodiments, the compound [ka] is a specific diastereomerically or enantiomerically enriched form, or isoform A [ka] and isoform B [ka] It is understood to include either racemic or scalemic mixtures of.

[0074] Compositions provided herein containing the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, can include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer, or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0075] Any formula or structure given herein also includes unlabeled and isotopically labeled forms of the compound. It is also intended to represent the form. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include, but are not limited to: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14 C. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or for the detection of radioactive isotopes in patients. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by following the procedures disclosed in the schemes or in the examples and preparations described below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0076] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein, in which 1 to n hydrogens attached to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and may therefore be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g., a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends See Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0077] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure have improved drug metabolism and pharmacokinetic (DMPK) profiles with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies.

[0078] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0079] Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0080] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that constitute the carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure can encompass any composition made by mixing at least one compound of the present disclosure with a pharmaceutically acceptable carrier.

[0081] As used herein, "pharmaceutically acceptable carriers" includes additives or agents, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are not deleterious to the disclosed compounds or their use. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0082] "I C 50 " or "EC 50 " refers to the inhibitory concentration required to achieve 50% of the maximum desired effect. Often, the maximum desired effect here is degradation of the IKZF2 protein. This term is obtained using an in vitro protein degradation assay, such as the HiBiT protein tagging assay, which evaluates the concentration-dependent degradation of the IKZF2 protein. "D max" refers to maximal protein (eg, IKZF2 or IKZF1 protein) degradation at the highest compound concentration tested in the assay.

[0083] "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the severity of the disease or condition); b) delaying or arresting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, partial remission or complete resolution of the disease or condition). providing complete remission, enhancing the effect of another agent, delaying disease progression, improving quality of life, and / or prolonging survival. In some embodiments, the term "treatment" or "treating" refers to administering a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, for the purpose of (i) delaying the onset of the disease, i.e., preventing or delaying the onset of clinical symptoms of the disease, (ii) inhibiting the disease, i.e., preventing the onset of clinical symptoms, and / or (iii) relieving the disease, i.e., causing regression of clinical symptoms or their severity.

[0084] "Prevention" or "preventing" means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0085] As used herein, an "IKZF-associated disease or condition" (e.g., an IKZF2- or IKZF4-associated disease or condition) means that reducing IKZF protein levels (e.g., IKZF2 or IKZF4 protein levels) can ameliorate the disease or disorder. In some embodiments, in an IKZF-associated disease or condition, degradation of the IKZF2 protein can ameliorate the disease or disorder. In some embodiments, in an IKZF-associated disease or condition, degradation of the IKZF2 protein and one or more additional IKZF proteins (e.g., IKZF4 protein) can ameliorate the disease or disorder. In some embodiments, in an IKZF-associated disease or condition, degradation of the IKZF4 protein can ameliorate the disease or disorder.

[0086] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0087] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to effect treatment and provide a therapeutic benefit, such as amelioration of symptoms or slowing of disease progression, when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce symptoms of a disease or condition in response to an IKZF2 degrading agent. A therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0088] As used herein, "degrader" or "proteolytic agent" refers to any agent capable of binding to a protein and inducing protein degradation. Proteolytic agents are generally believed to induce targeted protein degradation through the recruitment of cellular ubiquitination and proteasome proteolytic machinery. For example, as used herein, "IKZF2 degrader" or "IKZF2 proteolytic agent" refers to any agent capable of binding to an IKZF2 protein and inducing degradation of the IKZF2 protein. In some embodiments, an IKZF2 degrader is IKZF2 selective. In some embodiments, an IKZF2 degrader can induce degradation of the IKZF2 protein and one or more additional IKZF2 proteins (e.g., IKZF1 or IKZF4).

[0089] IKZF2, also known as Helios, is a zinc finger transcription factor of the IKAROS family that is generally believed to be required for maintaining a stable Treg cell phenotype, particularly in inflammatory tumor microenvironments. In humans, IKZF2 or Helios protein is encoded by the IKZF2 gene. Exemplary reference sequences for IKZF2 (NCBI gene ID: 22807 (human); 22779 (mouse)) include NCBI reference sequences NP_001072994 (human protein), NP_035900 (mouse protein), NM_001079526 (human mRNA), and NM_0011770 (mouse mRNA). Related family members include IKZF1 (Ikaros; NCBI Gene ID: 10320 (human); 22778 (mouse)) and IKZF4 (Eos; NCBI Gene ID: 64375 (human); 22781 (mouse). The activity of IKZF (e.g., IKZF2) degraders can be measured by methods known in the art, such as those described and cited in Wang et al., 2021 Nature Chemical Biology 17, 711-717. In some embodiments, IKZF protein degradation is measured using a HiBiT protein tagging assay, such as the Nano Glo® HiBiT Extracellular Detection System (Promega).

[0090] Spalt-like protein 4 (SALL4) is a member of the Spalt-like (SALL) family of zinc finger transcription factors. In humans, the SALL4 protein is encoded by the SALL4 gene (NCBI Gene ID: 57167). SALL4 biology is described, for example, in Donovan et al., 2018 eLife 7:e38430 and Matyskiela et al. 2020 Nat Struct Mol Biol 27, 319-322. SALL4 degradation activity can be measured by any method known in the art. In some embodiments, SALL4 proteolysis is measured using a HiBiT system, such as the Nano Glo® HiBiT Extracellular Detection System (Promega). Measured using a protein tagging assay. [Table 28-1] [Table 28-2] compound

[0091] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H, -F, or -Cl; R 21 is -H, F, or -Cl; R 3 is -H, -F, or -Cl; R 4a and R 4b each independently represents -H, a halogen, -OH, or C 1~6 is alkyl, Ring A is C 3~10 is cycloalkyl or heterocyclyl, n is 0, 1, 2, 3, or 4; R 5 are each independently a halogen, ═O, ═CH2, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -O-(R 51 ), or -N(R 51 )(R 52 ) and R 5 ═CH2, alkyl, alkenyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, may be substituted by 1 to 4 R 5a and optionally substituted with R 5a are each independently a halogen, -CN, C 1~6 Alkyl, C 6~10 Aryl, or -O(R 51 ) and R, which can be the same or different 51 and R 52 are each independently -H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 6 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)N(R 1a )(R 1b ), -S(O)(NR 1a )(R 1b ), -C(O)R 1c , S(O2)R 1c , or -C(O)OR 1d and R 6each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)N(R 2a )(R 2b ), -S(O)(NR 2a )(R 2b ), -C(O)R 2c , S(O2)R 2c , or -C(O)OR 2d and R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3-20 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, imino, -NO2, -N3, -CN, -OR 3a, -C(O)-R 3a , -C(O)OR 3a , -C(O)-N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )C(O)-R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -NR 3a S(O)2N(R 3b )(R 3c ), -NR 3a S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , -S(O)(NR 3a )N(R 3b )(R 3c ), -SF5, or -Si(R 3a )3, each Z 1 , Z 2 , or Z 3 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, -NO2, -CN, -N3, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )-C(O)R 3b , -N(R 3a )C(O)O(R 3b ), -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -N(R 3a )S(O)2-N(R 3b )( R 3c ),-N(R 3a )S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , or -Si(R 3a )3, Z 1aalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~ 9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 optionally substituted with alkyl; R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c are each independently -H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Each aryl in the compounds of formula (I) is, unless otherwise specified, C 6~10 is aryl, each heteroaryl in the compounds of formula (I) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified; Provided is a compound or a pharmaceutically acceptable salt thereof, wherein each heterocyclyl in the compound of formula (I) is a 3- to 20-membered heterocyclyl having 1 to 4 heteroatoms, each independently being N, O, or S, unless otherwise specified.

[0092] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H, -F, or -Cl; R 21 is -H, R 3 is -H, -F, or -Cl; R 4a and R 4b each independently represents -H, a halogen, -OH, or C 1~6 is alkyl, Ring A is C 3~10 is cycloalkyl or heterocyclyl, n is 0, 1, 2, 3, or 4; R 5 are each independently halogen, ═O, —CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkoxy, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -O-(R 51 ), or -N(R 51 )(R 52 ) and R 5 alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 R 5a and optionally substituted with R 5aare each independently a halogen, -CN, C 1~6 Alkyl, C 6~10 Aryl, or -O(R 51 ) and R, which can be the same or different 51 and R 52 are each independently -H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 6 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)N(R 1a )(R 1b ), -S(O)(NR 1a )(R 1b ), -C(O)R 1c , -S(O2)R 1c , or -C(O)OR 1d and R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl-C(O)N(R 2a )(R 2b ), -S(O)(NR 2a )(R 2b ), -C(O)R 2c , S(O2)R 2c , or -C(O)OR 2d and R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3-20 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, imino, -NO2, -N3, -CN, -OR 3a , -C(O)-R 3a , -C(O)OR 3a , -C(O)-N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )C(O)-R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -NR 3a S(O)2N(R 3b )(R 3c ), -NR 3a S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , -S(O)(NR 3a )N(R 3b )(R 3c ), -SF5, or -Si(R 3a )3, each Z 1 , Z 2 , or Z 3 Each of the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different. 1 to 4 Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, -NO2, -CN, -N3, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )-C(O)R 3b , -N(R 3a )C(O)O(R 3b ), -N(R 3a)C(O)N(R 3b )(R 3c ),-N(R 3a )S(O)2(R 3b ), -N(R 3a )S(O)2-N(R 3b )(R 3c ),-N(R 3a )S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , or -Si(R 3a )3, Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 optionally substituted with alkyl; R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b, and R 3c are each independently -H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Each aryl in the compounds of formula (I) is, unless otherwise specified, C 6~10 is aryl, Each heteroaryl in the compounds of formula (I), unless otherwise specified, is independently N , O, or S; Each heterocyclyl in a compound of formula (I) is a 3-20 membered heterocyclyl having from 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified.

[0093] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H, -F, or -Cl; R 3 is -H, -F, or -Cl; R 4a and R 4b each independently represents -H, a halogen, -OH, or C 1~6 is alkyl, Ring A is C 3~10is cycloalkyl or heterocyclyl, n is 0, 1, 2, 3, or 4; R 5 are each independently halogen, ═O, —CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -O-(R 51 ), or -N(R 51 )(R 52 ) and R 5 alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 R 5a and optionally substituted with R 5a are each independently a halogen, -CN, C 1~6 Alkyl, C 6~10 Aryl, or -O(R 51 ) and R, which can be the same or different 51 and R 52 are each independently -H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 6 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, -C(O)N(R 1a )(R 1b ), -S(O)(NR 1a )(R 1b ), -C(O)R 1c , -S(O2)R 1c , or -C(O)OR 1d and R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z1 and optionally substituted with R 7 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, -C(O)N(R 2a )(R 2b ), -S(O)(NR 2a )(R 2b ), -C(O)R 2c , S(O2)R 2c , or -C(O)OR 2d and R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3-20 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, imino, -NO2, -N3, -CN, -OR 3a , -C(O)-R 3a , -C(O)OR 3a , -C(O)-N(R 3a )(R 3b), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )C(O)-R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -NR 3a S(O)2N(R 3b )(R 3c ), -NR 3a S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , -S(O)(NR 3a )N(R 3b )(R 3c ), -SF5, or -Si(R 3a )3, each Z 1 , Z 2 , or Z 3 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, -NO2, -CN, -N3, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )-C(O)R 3b , -N(R 3a )C(O)O(R 3b ), -N(R 3a )C(O)N(R 3b )(R 3c ),-N(R 3a )S(O)2(R 3b ), -N(R 3a )S(O)2-N(R 3b )(R 3c ),-N(R 3a )S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , or -Si(R 3a )3, Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C( O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 optionally substituted with alkyl; R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c are each independently -H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c Alkyl, alkenyl, alkynyl, cycloalkynyl each of which is selected from the group consisting of 1 to 4 Z, which may be the same or different; 1b and optionally substituted with Each aryl in the compounds of formula (I) is, unless otherwise specified, C 6~10 is aryl, each heteroaryl in the compounds of formula (I) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified; Each heterocyclyl in a compound of formula (I) is a 3-20 membered heterocyclyl having from 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified.

[0094] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H, -F, or -Cl; R 3 is -H, -F, or -Cl; R 4a and R 4b each independently represents -H, a halogen, -OH, or C 1~6 is alkyl, Ring A is C 3~10 is cycloalkyl or heterocyclyl, n is 0, 1, 2, 3, or 4; R 5 are each independently halogen, ═O, —CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -O-(R 51 ), or -N(R 51 )(R 52 ) and R 5 alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 R 5a and optionally substituted with R 5a are each independently a halogen, -CN, C 1~6 Alkyl, C 6~10 Aryl, or -O(R 51 ) and R, which can be the same or different 51 and R 52 are each independently -H, C 1~6 Alkyl, C3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 6 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, -C(O)N(R 1a )(R 1b ), -S(O)(NR 1a )(R 1b ), -C(O)R 1c , -S(O2)R 1c , or -C(O)OR 1d and R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, aryl, heteroaryl-C(O)N(R 2a )(R 2b ), -S(O)(NR 2a )(R 2b ), -C(O)R 2c , S(O2)R 2c , or -C(O)OR 2d and R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7is a 3-20 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, ═O, imino, -NO2, -N3, -CN, -OR 3a , -C(O)-R 3a , -C(O)OR 3a , -C(O)-N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )C(O)-R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -NR 3a S(O)2N(R 3b )(R 3c ), -NR 3a S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a, -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , -S(O)(NR 3a )N(R 3b )(R 3c ), -SF5, or -Si(R 3a )3, each Z 1 , Z 2 , or Z 3 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, =O, -NO2, -CN, -N3, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), -N(R 3a )2(R 3b ) + , -N(R 3a )-C(O)R 3b , -N(R 3a )C(O)O(R 3b ), -N(R 3a )C(O)N(R 3b )(R 3c ), -N(R 3a )S(O)2(R 3b ), -N(R 3a )S(O)2-N(R 3b )(R 3c),-N(R 3a )S(O)2O(R 3b ), -OC(O)R 3a , -OC(O)OR 3a , -OC(O)-N(R 3a )(R 3b ), -SR 3a , -S(O)R 3a , -S(O)(NH)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NR 3a )R 3b , or -Si(R 3a )3, Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 -C(O)O(aryl), -C(O)O(heteroaryl) , -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15-cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2 is optionally substituted, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c are each independently -H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1a , R 1b , R1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with each heteroaryl in the compounds of formula (I) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified; Each heterocyclyl in a compound of formula (I) is a 3-20 membered heterocyclyl having from 1 to 4 heteroatoms, each independently N, O, or S, unless otherwise specified.

[0095] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 21 is -H, R 3 is -H or -F, R 4a and R 4b are each independently -H, -F, or -CH; Ring A is a cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, or tetrahydropyranyl ring; n is 0, 1, or 2; R 5 are each independently -F, -OH, -CH3, ═CH2, -CH2-OH, or -O-CH3; R 6 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3- to 12-membered heterocyclyl having 0-3 additional heteroatoms, each independently being N, O, or S; Z 1 , Z 2 , or Z 3 are each independently deuterium, halogen, =O, -CN, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, or -OR 3a and each Z 1 , Z 2 , or Z 3alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 3a , or -S(O)R 3a in can be, Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, or -CN; Z 1b wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted; R 3a are each independently -H, C 1~9 Alkyl, C 6~10 aryl or heteroaryl, and R 3a each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1band optionally substituted with each heteroaryl of the compound of Formula (I) or Formula (Ia) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl in a compound of Formula (I) or Formula (Ia) is a 3-20 membered heterocyclyl having 1 to 4 heteroatoms which are each independently N, O, or S.

[0096] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 21 is -H or -F, R 3 is -H or -F, R 4a is -H, -F, or -CH3, and R 4b is -H, Ring A is [ka] and n is 0, 1, or 2; R 5 are each independently -F, -OH, -CH3, ═CH2, -CH2-OH, or -O-CH3; R 6 -H or one Z 1 C optionally substituted with 1~6 is alkyl, and Z 1 is non-substituted, R 7 But -H, C 1~8 Alkyl, C 3~12 Cycloalkyl, C 6~10 a 4- to 12-membered heterocyclyl having 1 to 2 heteroatoms independently selected from aryl, nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 7each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3- to 7-membered heterocyclyl optionally having an additional N; Z 1 , Z 2 , or Z 3 are each independently deuterium, halogen, =O, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~15 Cycloalkyl, C 6~10 aryl, heterocyclyl, heteroaryl, or -OR 3a and Z 1 , Z 2 , or Z 3 each of the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one to four Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, halogen, -CN, or -S(O)R 3a and Z 1a each alkyl is 1 to 4 Z 1b and optionally substituted with Z 1b are each independently a halogen, C 3~15 Cycloalkyl, or C 6~10 is aryl, Z1b wherein the cycloalkyl or aryl is each unsubstituted; R 3a independently, C 1~9 Alkyl or C 6~10 aryl, and R 3a each of the alkyl or aryl groups may be the same or different from 1 to 4 Z 1b and optionally substituted with each heteroaryl of the compound of formula (I) or formula (Ia) is a 5-6 membered heteroaryl having one or two heteroatoms which are each independently N or S; Each heterocyclyl in a compound of formula (I) or formula (Ia) is a 3-7 membered heterocyclyl having 1 to 2 heteroatoms which are each independently N or O.

[0097] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments of the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 3 is -H or -F, R 4a and R 4b are each independently -H, -F, or -CH; Ring A is a cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, or tetrahydropyranyl ring; n is 0, 1, or 2; R 5 are each independently -F, -OH, -CH3, ═CH2, -CH2-OH, or -O-CH3; R 6 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3-12 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 are each independently deuterium, halogen, =O, -CN, C 1~9 Alkyl, C 1~8 Haloalkyl, C1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, or -OR 3a and each Z 1 , Z 2 , or Z 3 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may be the same or different, and 1 to 4 Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 3a , or -S(O)R 3a and Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, or -CN; Z 1bwherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted; R 3a are each independently -H, C 1~9 Alkyl, C 6~10 aryl or heteroaryl, and R 3a each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 b and optionally substituted with Each heteroaryl in the compounds of Formula (I) or Formula (Ia) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl in a compound of Formula (I) or Formula (Ia) is a 3-20 membered heterocyclyl having 1 to 4 heteroatoms which are each independently N, O, or S.

[0100] In some embodiments of the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 3 is -H or -F, R 4a and R 4b are each independently -H, -F, or -CH; Ring A is a cyclopentyl, cyclohexyl, cyclohexenyl, or tetrahydropyranyl ring; n is 0, 1, or 2; R 5 are each independently -F, -OH, -CH3, or -O-CH3; R 6 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10aryl, heteroaryl, R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~8 Alkyl, C 1~6 Haloalkyl, C 3~12 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 7 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3- to 12-membered heterocyclyl having 0-3 additional heteroatoms, each independently being N, O, or S; Z 1 , Z 2 , or Z 3 are each independently deuterium, halogen, =O, -CN, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, or -OR 3a and each Z 1 , Z 2 , or Z 3alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 3a , or -S(O)R 3a and Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, or -CN; Z 1b alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl aryl, or heteroaryl is each unsubstituted; R 3a are each independently -H, C 1~9 Alkyl, C 6~10 aryl or heteroaryl, and R 3a each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1band optionally substituted with Each heteroaryl in the compounds of Formula (I) or Formula (Ia) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl in a compound of Formula (I) or Formula (Ia) is a 3-20 membered heterocyclyl having 1 to 4 heteroatoms which are each independently N, O, or S.

[0101] In some embodiments, the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 3 is -H or -F, R 4a and R 4b are each independently -H or -F; Ring A is a cyclohexyl, cyclohexenyl, or tetrahydropyranyl ring; n is 0, R 6 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, R 6 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 7 But -H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; R 7each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3-12 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; Z 1 , Z 2 , or Z 3 are each independently halogen, ═O, —CN, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, or -OR 3a and each Z 1 , Z 2 , or Z 3 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with Z 1a However, each independently, -D, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C6~10 Aryl, heteroaryl, -CN, -OR 3a , or -S(O)R 3a and Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, or -CN; Z 1b wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted; R 3a are each independently -H, C 1~9 Alkyl, C 6~10 aryl or heteroaryl, and R 3a each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Each heteroaryl in the compounds of Formula (I) or Formula (Ia) is a 5-12 membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl in a compound of Formula (I) or Formula (Ia) is a 3-20 membered heterocyclyl having 1 to 4 heteroatoms which are each independently N, O, or S.

[0102] In some embodiments of the compound of Formula (I), Formula (Ia), or Formula (1b), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2is -H or -F, R 3 is -H or -F, R 4a is -H, -F, or -CH3, and R 4b is -H, Ring A is [ka] and n is 0, 1, or 2; R 5 are each independently -F, -OH, -CH3, ═CH2, -CH2-OH, or -O-CH3; R 6 -H or one Z 1 C optionally substituted with 1~6 is alkyl, and Z 1 is non-substituted, R 7 But -H, C 1~8 Alkyl, C 3~12 Cycloalkyl, C 6~10 a 4- to 12-membered heterocyclyl having 1 to 2 heteroatoms each independently selected from aryl, nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; R 7 each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7 is a 3- to 7-membered heterocyclyl optionally having an additional N; Z 1 , Z 2 , or Z 3 are each independently deuterium, halogen, =O, C1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~15 Cycloalkyl, C 6~10 aryl, heterocyclyl, heteroaryl, or -OR 3a and Z 1 , Z 2 , or Z 3 each of the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one to four Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, halogen, -CN, or -S(O)R 3a and Z 1a each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b are each independently a halogen, C 3~15 Cycloalkyl, or C 6~10 is aryl, Z 1b wherein the cycloalkyl or aryl is each unsubstituted; R 3a independently, C 1~9 Alkyl or C 6~10 aryl, and R 3a each of the alkyl or aryl groups may be the same or different from 1 to 4 Z 1b and optionally substituted with each heteroaryl of the compound of formula (I) or formula (Ia) is a 5-6 membered heteroaryl having one or two heteroatoms which are each independently N or S; Each heterocyclyl in a compound of formula (I) or formula (Ia) is a 3-7 membered heterocyclyl having 1 to 2 heteroatoms which are each independently N or O.

[0103] In some embodiments of the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 3 is -H or -F, R 4a is -H, -F, or -CH3, and R 4b is -H, Ring A is [ka] and n is 0, 1, or 2; R 5 are each independently -F, -OH, -CH3, or -O-CH3; R 6 -H or one Z 1 C optionally substituted with 1~6 is alkyl, and Z 1 is non-substituted, R 7 But -H, C 1~8 Alkyl, C 3~12 Cycloalkyl, C 6~10 a 4- to 12-membered heterocyclyl having 1 to 2 heteroatoms each independently selected from aryl, nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; R 7 each of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R7 formed by heterocyclyl is a 3- to 7-membered heterocyclyl optionally having an additional N; Z 1 , Z 2 , or Z 3 are each independently deuterium, halogen, =O, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~15 Cycloalkyl, C 6~10 aryl, heterocyclyl, heteroaryl, or -OR 3a and Z 1 , Z 2 , or Z 3 each of the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one to four Z 1a and optionally substituted with Z 1a are each independently deuterium, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, halogen, -CN, or -S(O)R 3a and Z 1a each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b are each independently a halogen, C 3~15 Cycloalkyl, or C 6~10 is aryl, Z 1b wherein the cycloalkyl or aryl is each unsubstituted; R 3a independently, C 1~9 Alkyl or C 6~10 aryl, and R 3a each of the alkyl or aryl groups may be the same or different from 1 to 4 Z 1b and optionally substituted with each heteroaryl of the compound of formula (I) or formula (Ia) is a 5-6 membered heteroaryl having one or two heteroatoms which are each independently N or S; Each heterocyclyl in a compound of formula (I) or formula (Ia) is a 3-7 membered heterocyclyl having 1 to 2 heteroatoms which are each independently N or O.

[0104] In some embodiments of the compound of Formula (I), Formula (Ia), or Formula (Ib), or a pharmaceutically acceptable salt thereof, R 1 is -H, R 2 is -H or -F, R 3 is -H or -F, R 4a and R 4b are -H, respectively, Ring A is [ka] and n is 0, R 6 -H or one Z 1 C optionally substituted with 1~6 is alkyl, and Z 1 is non-substituted, R 7 But -H, C 1~6 Alkyl, C 3~10 cycloalkyl, or heterocyclyl; R 7 each of the alkyl, cycloalkyl, or heterocyclyl groups is selected from 1 to 4 Z 2 optionally substituted with R 6 and R 7 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 3 and R 6 and R 7is a 3- to 7-membered heterocyclyl optionally having an additional N; Z 1 , Z 2 , or Z 3 are each independently halogen, ═O, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, or -OR 3a and Z 1 , Z 2 , or Z 3 each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1a and optionally substituted with Z 1a However, each independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, halogen, -CN, or -S(O)R 3a and Z 1a each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with Z 1b are each independently a halogen, C 3~15 Cycloalkyl, or C 6~10 is aryl, Z 1b wherein the cycloalkyl or aryl is each unsubstituted; R 3a independently, C 1~9 Alkyl or C 6~10 aryl, and R 3a each of the alkyl or aryl groups may be the same or different from 1 to 4 Z 1b and optionally substituted with each heteroaryl of the compound of formula (I) or formula (Ia) is a 5-6 membered heteroaryl having one or two heteroatoms which are each independently N or S; Each heterocyclyl in a compound of formula (I) or formula (Ia) is a 3-7 membered heterocyclyl having 1 to 2 heteroatoms which are each independently N or O.

[0105] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIb): [ka] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIc): [ka] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IId): [ka] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIe): [ka] or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIf): [ka] or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, has the formula: IIg) compounds, [ka] or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIh): [ka] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIi): [ka] or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIj): [ka] or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIk): [ka] or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 4b In some embodiments of a compound of Formula (I), (Ia), (Ib), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 5 is, each independently, -F, -OH, -CH3, or -O-CH3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 6 But it is -H.

[0117] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 6 But C 1~6 Alkyl or C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 6 But unsubstituted C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 6 but, [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 6 is -CH3 or [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 7 But Z 2 One or two halogens or C 6~10 C, each optionally substituted with aryl 1~6 Alkyl or C 3ー10 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), or a pharmaceutically acceptable salt thereof, R 7 However, each Z 2 C optionally substituted with one or two -F or phenyl 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R7 but, [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, , R 7 but, [ka] is.

[0118] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIIa) [ka] or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIa-1): [ka] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIa-2): [ka] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIIa-3). [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3) or a pharmaceutically acceptable salt thereof, R 7 But -H, C 1~8 Alkyl, C 3~12 Cycloalkyl, C 6~10 aryl, 4-12 membered heterocyclyl having 1 to 2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, or 5-12 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; R 7 each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 2 and optionally substituted with Z 2 are each independently deuterium, halogen, =O, -CN, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~10 Cycloalkyl, C 6~10 5-12 membered heteroaryl having 1 to 3 heteroatoms each independently selected from aryl, nitrogen, oxygen, and sulfur, or —C(O)—R 3a and R 3a is -H or unsubstituted C 1~6 is alkyl, and Z 2 C 1~6 Each alkyl is selected from 1 to 3 Z 1a and optionally substituted with Z 1a are independently cyano or C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3) or a pharmaceutically acceptable salt thereof, R 7But -H, C 1~8 Alkyl, C 3~12 Cycloalkyl, C 6~10 aryl, 4-12 membered heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-12 membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 7 each of the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 2 and optionally substituted with Z 2 are each independently deuterium, halogen, =O, -CN, C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~10 Cycloalkyl, C 6~10 Aryl, or -C(O)-R 3a and R 3a is -H or unsubstituted C 1~6 is alkyl, and Z 2 C 1~6 The alkyl is one to three Z 1a and optionally substituted with Z 1a each independently represents cyano or C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3), or a pharmaceutically acceptable salt thereof, R 7 But -H, C 1~6 Alkyl, C 3~12 cycloalkyl, or 4-12 membered heterocyclyl having heteroatoms selected from nitrogen and oxygen; R 7 and the alkyl, cycloalkyl, or heterocyclyl is selected from 1 to 3 Z 2 and optionally substituted with Z 2 are each independently halogen, ═O, C 1~6Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, or -C(O)-R 3a and R 3a is -H or unsubstituted C 1~6 A compound of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3) or a pharmaceutically acceptable salt thereof. In some embodiments of the salt, R 7 But -H, C 1~8 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, oxetanyl, oxepanyl, dioxanyl, oxaspiro[3.3]heptyl, oxaspiro[3.5]nonyl, oxabicyclo[3.2.1]octyl, (3aR,6aS)-hexahydro-1H-cyclopenta[c]furanyl, bicyclo[3.2.1]octyl, (1R,5S)-bicyclo[3.1.0]hexyl, (1R,5S)-bicyclo[3.2.0]heptyl, (3aR,6aS)-2-methylo oxahydropentalenyl, (1R,5S)-6,6-dimethylbicyclo[3.1.0]hexyl, spiro[2.4]heptyl, 7,7-difluoro-spiro[3.5]nonanyl, (4s,7s)-1-oxaspiro[3.5]nonanyl, (4r,7r)-oxaspiro[3.5]nonanyl, oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.2.1]octanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, tetrahydrothiopyranyl, 2,3-dihydro-1H-indel, chroman, or 4,5,6,7-tetrahydro-1H-indazolyl, each of which may be the same or different, and 2 and optionally substituted with Z 2and each independently is deuterium, =O, -CN, -CH, -CH-O-CH-CH-CN, -O-CH-O-CF-CF-O-C2H5-O-C3H7, -C(O)-CH, -F, cyclopropyl, phenyl, triazolyl, or pyridyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3) or a pharmaceutically acceptable salt thereof, R 7 But -H, C 1~8 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, oxetanyl, oxepanyl, dioxanyl, oxaspiro[3.3]heptyl, oxaspiro[3.5]nonyl, oxabicyclo[3.2.1]octyl, (3aR,6aS)-hexahydro-1H-cyclopenta[c]furanyl, bicyclo[3.2.1]octyl, (1R,5S)-bicyclo[3.1.0]hexyl, (1R,5S)-bicyclo[3.2.0]heptyl, (3aR,6aS)-2-methylo oxahydropentalenyl, (1R,5S)-6,6-dimethylbicyclo[3.1.0]hexyl, spiro[2.4]heptyl, 7,7-difluoro-spiro[3.5]nonanyl, (4s,7s)-1-oxaspiro[3.5]nonanyl, (4r,7r)-oxaspiro[3.5]nonanyl, oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.2.1]octanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, tetrahydrothiopyranyl, 2,3-dihydro-1H-indel, chroman, or 4,5,6,7-tetrahydro-1H-indazolyl, each of which may be the same or different, and 2 and optionally substituted with Z 2is, each independently, deuterium, =O, -CN, -CH, -CH-O-CH, CH-CN, -O-CH, -O-CF, -CF, -O-C2H, -O-C3H, -C(O)-CH, -F, cyclopropyl, or phenyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3), or a pharmaceutically acceptable salt thereof, R 7 But -H, C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, oxetanyl, oxaspiro[3.3]heptyl, oxaspiro[3.5]nonyl, oxabicyclo[3.2.1]octyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, or tetrahydrothiopyranyl, each of which may be the same or different, and 2 and optionally substituted with Z 2 are each independently ═O, -CH3, -CF3, -O-C2H5, -C In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3), or a pharmaceutically acceptable salt thereof, R 7 But -H, [ka] [ka] [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3) or a pharmaceutically acceptable salt thereof, R 7 But -H, [ka] [ka] [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), or (IIIa-3), or a pharmaceutically acceptable salt thereof, R 7 But -H, [ka] is.

[0122] In some embodiments, the compound of Formula (I), (IIa), (IId), or (IIIa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IVa): [ka] q is 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments of the compound of Formula (IVa), or a pharmaceutically acceptable salt thereof, q is 1 or 2. In some embodiments of the compound of Formula (IVa), or a pharmaceutically acceptable salt thereof, q is 1.

[0124] In some embodiments, the compound of Formula (I), (IIa), (IId), (IIIa), or (IVa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IVa-1): [ka] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound of Formula (I), (IIa), (IId), (IIIa), or (IVa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IVa-2): [ka] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, Z 2 -OR 3a ,C 3~15 cycloalkyl, 4-14 membered heterocyclyl having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; C 6~10 a 5-14 membered heteroaryl having 1 to 2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur; Z 2 each of which may be the same or different, 1 to 4 Z 1a and optionally substituted with Z 1a independently, deuterium, cyano, halogen, C 1~6 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, or -S(O)R 3a and R 3a However, each independently, C 1~9 Alkyl or C 6~10 aryl, and R 3aIn some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIa), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, Z 2 But, -OR 3a , cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl thiazolyl, pyrazolyl, pyridyl, or pyrazinyl, each of which has one or three Z 1a and optionally substituted with Z 1a are each independently cyano, -F, -Cl, -OCH3, -CF3, or phenyl; R 3a are each independently methyl, ethyl, or phenyl; R 3a In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIa), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, Z 2 But, -OR 3a , cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, phenyl, naphthyl, thiazolyl, pyrazolyl, pyridyl, or pyrazinyl, each of which is substituted by one or two Z 1a and optionally substituted with Z 1a are each independently cyano, -F, -Cl, -OCH3, or -CF3, and R 3a are each independently methyl, ethyl, or phenyl; R 3aIn some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, Z 2 but, [ka] is. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, Z 2 but, [ka] is.

[0127] In some embodiments, the compound of Formula (I), (IIa), (IId), or (IIIa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IVb): [ka] Z 2 may each be the same or different, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 2 However, each independently, C 1~6 Alkyl, C 3~15 cycloalkyl, 4-14 membered heterocyclyl having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; C6~14 Aryl, or C 1~6 alkoxy, each of which is one or three Z 1a and optionally substituted with Z 1a are each independently halogen, cyano, ═O, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, or C 6~14 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, are aryl. 2 However, each independently, C 1~6 Alkyl, C 3~15 cycloalkyl, 4-14 membered heterocyclyl having 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, C 6~14 Aryl, or C 1~6 alkoxy, each of which is one or three Z 1a and optionally substituted with Z 1a are each independently a halogen, a cyano, or a C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~14 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, are aryl. 2 However, each independently, C 1~6 Alkyl, C 3~15 Cycloalkyl, C 6~14 Aryl, or C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 2are each independently methyl, ethyl, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, bicyclo[1.1.1]pentanyl, phenyl, or thiopyranyl, and each independently one or three Z 1a and each Z 1a is independently -F, -CH, -CHF, -CN, =O, or cyclopropyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 2 are each independently methyl, ethyl, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, bicyclo[1.1.1]pentanyl, or phenyl, and each independently one or three Z 1a and each Z 1a is independently -F, -CH, -CHF, -CN, or cyclopropyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 2 are each independently -CH3, -C2H5, [ka] is. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 2 are each independently -CH3, -C2H5, [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), or (IVb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 2 However, each independently, -CH3 [ka] is.

[0129] In some embodiments, the compound of Formula (I), (IIa), or (IId), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIIb), [ka] p or q, which may be the same or different, are each independently 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments of the compound of Formula (IIIb), or a pharmaceutically acceptable salt thereof, p and q are each 1. In some embodiments of the compound of Formula (IIIb), or a pharmaceutically acceptable salt thereof, Z, which may be the same or different, 1 or Z 2 are each independently -H, C 6~10 aryl or a 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; Z 1 or Z 2 In some embodiments of the compound of Formula (IIIb) or a pharmaceutically acceptable salt thereof, Z 1 or Z 2 and each independently represent hydrogen, unsubstituted phenyl, or unsubstituted tetrahydropyranyl. In some embodiments of a compound of Formula (IIIb), or a pharmaceutically acceptable salt thereof, Z 1 or Z 2 However, each independently, [ka] is.

[0131] In some embodiments, the compound of Formula (I), (IIa), or (IId), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIIc): [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments of the compound of Formula (IIIc) or a pharmaceutically acceptable salt thereof, Z 3 -H, C 6~10 Aryl or -OR 3a and R 3a -H, C 1~6 Alkyl or C 6~10 aryl, and R 3a The alkyl and aryl are each selected from halogen, C 3~10 Cycloalkyl, or C 6~10 Optionally substituted aryl In some embodiments of the compound of Formula (IIIc), or a pharmaceutically acceptable salt thereof, Z 3 is methyl, phenyl, or -OR 3a and R 3a is methyl, ethyl, or phenyl, and R 3a In some embodiments of the compound of Formula (IIIc), or a pharmaceutically acceptable salt thereof, Z is optionally substituted with -Cl, cyclopropyl, or phenyl, respectively. 3 but, [ka] is.

[0133] In some embodiments, the compound of Formula (I), (IIa), or (IId), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIId): [ka] or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIId), or a pharmaceutically acceptable salt thereof, Z 3 But Z 1a One C of 6~10 C optionally substituted with aryl 1~6 is alkyl, and Z 1a C 6~10 Aryl is Z 1b In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIId), or a pharmaceutically acceptable salt thereof, Z 3 But Z 1a methyl optionally substituted with one phenyl of the formula 1a The phenyl in Z 1b In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIId), or a pharmaceutically acceptable salt thereof, Z 3 but, [ka] is.

[0135] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIIe): [ka] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIe), or a pharmaceutically acceptable salt thereof, R 7 But C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIe), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] is.

[0137] In some embodiments, the compound of Formula (I), (IIc), or (IIf), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IIIf): [ka] or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf), or a pharmaceutically acceptable salt thereof, R 7 But C 1~8 Alkyl, C 3~12 cycloalkyl, or a 4- to 12-membered heterocyclyl having 1 to 2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; R 7 each of the alkyl, cycloalkyl, or heterocyclyl groups is selected from 1 to 3 Z 2 and optionally substituted with Z 2 are each independently deuterium, halogen, C 3~10 Cycloalkyl, C 1~8 Alkyl, C 1~8 Haloalkyl, C1~6 Alkoxy, C 1~6 haloalkoxy, or a 4- to 12-membered heterocyclyl having 1 to 2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; Z 2 C 1~6 The alkyl of each , 1 to 3 Z 1a and optionally substituted with Z 1a each independently represents a halogen or C 1~6 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf), or a pharmaceutically acceptable salt thereof, R 7 But C 1~8 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, piperidyl, or tetrahydroindazolyl, and one to three Z, which may be the same or different. 2 and optionally substituted with Z 2 are each independently deuterium, -F, -CH3, -CHF2, -CH2, -CHF2, -CF3, CH2, -CF3, -O-CH3, -O-CHF2, -CH2, -O-CH3, -O-C3H7, cyclobutyl, oxetanyl, or tetrahydropyranyl, wherein the cyclobutyl, oxetanyl, or tetrahydropyranyl is each optionally substituted with 1 to 3 -F. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf) or a pharmaceutically acceptable salt thereof, R 7 But C 1~8 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, spiro[3.5]nonanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, or piperidyl, each of which may be the same or different, and 1 to 3 Z 2and optionally substituted with Z 2 are each independently deuterium, -F, -CH3, -CHF2, -CH2, -CHF2, -CF3, CH2, -CF3, -O-CH3, -O-CHF2, -CH2, -O-CH3, -O-C3H7, cyclobutyl, oxetanyl, or tetrahydropyranyl, wherein the cyclobutyl, oxetanyl, or tetrahydropyranyl is each optionally substituted with 1 to 3 -F. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf) or a pharmaceutically acceptable salt thereof, R 7 C optionally substituted with 1 to 3 halogens 3~12 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf), or a pharmaceutically acceptable salt thereof, R 7 is cyclohexyl optionally substituted with 1 to 3 -F. In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] In some embodiments of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIIf), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] is.

[0139] In some embodiments of the compounds of Formula (I), (Ia) or (IIa) or pharmaceutically acceptable salts thereof, R 1 In some embodiments of a compound of Formula (I), (Ia), (IIb), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, R 2 is -H or -F. In some embodiments of a compound of Formula (I), (Ia), (IIb), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, R 2 In some embodiments of a compound of Formula (I), (Ia), (IIb), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, R 2In some embodiments of a compound of Formula (I), (Ia), (IIb), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, R 3 is -H or -F. In some embodiments of a compound of Formula (I), (Ia), (IIb), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, R 3 In some embodiments of a compound of Formula (I), (Ia), (IIb), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, R 3 In some embodiments of a compound of Formula (I), (Ia), (Ib), (IId), (IIe), (IIIf), (IIg), (IIh), or (IIi), or a pharmaceutically acceptable salt thereof, R 4a and R 4b are -H, respectively.

[0140] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 is -H or -F, R 21 is -H or -F, R 3 is -H or -F, R 7 But C 1~8 Alkyl or C 3~12 is cycloalkyl, R 7 each of the alkyl or cycloalkyl groups may be the same or different, and ... 2 and optionally substituted with Z 2 are each independently deuterium, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 6~10 It is aryl.

[0141] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of Formula (Va): [ka] or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments of the compound of Formula (V) or (Va), or a pharmaceutically acceptable salt thereof, R 2 is -H and R 2a is -H and R 3 is —H or —F. In some embodiments of the compound of Formula (V) or (Va), or a pharmaceutically acceptable salt thereof, R 7 But C 1~8alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, bicyclo[3.2.1]octyl, (1R,5S)bicyclo[3.1.0]hexyl, (1R,5S)bicyclo[3.2.0]heptyl, spiro[2.4]heptyl, each of which may be the same or different, 1 to 3 Z 2 and optionally substituted with Z 2 is, each independently, deuterium, —CH—C—F, —CHF, —CF, —F, or phenyl. In some embodiments of a compound of Formula (V) or (Va), or a pharmaceutically acceptable salt thereof, R 7 1-2 Z's which may be the same or different 2 C, each optionally substituted with 1~3 alkyl or cyclohexyl, Z 2 is, each independently, hydroxy, fluoro, or phenyl. In some embodiments of a compound of Formula (V) or (Va), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] [ka] In some embodiments of the compound of Formula (V) or (Va), or a pharmaceutically acceptable salt thereof, R 7 but, [ka] is.

[0143] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 7 1 to 4 Z's which may be the same or different 2 C optionally substituted with 3~12 is cycloalkyl, Z 2 are each independently deuterium, halogen, C 1~3 Alkyl, or C 1~3 It is haloalkyl.

[0146] In some embodiments, the compound of formula (VI), or a pharmaceutically acceptable salt thereof, is a compound of formula (VIa): [ka] or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments of the compound of Formula (VI) or (VIa), or a pharmaceutically acceptable salt thereof, R 7 1 to 4 Z's which may be the same or different 2 cyclohexyl optionally substituted with Z 2 is each independently deuterium, —CH, —CF, —CHF, —CF, or —F. In some embodiments,

[0148] In some embodiments, the compound of formula (VI), or a pharmaceutically acceptable salt thereof, is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the compound of formula (VI), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound of Formula (I) or (IId), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the compound of Formula (I), (IIk), or (IIIa-1), or a pharmaceutically acceptable salt thereof, is [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound of Formula (I) or (IIb), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, a compound of Formula (I) or (IIc), or a pharmaceutically acceptable salt thereof, Acceptable salts are: [ka] or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the compound of Formula (I) or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound of Formula (I) or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the compound of Formula (I) or (IIg), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound of Formula (I) or (IIh), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the compound of Formula (I) or (IIi), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the compound of Formula (I) or (IIj), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound of Formula (I) or (IIk), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound of Formula (I), (Ia), or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compound of Formula (I), (Ib), or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound of Formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the compound of Formula (I), (Ia), or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the compound of Formula (I), (Ib), or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the compound of Formula (I), (Ia), or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the compound of Formula (I), (Ib), or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the compound of Formula (I), (Ia), or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the compound of Formula (I), (Ib), or (IIc), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the present disclosure provides a racemic mixture comprising a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a racemic mixture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a scalemic mixture comprising a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a scalemic mixture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0183] Those skilled in the art will recognize the groups disclosed herein (e.g., R 1 ) each and every embodiment of the remaining groups (e.g., R 2 , R 3 , Z 1 , Z 2 It is recognized that each of the above-described compounds (I), (II), (III), (IV), (IV), (IV), (V), (VI), (VII ... Pharmaceutical Compositions and Modes of Administration

[0184] Furthermore, the present disclosure provides pharmaceutical compositions comprising, as an active ingredient, at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0185] The pharmaceutical compositions of the present disclosure may further include one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0186] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (intranasal or buccal inhalation) or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts.

[0187] In practical use, the compounds of the present disclosure can be combined as active ingredients in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. for oral liquid preparations such as suspensions, elixirs, and solutions, or starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. for oral solid preparations such as powders, hard capsules, soft capsules, and tablets, and solid oral preparations are preferred over liquid preparations.

[0188] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of active compound in these compositions can, of course, be varied and may conveniently be from about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compound can also be administered intranasally, for example, as drops or spray.

[0189] Tablets, pills, capsules, etc. may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid, etc., lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0190] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0191] In some embodiments, the compounds of the present disclosure can also be used as salts with various counter cations to obtain orally available formulations.

[0192] The compounds of the present disclosure can also be administered parenterally.These active compounds can be prepared in water, suitably mixed with a surfactant such as hydroxypropylcellulose, in a solution or suspension.Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0193] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the forms are sterile. It must be fluid to the extent that easy syringability is possible. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0194] Any suitable route of administration can be used to provide an effective dose of a compound of the present disclosure to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compound of the present disclosure is administered orally. kit

[0195] Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0196] Also provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, in a suitable container, which can be a vial, bottle, ampoule, pre-filled syringe, and infusion bag. Treatment Methods and Uses

[0197] The compounds provided herein or pharmaceutically acceptable salts thereof, or compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, can be used for pharmaceutical purposes. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof, or compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, are for treating an IKFZ2-related disease or condition. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof, or compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, are for treating cancer. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof, or compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, can be used for the manufacture of a medicament for the treatment of an IKFZ2-related disease or condition. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof, or compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, can be used for the manufacture of a medicament for the treatment of cancer.

[0198] The present disclosure further relates to the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of a disease and / or condition mediated by the binding and degradation of an IKZF protein (e.g., an IKZF2 or IKZF4 protein) by the compound. Furthermore, the present disclosure relates to the use of the compound, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and / or prevention of an IKZF-related disease and / or condition mediated by the binding and degradation of an IKZF protein (e.g., an IKZF2 or IKZF4 protein) by the compound. In some embodiments, the IKZF-related disease or condition is alleviated by selective degradation of the IKZF2 protein. In some embodiments, the IKZF-related disease or condition is alleviated by degradation of the IKZF2 protein. In some embodiments, the IKZF-related disease or condition is alleviated by degradation of the IKZF2 protein. In some embodiments, the IKZF-associated disease or condition is alleviated by degradation of the IKZF2 protein and one or more additional IKZF2 proteins (e.g., IKZF1 and / or IKZF4 protein). In some embodiments, the IKZF-associated disease or condition is alleviated by degradation of the IKZF4 protein.

[0199] In some embodiments, the IKZF-associated disease and / or condition is an IKZF2-associated disease and / or condition. In some embodiments, the IKZF2-associated disease or condition is alleviated by selective degradation of the IKZF2 protein. In some embodiments, the IKZF2-associated disease and / or condition is alleviated by degradation of the IKZF2 protein and one or more additional IKZF proteins (e.g., IKZF1 and / or IKZF4 protein).

[0200] The medicaments referred to herein can be prepared by conventional processes comprising combining a compound according to the present disclosure with a pharmaceutically acceptable carrier.

[0201] In some embodiments, a method for treating and / or preventing an IKZF protein (e.g., an IKZF2 protein) associated disease or condition in a patient in need thereof includes administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (

[0023] Provided herein are methods comprising administering a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, a method for degrading an IKZF protein (e.g., an IKZF2 protein) includes administering to a patient in need thereof (e.g., a patient having an IKZF protein-associated disease or condition) a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), (VI (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof.

[0203]

[0023] In some embodiments, there is provided a method for reducing proliferation of a cell, comprising treating the cell with a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIi), (IIIj), (IIIk), (IIIi), (IIIi), (IIIj), (IIIi ... Provided herein are methods comprising contacting a cell with a compound of formula (Illa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, and reducing IKZF protein (e.g., IKZF2 protein) levels in the cell.

[0204] In some embodiments, a method for decreasing IKFZ protein (e.g., IKZF2 protein) levels in a patient in need thereof (e.g., a patient having an IKZF2-associated disease or condition) includes administering to the patient a therapeutically effective amount of a compound represented by Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2),

[0013] Provided herein are methods comprising administering a compound of Formula (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition comprises cancer. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a malignant tumor. In some embodiments, the cancer comprises a metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies. In some embodiments, more than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "hot" cancers or tumors). In some embodiments, the cancer cells More than about 1% and less than about 50% detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "warm" cancers or tumors). In some embodiments, less than about 1% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancers or tumors).

[0206] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition is a hematological cancer, e.g., leukemia (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), anaplastic leukemia, lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), primary macroglobulinemia (WM)), and / or myeloma (e.g., multiple myeloma (MM)).

[0207] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition is an epithelial tumor (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasia), a ductal tumor (e.g., adenocarcinoma, adenoma, adenomyoma), a mesenchymal or soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, chondroma, chondrosarcoma, alveolar soft part sarcoma, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), and lymphoma.

[0208] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition includes a solid tumor in or arising from a tissue or organ, e.g., Bone (e.g., ameloblastoma, aneurysmal bone cyst, angiosarcoma, chondroblastoma, chondroma, chondromyxofibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid, osteoma, periosteal chondroma, desmoid, Ewing's sarcoma); Lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumor); Esophagus (e.g., Barrett's esophagus, dysplasia, and adenocarcinoma); Gastrointestinal tract (including stomach (e.g., gastric adenoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric carcinoid, gastric sarcoma, neuroendocrine carcinoma, primary gastric squamous cell carcinoma, gastric adenocarcinoma), small intestine and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, and anus); Pancreas (e.g., serous neoplasms (including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, von Hippel-Lindau (VHL)-associated serous cystic neoplasm, and serous cystadenocarcinoma); mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), intraductal tubular neoplasm, cystic acinar neoplasm (including acinar cell cystadenoma, acinar cell cystadenocarcinoma, and pancreatic adenocarcinoma), invasive ductal adenocarcinoma (including tubular adenocarcinoma, adenomatous adenocarcinoma, and adenocarcinoma of the pancreas) including squamous cell carcinoma), mucinous carcinoma, medullary carcinoma, hepatocarcinoma-like carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumor, neuroendocrine microadenoma, neuroendocrine tumor (NET), neuroendocrine carcinoma (NEC) (including small cell or large cell NEC), islet cell adenoma, gastrinoma, glucagonoma, serotoninoma, somatostatinoma, VIPoma, solid pseudopapillary tumor (SPN), pancreatoblastoma); Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); Neuroendocrine (e.g., adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma); Thyroid gland (e.g., poorly differentiated (anaplastic) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma); liver (e.g., adenoma, mixed hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal tumor, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, cholangiocyst adenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor); Kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, renal clear cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, renal mucinous tubular spindle cell carcinoma, renal neoplasm, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); Breast (e.g., invasive ductal carcinoma (including but not limited to acinic cell carcinoma, adenoid cystic carcinoma, apocrine adenocarcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, malignant oncocytoma, papillary carcinoma, sebaceous gland carcinoma, secretory carcinoma, tubular carcinoma); lobular carcinoma, including but not limited to pleomorphic carcinoma, signet ring cell carcinoma; Peritoneum (e.g., mesothelioma; primary peritoneal cancer); Ovary (e.g., choriocarcinoma, epithelial tumor, germ cell tumor, sex cord-stromal tumor), fallopian tube (e.g., serous adenocarcinoma, mucinous carcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblastic tumor), uterus (e.g., cervical carcinoma, endometrial polyp, endometrial hyperplasia, carcinoma in situ (EIC)), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasm), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumor), mixed epithelial and mesenchymal tumor (e.g., Female genital tissues, including adenofibroma, carcinoma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma (MMMT)), endometrial stromal tumor, malignant mixed Müllerian tumor of the endometrium, gestational trophoblastic tumor (partial hydatidiform mole, complete hydatidiform mole, invasive hydatidiform mole, placenta accreta tumor), vulva, and vagina; Male reproductive tissues, including the prostate, testes (e.g., germ cell tumors, spermatocytic seminomas), and penis; Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); Brain (e.g., gliomas (e.g., astrocytomas (including non-invasive, low-grade, poorly differentiated, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurinomas), craniopharyngiomas, chordoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, pituitary tumors); Eyes (e.g., retinoma, retinoblastoma, intraocular melanoma, posterior uveal melanoma, iris hamartoma); Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal carcinoma (including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, and combined laryngeal carcinoma), carcinoma in situ, verrucous, spindle cell, and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, and laryngeal sarcoma)), head and neck paraganglioma (e.g., carotid body paraganglioma, vagus nerve paraganglioma); · Thymus (e.g., thymoma); Heart (e.g. cardiac myxoma); Lungs (e.g. small cell carcinoma (SCLC), non-small cell lung cancer (NSCLC) (including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, pleuropulmonary blastoma); Lymphatic (e.g., lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL), Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (including B-cell lymphoma and T-cell lymphoma (e.g., Burkitt's lymphoma); large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T-cell lymphoma, nasal type; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; and systemic T-cell lymphoma), lymphangioleiomyomatosis); Central nervous system (CNS) (e.g., gliomas (astrocytomas (e.g., pilocytic astrocytoma, pilocytic myxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrous astrocytoma, large round cell astrocytoma, protoplasmic astrocytoma, undifferentiated astrocytoma) cell tumors, glioblastomas (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and gliomatosis cerebri), oligodendrogliomas (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., Subependymomas, myxopapillary ependymomas, ependymomas (e.g., cellular, papillary, clear cell, elongated ependymal cell), poorly differentiated ependymomas, optic gliomas, and non-gliomas (including, e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paraspinal nerve tumors, and astrocytic region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, neuroblastoma group tumors (neuroblastoma, ganglioneuroblastoma, ganglioneuromatosis), and trisomy 19 ependymomas; Neuroendocrine tissues (e.g., including the preganglionic system (adrenal medulla (pheochromocytoma) and extra-adrenal paraganglioma (extra-adrenal paraganglioma)); Skin (including, for example, clear cell hidradenoma, cutaneous benign fibrous histiocytoma, cylindroma, hidradenoma, melanoma (cutaneous melanoma, mucosal melanoma), pilomatricoma, and Spitz tumor); and Soft tissue (e.g., invasive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, protuberant dermatofibroma) The patient has a solid tumor arising from a tissue or organ selected from the group consisting of sarcoma, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastoma, embryonal rhabdomyosarcoma, Ewing's sarcoma / neuroectodermal tumor (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipoma-like tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft tissue, myoepithelial carcinoma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, hemangiopericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, and well-differentiated liposarcoma.

[0209] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition is a cancer selected from lung cancer, colorectal cancer, breast cancer, prostate cancer, cervical cancer, pancreatic cancer, and head and neck cancer. In some embodiments, the cancer is metastatic.

[0210] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition is a cancer selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, and gastrointestinal stromal tumor (GIST). In some embodiments, the cancer is metastatic. Dosage

[0211] The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated, and such dosage may be readily ascertained by one skilled in the art.

[0212] When treating or preventing a disease or condition associated with an IKZF protein (e.g., an IKZF2 protein) for which a compound of the present disclosure is indicated, satisfactory results are generally obtained when the compound of the present disclosure is administered at a daily dosage of about 0.1 milligrams to about 300 milligrams per kilogram of animal body weight. In some embodiments, the compound of the present disclosure is administered as a single daily dose, in divided doses two to six times daily, or in sustained-release form. For most large mammals, the total daily dosage is about 1 milligram to about 1000 milligrams, or about 1 milligram to about 50 milligrams. For a 70 kg adult human, the total daily dosage would generally be about 0.1 milligrams to about 200 milligrams. This dosage regimen can be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dose is from about 1 milligram to about 900 milligrams, from about 1 milligram to about 800 milligrams, from about 1 milligram to about 700 milligrams, from about 1 milligram to about 600 milligrams, from about 1 milligram to about 400 milligrams, from about 1 milligram to about 300 milligrams, from about 1 milligram to about 200 milligrams, from about 1 milligram to about 100 milligrams, from about 1 milligram to about 50 milligrams, from about 1 milligram to about 20 milligrams, or from about 1 milligram to about 10 milligrams.

[0213] The compounds of the present application or compositions thereof can be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compounds can continue for several days; for example, treatment typically lasts for at least 7, 14, or 28 days per treatment cycle. Treatment cycles alternate periodically, with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments.

[0214] In some embodiments, the method includes administering to a subject an initial daily dose of about 1-800 mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice weekly, or weekly. It is possible. combination

[0215] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents is one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is two additional therapeutic agents, in some embodiments, the one or more additional therapeutic agents is three additional therapeutic agents, in some embodiments, the one or more additional therapeutic agents is four additional therapeutic agents.

[0216] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is two additional therapeutic agents, in some embodiments, the one or more additional therapeutic agents is three additional therapeutic agents, in some embodiments, the one or more additional therapeutic agents is four additional therapeutic agents.

[0217] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist, or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (e.g., monospecific and multispecific antibodies in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimic (e.g., adnectin, affibody molecule, affilin, affimer, afftin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein, and the like). proteins, DARPins®, finomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifying or editing agents, cells containing chimeric antigen receptors (CARs), e.g., T cell immune cells, The therapeutic agent may be an engineered T cell receptor (TCR-T) containing immunotherapeutic, NK cell immunotherapeutic, or macrophage immunotherapeutic, or any combination thereof. Exemplary Targets

[0218] In some embodiments, the one or more additional therapeutic agents are targeted to a target such as, for example, Examples of suitable anti-cancer agents include inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or suppressors of a polypeptide or polynucleotide. These include 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); absent in melanoma 2 (AIM2; NCBI Gene ID: 9447); acetyl-CoA acylation transferase 2 (ACAA2; NCBI Gene ID: 10499); acid phosphatase 3 (ACP3; NCBI Gene ID: 55); adenosine deaminase (ADA, ADA1; NCBI Gene ID: 100); adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI Gene IDs: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha-fetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene IDs: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (A NGPT1, ANGPT2; NCBI Gene ID: 284, 285); angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis-inducing factor mitochondrial-associated 1 (AIFM1, AIF; NCBI Gene ID: 9131); arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG;NCBI Gene ID: 374569); ASTERADE homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472); ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI Gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI Gene ID: 546 Gene ID: 558); B and T lymphocyte-associated (BTLA, CD272; NCBI Gene ID: 151888); Baculovirus IAP repeat-containing protein (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene ID: 329, 330, 331, 332); Basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 682); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; N NCBI Gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene ID: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-carboxyglutamic acid protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptor (e.g., BDKRB1, BDKRB2; NCBI Gene ID: 623, 624 ); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004);Cancer / testis antigens (e.g., CTAG1A, CTAG1B; CTAG2; NCBI Gene ID: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene ID: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363); carbonic anhydrase (CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene ID: 759, 760, 761, 762, 763, 765, 766 , 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI Gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI Gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene IDs: 836, 840, 841, 86 4); catenin β1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC motif chemokine ligand 21 (CCL21; NCBI Gene ID: 6366); CC motif chemokine receptor 2 (CCR2; NCBI Gene ID: 729230); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); N NCBI Gene ID: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NCBI Gene ID: 8317); cell communication network factor 2 (CCN2; NCBI Gene ID: 1490); cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2);NCBI Gene ID: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropic hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene ID: 9074, 51208); markers of cluster of differentiation (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD3 beta (TR) B), CD gamma (TRG), CD delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD55 (DAF), CD58 (LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CSF1R), CD116(GMCSFR, CSF2RA) , CD122(IL2RB), CD123(IL3RA), CD128(IL8R1), CD132(IL2RG), CD135(FLT3), CD137(TNFRSF9, 4-1BB), CD142(TF, TFA), CD1 52(CTLA4), CD160, CD182(IL8R2), CD193(CCR3), CD194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223 (LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, ; 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI Gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI Gene IDs: 2155, 2159); collagen type IV alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5) ; NCBI Gene ID: 1282, 1284, 1285, 1286, 1287); collectin subfamily member 10 (COLEC10; NCBI Gene ID: 10584); colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene ID: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene ID: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI Gene ID: 10987); C-type lectin C-X-C motif chemokine ligand 12 (CXCL12; NCBI gene ID: 6387); C-X-C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184)); ;NCBI Gene ID: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI Gene ID: 595); cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene ID: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI Gene ID: 900);Cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductases (; POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicases (e.g., DDX5, DDX6, DDX58; NCBI Gene IDs: 1655, 1656, 23586); delta-like canonical Notch ligands (e.g., DLL3, DLL4; NCBI Gene ID : 10683, 54567); diabloIAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinase (e.g., DGKA, DGKZ; NCBI Gene ID: 1606, 8525); Dickkopf WNT signaling pathway inhibitor (e.g., DKK1, DKK3; NCBI Gene ID: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719) dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI Gene ID: 780, 4921); DNA-dependent protein kinase (PRKDC; NCBI Gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, T OP2B, TOP3A, TOP3B; NCBI Gene IDs: 7150, 7153, 7155, 7156, 8940); dopachrome tautomer (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 5169); EMAP-like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene IDs: 51752, 64167); enhancer of zeste2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4); NCBI Gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epidermal mitogen (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene ID: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI Gene ID: 1973, 1984); exopolitin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, FASL, CD95 L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI Gene ID: 83416); fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191);Fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene IDs: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene IDs: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF; NCBI Gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1) ), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI Gene ID: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI Gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); Phosphokinase (Fururin, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534); galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene IDs: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate transfer receptor 1 (GRM1; NCBI Gene ID: 2911); glutaminase (GLS; NCBI Gene ID: 2912) I Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI Gene ID: 10457);Growth differentiation factor 2 (GDF2, BMP9; NCBI gene ID: 2658); growth factor receptor-binding protein 2 (GRB2, ASH; NCBI; Gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI Gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI Gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK; NCBI Gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), H SP90B1 (GP96); NCBI Gene ID: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene ID: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatic growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associated 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone deacetylases (e.g., HDAC1, HDAC7, HDAC9; NCBI Gene IDs: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IK ZF1 (LYF1), IKZF3; NCBI Gene ID: 10320, 22806); immunoglobulin superfamily member 11 (IGSF11; NCBI Gene ID: 152404); indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI Gene ID: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI Gene ID: 3480, 3482);Insulin-like growth factors (e.g., IGF1, IGF2; NCBI Gene ID: 3479, 3481); insulin receptor (INSR, CD220; NCBI Gene ID: 3643); integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene ID: 3678, 3685, 3688, 3695, 3698); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene ID: 3383); interleukin-1 Receptor-associated kinase 4 (IRAK4; NCBI Gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI Gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8 (CXCL8), IL10 (TGIF), IL 12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-29 (IFNL1); NCBI Gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); isocitrate dehydrogenase (NADP()1) (e.g., IDH1, IDH2; NCBI Gene IDs: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI Gene IDs: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI gene ID: 354); killer cell immunoglobulin-like receptors, Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J);NCBI gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57; 292, 553128, 548594, 100132285); killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene ID: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1; NCBI Gene ID: 3814); KIT proto-oncogene, receptor tyrosine kinase (KIT, c-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene, GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4035) ; leucine-rich repeat-containing 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI gene ID: 27076); lymphocyte activation 3 (LAG3; CD223; NCBI gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI gene ID: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI gene ID: 3937); Lysine demethylase 1A (KDM1A; NCBI Gene ID: 23028); lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI Gene ID: 1902); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase-like 2 (LOXL2, NCBI Gene ID: 4017); macrophage migration inhibitor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136; NCBI Gene ID: 4486);MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 514 38, 266740); major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene ID: 3105, 3133, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK 2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene IDs: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator; Regulatory factors, BCL2 family members (MCL1; NCBI Gene ID: 4170); MDM2 oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI Gene ID: 2475); melan-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene ID: 4157, 41 48); MER proto-oncogene, tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN; NCBI Gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequence (e.g., MICA, MICB; NCBI Gene ID: 4277, 10 0507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2, NCBI Gene ID: 4217, 1326); mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene ID: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125);NCBI Gene IDs: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, MAGE family members (NDN; NCBI Gene ID: 4692); nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI Gene IDs: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene IDs: 8828, 8829); neurotrophin receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (T RKB), NTRK3 (TRKC); NCBI Gene ID: 4914, 4915, 4916); NFKB-activating protein (NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase ( NRAS; NCBI Gene ID: 4893); nuclear factor kappa B (NFKB1, NFKB2; NCBI Gene ID: 4790, 4791); nuclear factor, erythroid 2-like 2 (NFE2L2; NRF2; NCBI Gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); nucleolin (NCL; NCBI Gene ID: 4691); nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); nucleotide-binding oligomerization domain-containing 2 (NOD2; NCBI Gene ID: 64127);Nudix hydrolase 1 (NUDT1; NCBI Gene I; D:4521); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI Gene ID: 4255); Opioid receptor delta 1 (OPRD1; NCBI Gene ID: 4985); Ornithine decarboxylase 1 (ODC1; NCBI Gene ID: 4953); Oxoglutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); Parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); Periostin (POSTN ; NCBI Gene ID: 10631); peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene IDs: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA (PI3K alpha), PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3 CG (PI3K gamma); NCBI Gene ID: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI Gene ID: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogene, serine / threonine kinases (e.g., For example, PIM1, PIM2, PIM3; NCBI Gene ID: 5292, 11040, 415116); placental growth factor (PGF); NCBI Gene ID: 5228); plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptors (for example, PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene ID: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364);poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); polo-like kinase 1 (PLK1; NCBI Gene ID: 5347); poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL; NCBI Gene ID: 6490); progesterone receptor receptor, PGR; NCBI Gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI Gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI Gene ID: 80380); prominin1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (PML; NCBI Gene ID: 5371); proprioceptor (PSAP; NCBI Gene ID: Gene ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene ID: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI Gene ID: 5698); protein arginine methyltransferase ( For example, PRMT1, PRMT5; NCBI Gene ID: 3276, 10419); protein kinase N3 (PKN3; NCBI Gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI Gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene ID: 5787, 5788); phospholipase alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf; NCBI Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); ras homolog family member C (RHOC; NCBI Gene ID: 389); Ras homolog, mTORC1-binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine / threonine protein kinase 1 (RIPK1; NCBI Gene ID: 8737); ret proto-oncogene (RET; NCBI Gene ID: 5979); retinoblastoma Retinoid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091); retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene IDs: 5914, 5916); retinoid X receptors (e.g., RXRA, RXRB, RXRG; NCBI Gene IDs: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinases (e.g., ROCK1, ROCK2; NCBI Gene IDs: 6093, 9475); ribosomal protein S 6 kinase B1 (RPS6KB1, S6K-beta1; NCBI Gene ID: 6198); RING finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS1; NCBI Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium-binding protein A9 (S100A9; NCBI Gene ID: 1 D:6280); secreted flurry-related protein 2 (SFRP2; NCBI Gene ID:6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID:6696); secretoglobin family 1A member 1 (SCGB1A1; NCBI Gene ID:7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene IDs:6401, 6402, 6403); semaphorin 4D (semaphorin, SEMA4D; CD100; NCBI Gene ID:10507); sialic acid acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene ID: 27036, 27180, 89790); signal regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); signal transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene ID: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI Gene ID: 23410);Signaling lymphocyte activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI Gene ID: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); smooth, frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (EPHX2; NCBI Gene ID: 2053); solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SL C6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI Gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI Gene IDs: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecule (SHH; NCBI Gene ID: 6469); Sp1 transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinase (e.g., SPHK1, SPHK2; NCBI Gene IDs: 8877, 8878; 848); sphingosine-1-phosphate receptor 1 (S1PR1, CD363; NCBI Gene ID: 1901); spleen-related tyrosine kinase (SYK; NCBI Gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI Gene ID: 23451); SRC proto-oncogene, non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family member 1 (STEAP1; NCBI Gene ID: 26872); steroid disulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interactor 1 (STING1; NCBI Gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene ID: 8651, 9021); synapsin 3 (SYN3; NCBI Gene ID: 8224); syndecan 1 (SDC1, CD138, syndecan; NCBI Gene ID: 140061); NCBI Gene ID: 6382); synuclein alpha (SNCA, PARK1; NCBI Gene ID: 6622); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene ID: 6869, 6870); TANK-binding kinase 1 (TBK1, NCBI Gene ID: 29110); tankyrase (TNKS, NCBI Gene ID: 8658); TATA box-binding protein-associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); lymphocyte-specific protein tyrosine kinase (TEC); NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010);human telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371); 3 prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombomodulin (THBD, CD141; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene IDs: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 1890); NCBI Gene ID: 7298); thyroid hormone receptors (THRA, THRB; NCBI Gene ID: 7606, 7608); thyroid-stimulating hormone receptor (TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2) , TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL); NCBI Gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD28 8), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793; transferrin (TF; NCBI Gene ID: 7018); transferrin receptor (TFRC, CD71; NCBI Gene ID: 7037); transforming growth factors (e.g., TGFA, TGFB1; NCBI Gene IDs: 7039, 7040); transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3;NCBI Gene ID: 7046, 704; 8, 7049); transforming protein E7 (E7; NCBI Gene ID: 1489079); transglutaminase 5 (TGM5; NCBI Gene ID: 9333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed in myeloid cells (e.g., TREM1 (CD354), TREM2; NCBI Gene IDs: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162); tryptophan 2,3-diphosphate dehydrogenase (TDR) receptor tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD137, 4-1BB), TNFRSF10A (CD26 1), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRSF12A, TNFRSF13B, TNFR13C (, CD268, BAFFR), TNFRSF1 4 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI gene ID: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7299); Tyro tyrosine hydroxylase (TH; NCBI Gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine protein phosphatase, non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme E2I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI Gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI Gene ID: 7874) ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16-binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing protein (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI Gene IDs: 7422, 7423); vimentin (VIM; NCBI Gene ID: 7431);Vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunoregulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRNRecQ-like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain-containing transcription factor; regulatory factor 1 (WWTR1; TAZ; NCBI Gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375); XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI Gene ID: 2829); Yes1-associated transcription factor (YAP1; NCBI Gene ID: 10413); or zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535).

[0219] In some embodiments, the one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Adenosine A receptor (ADORA2A; NCBI gene ID: 135) 2Breceptor (ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin-associated protein (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI gene ID: 3845; KRAS G12C or G12D, etc. including mutations of); mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death-ligand 1 (PD-L1, C D274; NCBI Gene ID: 29126; programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); signal-regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); contains Ig and ITIM domains T cell immunoreceptor (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, CD134, OX40; NCBI Gene ID: 4070) IKZF2; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily, member 9 (TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily, member 18 (TNFRSF18, CD357, GITR; NCBI Gene ID: 8784); WRNRecQ-like helicase (WRN; NCBI Gene ID: 7486); or zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807). Exemplary Mechanisms of Action Immune Checkpoint Modulators

[0220] In some embodiments, the hydroxyl group represented by formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), ( The compound of formula (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor environment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, the immune checkpoint protein or receptor regulates T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T cells (Tregs) or Treg depletion can relieve their suppression of anti-tumor immune responses and have anti-cancer effects (e.g., reviewed in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0221] Examples of immune checkpoint proteins or receptors that can be combined with the compounds provided herein, or pharmaceutically acceptable salts thereof, include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 140885), and CD47 (NCBI Gene ID: 140885). Gene ID: 10225), CD160 (NCBI Gene ID: 11126), MS4A1 (CD20; NCBI Gene ID: 931), CD244 (SLAMF4; NCBI Gene ID: 51744); CD276 (B7H3; NCBI Gene ID: 80381); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L;NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA), NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI; Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); Programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); Cytotoxic T lymphocyte related protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI Gene ID: 5819); CD226 (DNAM-1; NCBI Gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037) ; T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4; NCBI Gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); Galectin 9 (LGALS9; NCBI Gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI Gene ID: 6504); lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI Gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI Gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI Gene ID: 57823); UL16 binding protein 1 (ULBP1; NCBI Gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI Gene ID: 80328); UL16 binding protein 3 (ULBP3;NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154064); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirilumab (li rilumab) (IPH-2102, IPH-4102); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A; NCBI Gene ID: 3821); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI Gene ID: 22914); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI Gene ID: 3822); killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI Gene ID: 3823); killer cell Killer cell immunoglobulin-like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 8302); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3; NCBI Gene ID: 3804); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1; NCBI gene ID: 3824); killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI gene ID: 10219); sialic acid-binding Ig-like lectin 7 (SIGLEC7; NCBI gene ID: 27036); and sialic acid-binding Ig-like lectin 9 (SIGLEC9; NCBI gene ID: 27180).

[0222] In some embodiments, the compounds of formula (I), (Ia), (Ib), (IThe compound of Formula Ia), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered in conjunction 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 CD274 (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-associated immunoglobulin domain-containing (PVR IG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1).In some embodiments, a compound or pharmaceutically acceptable salt provided herein is administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0223] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered 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 killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and a long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, one Ig domain and a long cytoplasmic tail 3 (KIR, CD158E2); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-binding Ig-like lectin 7 (SIGLEC7); and sialic acid-binding Ig-like lectin 9 (SIGLEC9). In some embodiments, a compound or pharmaceutically acceptable salt provided herein is administered 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 CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol.(2018)18(11):671-688.

[0224] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0225] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, and KN-04. 4, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, 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).

[0226] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, and CS-10 03, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimuzumab (CBT-501), LZM-009, prorugolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB 0010718C), CX-072, CBT-502, dostarimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), embafolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS -4224, GS-4416, INCB086550, MAX10181, dimvelelimab (AB122), spartalizumab (PDR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD -013(PD-1 / LAG-3), FS-118(LAG-3 / PD-L1)RO-7247669(PD-1 / LAG-3), MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-57 52(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), RG7769(PD-1 / TIM-3), TAK-252(PD-1 / OX40L), XmAb-20717(PD-1 / CTLA4), AK-10 4 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0227] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vibostolimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0228] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0229] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate the suppression of anti-tumor immune responses and may have anti-cancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment.

[0230] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can modulate cell phenotype and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include CCR4 (NCBI Gene ID: 1233) antagonists, as well as Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI Gene ID: 10320), Helios (IKZF1; NCBI Gene ID: 10320), and the like. ZF2; NCBI gene ID: 22807), Aiolos (IKZF3; NCBI gene ID: 22806), and Eos (IKZF4; NCBI gene ID: 64375).

[0231] Examples of Helios degraders that may be co-administered include, but are not limited to, I-57 (Novartis) and compounds disclosed in WO 2019 / 038717, WO 2020 / 012334, WO 2020 / 0117759, and WO 2021 / 101919.

[0232] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Exemplary targets of Treg depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0233] In some embodiments, Treg inhibitors or Treg depletors that may be co-administered include C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic Treg receptor 4 (CCR4; CD184), TNFRSF18 (GITR, CD357), TNFRSF18 ... Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit and combinations thereof.

[0234] Examples of Treg-depleting anti-CCR8 antibodies that can be administered include JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and the antibody disclosed in International Publication No. Examples of antibodies include, but are not limited to, antibodies disclosed in WO 2021163064, WO 2020138489, and WO 2021152186.

[0235] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0236] Inhibition, depletion, or reprogramming of unstimulated myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550; WO 2016049641). Exemplary targets for depleting or reprogramming unstimulated myeloid cells include triggering receptors expressed on myeloid cells, TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more myeloid cell depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; an antibody disclosed in WO2019032624) or an anti-TREM-2 antibody (e.g., PY314; an antibody disclosed in WO2019118513). Cluster of differentiation agonists or activators

[0237] In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an agent that targets a cluster of differentiation (CD) marker. Exemplary agents that target CD markers that may be co-administered include the following: A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402 / HLA-A0201 restricted enzyme Pitopes peptide vaccines, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranelgene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lusitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, Orbele tamvatinib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and International Publication Nos. 2016196388, 2016033570, 2015157386, and 199203459, International Publication No. 199221766, International Publication No. 2004080462, International Publication No. 2005020921, International Publication No. 2006009755, International Publication No. 2007078034, International Publication No. 2007092403, International Publication No. 2007127317, International Publication No. 2008005877, International Publication No. 2012154480, International Publication No. 2014100620, International Publication No. 2014039714, International Publication No. 2015134536,International Publication No. 2017167182, International Publication No. 2018112136, International Publication No. 2018112140, International Publication No. 2019155067, International Publication No. 2020076105, International Application PCT No. US2019063091, International Publication No. 19173692, International Publication No. 2016179517, International Publication No. 2017096179, International Publication No. 2017096182, International Publication No. 2017096281, International Publication No. 2018089628, International Publication No. 2017096179, International Publication No. 2018089628, International Publication No. 2018195321, Country, International Publication No. 2020014643, International Publication No. 2019160882, International Publication No. 2018195321, International Publication No. 200140307, ​​International Publication No. 2002092784, International Publication No. 2007133811, International Publication No. 2009046541, International Publication No. 2010083253, International Publication No. 2011076781, International Publication No. 2013056352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205 042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669, International Publication No. 2018107058, International Publication No. 2018190719, International Publication No. 2018210793, International Publication No. 2019023347, International Publication No. 2019042470, International Publication No. 2019175218, International Publication No. 2019183266, International Publication No. 2020013170, International Publication No. 2020068752, Cancer Discov. 2019 Jan 9(1):8; and Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0238] In some embodiments, CD marker targeting agents that may be co-administered include small molecule inhibitors, such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, lobritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, and BLU-263. , CD117-ADC, AZD3229, telatinib, borolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), plerixafor, CTX-5861, and REGN-5678 (PSMA / CD28).

[0239] In some embodiments, agents targeting CD markers that may be co-administered include the following: interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly ICLC (NSC-301463), reboxone, apoxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, levothyroxine ... Small molecule agonists such as siquimod, sergantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, ritenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0240] In some embodiments, agents targeting CD markers that may be co-administered include the following: tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzalutamab (MOR-202), TAK-079, TAK573, da Latumumab (DARZALEX®), TTX-030, Celicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, Mitazarimab (JNJ-64457107), Lenzilumab, Alemtuzumab, Emactuzumab, AMG-820, FPA-008 (Cabilaritumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulukafusp alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159, and FSI-174, leratolimab (ONO-4482), LAG-525, MK-4280, and fianlimab (REGN-3767). , INCAGN2385, enselimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20.5), MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006 , INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and antibodies such as the compounds disclosed in WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018 / 089628.

[0241] In some embodiments, agents targeting CD markers that may be co-administered include the following: CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, l iso-cel, lysocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL-armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silent IL-6 expression, cancer, Shanghai Unicar therapy (biological medicine therapy technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, Dual anti-CD19 / anti-CD20 CAR T-cell (chronic leukemia / B-cell leukemia), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-emergent Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, cisagecroicel-T, CART-19, cisagecroicel (CTL-019)), anti-CD20 CAR T-cell therapy (non-hoc kinase), MB-CART2019.1 (CD19 / CD20), WZTL-002 deuterated anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR, CD33, CD33CAR, Dual anti-BCMA / anti-CD38 CAR T-cell therapy, CAR-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 nock-and-out T-cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 nock-and-out T-cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR Included are cell therapies such as T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D LIGAND MODULATOR), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or therapies disclosed in WO2012079000 or WO2017049166. Cluster of differentiation 47 (CD47) inhibitors

[0242] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), or (IVa-2), or a pharmaceutically acceptable salt thereof, provided herein is administered in conjunction with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include the following: CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188) (retaplimab), lemzoparimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H1 2, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or International Publication No. 199727873, International Publication No. 199940940, International Publication No. 2002092784, International Publication No. 2005044857, International Publication No. 2009046541, International Publication No. 2010070047, International Publication No. 2011143624, International Publication No. 2012170250, International Publication No. 2013109752, International Publication No. 2013119714, International Publication No. 2014087248, International Publication No. 2015191861, International Publication No. 2016022971, International Publication No. 2016023040, International Publication No. 2016024021, International Publication No. 2016081423, International Publication No. 2016109415, International Publication No. 2016141328, International Publication No. 2016188449, International Publication No. 2017027422, International Publication No. 2017049251, International Publication No. 2017053423,International Publication No. 2017121771, International Publication No. 2017194634, International Publication No. 2017196793, International Publication No. 2017215585, International Publication No. 2018075857, International Publication No. 2018075960, International Publication No. 2018089508, International Publication No. 2018095428, International Publication No. 2018137705, International Publication No. 2018233575, International Publication No. 2019027903, International Publication No. 2019034895, International Publication No. 2019042119 , International Publication No. 2019042285, International Publication No. 2019042470, International Publication No. 2019086573, International Publication No. 2019108733, International Publication No. 2019138367, International Publication No. 2019144895, International Publication No. 2019157843, International Publication No. 2019179366, International Publication No. 2019184912, International Publication No. 2019185717, International Publication No. 2019201236, International Publication No. 2019238012, International Publication No. 2019241732, Examples of compounds disclosed in WO 2020019135, WO 2020036977, WO 2020043188, and WO 2020009725. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is magrolimab.

[0243] In some embodiments, the CD47 inhibitor is 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), or any combination thereof. GF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801. SIRPα targeting agent

[0244] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with a SIRPα targeting agent (NCBI Gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents that may be co-administered include SIRPα inhibitors, e.g., AL-008, RRx-001, and CTX-5861, and anti-SIRPα antibodies, e.g., FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPα / PD-L1). Additional SIRPα targeting agents of use are described, for example, in WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 2013056352, WO 2015138600, WO 2016179399, WO 2016205042, WO 20171 78653, WO 2018026600, WO 2018057669, WO 2018107058, WO 2018190719, WO 2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO 2019183266, WO 2020013170 and WO 2020068752. FLT3R agonists

[0245] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with an FLT3R agonist. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered together with an FLT3 ligand. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with an FLT3L-Fc fusion protein, for example, as described in WO 2020 / 263830. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with GS-3583 or CDX-301. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with GS-3583. Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF)

[0246] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, provided herein, comprise one or more Agonists of TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (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) agonists.

[0247] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tabolixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0248] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0249] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0250] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0251] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0252] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO 2017096179 and WO 2018089628.

[0253] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20). TGFβ antagonists

[0254] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with a TGFβ antagonist. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. TGFβ-specific antibodies can be prepared and characterized using methods known to those skilled in the art, for example, those described in PCT Publication WO 2018 / 129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist is TGFβ latency-associated peptide (TGFβ). TGFβ1-LAP specific antibodies can be prepared and characterized using methods known to those skilled in the art, for example, those described in U.S. Pat. No. 8,198,412 or U.S. Pat. No. 10,017,567. In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-independent manner (e.g., independent of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) localized in the extracellular matrix, e.g., connective tissue of the liver. In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) localized in the thymus, lymph nodes, or tumor microenvironment (e.g., in patients with liver cancer). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ binding protein (Latent TGFβ B The latent TGFβ (e.g., latent TGFβ1) is inhibited by the LTBP. In some embodiments, the TGFβ antagonist blocks activation of TGFβ by glycoprotein-A repeats predominant protein (GARP), as described, for example, in U.S. Pat. No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is SK-181. In some embodiments, the TGFβ antagonist is an anti-latency associated peptide (LAP) antibody that specifically binds to the LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in the extracellular matrix (ECM), for example, of connective tissue in the liver. Specific binding. In some embodiments, the anti-LAP antibody specifically binds to LAP-TGFβ complexes on the surface of certain immunosuppressive cell types, such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived suppressor cells, for example, in the tumor microenvironment. In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to LAP-TGFβ complexes in any context. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. TGFβ antagonists, including TGFβ receptors, that may be useful in connection with the compositions and methods provided herein are described, for example, in PCT Publication Nos. WO 2019 / 113123(A1) and WO 2019 / 113464(A1). Bispecific T cell engager

[0255] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with a bispecific T cell engager (e.g., Fc-less) or an anti-CD3 bispecific antibody (e.g., Fc-bearing).Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), and flotetuzumab. (CD123 / CD3), odronextamab (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), AMG-757 (DLL3-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), AMG-211(CE A / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY974 (GPC3 / CD3), GEMoab (CD3 / PSCA), RG6026 (CD20 / CD 3), RG6194(HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123), JNJ-9383(MGD-015), AMG-424(CD 38 / CD3), tidutamab (XmAb-18087(SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(. Examples of suitable anti-CD3 binding bispecific molecules include CD3 / B7H3, IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), tidutamab (XmAb-18087; SSTR2 / CD3), catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230). Bispecific and trispecific natural killer (NK) cell engagement Ja

[0256] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) described herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of a bispecific NK cell engager (BiKE) and a trispecific NK cell engager (TriKE), e.g., The antibody may be administered with an Fc-free antibody, or a bispecific antibody (e.g., with an Fc) against an NK cell activating receptor, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE, that may be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0257] In some embodiments, the compounds of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), Compound (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered in conjunction with an MCL1 apoptosis regulator, an inhibitor of BCL2 family members (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO 2018183418, WO 2016033486, and WO 2017147410. SHP2 inhibitors

[0258] In some embodiments, the compound of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), Compound (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered together 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, and those described in WO2018172984 and WO2017211303. Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders

[0259] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184).

[0013] Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300. Apoptosis signal-regulating kinase (ASK) inhibitors

[0260] In some embodiments, the hydroxyl group represented by formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), ( The compound of formula (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered together with an ASK inhibitor, such as mitogen-activated protein kinase kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO 2011008709 (Gilead Sciences) and WO 2013112741 (Gilead Sciences). Bruton's tyrosine kinase (BTK) inhibitors

[0261] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315. Cyclin-dependent kinase (CDK) inhibitors

[0262] In some embodiments, the compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CD KN2; 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), or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02. Discoidin domain receptor (DDR) inhibitors

[0263] In some embodiments, the compounds of formula (I), (Ia), (Ib), (I A compound of formula Ia), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof. is 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 dasatinib, and the compounds described in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), No. 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations). Targeted E3 ligase ligand conjugates

[0264] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with a targeted E3 ligase ligand conjugate. Such a conjugate comprises a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, cIAP, AP1, c-IAP2, NIL-IAP, Bruce, and Survival E3 ubiquitin ligase binding site, Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding site, and cereblon E3 ubiquitin ligase binding site minute, mouse double minute 2 homolog (MDM2) E3 The targeting E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein described herein and an E3 ligase ligand or binding moiety. In some embodiments, the targeting E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeting E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., WO 2018098280. In some embodiments, the targeting E3 ligase ligand conjugate comprises an interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); a rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and a binding moiety that targets or binds to the E3 ligase ligand or binding moiety. See, e.g., WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, WO 2019079701. Additional targeting E3 ligase ligand conjugates that may be co-administered are described, e.g., in WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, and WO 2019079701. No. 8237026, WO 2019084026, WO 2019084030, WO 2019067733, WO 2019043217, WO 2019043208, and WO 2018144649. Histone deacetylase (HDAC) inhibitors

[0265] In some embodiments, the compounds of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa ), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of histone deacetylase, for example, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0266] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus kinase (JAK) inhibitors

[0267] In some embodiments, the hydroxyl group represented by formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va ... The compound of formula (VI) or (VIa), or a pharmaceutically acceptable salt thereof, is administered in combination 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 AT9283, AZD1480, and baric acid. These include tinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. Lysyl oxidase-like protein (LOXL) inhibitors

[0268] In some embodiments, the compounds of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IV ...3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa), (IVa-1), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IVa), (IV The compound of formula (a-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is administered together with an inhibitor of a LOXL protein, such as LOXL1 (NCBI Gene ID: 4016), LOXL2 (NCBI Gene ID: 4017), LOXL3 (NCBI Gene ID: 84695), LOXL4 (NCBI Gene ID: 84171), and / or LOX (NCBI Gene ID: 4015). Examples of LOXL2 inhibitors include the antibodies described in WO 2009017833 (Arresto Biosciences), WO 2009035791 (Arresto Biosciences), and WO 2011097513 (Gilead Biologics). Matrix metalloproteinase (MMP) inhibitors

[0269] In some embodiments, the compounds of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (IVa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (III ... ), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, is 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), MMP18 (NCBI Gene ID: 4327), MMP19 (NCBI Gene ID: 4328), MMP18 (NCBI Gene ID: 4329), MMP19 (NCBI Gene ID: 4330), MMP19 (NCBI Gene ID: 4331), MMP11 (NCBI Gene ID: 4332), MMP12 (NCBI Gene ID: 4333), MMP13 (NCBI Gene ID: 4334), MMP14 (NCBI Gene ID: 4335), MMP15 (NCBI Gene ID: 4336), MMP16 (NCBI Gene ID: 4337), MMP17 (NCBI Gene ID: 4338), MMP18 (NCBI Gene ID: 4339), MMP19 (NCBI Gene ID: 4340), MMP19 (NCBI Gene ID: 4341), MMP19 (NCBI Gene ID: 43 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), MMP18 (NCBI Gene ID: 4328), MMP19 (NCBI Gene ID: 4329), MMP19 (NCBI Gene ID: 4330), MMP19 (NCBI Gene ID: 4331), MMP19 (NCBI Gene ID: 4332), MMP19 (NCBI Gene ID: 4333), MMP19 (NCBI Gene ID: 4334), MMP19 (NCBI Gene ID: 4335), MMP19 (NCBI Gene ID: 4336), MMP19 (NCBI Gene ID: 4337), MMP19 (NCBI Gene ID: 4338), MMP19 (NCBI Gene ID: 4339), MMP19 (NCBI Gene ID: 4341), MMP19 (NCBI Gene ID: 4342), MMP19 (NCBI Gene ID: 4343), MMP19 (NCBI Gene ID: 4344), MMP19 (NCBI Gene ID: 4345), MMP19 (NCBI Gene ID: 4346), MMP19 (NCBI Gene ID: 4347), MMP19 (NCBI Gene ID: 4348), MMP19 (NCBI Gene ID: 4349), MMP19 (NCBI Gene ID: 4350), MMP19 (NCBI and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0270] In some embodiments, the compounds of formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), The compounds of formula (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or pharmaceutically acceptable salts thereof, are inhibitors of the KRAS proto-oncogene, GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4). A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene, GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that may be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1(G12C), adagrasib (MRTX-849), ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602(Ras GTP), RT11, MRTX-849(G12C), and K-Ras(G12D) selective inhibitory peptides, including KRpep-2 and KRpep-2d.Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adaptor, AZD-4785, siG12D-LODER™, and siG12D exosomes. Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, rabocertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include lidigosertib. Exemplary PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Exemplary AKT inhibitors that can be co-administered include capivasertib and GSK2141795. Exemplary PI3K / mTOR inhibitors that may be co-administered include daptolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, cancer), racemetyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by coadministration of the MEK inhibitor selumetinib with the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Additionally, K-RAS and mutant N-RAS can be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4.For example, Booth, et al., Cancer Biol Ther. 2. See 018 Feb 1;19(2):132-137. Mitogen-activated protein kinase (MEK) inhibitors

[0271] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uplosertib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0272] In some embodiments, the compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS 5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha; 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 ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, and copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY1 11A, PA799, PX-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and International Publication No. 2000. 5113556 (ICOS), WO 2013052699 (Gilead Calistoga), WO 2013116562 (Gilead Calistoga), WO 2014100765 (Gilead Calistoga), WO 2014100767 (Gilead Calistoga), and WO 2014201409 (Gilead Sciences). Spleen Tyrosine Kinase (SYK) inhibitor

[0273] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celdulatinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut), and U.S. Patent Application Publication No. 20150175616. Toll-like receptor (TLR) agonists

[0274] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa) provided herein, or a pharmaceutically acceptable salt thereof, are compounds that bind to toll-like receptors (T The present invention is directed to administering the therapeutic agent in combination with an agonist of TLR1 (TCR1), e.g., 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). Examples of TLR7 agonists that may be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod derivatives, and the like. analogs, 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, BDB-001, DSP-0509, and U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences). Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014056953 (Janssen), WO 2014076221 (Janssen), WO 2014128189 (Janssen), U.S. Patent Application Publication No. 201 No. 40350031 (Janssen), WO 2014023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that may be co-administered is NKTR-262.Examples of TLR8 agonists that can be co-administered include 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 U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 201400736 42 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Examples of compounds disclosed in US Patent Application Publication No. 20130251673 (Novira Therapeutics) include compounds disclosed in US Pat.Exemplary TLR9 agonists that may be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Tyrosine kinase inhibitors (TKIs)

[0275] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, provided herein is It is administered in combination with a thyroid kinase inhibitor (TKI). TKIs can target the epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, and KX2-391 (Src ), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib, L-malic acid, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeted agents include neratinib, tucatinib (ONT-380), tecevatinib, mobocertinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®), and those described in Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Antibodies that target EGFR include, but are not limited to, modotuximab, cetuximab sarotarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab. chemotherapy drugs

[0276] In some embodiments, a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIIa), (IIIa-1), (IIIa-2), (IIIa-3), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IVa), (IVa-1), (IVa-2), (V), (Va), (VI), or (VIa), or a pharmaceutically acceptable salt thereof, provided herein is administered in combination with a chemotherapeutic or anti-neoplastic agent.

[0277] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents inclu...

Claims

[Claim 1] The invention described in the specification.

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