Ikaros zinc finger family degraders and uses thereof

Abstract

To provide a method for treating a disease.SOLUTION: The present disclosure relates generally to compounds that bind to and act as degraders of an IKAROS Family Zink Finger (IKZF) protein, such as IKZF2 (Helios) and / or IKZF4 (Eos). The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and / or conditions through binding and degradation of an IKZF protein, such as IKZF2 and / or IKZF4, including cancer. As is described in detail and specifically exemplified herein, the present invention unexpectedly achieves remarkable effects, which could not have been easily anticipated by a skilled person based on the prior art.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 292,650, filed December 22, 2021, which is incorporated herein in its entirety for all purposes.

[0002] 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 December 1, 2022, is named 1405-WO-PCT.xml and is 2,747 bytes in size.

[0003] 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. [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 co-expressed 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 involved in maintaining normal immune tolerance and homeostasis. Helios is a subset of CD4+ T cells that maintain Treg activity. Treg activity can also suppress antitumor immune responses. Helios is thought to be required for maintaining a stable Treg phenotype, especially 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 shown 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 disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions mediated by the binding and degradation of IKZF2 protein by the compounds.

[0008] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 4 is H, F, or Cl, R 5 is H, F, or Cl, R 7 is H, R 1 is H, C 1~6 Alkyl, C1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 1b )(R 1c ), -C(O)R 1b , or -C(O)OR 1c and R 1 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 2 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 2b )(R 2c ), -C(O)R 2b , or -C(O)OR 2c , -S(O)2R 2b and R 2 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 or optionally replaced by Alternatively, R 1 and R 2 together with the nitrogen to which they are attached, one to four Z, which may be the same or different. 4 and R 1 and R 2 is a 3- to 20-membered heterocyclyl which may have 0-3 additional heteroatoms, each independently being N, O, or S; R 3 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 3b )(R3c ), -C(O)R 3b , or -C(O)OR 3c , -S(O)2R 3b and R 3 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 3 and optionally substituted with Each R 6 independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 haloalkoxy, halogen, -OH, =O, or -NH2, or two R 6 atoms or atoms to which they are attached, C 3~10 cycloalkyl or heterocyclyl, each of which may be the same or different, and each of which may be the same or different, may be 1 to 4 R 6a and each R 6a independently, C 1~9 alkyl or halogen; each Z 1 , Z 2 , Z 3 , or Z 4 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, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, each Z 1 , Z 2 , Z 3 , or Z 4 each of the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1a and optionally substituted with each Z 1a 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 6~10Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, Z 1a each of the alkyl, haloalkyl, 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 Z 1b independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C2~6 alkynyl), -C(O)(C 3~15 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 -C(O)NH(heterocycloalkyl) -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(C1~8 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 1~9 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 3~15cycloalkyl), -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 The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of 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 optionally substituted with alkyl; Each R 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , and R 12c are 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 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , or R 12c each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different and may be substituted with 1 to 4 Z 1b and optionally substituted with each n and m is independently 1, 2, or 3, and n+m≦4; q is 0, 1, or 2; each heteroaryl is a 5- to 12-membered heteroaryl having 1-4 heteroatoms, each independently N, O, or S; Each heterocyclyl is a 3- to 20-membered heterocyclyl having 1 to 4 heteroatoms, each independently N, O, or S.

[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 for degrading IKZF2 protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (Ib), or (Ic)), 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), (Ib), or (Ic)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0013] 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, comprising IKZF2 protein degraders in combination with one or more additional therapeutic agents.

[0014] 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.

[0015] Definitions and general parameters The following description should be considered an example of the present disclosure and is intended to be illustrative of the claimed subject matter. It is made with the understanding that the appended claims are not intended to limit the scope of 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.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. 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 of ordinary skill in the art, etc.

[0017] 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.

[0018] 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 R a can be replaced with [ka]

[0019] "C u~v " prefix indicates that the following group has u to v carbon atoms. For example, "C 1~6 "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") refers to a ring containing x to y atoms (e.g., 3 to 12), up to 80% of which can be heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon.

[0020] 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.

[0021] "Compounds disclosed herein" or "compounds of the disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of Formula (I), (Ia), (Ib), or (Ic). Also included are the specific compounds of Examples 1-98 provided herein.

[0022] Reference herein to "about" a value or parameter means that the value or parameter itself is The term "about" includes (and describes) embodiments relating to the entire amount. 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 those terms, "about X" includes the description of "X." Also, 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.

[0023] "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 1~3Examples 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 residue having a particular number of carbons is designated by a chemical name or specified 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).

[0024] "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).

[0025] "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.

[0026] "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.

[0027] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment (alkyl-O-). With respect to alkyl groups, alkoxy groups include C 1~6 Alkoxy groups may have any suitable number of carbon atoms, such as , ...

[0028] "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.

[0029] "Amino" is -NRy 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.

[0030] 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 members (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.

[0031] "Cyano" or "carbonitrile" refers to the group --CN.

[0032] "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.

[0033] "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.

[0034] "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.

[0035] "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.

[0036] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0037] "Haloalkyl," as used herein, 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, C 1~4 One or more of the hydrogen atoms of the alkyl is replaced by a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0038] "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 1~6 Any suitable The alkoxy group may have any number of carbon atoms. The alkoxy group may be substituted with one, two, three or more halogens. If 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.

[0039] The term "heteroaryl," as used herein, refers to a single aromatic ring or a polycyclic ring. This term includes single aromatic monocyclic rings containing 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 the 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-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, and thianaphthenyl.

[0040] "Heterocyclyl" or "heterocyclic ring" or "heterocycle," as used herein, refers to a single saturated or partially unsaturated ring or polycyclic ring. The term includes saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) of 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) can be linked to two adjacent atoms (fused heterocycles) with one or more heterocyclic (e.g., decahydronaphthyridinyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthyridinyl), carbocyclic (e.g., decahydroquinolyl), or aryl. It is understood that the point of attachment of a heterocyclic polycyclic ring can be at any position on the ring, including on the heterocyclic, heteroaryl, aryl, or carbocyclic portions of the ring, as defined above. Exemplary heterocycles 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:

[0041] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0042] "Oxo" refers to the (=O) or (O) radical.

[0043] "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.

[0044] Whenever the graphical representation of a group ends in a singly bonded nitrogen atom, that group represents an —NH group unless otherwise indicated. Similarly, unless otherwise specified, 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.

[0045] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur. 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.

[0046] 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 the substituents 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 stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is called a (substituted aryl group). The term "substituted aryl" is limited to substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary 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.

[0047] 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.

[0048] In some embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl include cycloalkyl, heterocyclyl, aryl, and / or heteroaryl groups having substituents on ring atoms, where the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl group is attached to the remainder of the compound. For example, in the moiety below, the cyclopropyl is substituted with a methyl group: [ka]

[0049] 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 "," are to be read broadly and are not limiting. In addition, the terms and expressions used in this specification 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.

[0050] The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids 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 bases or acids and organic bases or acids. When the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes the corresponding pharmaceutically or toxicologically acceptable salts of the compounds, particularly pharmaceutically usable salts of the compounds. Thus, compounds of the present disclosure containing acidic groups may exist in these groups and may 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. The compounds of the present disclosure may contain one or more basic groups, i.e., groups that can be protonated, and may be used in the form of their addition salts with inorganic or organic acids according to 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.

[0051] 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.

[0052] The present disclosure also includes all salts of the compounds of the present disclosure that are not directly suitable for use in medicine 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 known to those skilled in the art and are disclosed, for example, in Berge, et al., Journal of Pharmaceutical Science, January 1977, Vol. 66, No. 1, and other sources.

[0053] 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.

[0054] 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, Inc., New York, 1991. Protecting groups are often utilized 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] "Stereoisomer" refers to a compound 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 indicated, 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).

[0059] The compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L)-. 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, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where 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. Where compounds are represented in their chiral form, it is understood that embodiments encompass, 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.

[0060] Compositions provided herein that include 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.

[0061] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the 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 These are compounds into which a radioactive isotope, such as C, has been incorporated. 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 in the administration of radioisotopes to 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.

[0062] 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 using starting materials in which one or more hydrogens have been replaced by deuterium.

[0063] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have beneficial DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer 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.

[0064] 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 stated, 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.

[0065] Further, 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. The present invention provides pharmaceutical compositions.

[0066] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that make up 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 include any composition made by mixing at least one compound of the present disclosure with a pharmaceutically acceptable carrier.

[0067] 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.)).

[0068] "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 herein 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.

[0069] "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may 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., ameliorating the disease state, reducing the severity of the disease or condition). or providing partial or complete remission of a condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival. In some embodiments, the term "treatment" or "treating" refers to the administration of a compound of Formula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptable salt 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) palliating the disease, i.e., causing a regression of clinical symptoms or their severity.

[0070] "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.

[0071] As used herein, an "IKZF-associated disease or condition" (e.g., IKZF2 or 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 improve 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 improve the disease or disorder. In some embodiments, in an IKZF-associated disease or condition, degradation of the IKZF4 protein can improve the disease or disorder.

[0072] "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.

[0073] 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 delay of disease progression, upon administration to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition in response to an IKZF2 degrading agent. The therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, 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.

[0074] As used herein, "degrading agent" 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 degrading agent" 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, the IKZF2 degrading agent is selective IKZF2. In some embodiments, the IKZF2 degrading agent can induce degradation of the IKZF2 protein and one or more additional IKZF2 proteins (e.g., IKZF1 or IKZF4).

[0075] IKZF2 (also known as Helios) is an IKAROS family zinc finger transcription factor generally believed to be necessary for maintaining a stable Treg cell phenotype, particularly in an inflammatory tumor microenvironment. 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 an IKZF (e.g., IKZF2) degrader 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). [Table A-1] [Table A-2]

[0076] compound In one embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 4 is H, F, or Cl, R 5 is H, F, or Cl, R 7 is H, R 1 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 1b )(R 1c ), -C(O)R 1b , or -C(O)OR 1c and R 1 The alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are each the same or can vary from 1 to 4 Z 1 and optionally substituted with R 2 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 2b )(R 2c ), -C(O)R 2b , or -C(O)OR 2c , -S(O)2R 2b and R 2 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 2 or optionally replaced by Alternatively, R 1 and R 2 together with the nitrogen to which they are attached, one to four Z, which may be the same or different. 4 and R 1 and R 2 is a 3- to 20-membered heterocyclyl which may have 0-3 additional heteroatoms, each independently being N, O, or S; R 3 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 3b )(R 3c ), -C(O)R 3b , or -C(O)OR 3c , -S(O)2R 3b and R 3 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 4 Z 3 and optionally substituted with Each R 6 independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 haloalkoxy, halogen, -OH, =O, or -NH2, or two R 6 atoms or atoms to which they are attached, C 3~10 cycloalkyl or heterocyclyl, each of which may be the same or different, and each of which may be the same or different, may be 1 to 4 R 6a and each R 6a independently, C 1~9 alkyl or halogen; each Z 1 , Z 2 , Z 3 , or Z 4 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, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, each Z 1 , Z 2 , Z 3 , or Z 4 each of the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1a and optionally substituted with each Z 1a 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, C3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, Z 1a each of the alkyl, haloalkyl, 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 Z 1b independently, C 1~9 Alkyl, C 1~8Haloalkyl, 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 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 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 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C1~9 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 Archi -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(C2~6 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 The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of 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 optionally substituted with alkyl; Each R 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , and R 12c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with each n and m is independently 1, 2, or 3, and n+m≦4; q is 0, 1, or 2; each heteroaryl is a 5- to 12-membered heteroaryl having 1-4 heteroatoms, each independently N, O, or S; Each heterocyclyl is a 3- to 20-membered heterocyclyl having 1 to 4 heteroatoms, each independently N, O, or S.

[0077] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is R 4 and R 5 is a compound in which each is H.

[0078] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is R 7is H, optionally deuterium. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound wherein R 7 is deuterium.

[0079] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound where n is 1 and m is 1. In some embodiments, n is 2 and m is 1.

[0080] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises at least one of: 6 But independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0081] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, n is 1. In some embodiments, n is 2.

[0082] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic): [ka] or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound: each Z 1 , Z 2 , Z 3 , or Z 4 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C2 ~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a, -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, Z 1 , Z 2 , Z 3 , or Z 4 each of the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a)(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, each Z 1a each of the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1b and optionally substituted with each Z 1b But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, or -N3; Each R 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , and R 12c However, independently, H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , and R 12c each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one to three Z 1b and optionally substituted with each heteroaryl is a 5-10 membered heteroaryl having 1-3 heteroatoms, each independently N, O, or S; Compounds in which each heterocyclyl is a 4- to 10-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S.

[0085] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound: each Z 1 , Z 2 , Z 3 , or Z 4 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ) and Z 1 , Z 2 , Z 3 , or Z 4 each of the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R12a )(R 12b ) and each Z 1a each of the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1b and optionally substituted with each Z 1b But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, or -NH; Each R 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , and R 12c However, independently, H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl, and R 1b , R 1c , R 2b , R 2c , R 3b , R 3c , R 12a , R 12b , and R 12c each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one to three Z 1b and optionally substituted with each heteroaryl is a 5-10 membered heteroaryl having 1-2 heteroatoms, each independently N or O; Compounds in which each heterocyclyl is a 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms, each independently N or O.

[0086] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound: R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, R 1 wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 3 halogens, which may be the same or different; R 1 is a 5- to 10-membered heteroaryl having 1 to 2 heteroatoms, each independently being N or O; R 1 is a 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms, each independently being N or O.

[0087] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound: R 2 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -C(O)N(R 2b )(R 2c ), -C(O)R 2b , or -C(O)OR 2c , -S(O)2R 2b and R 2 each of the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups is selected from the group consisting of 1 to 3 Z 2 and optionally substituted with each Z 2 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~6Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, and Z 2 each of the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , or -C(O)R 12a and Each R 2b , R 2c , and R 12a However, independently, H, C 1~6 Alkyl, C 1~6 Halo Alkyl, C 6~10 aryl or heteroaryl, and R 2b , R 2c , and R 12a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 3 Z 1b and optionally substituted with each Z 1b But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 6~10 aryl or heteroaryl; each heteroaryl is a 5-10 membered heteroaryl having 1-2 heteroatoms, each independently N or O; Compounds in which each heterocyclyl is a 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms, each independently N or O.

[0088] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound comprising R 1 and R2 together with the nitrogen to which they are attached, 1 to 3 Z which may be the same or different 4 and R 1 and R 2 wherein the heterocyclyl formed by: is a 3-10 membered heterocyclyl which may have 0-2 additional heteroatoms, each independently being N or O.

[0089] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound comprising R 1 and R 2 together with the nitrogen to which they are attached, 1 to 3 Z which may be the same or different 4 and R 1 and R 2 wherein the heterocyclyl formed by the formula: is a 3- to 10-membered heterocyclyl which may have 0 to 1 additional N.

[0090] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound: each Z 4 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ) and Z 4 each of the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one, two, or three Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ) and Each R 12a and R 12b However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 aryl or heteroaryl, and R 12a and R 12b each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may be the same or different from one to three Z 1b and optionally substituted with each Z 1b But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, —OH, —CN, —NO, or —NH; each heteroaryl is a 5-10 membered heteroaryl having 1-2 heteroatoms, each independently N or O; Compounds in which each heterocyclyl is a 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms, each independently N or O.

[0091] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound: R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, Heterocyclyl, C 6~10aryl, heteroaryl, and alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which may be the same or different, is selected from 1 to 3 Z 3 and optionally substituted with each Z 3 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, halogen, C 3~6 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -N3, -CN; Z 3 each of the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN; each heteroaryl is a 5-10 membered heteroaryl having 1-2 heteroatoms, each independently N or O; Compounds in which each heterocyclyl is a 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms, each independently N or O.

[0092] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound where each n and m is independently 1 or 2. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound where each R 6 But independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6In some embodiments, q is 1 or 2. In some embodiments, q is 0.

[0093] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 2 is H, C 6~10 Aryl, C 3~6 Cycloalkyl, heteroaryl, -C(O)R 2b , -S(O)2R 2b , -C(O)NH(R 2c ), C 1~6 Haloalkyl, or C 1~6 alkyl, and R 2 Each of the alkyl, aryl, cycloalkyl, or heteroaryl groups may be the same or different and may be substituted with 1 to 3 Z 2 or optionally replaced by Alternatively, R 1 and R 2 together with the nitrogen to which they are attached, one to three Z's which may be the same or different 4 forming a 4- to 10-membered heterocyclyl optionally substituted with R 2b is C 1~6 C optionally substituted with alkyl or halo 6~10 is aryl, R 2c C optionally substituted with halo 1~6 Alkyl or C 6~10 is aryl, Z 2 is heteroaryl, C 3~6 Cycloalkyl, or C 6~10aryl, wherein each of the heteroaryl, cycloalkyl, or aryl is optionally substituted with 1 to 3 halo, which may be the same or different; Z 4 -OR 12a and R 12a is C 1~6 Alkyl or C 6~10 aryl, and R 12a wherein the alkyl or aryl is optionally substituted with 1 to 3 halo, which may be the same or different; R 3 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, or C 6~10 aryl, and R 3 Each of the alkyl, cycloalkyl, or aryl groups may be the same or different and may be substituted with 1 to 3 Z 3 and optionally substituted with Z 3 -CN, halo, C 1~3 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, cycloalkyl, or heteroaryl, each of which may be the same or different, and which may be one to three Z 1a and optionally substituted with Z 1a Ha, halo, -OC 1~6 Alkyl, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 6~10 is aryl, n is 1 or 2, Each heteroaryl is a 5- or 6-membered heteroaryl having one or two N's.

[0094] In some embodiments, the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is Z 3 But -CN, C 3~6 Cycloalkyl, C 6~10 aryl or heteroaryl, Z 3aryl, cycloalkyl, or heteroaryl, and 1 to 3 Z 1a is a compound optionally substituted with

[0095] In some embodiments, the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound where n is 1. In some embodiments, n is 2.

[0096] In some embodiments, a compound of formula (Ia-1): [ka] is provided herein.

[0097] In some embodiments, a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, is provided herein.

[0098] In some embodiments, a compound of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, is provided herein.

[0099] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 1 is H. In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is C 1~3 It is alkyl.

[0100] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound comprising R 2 But H, C 6~10 Aryl, C 3~6 Cycloalkyl, heteroaryl, -C(O)R 2b , -S(O)2R 2b , -C(O)NH(R 2c ), C 1~6 Haloalkyl, or C 1~6 alkyl, and R 2 each of the alkyl, aryl, cycloalkyl, or heteroaryl groups may be the same or different from one to three Z 2 and optionally substituted with Z 2 Heteroaryl, C 3~6 Cycloalkyl, or C 6~10 aryl, and Z 2 wherein each of the heteroaryl, cycloalkyl, or aryl is optionally substituted with 1 to 3 halo, which may be the same or different.

[0101] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound comprising R 2 But H, C 6~10 Aryl, -C(O)R 2b , -S(O)2R 2b , -C(O)NH(R 2c ), C 1~6 haloalkyl or 1 to 3 Z which may be the same or different 2 C optionally substituted with 1~6 is alkyl, and Z 2 Heteroaryl, C 3~6 Cycloalkyl, or C 6~10 aryl, and Z 2 wherein each of the heteroaryl, cycloalkyl, or aryl is optionally substituted with 1 to 3 halo, which may be the same or different.

[0102] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound comprising R 2 1 to 3 Z's which may be the same or different 2 optionally substituted with H, C 1~6 Haloalkyl, or C 1~6 is alkyl, and Z 2 Heteroaryl, C 3~6 Cycloalkyl, or C 6~10 aryl, wherein each of the heteroaryl, cycloalkyl, or aryl is optionally substituted with 1 to 3 halo, which may be the same or different.

[0103] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 1 to 3 Z's which may be the same or different 2 C optionally substituted with 1~6 In some embodiments, R 2 is one or two Z's which may be the same or different 2 C is replaced by 1~6 In some embodiments, R 2 is one Z 2 C is replaced by 1~6 It is alkyl.

[0104] In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptable salt thereof, R 2 But H, C 1~6 Alkyl, or C 1~6 A compound that is a haloalkyl.

[0105] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 But H, C 1~6 Alkyl, or C 1~6In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein R 2 is H, —CH2CF3, —CH2CHF2, —CH2CH3, or —CH(CH3)2.

[0106] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 1 to 3 Z's which may be the same or different 2 C is replaced by 1~6 is alkyl, and Z 2 Heteroaryl, C 3~6 Cycloalkyl, or C 6~10 aryl, wherein each of the heteroaryl, cycloalkyl, or aryl is optionally substituted with 1 to 3 halo, which may be the same or different.

[0107] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 but one or two Z's which may be the same or different 2 C is replaced by 1~6 In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein R 2 But one Z 2 C is replaced by 1~6 It is a compound that is alkyl.

[0108] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 1 to 3 Z's which may be the same or different 2 C is replaced by 1~3 is alkyl, and Z 2 But C 3~6cycloalkyl or phenyl, each of which is optionally substituted with 1 to 3 halo, which may be the same or different.

[0109] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 But benzyl, [ka] In some embodiments, R 2 is benzyl.

[0110] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 2 is H. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 is -SO2CH3.

[0111] In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen to which they are attached, 1 to 4 Z which may be the same or different 4 and Z forms a 4- to 10-membered heterocyclyl optionally substituted by 4 But, -OR 12a R 12a is optionally substituted with 1 to 3 halo, which may be the same or different; 6~10 In some embodiments, Z is aryl. 4 -OR 12a and R 12a is optionally substituted with 1 to 3 halo, which may be the same or different; 1~6It is alkyl.

[0112] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 1 and R 2 together with the nitrogen to which they are attached, 1 to 3 Z which may be the same or different 4 In some embodiments, R 1 and R 2 is a group consisting of two Z groups which may be the same or different, together with the nitrogen to which they are attached. 4 In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, form one Z 4 Form a 4- to 10-membered heterocyclyl substituted with

[0113] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, -OR 12a forming a 4- to 6-membered heterocyclyl substituted with R 12a is phenyl optionally substituted with 1 to 3 halo, which may be the same or different. In some embodiments, -NR1R2 is [ka] In some embodiments, -NR1R2 is [ka] is.

[0114] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 3 But C 1~6 Haloalkyl, or -CN or C 3~6 C optionally substituted with cycloalkyl 1~6In some embodiments, R 3 is C 1~6 Haloalkyl or C 1~6 In some embodiments, R 3 is —CH, —CHCH(CH), —C, H, —CH(CH), —CHCHF, —CHCHCF, —CHCHF, or —CHCF. In some embodiments, R 3 is —CH 2 CN or cyclopropyl.

[0115] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 3 But C 6~10 C substituted with aryl or heteroaryl 1~6 alkyl, and aryl or heteroaryl are 1 to 3 Z 1a and optionally substituted with Z 1a But, Hello, -OC 1~6 Alkyl, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 6~10 In some embodiments, R 3 is C 6~10 Aryl-substituted C 1~3 alkyl, and aryl is optionally 1 to 3 halo, which may be the same or different. In some embodiments, R 3 is benzyl, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 is benzyl.

[0116] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 3 but, [ka] is a compound.

[0117] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 3 is substituted with heteroaryl 1~3 In some embodiments, R is an alkyl group and heteroaryl is optionally substituted with 1 to 3 halo groups, which may be the same or different. 3 C is substituted with pyridyl 1~3 In some embodiments, R 3 teeth, [ka] is.

[0118] In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, comprises R 3 is phenyl.

[0119] In some embodiments, the disclosure provides a compound of any one of Examples 1-55. In some embodiments, the disclosure provides a compound of Example 2a or 42a.

[0120] In some embodiments, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound in Tables 1-5, or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the present disclosure provides: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the present disclosure provides a compound [ka] or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the present disclosure provides a compound [ka] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the present disclosure provides a racemic mixture comprising a compound of Formula (I), (Ia), (Ib), or (Ic), 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), or (Ic), 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.

[0138] 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 2It is recognized that each of the above-described compounds (I), (II), (III), (IV), (IV), (IV), (V), (VI), (VII ...

[0139] Pharmaceutical Compositions and Modes of Administration Additionally, 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.

[0140] 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.

[0141] 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.

[0142] In practical use, the compounds of the present disclosure may be combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The active ingredient can be combined as an intimate admixture with the active ingredient. The carrier can take a wide 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 form, 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 starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. for oral solid preparations such as powders, hard capsules, soft capsules, and tablets, with solid oral preparations being preferred over liquid preparations.

[0143] 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 the active compound in these compositions can, of course, be varied and can 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 a spray.

[0144] 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.

[0145] 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, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0146] In some embodiments, the compounds of the present disclosure can also be used as salts with various counter cations to obtain orally available formulations.

[0147] 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 glycol, and mixtures thereof in oils.Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0148] Pharmaceutical forms suitable for use in injections include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. 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.

[0149] Any suitable route of administration may be used to provide a mammal, particularly a human, with an effective dose of a compound of the present disclosure, for example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of the present disclosure are administered orally.

[0150] kit 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.

[0151] 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 analog thereof, in a suitable container, which can be a vial, bottle, ampoule, pre-filled syringe, and infusion bag.

[0152] Treatment Methods and Uses The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions mediated by the binding and degradation of an IKZF protein (e.g., an IKZF2 or IKZF4 protein) by the compounds. Furthermore, the present disclosure relates to the use of the compounds 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 compounds. In some embodiments, an IKZF-related disease or condition is alleviated by selective degradation of the IKZF2 protein. In some embodiments, an IKZF-related disease or condition is alleviated by degradation of the IKZF2 protein. In some embodiments, an IKZF-related disease or condition is alleviated by degradation of the IKZF2 protein and one or more additional IKZF2 proteins (e.g., an IKZF1 and / or IKZF4 protein). In some embodiments, the IKZF-associated disease or condition is alleviated by degradation of the IKZF4 protein.

[0153] 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).

[0154] 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.

[0155] In some embodiments, provided herein are methods for treating and / or preventing an IKZF protein (e.g., an IKZF2 protein)-associated disease or condition in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, an IKZF protein (e.g., an IKZF2 protein) is isolated. Provided herein are methods for treating a disease or condition associated with an IKZF protein, the methods comprising 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), or (Ic), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, a method for reducing cell proliferation is provided, comprising contacting a cell with a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, and reducing IKZF protein (e.g., IKZF2 protein) levels in the cell.

[0158] In some embodiments, provided herein are methods for reducing IKFZ protein (e.g., IKZF2 protein) levels in a patient in need thereof (e.g., a patient having an IKZF2-associated disease or condition), the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof.

[0159] 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 comprises a solid tumor. In some embodiments, the cancer comprises 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, In embodiments, more than about 1% and less than about 50% of the cancer cells 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 the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancers or tumors).

[0160] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition is a hematological cancer, e.g., leukemia (e.g., acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), Myeloproliferative disease (MPD), chronic myeloid leukemia myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), undifferentiated 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), Waldenstrom's macroglobulinemia (WM), and / or bone marrow tumors (e.g., multiple myeloma (MM)).

[0161] 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 tumor, or a soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, chondroma, chondrosarcoma, alveolar soft tissue tumor, etc.). tumor, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), or lymphoma.

[0162] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition includes solid tumors in or arising from tissues or organs such as: 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 adenocarcinoma, 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-Landau (VHL)-associated serous cystic neoplasm, and serous cystadenocarcinoma); mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IPMN) , IOPN), intraductal tubular neoplasm, cystic acinar neoplasm (including acinar cell cystadenoma, acinar cell cystadenocarcinoma, and pancreatic adenocarcinoma), invasive pancreatic ductal adenocarcinoma (including tubular adenocarcinoma and adenosquamous carcinoma), mucinous carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinic 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 neoplasm (SPN), and pancreatoblastoma); Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile duct, intrahepatic bile duct cancer); 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 carcinoma, secretory carcinoma, and tubular carcinoma)); lobular carcinoma (including but not limited to pleomorphic carcinoma and signet ring cell carcinoma); · Peritoneum (e.g., mesothelioma; primary peritoneal cancer); Ovarian (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord stromal tumors), fallopian tuberculosis Pius 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 cancer, endometrial polyp, endometrial hyperplasia, intraepithelial carcinoma (EIC)), endometrial cancer (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 tumor Female genital tissues, including dermal and mesenchymal tumors (e.g., adenofibroma, carcinoma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma, MMMT)), endometrial stromal tumor, malignant mixed Mullerian 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 lymphoma (NHL), mitral nephroma, thyroid cancer ... Chronic non-Hodgkin's lymphoma (iNHL), refractory i NHL, pituitary tumor; Eyes (e.g., retinoma, retinoblastoma, intraocular melanoma, posterior uveal melanoma, iris hamartoma); Head and neck (e.g., nasopharyngeal cancer, endolymphatic sac tumor, E LST, epidermoid carcinoma, laryngeal cancer (squamous cell carcinoma, SCC) ) (e.g., glottic cancer, supraglottic cancer, subglottic cancer, and combined laryngeal cancer), carcinoma in situ, including 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); Lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC) (including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, and pleuropulmonary blastoma); Lymphoma (e.g., lymphoma (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 (B-cell lymphoma and T-cell lymphoma) cell lymphomas (e.g., Burkitt 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; systemic T-cell lymphoma), including lymphangioleiomyomatosis); · central nervous system system, CNS) (e.g., glioma (astrocytoma (e.g., pilocytic astrocytoma, pilocytic myxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse sexual astrocytoma, fibrous astrocytoma, large round cell astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (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., subependymoma, myxopapillary ependymomas, ependymomas (e.g., cells, papillae, clear cells, elongated ependymal cells), poorly differentiated ependymomas), optic gliomas, as well as non-gliomas (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 tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, neuroblastoma group tumors (including, but not limited to, neuroblastoma, ganglioneuroblastoma, and ganglioneuromatosis), and trisomy 19 ependymoma; Neuroendocrine tissues (e.g., the preganglionic system, including the adrenal medulla (pheochromocytoma) and extra-adrenal paraganglia (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, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastoma, embryonal rhabdomyosarcoma, Ewing's sarcoma / primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myosinogen deficiency syndrome (IMDS) syndrome) Fibroblastic 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, well-differentiated liposarcoma.

[0163] 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.

[0164] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-associated disease or condition is selected from the group consisting of non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NDC), and leukemia. In some embodiments, the cancer is selected from: non-small cell lung cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, and gastrointestinal stromal tumor (GIST). In some embodiments, the cancer is metastatic.

[0165] Dosage The effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosage may be readily ascertained by one skilled in the art.

[0166] When the compounds of the present disclosure are used to treat or prevent diseases or conditions associated with an IKZF protein (e.g., an IKZF2 protein), satisfactory results are generally obtained when the compounds of the present disclosure are administered at a daily dose of about 0.1 milligrams to about 300 milligrams per kilogram of animal body weight. In some embodiments, the compounds of the present disclosure are 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 dose would generally be about 0.1 milligram 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.

[0167] 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 also continue for several days; for example, treatment will generally continue 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.

[0168] In some embodiments, the methods provided herein include administering to a subject an initial daily dose of about 1 to 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.

[0169] combination In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, provided herein 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.

[0170] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula (I), (Ia), (Ib), or (Ic) 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 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.

[0171] In some embodiments, the one or more additional therapeutic agents can be, 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, or fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimetic (e.g., adnectin, affibody, affilin, affimer, afftin, alphabody, anticalin, peptide aptamer, armadillo repeat protein, etc.), 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, or fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimetic (e.g., adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein, etc.), a chemotherapeutic agent, an anti-inflammatory agent, an anti-inflammatory drug, an anti-inflammatory drug, an anti-inflammatory drug, an anti-inflammatory drug, an anti-inflammatory drug, an anti-inflammatory drug, an anti- antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifying or editing agents, cells comprising chimeric antigen receptors (CARs), e.g., T cell immunotherapeutics, NK cell immunotherapeutics, or These may include cells containing macrophage immunotherapeutics, cells containing engineered T-cell receptors (TCR-T), or any combination thereof.

[0172] illustrative target In some embodiments, the one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or suppressors of the following targets (e.g., polypeptides or polynucleotides): 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-nucleotidase ect (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 acyltransferase 2 (acetyl-CoA acyltransferase 2, ACAA2; NCBI Gene ID: 10499); acid phosphatase 3 (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 (alanyl aminopeptidase, ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha fetoprotein (AFP; NCBI Gene ID: 174); copper-containing amine oxidases (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene IDs: 26, 314, 8639); androgen receptor (androgen receptor, AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI Gene ID: 284, 285); angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (angiotensinogen, AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis-inducing factor mitochondria-associated 1 (apoptosis-inducing factor mitochondria-associated 1) 1, AIFM1, AIF; NCBI Gene ID: 9131); arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (asparaginase, ASPG; NCBI Gene ID: 374569); asteraid 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: 558); B and T lymphocyte-associated (B and T lymphocyte-associated) associated, BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing proteins (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 component 3 (BBC3, PUMA; 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-carboxyglutamate proteinbone gamma-carboxyglutamate protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI Gene IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and external domain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BRT) 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 IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (C15) 15, CHST15; NCBI Gene ID: 51363); carbonic anhydrase (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 37767) 7); 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, 864); catenin beta 1 (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); NCBI Gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer binding protein alpha (CCAAT). 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); cellular communication network factor 2 ( factor 2, CCN2; NCBI Gene ID: 1490; cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropin hormone 1 (CSH) 1, CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene ID: 9074, 51208); cluster of differentiation markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD4 beta (TRB), CD5 gamma (TRG), CD6 delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD 24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD5 5(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CSF1R), CD116(GMCSFR, CSF2RA), CD1 22 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8 R2), CD193(CCR3), CD194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H 3), 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, 3 480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (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 IDs: 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 IDs: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene IDs: 718, 727); COP9 signalosome subunit 5 (C; OPS5; NCBI Gene ID: 10987; C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI Gene IDs: 160364, 170482, 283420); 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 IDs: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI gene ID: 595); cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK 4, 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, CY P11B2, CYP17A1, CYP19A1, CYP51A1 (NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductase (POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte associated protein 4 (cytotoxic T-lymphocyte associated protein 4) 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 IDs: 10683, 54567); Diablo IAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI Gene IDs: 1606, 8525); Dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene IDs: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DHDP) 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 IDs: 780, 4921); DNA-dependent protein kinase (PRKDC; NCBI Gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene IDs: 7150, 7153, 7155, 7156, 8940); dopachrome tautomers (dopachrome 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 aminopeptidase (ERAP1, ERAP2; NCBI Gene ID: 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 ID: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene ID: 1942, 1 945, 1948); epidermal growth factor receptor (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); epithelial mitogen (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factor (e.g., E EF1A2, 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, CD95L, 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 receptor (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene ID: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene ID: 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 (folate receptor 1, FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); furin (furin, 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 (glucuronidase beta, GUSB; NCBI Gene ID: 2990); glutamate metabotropic receptor 1 (glutamate metabotropic receptor 1) 1, GRM1; NCBI Gene ID: 2911; glutaminase (GLS; NCBI Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); glycogen synthase kinase 3 beta 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-bound protein 2 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), HSP90B1 (GP96); NCBI Gene IDs: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene IDs: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (hepatitis A virus cellular receptor 2, HAVCR2, TIM3, CD366; NCBI Gene ID: 84868; hepatocyte growth factor, HGF; NCBI Gene ID: 3082; HERV-H LTR-associating 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, 309; 1); I-kappa-B kinase (IKK beta; NCBI gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI gene IDs: 10320, 22806); immunoglobulin superfamily member 11 (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 costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2 R; 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 (IL-1R-4) 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), IL12A, 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 domains and long cytoplasmic tails (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, 57292, 553128, 548594, 100132285); killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (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 (lactotransferrin, LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src kinase; 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 IDs: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / choriogonadotropin receptor (LAT; NCBI Gene ID: 27040); receptor, LHCGR; NCBI Gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI Gene ID: 27076); lymphocyte activating 3 (LAG3; CD223; NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene IDs: 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 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 inhibitory factor (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, 51438, 266740); major histocompatibility complex (HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: 3105, 3133, 3134, 3135); major vault proteins (major vault proteins) protein, MVP, VAULT1; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; 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, 4315, 4316, 4317, 4318, 4319, 4419, 4420, 4421, 4422, 4423, 4424, 4425, 4426, 4427, 4428, 4429, 4430, 4431, 4432, 4433, 4434, 4435, 4436, 4437, 4438, 4439, 4449, 4450, 4451, 4452, 4453, 4454, 4455, 4456, 4457, 4458, 4459, 4460, 4461, 4462, 4463, 316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI Gene ID: 4170); MDM2 proto-oncogene (MDM2; NCBI Gene ID: 4170) 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 (melan-A, MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene IDs: 4157, 4148);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 IDs: 4277, 100507436); mitogen-activated protein kinase (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 Protein kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI Gene IDs: 4217, 1326); mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene IDs: 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 (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 (NPR3; NCBI Gene ID: 4883). killer cell cytotoxicity receptor 3 ligand 1, NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, a MAGE family member (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 (NEA) 1, NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829); neurotrophin receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), 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 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 (nucleolin, NCL; NCBI Gene ID: 4691); nucleophosmin 1 (nucleophosmin 1, NPM1; NCBI Gene ID: 4869); nucleotide-binding oligomerization domain-containing 2 (NOD2; NCBI Gene ID: 64127); Nucleotidyl hydrolase O-6-methylguanine-DNA methyltransferase 1 (NUDT1; NCBI Gene ID: 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, PPAR delta), PPARG (PPAR gamma, 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), PIK3CG (PI3K gamma); NCBI Gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2 G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); placenta growth factor (PGF); NCBI Gene ID: 5228);Plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene IDs: 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 (porcupine O-acyltransferase, PORCN; NCBI Gene ID: 64840; nuclear receptor transcriptional regulator, PRAME (NCBI Gene ID: 23532); premelanosome protein, PMEL (NCBI Gene ID: 6490); progesterone 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); prominin 1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia, PML; NCBI Gene ID: 5371); prosaposin (PSAP; NCBI 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 IDs: 5742, 5743); proteasome; 20S subunit beta 9 (PSMB9; NCBI Gene ID: 5698); protein arginine methyltransferase (e.g., PRMT1, PRMT5; NCBI Gene IDs: 3276, 10419); protein kinase N3 (PKN3; NCBI Gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); protein tyrosine kinase 7 (inactive) (protein tyrosine kinase 7, PTK7; NCBI Gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene IDs: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (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 proto-oncogene, RET; NCBI Gene ID: 5979); retinoic acid 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 ID: 6093, 9475); ribosomal protein S6 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: 6280); secreted frizzled related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (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 (SEMA4D; CD100; NCBI Gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene IDs: 27036, 27180, 89790); signal regulatory protein alpha (SIGLEC alpha, SIRPA, CD172A; NCBI Gene ID: 140885); signal transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (sirtuin-3, SIRT3; NCBI Gene ID: 23410);signaling lymphocytic activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NC; NCBI Gene IDs: 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, SLC6A2, 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 ID: 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 ID: 8877, 56848); sphingosine-1-phosphate receptor 1 agonists (sphingosine-1-phosphate receptor 1, S1PR1, CD363; NCBI Gene ID: 1901; spleen associated tyrosine kinase, SYK; NCBI Gene ID: 6850; splicing factor 3B factor 1 ctor 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 sulfatase (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 IDs: 8651, 9021); synapsin 3 (synapsin 3, SYN3; NCBI Gene ID: 8224; syndecan 1 (SDC1, CD138, syndecan; 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 IDs: 6869, 6870); TANK binding kinase 1 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); tec protein tyrosine kinase (TEC; NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); 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, 11278); 19); 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: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene IDs: 7606, 7608); thyroid stimulating hormone receptor (THR). 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 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); transferrin (transferrin, TF; NCBI Gene ID: 7018); transferrin receptor (transferrin receptor, TFRC, CD71; NCBI Gene ID: 7037); transforming growth factors (e.g., transforming growth factor, TGFA, TGFB1; NCBI Gene ID: 7039, 7040);Transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 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 (TGM5; NCBI Gene ID: 9333); 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 ID: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162); tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor-associated calcium signal transducer 2 (T2D) 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 (CD261), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRSF12A, TNFRSF13B, TNFRSF14; FR13C (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI Gene IDs: 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 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); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); tyrosine kinase with 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 I, 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 (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); WRN RecQ-like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain containing transcription factor 1 (WW domain containing transcription regulator 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 regulator (YAP1; NCBI Gene ID: 10413); or zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 75 35) etc.

[0173] In some embodiments, the one or more additional therapeutic agents may be, for example, Drugs targeted to this include: 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 alpha (DGKA, DAGK, DAGK1, or DGK-alpha; 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; including mutations such as KRAS G12C or G12D; 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, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD2 79; 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); T-cell immunoreceptor with Ig and ITIM domains (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: 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); WRN; RecQ-like helicase (WRN; NCBI gene ID: 7486); or zinc finger protein Helios (IKZF2; NCBI gene ID: 22807).

[0174] Illustrated mechanism of action Immune Checkpoint Modulators In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination 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 microenvironment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In some embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, the immune checkpoint protein or receptor regulates NK cell responses (see, e.g., 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 (reviewed, e.g., in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0175] Examples of immune checkpoint proteins or receptors that may 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: 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: 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-associated 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 cell receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); galectin 9 (LGALS9; NCBI Gene ID: 3965); lymphocyte activation signaling lymphocyte activation molecule family member 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 (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 (; 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 lectin-like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 830 2); 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 (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).

[0176] 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 blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Illustrative T cell inhibitory immune checkpoint proteins or receptors include: CD274 (CD274, PDL1, PD-L1); Programmed Cell Death 1 Ligand; PD-1LG2, PD-L2, CD273; programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TI GIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular 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, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Illustrative T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator 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. See Cancer Res.(2018)37:110.

[0177] 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 blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Illustrative 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, two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 3 (KIR3DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); 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 provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more agonists or activators of one or more NK cell-stimulatory immune checkpoint proteins or receptors. Illustrative 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 (SLAM) MF7). 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.

[0178] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody or fragment thereof, or 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 (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of LAG3.

[0179] 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).

[0180] 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, CS-1003, HLX-1 0, 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 (MSB0010718C), CX-072, C BT-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, zimbelelimab (AB122), spartalizumab (P DR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, as well as 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), A4), MEDI-5752(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-104(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).

[0181] 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.

[0182] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0183] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate its suppression of anti-tumor immune responses and 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.

[0184] 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 may suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor may reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor may modulate cell phenotype and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI Gene ID: 1233) antagonists and degraders of Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI Gene ID: 10320), Helios (IKZF2; NCBI Gene ID: 22807), Aiolos (IKZF3; NCBI Gene ID: 22806), and Eos (IKZF4; NCBI Gene ID: 64375).

[0185] Examples of Helios degraders that may be co-administered include, but are not limited to, I-57 (Novartis) and compounds disclosed in WO 2019038717, WO 2020012334, WO 20200117759, and WO 2021101919.

[0186] 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 cytotoxicity (ADCC) activity. In this study, Treg-depleting antibodies have been Fc-engineered to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Illustrative 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).

[0187] In some embodiments, Treg inhibitors or Treg depleting agents that may be co-administered include CC motif chemokine receptor 4 (CCR4), CC motif chemokine receptor 7 (CCR7), CC motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic Tregs, 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 alpha and antibodies or antigen-binding fragments thereof that selectively bind to a cell surface receptor selected from the group consisting of T cell surface receptor E (ITGAE; CD103), interleukin-7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor alpha (FOLR1), folate receptor beta (FOLR2), leucine-rich repeat-containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulatory factor (ICOS; CD278), lymphocyte activation 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cell receptor 2 (HAVCR2; CD366; TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), or a combination thereof.

[0188] Examples of Treg-depleting anti-CCR8 antibodies that can be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Antibodies disclosed in WO 2021163064, WO 2020138489, and WO 2021152186 include antibodies disclosed in WO 2021163064, WO 2020138489, and WO 2021152186, as well as antibodies disclosed in WO 2021163064, WO 2020138489, and ...

[0189] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0190] 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). Illustrative targets for depleting or reprogramming unstimulated myeloid cells include the triggering receptors TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209) expressed on myeloid cells. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may be administered in combination with an anti-TREM-1 antibody (e.g., PY159; disclosed in WO 2019032624). The antibody is administered in combination with one or more myeloid cell depleting or reprogramming agents, such as an anti-TREM-2 antibody (e.g., PY314; the antibody disclosed in WO2019118513).

[0191] Cluster of differentiation agonists or activators 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 CD marker targeting agents that may be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tecevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A 2402 / HLA-A0201 restricted epitope peptide vaccine, 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, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverenvatinib dimesylate (HQP-1351), cabozantinib nib, 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 the disclosures of International Publication Nos. 2016196388, 2016033570, 2015157386, 199203459, 199221766, 2004080462, 2005020921, 2006009755, and 200701 ... 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 No. PCT / US2019 / 063091, 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, 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. 2016205042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 201805 7669, 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), Examples of compounds that are

[0192] In some embodiments, CD marker targeting agents that may be co-administered include PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, robritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117- These include small molecule inhibitors such as ADCs, 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), prexafor, CTX-5861, and REGN-5678 (PSMA / CD28).

[0193] In some embodiments, CD marker targeting agents that may be co-administered include interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly-ICLC (NSC-301463), Riboxxon, Apoxxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, Small molecule agonists such as resiquimod, 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.

[0194] In some embodiments, CD marker-targeting agents that may be co-administered include 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, daratumumab (DARZALEX®), TTX-030, cericlerumab (R G7876), APX-005M, ABBV-428, ABBV-927, mitazarimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (caviralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulcafusp alfa 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, fianlimab (REGN-3767 ), INCAGN2385, encelimab (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, INCA Antibodies such as GN-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 compounds disclosed in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.

[0195] In some embodiments, CD marker targeting agents that may be co-administered include CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, liso-cel, lisocabtagenemaraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, taveleclucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3 zeta-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 leukemia / non-Hodgkin lymphoma, University Hospital Heidelberg), anti-CD19 CAR T cell therapy (Silence IL-6 development, Shanghai Unicar Therapy BioPharmaceutical 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 cells (chronic leukemia / B-cell leukemia), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3 zeta-EGFRt, Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, Trisagenleukocyte-T, CART-19, Trisagenleukocyte (CTL-019), anti-CD20 CAR T cell therapy (non-Hodgkin lymphoma), MB-CART2019.1 (CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR 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 and cell therapies such as those disclosed in WO 2012079000 or WO 2017049166.

[0196] Cluster of differentiation 47 (CD47) inhibitors In some embodiments, the compounds of formula (I), (Ia), (Ib), or The compound of formula (Ic), or a pharmaceutically acceptable salt thereof, is administered together 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 blocking agents, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include 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, B6H12, 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. 201310 9752, 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. 201702742 2, 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, Examples of suitable CD47 inhibitors include compounds disclosed in International Publication Nos. 2019179366, 2019184912, 2019185717, 2019201236, 2019238012, 2019241732, 2020019135, 2020036977, 2020043188, and 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.

[0197] 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 / V and bispecific antibodies targeting CD47, such as EGF), 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.

[0198] SIRPα targeting agent In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with a SIRPα targeting agent (NCBI Gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents that may be co-administered include SIRPα inhibitors such as AL-008, RRx-001, and CTX-5861, and anti-SIRPα antibodies such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and 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.

[0199] FLT3R agonists In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an FLT3R agonist. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered 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 WO2020263830. 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.

[0200] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In some embodiments, a compound provided in Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is an agonist of one or more TNF receptor superfamily (TNFRSF) members, for example, 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, TRAIL ... ILR1, 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, CD 269, 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.

[0201] 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 those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0202] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0203] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0204] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0205] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0206] Exemplary anti-TNFRSF18 (GITR) antibodies that can 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 2017 / 096276, WO 2017096189, and WO 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO 2017 / 096179 and WO 2018089628.

[0207] 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).

[0208] TGFβ antagonists In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with a TGFβ antagonist. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. TGFβ-specific antibodies can be administered by methods known to those skilled in the art, for example, PCT International Publication No. No. 2018 / 129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist is a TGFβ latency-associated peptide (LAP), e.g., Binds to TGFβ1-LAP. 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 presence 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., patients with liver cancer). In some embodiments, the TGFβ antagonist is a latent TGFβ binding protein (LTFβ). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) 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 TGFβ complex, e.g., the liver. LAP- in the extracellular matrix (ECM) of connective tissue within the Specifically binds to TGFβ complexes. 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).

[0209] Bispecific T cell engager In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) 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). Illustrative anti-CD3 bispecific antibodies or BiTEs that may 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), flotetuzumab (CD123 / CD3), odronectumab (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), AMG-330 (CD 33 / 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 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsA b(CD3 / GD2), ERY974(GPC3 / CD3), GEMoab(CD3 / PSCA), RG6026(CD20 / CD3), RG6194(HER2 / CD3), PF-06863135( BCMA / CD3), SAR440234 (CD3 / CDw123), JNJ-9383 (MGD-015), AMG-424 (CD38 / CD3), Tidutamab (XmAb-1 8087(SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp1 00 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), Tizutamab (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. Illustrative bispecific T cell engagers that may be co-administered target CD3 and a tumor-associated antigen described herein, e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230).

[0210] Bispecific and trispecific natural killer (NK) cell engagement Ja In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is used as a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager. The antibody may be administered with a tri-specific NK-cell engager (TriKE) (e.g., without Fc), or a bispecific antibody (e.g., with 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 can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., including CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKE and TriKE can be co-administered using methods described, for example, in Felices, et al., Methods Mol Biol.(2016)1441:333-346;Fang,et al. ,Semin Immunol.(2017)31:37-54.

[0211] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an MCL1 apoptosis regulator, an inhibitor of a BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include 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 WO2018183418, WO2016033486, and WO2017147410.

[0212] SHP2 inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered 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.

[0213] Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors and degraders In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) 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 hematopoietic progenitor kinase 1 (HPK1) inhibitors include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300.

[0214] Apoptosis Signal-Regulating Kinase (ASK) inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an ASK inhibitor, such as mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO2013112741 (Gilead Sciences).

[0215] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, the compounds of formula (I), (Ia), (Ib), or Compound (Ic), or a pharmaceutically acceptable salt thereof, is administered together 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.

[0216] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the compounds of Formula (I), (Ia), (Ib), or (Ic) provided herein, or pharmaceutically acceptable salts thereof, are selected from the group consisting of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CM M3; 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, selinexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02.

[0217] Discoidin Domain Receptor (DDR) inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, 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 those disclosed in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0218] Targeted E3 ligase ligand conjugates In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) 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, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survival E3 ubiquitin ligase binding domain, von Hippel-Lindau E3 ubiquitin ligase (VHL) binding domain, cereblon E3 ubiquitin ligase binding domain, mouse double minute 2 homolog (mouse double minute 2 homolog, MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase degradation of targeted proteins, e.g., via the ubiquitin pathway. In some embodiments, the targeted 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 targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets and 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 targeted 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., International Publication No. 2018098280. In some embodiments, the targeting E3 ligase ligand conjugate comprises an interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); a RAF (Rapidly Accelerated Fibrosarcoma, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and a binding moiety that targets or binds the E3 ligase ligand or binding moiety. See, e.g., International Publication Nos. 2019099926, 2018226542, 2018119448, 2018223909, and 2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, for example, in WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649.

[0219] Histone deacetylase (HDAC) inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of a 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.

[0220] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) 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), and resorcinolone. These include minostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0221] Janus Kinase (JAK) inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered 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, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0222] Lysyl Oxidase-Like Protein (LOXL) Inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered 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).

[0223] Matrix Metalloprotease (MMP) Inhibitors In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, 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: 4330), MMP20 (NCBI Gene ID: 4331), MMP21 (NCBI Gene ID: 4332), MMP22 (NCBI Gene ID: 4333), MMP23 (NCBI Gene ID: 4334), MMP24 (NCBI Gene ID: 4335), MMP25 (NCBI Gene ID: 4336), MMP26 (NCBI Gene ID: 4337), MMP27 (NCBI Gene ID: 4338), MMP28 (NCBI Gene ID: 4339), MMP29 (NCBI Gene ID: 4340), MMP30 (NCBI Gene ID: 4341), MMP31 (NCBI Gene ID: 4342), MMP32 (NCBI Gene ID: 4343), MMP3 MMP14 (NCBI Gene ID: 4322), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP19 (NCBI Gene ID: 4327), MMP20 (NCBI Gene ID: 9313), MMP21 (NCBI Gene ID: 118856), MMP24 (NCBI Gene ID: 10893), MMP25 (NCBI Gene ID: 64386), MMP26 (NCBI Gene ID: 56547), MMP27 (NCBI Gene ID: 64066), and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012027721 (Gilead Biologics).

[0224] RAS and RAS pathway inhibitors In some embodiments, the compounds of Formula (I), (Ia), (Ib), or (Ic) provided herein, or pharmaceutically acceptable salts thereof, are directed against the KRAS proto-oncogene, GTPases (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS ... The treatment is administered in combination with an inhibitor of the NRAS proto-oncogene (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or the HRAS proto-oncogene, or a GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). The Ras inhibitor 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. Illustrative 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. Illustrative KRAS mRNA inhibitors include anti-KRAS U1 adaptor, AZD-4785, siG12D-LODER™, and siG12D-exosomes.Illustrative MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Illustrative Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Illustrative ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, rabocertinib, and ulixertinib. Illustrative Ras GTPase inhibitors that can be co-administered include rigosertib. Illustrative PI3K inhibitors that may be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pictilisib, inavolisib (RG6114), and ASN-003. Illustrative AKT inhibitors that may be co-administered include capivasertib and GSK2141795. Illustrative PI3K / mTOR inhibitors that may be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), and racemetyrosine (TYME-88 (mTOR / cytochrome P450 inhibitor). 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 co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Also, K-RAS and mutant N-RAS can be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0225] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) 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), uprosertib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib.

[0226] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit The PI3K inhibitor is administered in combination with an inhibitor of beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110delta, 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, buparlisib (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, OXY111A, PA799, PX-866, RG 7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication No. 2005113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Sciences, Inc.). Calistoga), WO 2013116562 (Gilead Calistoga), WO 2014100765 (Gilead Calistoga), WO 2014100767 (Gilead Calistoga), and WO 2014201409 (Gilead Sciences).

[0227] Spleen Tyrosine Kinase (SYK) inhibitor In some embodiments, the compounds of Formula (I), (Ia), (Ib), or (Ic) provided herein, or pharmaceutically acceptable salts thereof, inhibit spleen-associated tyrosine kinase ( It is administered in conjunction with an inhibitor of 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. Patent No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 20150175616.

[0228] Toll-like receptor (TLR) agonists In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an agonist of a Toll-like receptor (TLR), for example, an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793).Exemplary TLR7 agonists that may be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod 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 those disclosed in 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. 20110098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead 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. 20140350031 (Janssen), WO 2014023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Examples include compounds disclosed in Therapeutics.An example of a TLR7 / TLR8 agonist that can be co-administered is NKTR-262. Exemplary 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, and 3M-052, as well as U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014056953 (Janssen), and WO 2014076221 (Janssen). WO 2014128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (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 (VentirxPharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx 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). 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.

[0229] Tyrosine kinase inhibitors (TKIs) In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with a tyrosine kinase inhibitor (TKI). TKIs inhibit epidermal growth factor receptor (EGFR) and fibroblast growth factor (GF) receptors. Targeting receptors for FGF, platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, 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, K X2-391 (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, barlitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®, and Booth, et al., Cancer Biol Ther. 2018 Feb. 1;19(2):132-137. Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab saratarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, and depatuxizumab. (ABT-806), and cetuximab.

[0230] chemotherapy drugs In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, provided herein is administered with a chemotherapeutic or anti-neoplastic agent.

[0231] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic drug" (or "chemotherapy" in the context of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including synthetic analogs of adozelesin, carzelesin, and bizelesin; and cryptophycins. , especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phiI1), dynemicins, including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dac Tinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptonigrin antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxy androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; radiotherapeutic agents such as radium-223; trichothecenes, especially T-2 toxin, veracrine A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), Ab; Laxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; sabizablin (Veru-111); platinum analogues such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine, hestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformucine; ethyl acetate Liptinium; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea, Lentinan; Leucovorin; Lonidamine; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Fluoropyrimidines; Folinic acid; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide K (P SK); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZAR®); 6-Thioguanine; Mercaptopurine; Meth Trexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoids Examples of suitable anti-cancer drugs include thiazolinone, capecitabine, NUC-1031, FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin), FOLFIRI (folinic acid, 5-fluorouracil, irinotecan), FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such drugs can be conjugated to an antibody or any of the targeting agents described herein to create an antibody-drug conjugate (ADC) or targeted drug conjugate.

[0232] Antihormonal drugs Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0233] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0234] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0235] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, and ODM-2. 01, APC-100, ODM-204, enoborsam (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antisense).

[0236] Exemplary progesterone receptor antagonists include onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethisterone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and bonorgestrel.

[0237] Antiangiogenic agents In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an antiangiogenic agent. Antiangiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necpranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, and l-azetidine-2-carboxylic acid. Modulators of matrix metabolism, including proline analogs such as cis-hydroxyproline, d,I-3,4-dehydroproline, thiaproline, α,α'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), and chymosin. Antiangiogenic agents include tatins, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, beta-1-anticollagenase serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthonylate disodium (CCA), thalidomide, angiogenesis-suppressing steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod. Other antiangiogenic agents include antibodies, preferably monoclonal antibodies, against the following angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2. Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, dirupacimab (ABT-165; DLL4 / VEGF), or nabicikizumab (OMP-305B83; DLL4 / VEGF).

[0238] antifibrotic agents In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an antifibrotic agent. Antifibrotic agents that may be co-administered include compounds such as beta-aminoproprionitrile (BAPN), as well as compounds disclosed in U.S. Pat. No. 4,965,288, which relates to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition, and U.S. Pat. No. 4,997,854, which relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, and are incorporated herein by reference. Further exemplary inhibitors are disclosed in U.S. Pat. Nos. 4,943,593, 5,021,456, 5,059,714, 5,120,764, 5,182,297, which relate to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, 2-(1-naphthyloxymemyl)- ... No. 5,252,608 for 3-fluoroallylamine, and U.S. Patent Application Publication No. 20040248871, which are incorporated herein by reference.

[0239] Exemplary antifibrotic agents also include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate resonance-stabilized products after binding to the carbonyl, such as the following primary amines: ethylenamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactone.

[0240] Other antifibrotic agents are copper chelators, which may or may not be cell-permeable. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butanesulfate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0241] anti-inflammatory agents In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, provided herein is administered with an anti-inflammatory agent. Exemplary anti-inflammatory agents include, but are not limited to, arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 3776), 77), CA14 (NCBI Gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0242] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that may be co-administered include mofezolac, Examples include GLY-230, and TRK-700.

[0243] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, mavacoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that may be co-administered include pormacoxib and imrecoxib. .

[0244] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include LY3023703, GRC27864, and the compounds disclosed in WO 2015158204, WO 2013024898, WO 2006063466, WO 2007059610, WO 2007124589, WO 201 0100249, International Publication No. 2010034796, International Publication No. 2010034797, International Publication No. 2012022793, International Publication No. 2012076673, International Publication No. 2012076672, International Publication No. 2010034798, International Publication No. 2010034799, International Publication No. 2012022792, International Publication No. 2009103778, International Publication No. 2011048004, International Publication No. 2 012087771, International Publication No. 2012161965, International Publication No. 2013118071, International Publication No. 2013072825, International Publication No. 2014167444, International Publication No. 2009138376, International Publication No. 2011023812, International Publication No. 2012110860, International Publication No. 2013153535, International Publication No. 2009130242, International Publication No. 2009146696, International Publication and compounds described in International Publication Nos. 2013186692, 2015059618, 2016069376, 2016069374, 2009117985, 2009064250, 2009064251, 2009082347, 2009117987, and 2008071173. Metformin has further been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0245] Carbonic anhydrases that may be co-administered (e.g., CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), C Examples of inhibitors of one or more of A9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)) include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. COX-2 / CA1 / CA2 dual inhibitors include CG100649.

[0246] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include meclofenamate sodium and zileuton.

[0247] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) inhibitors that may be co-administered include the compounds described in WO 2015148954. Dual inhibitors of COX-2 / SEH that may be co-administered include the compounds described in WO 2012082647. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that may be co-administered include the compounds described in WO 2017160861.

[0248] Examples of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) compounds that can be co-administered include GS-4875, GS-5290, BHM-078, and those described, for example, in WO 2006124944, WO 2006124692, WO 2014064215, WO 2018005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4): 558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9): 1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13): 3485-8; Kaila, et al., Bioorg Med Chem. (2007) 15(19): 6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16): 4758-61.

[0249] Tumor oxygenators In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, provided herein is administered with an agent that promotes or increases tumor oxygenation or reoxygenation or prevents or reduces tumor hypoxia. Illustrative agents that may be co-administered include, for example, hypoxia-inducible factor-1 alpha (HIF-1α) inhibitors, e.g., PT-2977, PT-2385; VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding protein (HNOX)), such as OMX-302 and HNOX proteins, e.g., as described in WO2007137767, WO2007139791, WO2014107171, and WO2016149562.

[0250] immunotherapy agents In some embodiments, a compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody. Exemplary immunotherapeutic agents that may be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutumumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, domba Narimab, drozitumab, durigotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituzumab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, framvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab Mab, inotumumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minletuzumab, mitumomab, mogamulitumab, moxetumomab, naptumomab, narutomab, necitomumab Tumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radletuzumab, ramucirumab (Cyramza®), rilocirumab Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy is particularly effective.

[0251] Exemplary therapeutic antibodies may be further labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0252] In some embodiments, the immunotherapeutic agent that may be co-administered is an antibody-drug conjugate (ADC). Illustrative ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein. Illustrative ADCs that may be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirin), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab sovatansine), depatuximab, vadasotuximab, labetuximab, and the like. Mabs, radilatuzumab (e.g., radilatuzumab vedotin), roncatuximab (e.g., roncatuximab tesirin), sacituzumab (e.g., sacituzumab govitecan), datopotomab (e.g., datopotomab deruxtecan; DS-1062; Dato-DXd), patritumab (e.g., patritumab deruxtecan), rifaztuzumab, indusatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab (coltuximab), upifitamab (e.g., upifitamab rilsodotin), indatuximab, milatuzumab, rovalpituzumab (e.g., rovalpituzumab tesirin), enfortumab vedotin (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab ravtansine), dicitamab (e.g., dicitamab vedotin), terisotumab Buvedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Hu max-TF-ADC, IMGN289, IMGN151, IMGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203(BMS936561), MEDI-547, P These include F-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140. ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0253] Illustrative therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin B (MMAE), monomethyl auristatin C (MMAE), monomethyl auristatin D (MMAE), monomethyl auristatin E (MMAE), monomethyl auristatin E (MMAE), monomethyl auristatin D (MMAE), monomethyl auristatin E (MMAE), monomethyl auristatin E (MMAE), monomethyl auristatin B ... Monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, Maytansine or its analogs (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinking agent SC-DR002 (D6.5), duocalmycin In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anti-cancer agent or an anti-neoplastic agent) that can be conjugated to the drug-conjugated antibody, fragment thereof, or antibody mimetic includes an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 comprises BPI-002.

[0254] In some embodiments, ADCs that may be co-administered include antibodies targeting tumor-associated calcium signaling factor 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Illustrative anti-TROP-2 antibodies include, but are not limited to, TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius) BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and International Publication No. 2020016662 (Abmart), International Publication No. 2020249063 (Bio-Thera Solutions), U.S. Patent Application Publication No. 20190048095 (Bio-Thera Solutions), U.S. Patent Application Publication No. 2013077458 (LivTech / Chiome), European Patent Application Publication No. 20110783675 (Chiome), International Publication No. 2015098099 (Daiichi Sankyo), International Publication No. 2017002776 (Daiichi Sankyo), International Publication No. 2020130125 (Daiichi Sankyo), International Publication No. 2020240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021093730 (Daiichi Sankyo), U.S. Patent Application Publication No. 9850312 (DaiichiSankyo), Chinese Patent No. 112321715 (Biosion), U.S. Patent Application Publication No. 2006193865 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2011068845 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2016296633 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017021017 (Immunomedics / Gilead), U.S. Patent Application Publication No. 20172095 94 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018271992 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018217227 (Immunomedics / Gilead) nomedics / Gilead), U.S. Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent Patent No. 8435529 (Immunomedics / Gilead), U.S. Patent No. 9492566 (Immunomedics / Gilead), International Publication No. 2003074566 (Gilead), International Publication No. 2020257648 (Gilead), International Publication No. 2013039861 (Gilead), International Publication No. 2014163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (Abruzzo In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, the hRS7 is as disclosed in U.S. Pat. Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate is The antibody drug conjugate comprises an anti-Trop-2 antibody and an anti-cancer drug linked by a linker. In some embodiments, the linker includes a linker disclosed in U.S. Pat. No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of the antibody drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is doxorubicin (DOX), epilepsy, or the like. Bicine, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38 , topotecan, lutotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxanes, geldanmycin, ansamycins, and epothilones. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with sacituzumab govitecan.

[0255] In some embodiments, ADCs that may be co-administered include antibodies targeting carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a; NCBI Gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in WO 1996011013). In some embodiments, the CEACAM1-ADC is as described in WO 2010093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, antibodies and / or fusion proteins provided herein are administered with CEACAM1-ADC IMMU-130.

[0256] In some embodiments, ADCs that may be co-administered include antibodies that target MHC class II cell surface receptors encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, antibodies and / or fusion proteins provided herein are administered with HLA-DR-ADC IMMU-140.

[0257] Cancer gene therapy and cell therapy In some embodiments, the compound of Formula (I), (Ia), (Ib), or (Ic) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modification to silence mutated genes; genetic approaches to directly kill cancer cells, such as injecting immune cells designed to enhance the immune response to cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to replace most of the patient's own immune system to detect and kill cancer cells; genetic approaches to modify cellular activity to further alter the patient's endogenous immune responsiveness to cancer.

[0258] cell therapy 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 cell therapies. Illustrative cell therapies include, but are not limited to, natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CKI) cells, and the like. In some embodiments, the cell therapy involves the co-administration of one or more of a population of T cell therapy, e.g., alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves the co-administration of NK cell therapy, e.g., NK-92 cells. Optionally, the cell therapy may involve the co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0259] In some embodiments, cell therapy involves the co-administration of cells containing a chimeric antigen receptor (CAR). In such therapy, a population of immune effector cells is engineered to express a CAR, which contains a tumor antigen-binding domain. In T cell therapy, T cell receptors (TCRs) are engineered to target tumor-derived peptides displayed on the surface of tumor cells.

[0260] Regarding the structure of the CAR, in some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a signaling functional domain of one or more proteins selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc epsilon Rlb), CD79a, CD79b, Fc gamma RIIa, DAP10, and DAP12.

[0261] In some embodiments, the costimulatory domain is selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, C CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 912), Gene ID: 912), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RA NKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), P The protein comprises one or more functional domains of proteins selected from the group consisting of SGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0262] In some embodiments, the transmembrane domain is selected from the group consisting of the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL-16, IL-16, IL-16R ... 2R beta, IL2R gamma, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4) , CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0263] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapeutic agent (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof, or antibody mimetic) described herein binds to a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also referred to as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (ECM). interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin 11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSC) A; protease serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM) prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropein) subunit, beta, 9 (LMP2); glycoprotein 100 (gp100); breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (A ... abl) (bcr-abl) oncogene fusion protein; tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl-GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HAA) Gen (high molecular weight melanoma associated antigen, HMWMAA); o-acetate OAcGD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR) ); G protein-coupled receptor class C group 5 member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADR) B3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); melanoma associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MADCT-1). melanoma cancer testis antigen-2 (MAD-CT-2) ; fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP) ; ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired-box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myeloma viral oncogene neuroblastoma-derived homolog (MYCN); ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (sibling of BORIS or regulator of imprinted sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired-box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (synovial sarcoma, X breakpoint 2, SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR) IgA receptor Fc fragment (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD30 OLF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like lymphocyte antigen 75 (LY75); glypican-3 (Glypican-3, GPC3); Fc receptor-like 5 (Fc receptor-like 5, FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of an MHC-presented tumor-associated antigen.

[0264] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factor, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, oncofetal The antigen is selected from the group consisting of: colon cancer antigen (CEA), cyclin D1, ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine receptor, folate-binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0265] In some embodiments, the antigen binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) presented on a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer-testis antigen. In some embodiments, the cancer testis antigen is acrosin binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI Gene ID: 84519), alpha fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI Gene ID: 174); A-kinase anchoring protein 4 (AKAP4; AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI Gene ID: 8852), ATPase family AAA domain containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI Gene ID: 29028), kinetochore scaffold 1 (KNL1; AF15Q14, CASC 5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI Gene ID: 57082), centrosomal protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI Gene ID: 55165), cancer / testis antigen 1A (CTAG1A; ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1; NCBI Gene ID: 246100), cancer / testis antigen 1B (CTAG1B; CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI Gene ID: 1485), cancer / testis antigen 2 (cancer / testis antigen 2, CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B; NCBI gene ID: 30848), CCCTC binding factor-like (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2; NCBI Gene ID: 140690), catenin alpha 2 (CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI Gene ID: 1496), cancer / testis antigen 83 (CT83; CXorf61, KK-LC-1, KKLC1; NCBI Gene ID: 203413), cyclin A1 (CCNA1; CT146; NCBI Gene ID: 8900), DEAD-box helicase 43 (DDX43; CT13, HAGE; NCBI Gene ID: 55510), developmental pluripotency associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testis expressed 1 1, FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 neighbor (FMR1 neighbor, FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI Gene ID: 158521), HORMA domain containing 1 (HORMAD1; CT46, NOHMA; NCBI Gene ID: 84072), insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3; CT98, IMP-3, IMP3, KOC, KOC1, VICKZ3; NCBI Gene ID: 10643), leucine zipper protein 4 (LEP4; CT98, IMP-3, IMP3, KOC1, VICKZ3; NCBI Gene ID: 10643), and leucine zipper protein 5 (LEP5; CT98, IMP-3, IMP3, KOC1, VICKZ3; NCBI Gene ID: 10643). 4, LUZP4; CT-28, CT-8, CT28, HOM-TES-85; NCBI Gene ID: 51213), lymphocyte antigen 6 family member K (LY6K; CT97, HSJ001348, URLC10, ly-6K; NCBI Gene ID: 54742), maelstrom spermatogenesis transposon silencer (MAEL; CT128, SPATA35; NCBI Gene ID: 84944), MAGE family member A1 (MAGEA1; CT1.1, MAGE1; NCBI Gene ID: 4100); MAGE family member A3 (MAGEA3; CT1.3, HIP8, HYPD, MAGE3, MAGEA6; NCBI Gene ID: 4102); MAGE family member A4 (MAGEA4; CT1.4, MAGE-41, MAGE-X2, MAGE4, ​​MAGE4A, MAGE4B; NCBI Gene ID: 4103); MAGE family member A11 (MAGEA11; CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI Gene ID: 4110); MAGE family member C1 (MAGEC1; CT7, CT7.1; NCBI Gene ID: 9947); MAGE family member C2 (MAGEC2; CT10, HCA587, MAGEE1; NCBI Gene ID: 51438); MAGE family member D1 (MAGED1; DLXIN-1, NRAGE; NCBI Gene ID: 9500); MAGE family member D 2 (MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI Gene ID: 10916), kinesin family member 20B (KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI Gene ID: 9585), NUF2 component of the NDC80 kinetochore complex (NUF2; CDCA1, CT106, NUF2R; NCBI Gene ID: 83540), nuclear export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI Gene ID: 56001), and PAS domain-containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI Gene ID: 139). 135), PDZ-binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI gene ID: 55124), melanoma preferentially expressed antigen (PRAME; CT130, MAPE, OIP-4, OIP4; NCBI gene ID: 23532), sperm associated antigen 9 (SEA-9) 9, SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI gene ID: 9043), nuclear X-linked family member A1-associated sperm protein (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCBI gene ID: 30014), SPANX family member A2 (SPANXA2; CT11.1, CT11.3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI gene ID: 728712), SPANX family member C (SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE; NCBI Gene ID: 64663), SPANX family member D (SPANXD; CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1; NCBI Gene ID: 64648), SSX family member 1 (SSX1; CT5.1, SSRC; NCBI Gene ID: 6756), SSX family member 2 (SSX2; CT5.2, CT5.3).2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757), synaptonemal complex protein 3 (synaptonemal complex protein 3, SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI Gene ID: 50511), testis-expressed 14 intercellular bridge forming factor (TEX14; CT113, SPGF23; NCBI Gene ID: 56155), transcription factor Dp family member 3 (TFDP3; CT30, DP4, HCA661; NCBI Gene ID: 51270), serine protease 50 (PRSS50; CT20, TSP50; NCBI Gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI Gene ID: 7272), and zinc finger protein 165 (ZNF165; CT53, LD65, ZSCAN7; NCBI Gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer-testis antigens presented on major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasia are described, for example, in Gibbs, et al., Trends Cancer 2018. Oct;4(10):701-712, and summarized in the CT database website at cta.lncc.br / index.php. Illustrative TCR and TCR-like antibodies that bind to MHC-presented epitopes of NY-ESO-1 are described, for example, in Stewart-Jones, et al., Proc Natl Acad Sci USA. 2009 Apr 7;106(14):5784-8; International Publication Nos. 2005113595, 2006031221, 2010106431, 2016177339, 2016210365, 2017044661, 2017076308, 2017109496, 2018132739, 2019084538, 2019162043, 2020086158, and 2020086647. Illustrative TCRs and TCR-like antibodies that bind to MHC-presented epitopes of PRAME are described, for example, in WO 2011062634, WO 2016142783, WO 2016191246, WO 2018172533, WO 2018234319, and WO 2019109821. Illustrative TCRs and TCR-like antibodies that bind to MHC-presented epitopes of MAGE variants are described, for example, in WO 2007032255, WO 2012054825, WO 2013039889, WO 201403225 ... and WO 2019204683. Illustrative TCR and TCR-like antibodies that bind to epitopes of MHC-presented alpha-fetoprotein (AFP) are described, for example, in WO 2013041865, WO 2014118236, WO 2016055785, WO 2017174822, WO 2017174823, WO 2017174824, WO 2017175006, WO 2018097951, WO 2018170338, WO 2018225732, and WO 2019204683. Illustrative TCR and TCR-like antibodies that bind to epitopes of MHC-presented alpha-fetoprotein (AFP) are described, for example, in WO 2015011450. Illustrative TCRs and TCR-like antibodies that bind to an MHC-presented epitope of SSX2 are described, for example, in WO 2020063488. Illustrative TCRs and TCR-like antibodies that bind to an MHC-presented epitope of KK-LC-1 (CT83) are described, for example, in WO 2017189254.

[0266] Examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogenreclucel (U.S. Pat. No. 9,089,520, WO 2016100236), AU-105, ACTR-087, activated allogeneic natural killer cells (CNDO-109-AANK), MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Immunoglobulins. Leclucel-T, valtalucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL These include CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0267] In some embodiments, the one or more additional co-administered therapeutic agents can be categorized by their mechanism of action, for example, into the following groups: Drugs that target adenosine deaminase, such as pentostatin or cladribine; · Drugs that target ATMs, such as AZD1390; MET-targeting agents such as servotinib, capmatinib, tetponitinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; Mitogen-activated protein kinase-targeting agents such as antroquinol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mirdametinib (PD-0325901), pimasertib, and refametinib, or agents disclosed in WO 2011 / 008709, WO 2013112741, WO 2006124944, WO 2006 / 124692, WO 2014064215, WO 2018005435, Zhou, et al., Cancer Lett. 2017 Nov 1, 408:130-137, Teli, et al., J Enzyme Inhib Med Chem.(2012)27(4):558-70;Gangwall,et al.,Curr Top Med Chem.(2013)13(9):1015-35;Wu,et al.,Bioorg Med Chem Lett. (2009) 19(13): 3485-8; Kaila, et al., Bioorg Med Chem. (2007) 15(19): 6425-42, or Hu, et al., Bioorg Med Chem Lett. (2011) 21(16): 4758-61; Agratimazine besadenovec (ProstAt drugs that target thymidine kinases, such as thymidine kinase (ATK), PancAtak, GliAtak, GMCI, or AdV-tk); · Targeted agents that target the interleukin pathway, such as pegilodecakin (AM-0010) (PEGylated IL10) and CA-4948 (IRAK4 inhibitor); Drugs that target members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, medistrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); Drugs that target CD73, such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 antibodies (e.g., oleculab); · Drugs that target DKK3, such as MTG-201; · Drugs that target EEF1A2, such as platydysine; Drugs that target EIF4A1, such as rohinitib; · Drugs that target endoglin, such as TRC105 (carotuximab); Drugs that target exopolitin-1, such as eltanexor; Agents that target fatty acid amide hydrolase, such as the compounds disclosed in WO2017160861; Heat shock protein 90 beta family members such as anlotinib Agents targeting member 1; · Drugs that target lactoferrin, such as ruxotemitide (LTX-315); Agents that target lysyl oxidase, such as the compounds disclosed in U.S. Pat. No. 4,965,288, U.S. Pat. No. 4,997,854, U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, or U.S. Patent Application Publication No. 20040248871; Drugs targeting MAGE family members, such as KITE-718, MAGE-A10C796T, or MAGE-A10TCR; Agents targeting MDM2, such as ALRN-6924, CMG-097, milademethane monotosylate monohydrate (DS-3032b), or AMG-232; · Agents that target MDM4, such as ALRN-6924; · Agents targeting Melan-A, such as MART-1F5 TCR-engineered PBMCs; Drugs that target mesothelin, such as CSG-MESO or TC-210; Drugs that target METAP2, such as M8891 or APL-1202; · Drugs targeting NLRP3, such as BMS-986299; Drugs that target oxoglutarate dehydrogenase, such as devimistat (CPI-613); · Drugs that target placental growth factors, such as aflibercept; agents that target SLC10A3, such as the compounds disclosed in WO2015148954, WO2012082647, or WO2017160861; agents that target transforming growth factor alpha (TGFα), such as the compounds disclosed in WO 2019103203; Drugs that target the tumor protein p53, such as kevetrin (stimulatory factor); · Drugs that target vascular endothelial growth factor A, such as aflibercept; Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250; Agents targeting CA-170 or VISTA, such as HMBD-002; WEE1-targeting drugs such as adavosertib (AZD-1775) drugs; · Small molecule inhibitors targeting ABL1, such as imatinib, rebastinib, asciminib, and ponatinib (ICLUSIG®); · Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, preladenant, etrumadenant (AB928), or PBF-509; · Small molecule inhibitors targeting arachidonate 5-lipoxygenase, such as meclofenamate sodium or zileuton; · Small molecule inhibitors targeting the ATR serine / threonine kinase, such as BAY-937, selarasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib); · Small molecule inhibitors targeting the AXL receptor tyrosine kinase, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); (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, posertinib (HM71224), ibrutinib (Imbruvica), M-2951 ( small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebrutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; Small molecule inhibitors targeting neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195); · Small molecule inhibitors targeting the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; · Small molecule inhibitors targeting the SRC proto-oncogene non-receptor tyrosine kinase, such as VAL-201, tirbanibulin (KX2-391), or irginatinib maleate (NS-018); · Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), and AT-101 (gossypol); small molecule inhibitors targeting bromodomain and ectodomain (BET) bromodomain-containing proteins, such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mibebresisb, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; · Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01; Small molecule inhibitors that target carbonic anhydrase, such as polmacoxib, acetazolamide, or methazolamide; · Small molecule inhibitors targeting catenin beta 1, such as CWP-291 or PRI-724; · Small molecule antagonists targeting CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Vicriviroc); blixafortide, a small molecule antagonist targeting C-X-C motif chemokine receptors (e.g., CXCR4); Avadomid (CC-122), CC-92480, CC-90009, or small molecule inhibitors that target cereblon, such as ludomide; · Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737; · Small molecule inhibitors targeting complement components, such as Imprime PGG (Biothera Pharmaceuticals); Small molecule inhibitors targeting C-X-C motif chemokine ligands (e.g., CXCL12), such as olaptesed pegol (NOX-A12); · Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; Dead box helicars such as spinoxin (RX-5902) small molecule inhibitors targeting Ze5; small molecule inhibitors targeting DGKα, as described, for example, in WO 2021130638; · Small molecule inhibitors targeting Diablo IAP-binding mitochondrial proteins, such as BI-891065; · Small molecule inhibitors that target dihydrofolate reductase, such as pralatrexed or pemetrexed disodium; · Small molecule inhibitors targeting DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin; · Small molecule inhibitors targeting MARCKS, such as BIO-11006; · Small molecule inhibitors targeting RIPK1, such as GSK-3145094; · Small molecule inhibitors targeting Rho-associated coiled-coil-containing protein kinases, such as AT13148 or KD025; Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecampegol, or amrubicin; · Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201; · Small molecule inhibitors targeting histone lysine methyltransferases such as DOT1, such as pinometostat (EPZ-5676); Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497; · Small molecule inhibitors targeting fatty acid synthase, such as TVB-2640 (Sagimet Biosciences); · Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144); Small molecule inhibitors targeting focal adhesion kinase (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; · Small molecule inhibitors targeting folate receptor 1, such as pralatrexate; · Small molecule inhibitors targeting FOXM1, such as thiostrepton; · Small molecule inhibitors targeting galectin-3, such as berapectin (GR-MD-02); Small molecule antagonists that target the glucocorticoid receptor, such as relacorilant (CORT-125134); including but not limited to CB-839 (telaglenastat) or small molecule inhibitors targeting glutaminase, including BPTES-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Small molecule inhibitors that target the GNRHR, such as elagolix, relugolix, or degarelix; · Small molecule inhibitors targeting EPAS1, such as velzutifan (PT-2977 (Merck & Co.)); Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as restricted ivosidenib (AG-120), vorasidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221) · Small molecule inhibitors targeting lysine demethylase 1A, such as CC-90011; Small molecule inhibitors targeting MAPK-interacting serine / threonine kinases, such as tomivosertib (eFT-508); · Small molecule inhibitors targeting Notch receptors, such as AL-101 (BMS-906024); · Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as volasertib or onvansertib; small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazolepali (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121 (e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102; · Small molecule inhibitors targeting the polycomb protein EED, such as MAK683; · Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974; HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, otenaproxyl (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reformulated celecoxib (DRGT-46), AAT-076, Macu Oshuri, lumiracoxib, me small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as roxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, mavacoxib, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, zaltoprofen, or imrecoxib; Small molecule inhibitors targeting protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715, or GSK3326595; small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in WO 2018172984 or WO 2017211303; · Small molecule antagonists that target retinoic acid receptors, such as tamibarotene (SY-1425); · Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A; · Small molecule inhibitors targeting the S100 calcium-binding protein A9, such as tasquinimod; Uproleselan sodium (GMI-1271), etc. small molecule inhibitors targeting selectin E; · Small molecule inhibitors targeting SF3B1, such as H3B-8800; · Small molecule inhibitors targeting sirtuin-3, such as YC8~02; Small molecule inhibitors targeting SMO, such as sonidegib (Odomzo®, formerly LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, or patidegib and taladegib Harmful agents; · Small molecule antagonists targeting somatostatin receptors, such as OPS-201; · Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva®, ABC294640); · Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608); · Small molecule inhibitors targeting tankyrase, such as G007-LK or stenoparib (2X-121(e-7499)); · Small molecule inhibitors targeting TFGBR1, such as galunisertib and PF-06952229; Thymidylate synthase inhibitors, such as idetrexed (ONX-0801) small molecule inhibitors targeting; · Small molecule inhibitors targeting the tumor protein p53, such as CMG-097; · Small molecule inhibitors targeting valosin-containing proteins, such as CB-5083; WT1-targeting drugs such as ombipepimut-S (DSP-7888) small molecule inhibitors; · Small molecule agonists that target adenosine receptors, such as namodenoson (CF102); small molecule agonists targeting asparaginase, such as crisantaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegaspargase; · Small molecule agonists targeting CCAAT enhancer binding protein alpha, such as MTL-501; · Small molecule agonists targeting the cytochrome P450 family, such as mitotane; · Small molecule agonists targeting DExD / H-box helicase 58, such as RGT-100; · Small molecule agonists targeting the GNRHR, such as leuprorelin acetate, leuprorelin acetate extended-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate; GRB2-targeting drugs such as prexigebersen (BP1001) small molecule agonists; NFE2L2-targeting drugs such as omaveloxolone (RTA-408) targeted small molecule agonists; · Small molecule agonists targeting NOD2, such as mifamurtide (liposomal); RAR-related orofensive drugs such as cintirorgon (LYC-55716) small molecule agonists targeting the angiotensin receptor gamma; Small molecule agonists that target the retinoic acid receptor (RAR), such as tretinoin; · Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic GAMP (cGAMP), or cyclic di-AMP; · Small molecule agonists that target thyroid hormone receptor beta, such as levothyroxine sodium; · Small molecule agonists targeting tumor necrosis factor, such as tasonermin; · Antisense agents targeting baculovirus IAP repeat-containing 5, such as EZN-3042; · Antisense agents targeting GRB2, such as plexigeneversen; · Antisense agents targeting heat shock protein 27, such as apatrusen; Danvatirsen (IONIS-STAT3-2.5Rx), etc. antisense agents targeting STAT3; · Gene therapy targeting CC motif chemokine receptors, such as SB-728-T; Interleukin-targeted gene therapies, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55; · Antibodies targeting claudin-18, such as claudiximab; · Antibodies targeting clusterin, such as AB-16B5; · Antibodies targeting complement components, such as ravulizumab (ALXN-1210); · Antibodies targeting C-X-C motif chemokine ligands, such as BMS-986253 (HuMax-Inflam); · Antibodies targeting Delta-like canonical Notch ligand 4 (DLL4) such as demcizumab and nabicixizumab (DLL4 / VEGF); · Antibodies targeting the EPH receptor A3, such as fivatuzumab (KB-004); · Antibodies targeting epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); · Antibodies targeting fibroblast growth factors, such as GAL-F2 and B-701 (vofatamab); · Antibodies targeting hepatocyte growth factor, such as MP-0250; Canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), Interleukin-targeting antibodies such as rutuximab or tocilizumab; · Antibodies targeting LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110); · Antibodies targeting mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; Antibodies that target myostatin, such as landogrozumab; Antibodies targeting Notch receptors, such as tarextumab; antibodies targeting TGFB1 (TGFβ1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089, or the compounds disclosed in WO 2019103203; Vaccines targeting fms-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201 restricted epitope peptide vaccines · Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); · PD-L1-targeting vaccines such as IO-120+IO-103 (PD-L1 / PD-L2 vaccine) or IO-103; · Vaccines targeting the tumor protein p53, such as MVA-p53; Vaccines targeting WT1, such as WT-1 analog peptide vaccines (WT1-CTL); · Baculovirus IAP repeat-containing 5-targeted cell therapies, such as tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccines; · Carbonic anhydrase-targeted cell therapies such as DC-Ad-GMCAIX; · Cellular therapies targeting CC motif chemokine receptors, such as CCR5-SBC-728-HSPC; Cellular therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN; · Cellular therapies targeting GSTP1, such as CPG3-CAR (GLYCAR); HLA-A targeted cell therapy such as FH-MCVA2TCR or NeoTCR-P1; · Cellular therapies targeting interleukins, such as CST-101; · KRAS-targeted cell therapies, such as anti-KRAS G12D mTCR PBL; · MET-targeted cell therapies, such as anti-cMet RNA CAR T; · MUC16-targeted cell therapies, such as JCAR-020; · Cell therapies targeting PD-1, such as PD-1 knockout T-cell therapy (esophageal cancer / NSCLC); · Cellular therapies targeting PRAME, such as BPX-701; · Cell therapies targeting the transforming protein E7, such as KITE-439; Cellular therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016.

[0268] Illustrative combination therapies Lymphoma or leukemia combination therapy Several chemotherapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, tin antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-arretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, brusulfan, campath-1H, carboplatin, carfilzomib (Ky prolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cycloporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide) , vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alfa-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafine gadolinium,Mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosin (perifosin, ), prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, thiazolinone These include pifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

[0269] One improved approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

[0270] The above-mentioned therapies may be supplemented or combined with stem cell transplantation or therapy, including peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibition therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, transplantation of in vitro treated peripheral blood stem cells, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0271] Combination therapy for non-Hodgkin's lymphoma Treatment of non-Hodgkin's lymphoma (NHL), particularly lymphomas of B-cell origin, includes the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, prednisolone), all optionally including rituximab®), radioimmunotherapy, and combinations thereof, particularly the integration of antibody therapy with chemotherapy.

[0272] Examples of unconjugated monoclonal antibodies for the treatment of NHL / B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0273] Examples of experimental antibody drugs used to treat NHL / B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0274] Examples of standard chemotherapy regimens for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0275] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[0276] Combination therapy for mantle cell lymphoma Curative treatments for mantle cell lymphoma (MCL) include combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above-mentioned therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0277] An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies, such as rituximab. Another uses cancer vaccines, such as GTOP-99, that are based on the genetic makeup of an individual patient's tumor.

[0278] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential treatment with CHOP.

[0279] Other approaches to treating MCL include the combination of autologous stem cell transplantation and high-dose chemotherapy, the administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or the administration of antiangiogenic agents such as thalidomide, particularly in combination with rituximab.

[0280] Another treatment approach is to administer drugs that cause the degradation of the Bcl-2 protein, increasing the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapy agents.

[0281] Further therapeutic approaches include the administration of mTOR inhibitors, which can cause inhibition of cell proliferation and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and combinations of temsirolimus with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0282] Other recent treatments for MCL have been disclosed, including flavopiridol, palbociclib (PD0332991), R-roscovitine (seliciclib, CYC202), styryl sulfones, obatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CC1-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).

[0283] Combination therapy for Waldenström macroglobulinemia Therapeutic agents used to treat Waldenstrom's macroglobulinemia (WM) include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta-arretin, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H, carboplatin, carmustine, and caspofungin acetate. , CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine Rabin, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (e.g., tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD 20, motexafine gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, urocuprumab, veltuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0284] Examples of therapeutic approaches used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biologic therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, transplantation of in vitro processed peripheral blood stem cells, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0285] Combination therapy for diffuse large B-cell lymphoma (DLBCL) Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and RICE. In some embodiments, therapeutic agents used to treat DLBCL include liximab (Rituxan®), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin®), prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, polatuzumab vedotin piiq, bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy® (polatuzumab vedotin), BR (bendamustine (Trea In some embodiments, therapeutic agents used to treat DLBCL include R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone), rituximab + bendamustine, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), rituximab + lenalomide, R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy® (polatuzumab), Vedotin) + BR (bendamustine (Treanda®) and rituximab (Rituxan®), R-GemOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafasit...

Claims

[Claim 1] The invention described in the specification.

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