IKAROS Zinc Finger Family Degrading Agent and its Use

Abstract

The present disclosure relates generally to compounds that bind to and act as degraders of IKAROS family zinc finger (IKZF) proteins, such as IKZF2 (Helios) and / or IKZF4 (Eos). 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 the binding and degradation of IKZF proteins, such as IKZF2 and / or IKZF4, including cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 292,617, filed on 22 December 2021, which is incorporated herein by reference in its entirety for all purposes.

[0002] This disclosure relates to compounds that bind to IKAROS family zinc finger (IKZF) proteins, such as IKZF2 (Helios) and / or IKZF4 (Eos), and act as degrading agents thereof. This disclosure further relates to the use of compounds for the treatment and / or prevention of diseases and / or conditions associated with one or more IKZF proteins, such as IKZF2 and / or IKZF4-related diseases or conditions, wherein a reduction in IKZF2 and / or IKZF4 protein levels may improve the disease or disorder.

[0003] Sequence List This application includes a sequence listing submitted electronically in XML file format, the entirety of which is incorporated herein by reference. The XML copy, created on December 1, 2022, is named 1404-WO-PCT.xml and is 2,571 bytes in size. [Background technology]

[0004] The IKZF 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, while Eos and Pegasus are more broadly expressed across different tissues.

[0005] Regulatory T cells (Tregs) are a subset of CD4+ T cells that maintain normal immune tolerance and homeostasis. Treg activity can also suppress the antitumor immune response. Helios is thought to be necessary to maintain a stable Treg phenotype, particularly in the context of an inflammatory tumor microenvironment. Genetic Helios knockout in Tregs has been shown to reduce Treg immunosuppressive activity and induce an effector T cell phenotype. First-generation small molecule Helios degraders have shown similar effects. Therefore, Helios has emerged as a promising immuno-oncological 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 demand for helios degrading agents that possess desirable selectivity, potency, metabolic stability, or reduced adverse effects. [Overview of the project]

[0007] This disclosure provides compounds useful as degrading agents for IKAROS family zinc finger (IKZF) protein 2 (IKZF2; Helios). This disclosure further relates to the use of such compounds for the treatment and / or prevention of diseases and / or conditions through binding and degradation of the IKZF2 protein.

[0008] In one embodiment, the compound of formula (I) provided herein, [ka] or a pharmaceutically acceptable salt thereof R 1 C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 A 4-14 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~14A 6-14 member heteroaryl having an aryl or 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-4 Zs which may be the same or different 1 and R 2 is hydrogen or C 1~3 alkyl X 1 and X 2 are each independently hydrogen, fluoro, or chloro Y is hydrogen Each Z 1 is independently cyano, hydroxy, oxo, imino, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, a 4-10 member heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, C 6~10 aryl, a 6-10 member heteroaryl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, -O-Z 1A , -C(O)-Z 1A , -C(O)O-Z 1A , -C(O)-NH2 -C(O)-NH(Z 1A ), -C(O)-N(Z 1A )2, -NH2, -NH(Z 1A ), -N(Z 1A )2, -NHC(O)-Z 1A , -N(Z 1A )C(O)-Z 1A , -NHC(O)O-Z 1A , -N(Z 1A )C(O)O-Z 1A , -NHC(O)N(Z 1A )2 -N(Z 1A )C(O)NH(Z 1A ), -NHC(O)NH(Z 1A [[ID=6)8]], -N(Z 1A )C(O)N(Z 1A )2, -NHS(O)2(Z 1A ) -N(Z 1A )S(O)2(Z 1A ), -NHS(O)2N(Z 1A )2,-NHS(O)2NH(Z 1A ), -N(Z 1A )S(O)2NH(Z 1A ), -N(Z 1A )S(O)2NH2,-N(Z 1A )S(O)2N(Z 1A )2,-NHS(O)2O(Z 1A ), -N(Z 1A )S(O)2O(Z 1A ), -OC(O)-Z 1A ,-OC(O)OZ 1A -OC(O)-NH2, -OC(O)-NH(Z 1A ), -OC(O)-N(Z 1A )2, -SZ 1A ,-S(O)-Z 1A ,-S(O)(NH)-Z 1A -S(O)2Z 1A -S(O)2N(Z 1A )2, or -S(O)(Z 1A )2, and each Z 1A They may be the same or different, and each Z 1 The imino, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl elements may be optionally the same or different from 1 to 4 Z. 1A Replaced by 、 each Z 1A These are independently hydroxy, halogen, oxo, cyano, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 6-10 membered heteroaryls having 1-2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur, -OZ 1B ,-C(O)-Z 1B ,-C(O)OZ 1B , -C(O)-NH2, -C(O)-NH(Z 1B ), -C(O)-N(Z 1B )2, -NH2, -NH(Z 1B ), -N(Z 1B )2, -NHC(O)-Z 1B , -N(Z 1B )C(O)-Z 1B , -NHC(O)O-Z 1B , -N(Z 1B )C(O)O-Z 1B , -N(Z 1B )C(O)N(Z 1B )2, -NHC(O)N(Z 1B )2, -N(Z 1B )C(O)NH(Z 1B ), -NHS(O)2(Z 1B ), -N(Z 1B )S(O)2(Z 1B ), -NHS(O)2N(Z 1B )2, -N(Z 1B )S(O)2NH(Z 1B ), -NHS(O)2NH(Z 1B ), -N(Z<000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​And each Z 1A They may be the same or different, and each Z 1A Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally consist of 1 to 4 Z, which may be the same or different. 1B Replaced by, each Z 1B These are independently hydroxy, halogen, oxo, cyano, and C 1~9 Alkyl, C 1~9 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 Ariel, A 6-10 membered heteroaryl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. -CO 2- R XXA -NH2, -SH, -OR XXA , -NH-R XXA , -N(R XXA )(R XXB ), -C(O)-R XXA , -C(O)OR XXA ,-C(O)N(R XXA )(R XXB ), -N(R XXA )C(O)(R XXB ), -N(R XXA )C(O)O(R XXB ), -N(R XXA )C(O)NH(R XXB ), -N(R XXA )S(O)(R XXB ), -SR XXA ,-S(O)N(R XXA )2, -S(O)(R XXA ), -S(O)2(R XXA ), -S(O)N(R XXA )(R XXB ), or -S(O)2N(R XXA )(R XXB ) and each R XXAand R XXB Hydrogen and C are independent of each other. 1~9 Alkyl, C 1~9 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 It is a 6-10 membered heteroaryl having an aryl or 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0009] In some embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable addition Pharmaceutical compositions comprising an agent or carrier are provided herein. 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 addition It includes an agent or carrier.

[0010] In some embodiments, the pharmaceutical composition provided herein further comprises one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof in a therapeutically effective amount.

[0011] In some embodiments, the Disclosure provides a method for inhibiting the degradation of the IKZF2 protein in a subject requiring degradation of the IKZF2 protein, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0012] In some embodiments, the present disclosure provides a method for 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., compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. [Modes for carrying out the invention]

[0013] This disclosure relates to degrading agents for IKZF family zinc finger (IKZF) proteins, such as IKZF2(Helios). This disclosure also relates to compositions and methods related to IKZF2 proteolytic agents, and to the use of such compounds for the treatment and / or prevention of IKZF2-mediated diseases and conditions. This disclosure also relates to compositions and methods for treating and / or preventing cancer or viral infections, including combinations of IKZF2 proteolytic agents 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 IKZF2 proteolytic agents and, optionally, one or more additional therapeutic agents.

[0015] Definitions and general parameters The following description is made with the understanding that this disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are for convenience only and should not be construed as limiting 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 those skilled in the art. Note that, as used herein and in the appended claims, the singular forms “a,” “and,” and “the” refer to multiple subjects unless otherwise explicitly indicated in the context. For example, a reference to “compound” includes multiple such compounds, and a reference to “assay” includes one or more assays and their equivalents known to those skilled in the art.

[0017] When used herein, the following words and phrases are intended to have the meanings set forth below, unless the context in which they are used suggests otherwise.

[0018] A dash ("-") that is not between two letters or symbols is used to indicate a bonding point for a substituent. For example, -CONH2 is bonded via a carbon atom. Dashes before or after a chemical group are for convenience only, and chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn across a line in a structure indicates a bonding point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply direction. A solid line protruding from the center of a ring indicates that the bonding point of a substituent in that ring may be on any of the ring atoms. For example, R in the following structure a It can bond to any of the five carbon ring atoms, or the hydrogen bonded to the nitrogen ring atom is R a It can be replaced with: [ka]

[0019] "C u~v The prefix "" indicates that the following groups have carbon atoms from u to v. For example, "C 1~6The term "alkyl group" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x-y membered" ring, where x and y are numerical ranges (e.g., "3-12 membered heterocyclyl"), means a ring having x-y atoms (e.g., 3-12), of which up to 80% may be heteroatoms such as N, O, S, and P, and the remaining atoms may be carbon.

[0020] Additionally, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, or alkylyl groups, respectively, or "arylene" or "aryrenyl" groups, or arylyl groups.

[0021] "Compounds disclosed herein," "compounds of this disclosure," "compounds provided herein," or "compounds described herein" refers to compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe). It also includes certain compounds of Examples 1 to 98 provided herein.

[0022] References to values ​​or parameters "about" in this specification include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, "about X" for that term includes a description of "X". Also, the singular forms "a" and "the" include plural references unless otherwise clearly indicated in the context. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0023] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1~20 Alkyl), 1 to 8 carbon atoms (i.e., C 1~8 Alkyl), 1 to 6 carbon atoms (i.e., C 1~6 Alkyl), 1 to 4 carbon atoms (i.e., C 1~4 Alkyl) or 1 to 3 carbon atoms (i.e., C 1~3 Alkyl compounds include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms can be included. 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] As used herein, “haloalkyl” means an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by halo substituents that may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 Alkyl, and C 1~4 C 1~4 It is an alkyl group. Examples of haloalkyl groups, but are not limited to, include fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0025] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkenyl), 2-6 carbon atoms (i.e., C 2~6 Alkenyls), or 2-4 carbon atoms (i.e., C 2~4 This refers to an aliphatic group containing an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0026] "Alkynyl" contains at least one carbon-carbon triple bond and 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 2-4 carbon atoms (i.e., C 2~4 This refers to an aliphatic group that has an alkynyl bond. The term "alkynyl" also includes alkynyl groups that have one triple bond and one double bond.

[0027] "Acyl" refers to a -C(=O)R group, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0028] "Amino" is -NR y R z It refers to the base, and in the formula, R y and R z The group is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, and each of them can be optionally substituted.

[0029] "Imino" refers to a group containing a carbon-nitrogen double bond with the structure: [ka] In the formula, R 1 , R 2 , and R 3 R is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which can be optionally substituted. 1 , R 2 , and R 3 Any one of them can function as a connection point.

[0030] "Aryl" refers to an aromatic carbon ring having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) structure including a condensed system, where at least one of the rings is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of aryls include phenyl radicals. Aryls also include multiple condensed ring systems having 9 to 20 carbon atoms, for example, 9 to 16 carbon atoms (e.g., ring systems containing 2, 3, or 4 rings), where at least one ring is aromatic and the other ring may or may not be aromatic (i.e., a carbon ring). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the polycyclic system. When referring to aryls with a specific range of member numbers (e.g., 6 to 10 membered aryls), it should be understood that the atomic range refers to the total ring atoms of the aryl. For example, phenyl is a six-membered aryl group, and naphthyl and 1,2,3,4-tetrahydronaphthyl are ten-membered aryl groups. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracenyl. However, aryl groups do not in any way include, and do not overlap with, heteroaryl groups as defined below. When one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl.

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

[0032] "Cycloalkyl" is Contains only carbon atoms Having monocyclic or polycyclic rings, including condensed ring systems, bridged ring systems, and spirocyclic systems. saturation Refers to a cyclic alkyl group. 。 As used herein, cycloalkyl refers to a ring of 3 to 20 carbon atoms (i.e., C 3~20 Cycloalkyl), 3-12 ring carbon atoms (i.e., C 3~12 Cycloalkyl), 3-10 ring carbon atoms (i.e., C3~10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3~6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] "Condensation" refers to a ring bonded to an adjacent ring. In some embodiments, the fused ring system is a heterocyclyl. In some embodiments, the fused ring system is an oxabicyclohexanyl. In some embodiments, the fused ring system is [ka] That is the case.

[0034] "Bridged" refers to a ring condensation in which non-adjacent atoms on a ring are bonded by divalent substituents 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] That is the case.

[0035] "Spiro" refers to a ring substituent bonded 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 spiroundenyl (e.g., spiro[5.5]undenyl). In some embodiments, the spiro substituent is [ka] That is the case.

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

[0037] "Heteroaryl" refers to an aromatic group having aromatic tautomers or resonance structures, possessing monocyclic, polycyclic, or multiple fused rings, and containing at least one heteroatom within the ring. This term includes 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. The sulfur and nitrogen atoms may be present in oxidized forms, provided the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. This term also includes polycyclic systems (e.g., cyclic systems containing two or three rings), where a heteroaryl group as defined above may condense with one or more heteroaryls (e.g., naphthilidinyl), carbocyclics (e.g., 5,6,7,8-tetrahydroquinolyl), or aryls (e.g., indazolyl) to form multiple fused rings. These multiple fused rings may optionally have the carbocyclic portion of the fused ring substituted with one or more (e.g., 1, 2, or 3) oxo groups. It should be understood that the bonding sites of the heteroaryl polyfused rings defined above can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portion of the ring. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, and thianaphthenyl. In some embodiments, the heteroaryl is, [ka] Therefore, a heteroaryl, as defined earlier, does not contain an aryl and does not overlap with an aryl.

[0038] A "heterocyclyl," "heterocyclyl ring," or "heterocycle" refers to a single saturated or partially unsaturated ring or polycyclic system. This term includes saturated or partially unsaturated monocycles (e.g., 3, 4, 5, 6, or 7-membered rings) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. 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. Examples of such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. This term also includes multiple fused ring systems (e.g., ring systems containing two or three rings), where a heterocyclic group (as defined above) can be bonded to one or more heterocycles (e.g., decahydronaphthilidinyl), heteroaryls (e.g., 1,2,3,4-tetrahydronaphthilidinyl), carbocyclics (e.g., decahydroquinolyl), or two adjacent atoms (fused heterocycles) having an aryl group. It should be understood that the bond points of multiple fused rings of the heterocycles defined above can be at any position on the ring, including the heterocyclyl, heteroaryl, aryl, or carbocyclic moieties of the ring. Exemplary heterocycles include, but are not limited to, azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydroxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydroxazolyl, chromanil, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl. Exemplary condensed bicyclic heterocycles are not limited to these, [ka] Includes.

[0039] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0040] "Oxo" refers to an (=O) group or an (O) group.

[0041] "Sulfonyl" is -S(O)2R c It refers to the base, and in the formula, R c These are alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl compounds. Examples of sulfonyl compounds include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0042] Whenever the graphical representation of a group ends with a single bonded nitrogen atom, that group represents a -NH2 group unless otherwise indicated. Similarly, unless specifically stated, hydrogen atoms are implied and assumed to be present where necessary, taking into account the knowledge of those skilled in the art, to complete the valence or provide stability.

[0043] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both the cases in which such event or situation occurs and the cases in which it does not occur. The term “optionally substituted” means that one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen part.

[0044] The term "substituted" means that one or more hydrogen atoms on any of the specified atoms or groups are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. Examples of one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar non-specific structures obtained by defining substituents with an infinitely increasing number of further substituents (e.g., substituted aryls having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” can describe other chemical groups as defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless otherwise specified, where a group is described as optionally substituted, any substituent of the group is itself unsubstituted.

[0045] In some embodiments, the term "substituted alkyl" refers to alkyl groups having one or more substituents, including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl alkyl groups. 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 a -S(O)2R group, where R is substituted with one or more substituents, including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0046] In some embodiments, the substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl comprises cycloalkyl, heterocyclyl, aryl, and / or heteroaryl having substituents on the ring atom, and the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl are bonded to the remainder of the compound. For example, in the following portion, cyclopropyl is substituted with a methyl group: [ka]

[0047] The disclosures described herein as illustrative examples may be preferably implemented in the absence of any or more elements, limitations, or restrictions not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” are to be read broadly and not limiting. Furthermore, the terms and expressions used herein are for illustrative purposes only and are not limiting, and there is no intention to exclude any equivalent or part thereof of the illustrated and described features, although it is recognized that various modifications are possible within the scope of the claimed disclosures.

[0048] The compounds of this disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including inorganic bases or acids and organic bases or acids. If a compound of this disclosure contains one or more acidic or basic groups, this disclosure also includes corresponding pharmaceutically or toxicologically acceptable salts of the compound, in particular pharmaceutically usable salts of the compound. Thus, a compound of this disclosure containing an acidic group may have these groups present and, according to this disclosure, may be used, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to those skilled in the art. Compounds of the present disclosure may contain one or more basic groups, i.e., groups that can be protonated, and may be used in accordance with the present disclosure in the form of addition salts thereof, including inorganic or organic acids. 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.

[0049] Where the compounds of this disclosure contain both an acidic and a basic group in the molecule, this disclosure also includes intramolecular salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with an organic or inorganic acid or a base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0050] This disclosure also includes all salts of the compounds herein that, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but may be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reaction with the underlying 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 underlying compounds (as disclosed) are known to those skilled in the art and are disclosed, for example, in Berge, at al., Journal of Pharmaceutical Science, Jan. 1977 vol. 66, No. 1, and other sources.

[0051] Furthermore, the compounds disclosed herein may be subject to tautomerism. If tautomerism, for example, keto-enol tautomerism of a compound or its prodrug, occurs, then individual forms such as keto and enol forms, each as well as mixtures thereof in any ratio, are within the scope of this disclosure. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformational isomers, etc.

[0052] The term "protecting group" refers to a part of a compound that shields 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 used to shield the reactivity of a particular functional group, thereby assisting the effectiveness of a desired chemical reaction, for example, to create and break chemical bonds in a regular and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0053] If the list of alternative substituents includes members that cannot be used to substitute a particular group due to the valence requirements of the members or for other reasons, it will be understood by those skilled in the art that the list is intended to be read as containing only the members of the list that are suitable for substituting a particular group.

[0054] Furthermore, the compounds of this disclosure may exist in the form of solvates, such as solvates containing water or pharmaceutically acceptable solvates of alcohols, particularly ethanol. The “solvates” are formed by the interaction of a solvent and a compound.

[0055] In certain embodiments, optical isomers, racemic compounds, or other mixtures thereof of the compounds described herein or pharmaceutically acceptable salts thereof are provided. If desired, the isomers can be separated by methods well known in the art, such as liquid chromatography. In these situations, a single enantiomer or diastereomer, i.e., the optically active form, 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 conventional methods such as chromatography using a chiral high-pressure liquid chromatography (HPLC) column.

[0056] A "stereoisomer" refers to a compound that has the same atoms bonded together by the same bonds but possesses different three-dimensional structures that are not interchangeable. This invention intends for various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed. A "diastereomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating 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).

[0057] The compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, contain a chiral center and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- for amino acids. Some embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or they may be separated 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 the decomposition of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included. When a compound is represented in its chiral form, the embodiments are understood to include, but not be limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but present, the embodiments are understood to cover either a specific diastereomeric or enantiomerically enriched form, or a racemic or scaremic mixture of such a compound. As used herein, “scaremic mixture” is a mixture of stereoisomers in a ratio other than 1:1.

[0058] The compounds described herein, or compositions provided herein, including pharmaceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures, mixtures containing an enantiomeric excess of one enantiomeric isomer or a single diastereomer, or diastereomer mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0059] Any formula or structure given herein is also intended to represent both the unlabeled and isotope-labeled forms of the compounds. An isotope-labeled compound has the structure represented 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 this 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 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotope-labeled compounds of this disclosure include, for example, 3 H, 13 C and 14These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy for patients. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below.

[0060] This disclosure also includes “deuterated analogues” of the compounds disclosed herein, in which 1 to n hydrogens bonded to carbon atoms are substituted with deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and may therefore be useful in increasing the half-life of any compound of formula (I) when administered to mammals, e.g., humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced with deuterium.

[0061] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo, reduced dose requirements, and / or improved therapeutic index. 18F-labeled compounds may be useful in PET or SPECT tests.

[0062] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in the isotopic composition of the natural abundance of hydrogen. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0063] Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, one of the compounds of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0064] "Pharmaceutical composition" means one or more active ingredients, one or more inactive ingredients constituting a carrier, and any products that arise directly or indirectly from any combination of two or more of the ingredients, from complex formation or aggregation, from the dissociation of one or more of the ingredients, or from one or more other types of reactions or interactions of the ingredients. Accordingly, the pharmaceutical compositions of this disclosure may encompass any composition prepared by mixing at least one of the compounds of this disclosure with a pharmaceutically acceptable carrier.

[0065] As used herein, “pharmaceutically acceptable carrier” includes solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders, etc., that are not harmful to the disclosed compound or its use. additionThis includes agents or pharmaceuticals. The use of such carriers and pharmaceuticals for preparing compositions of pharmaceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (see GS Banker & C.T. Rhodes, Eds.)).

[0066] "I C 50 " or "EC 50 "D" refers to the inhibitory concentration required to achieve 50% of the maximum desired effect. Often, the maximum desired effect here is the degradation of the IKZF2 protein. This term is obtained using in vitro proteolytic assays, such as the HiBiT protein-tagging assay, which assess the concentration-dependent degradation of the IKZF2 protein. max "Maximum protein degradation (e.g., IKZF2 or IKZF1 protein) at the highest compound concentration tested in the assay" refers to the maximum protein degradation at the highest compound concentration tested in the assay.

[0067] "Treatment" or "treating" is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes 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 reducing the severity of the disease or condition); b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing a regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, or delaying the progression of the disease). The objectives are to improve quality of life and / or prolong survival. In some embodiments, the terms “treatment” or “to treat” mean administering a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof, for the purpose of (i) delaying the onset of the disease, i.e., preventing the onset of the clinical symptoms of the disease or delaying the onset of the disease; (ii) inhibiting the disease, i.e., preventing the onset of the clinical symptoms; and / or (iii) alleviating the disease, i.e., causing regression of the clinical symptoms or their severity.

[0068] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0069] As used herein, “IKZF-related disease or condition” (e.g., IKZF2 or IKZF4-related disease or condition) means that a decrease in IKZF protein levels (e.g., IKZF2 or IKZF4 protein levels) can improve the disease or disorder. In some embodiments, in IKZF-related disease or condition, degradation of IKZF2 protein can improve the disease or disorder. In some embodiments, in IKZF-related disease or condition, degradation of IKZF2 protein and one or more additional IKZF proteins (e.g., IKZF4 protein) can improve the disease or disorder. In some embodiments, in IKZF-related disease or condition, degradation of IKZF4 protein can improve the disease or disorder.

[0070] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful in human therapeutic and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0071] The terms “therapeutic effective dose” or “effective dose” of the compounds described herein, or their pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, mean an amount sufficient to, when administered to a subject, produce a therapeutic effect and provide a therapeutic benefit such as improvement of symptoms or delay of disease progression. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of a disease or condition in response to an IKZF2 degrader. The therapeutic effective dose may 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 those skilled in the art.

[0072] As used herein, “degradant” or “proteolyticant” refers to any agent capable of binding to a protein and inducing its degradation. Generally, proteolyticants are thought to induce target protein degradation through cellular ubiquitination and the recruitment of proteasome proteolytic mechanisms. For example, as used herein, “IKZF2 degradant” or “IKZF2 proteolyticant” refers to any agent capable of binding to the IKZF2 protein and inducing its degradation. In some embodiments, the IKZF2 degradant is IKZF2 selective. In some embodiments, the IKZF2 degradant can induce the degradation of the IKZF2 protein and one or more additional IKZF2 proteins (e.g., IKZF1 or IKZF4). IKZF2, also known as Helios, is a zinc finger transcription factor of the IKAROS family that is generally considered necessary to maintain a stable Treg cell phenotype, particularly in the inflammatory tumor microenvironment. In humans, the IKZF2 or Helios protein is encoded by the IKZF2 gene. Exemplary reference sequences for IKZF2 (NCBI gene ID: 22807 (human); 22779 (mouse)) include the NCBI reference sequences NP_001072994 (human protein), NP_035900 (mouse protein), NM_001079526 (human mRNA), and NM_0011770 (mouse mRNA). Related family members include IKZF1 (Ikaros; NCBI gene ID: 10320 (human); 22778 (mouse)) and IKZF4 (Eos; NCBI gene ID: 64375 (human); 22781 (mouse)). The activity of IKZF (e.g., IKZF2) degradants 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 proteolysis is measured using HiBiT protein-tagging assays such as the Nano Glo® HiBiT Extracellular Detection System (Promega). [Table A-1] [Table A-2]

[0073] compound In one embodiment, the compound of formula (I) provided herein, [ka] or a pharmaceutically acceptable salt thereof R 1 C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 A 4-14 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~14 A 6-14 membered heteroaryl having aryl or 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally have 1-4 Z atoms, which may be the same or different. 1 Replaced by, R 2 is hydrogen or C 1~3 It is alkyl, X 1 and X 2 However, each is independently hydrogen, fluoro, or chloro. Y is hydrogen, each Z 1 These are independently cyano, hydroxy, oxo, imino, halogen, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 6-10 membered heteroaryls having 1-2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur, -OZ 1A ,-C(O)-Z 1A ,-C(O)OZ 1A, -C(O)-NH2, -C(O)-NH(Z 1A ), -C(O)-N(Z 1A )2, -NH2, -NH(Z 1A ), -N(Z 1A )2, -NHC(O)-Z 1A , -N(Z 1A )C(O)-Z 1A , -NHC(O)O-Z 1A , -N(Z 1A )C(O)O-Z 1A , -NHC(O)N(Z 1A )2, -N(Z 1A )C(O)NH(Z 1A ), -NHC(O)NH(Z 1A ), -N(Z 1A )C(O)N(Z 1A )2, -NHS(O)2(Z 1A ), -N(Z 1A )S(O)2(Z 1A ), -NHS(O)2N(Z 1A )2, -NHS(O)2NH(Z 1A ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1A They may be the same or different, and each Z 1 1 to 4 Z cells, which may be the same or different, are optionally composed of imino, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl cells. 1A Replaced by 、 each Z 1A These are independently hydroxy, halogen, oxo, cyano, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 6-10 membered heteroaryls having 1-2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur, -OZ 1B ,-C(O)-Z 1B ,-C(O)OZ 1B , -C(O)-NH2, -C(O)-NH(Z 1B ), -C(O)-N(Z 1B )2, -NH2, -NH(Z 1B ), -N(Z 1B )2, -NHC(O)-Z 1B , -N(Z 1B )C(O)-Z 1B ,-NHC(O)OZ 1B , -N(Z 1B )C(O)OZ 1B , -N(Z 1B )C(O)N(Z 1B )2, -NHC(O)N(Z 1B )2, -N(Z 1B )C(O)NH(Z 1B ), -NHS(O)2(Z 1B ), -N(Z 1B )S(O)2(Z 1B ), -NHS(O)2N(Z 1B )2, -N(Z 1B )S(O)2NH(Z 1B ), -NHS(O)2NH(Z 1B ), -N(Z 1B)S(O)2N(Z 1B )2, -N(Z 1A )S(O)2NH2, -N(Z 1B )S(O)2O(Z 1B ), -NHS(O)2O(Z 1B ), -OC(O)Z 1B , -OC(O)OZ 1B , -OC(O)-N(Z 1B )2, -OC(O)-NH(Z 1B ), -OC(O)-NH2-SZ 1B ,-S(O)Z 1B , -S(O)(NH)Z 1B -S(O)2Z 1B -S(O)2N(Z 1B )2, -S(O)2NH(Z 1B ), or -S(O)(NZ 1B )Z 1B And each Z 1A They may be the same or different, and each Z 1A Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally consist of 1 to 4 Z, which may be the same or different. 1B Replaced by, each Z 1B These independently comprise hydroxyl, halogen, oxo, cyano, and C. 1~9 Alkyl, C 1~9 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 A 6-10 membered heteroaryl having 1-2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur, -CO 2- R XXA -NH2, -SH, -OR XXA , -NH-R XXA , -N(R XXA )(R XXB ), -C(O)-R XXA , -C(O)ORXXA ,-C(O)N(R XXA )(R XXB ), -N(R XXA )C(O)(R XXB ), -N(R XXA )C(O)O(R XXB ), -N(R XXA )C(O)NH(R XXB ), -N(R XXA )S(O)(R XXB ), -SR XXA ,-S(O)N(R XXA )2, -S(O)(R XXA ), -S(O)2(R XXA ), -S(O)N(R XXA )(R XXB ), or -S(O)2N(R XXA )(R XXB ) and each R XXA and R XXB Hydrogen and C are independent of each other. 1~9 Alkyl, C 1~9 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 A 4-10 membered heterocycline having 1-2 heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C 6~10 It is a 6-10 membered heteroaryl having an aryl or 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0074] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ia): [ka] It is a compound of [the compound].

[0075] In some embodiments of the compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, X 1 and X 2 Each of them is hydrogen.

[0076] In some embodiments of the compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, Y is deuterium or hydrogen. In some embodiments, Y is deuterium.

[0077] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~14 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally have 1-4 Z atoms, which may be the same or different. 1 Replaced by, R 2 However, hydrogen or C 1~3 It is alkyl, X 1 and X 2 However, each is hydrogen, Y is hydrogen, each Z 1 These independently produce cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, C 3~6 Cycloalkyl, -OZ 1A , -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 5-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl may optionally be the same or different from 1-4 Z 1A Replaced by, each Z 1A These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, C 6~10An aryl or a 6-10 membered heteroaryl having 1-2 nitrogen atoms, wherein each alkyl, aryl, or heteroaryl may optionally have 1-4 Z atoms, which may be the same or different. 1B Replaced by, Z 1B However, halogen or unsubstituted C 6~10 It is Ariel.

[0078] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally have 1-4 Z atoms, which may be the same or different. 1 Replaced by, R 2 However, hydrogen or C 1~3 It is alkyl, X 1 and X 2 However, each is hydrogen, Y is hydrogen, each Z 1 These independently produce cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, -OZ 1A , -NH(Z 1A ), C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 5-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl may optionally be the same or different from 1-4 Z 1A Replaced by, each Z 1AThese independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, or C 6~10 Each alkyl or aryl is an aryl group, and each alkyl or aryl group may be the same or different from 1 to 4 Z groups. 1B It is optionally replaced by, Z 1B However, halogen or unsubstituted C 6~10 It is Ariel.

[0079] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIa) [ka] It is a compound of, R 1 However, it is a non-substitution.

[0080] In some embodiments of the compound of formula (IIa), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~14 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted. In some embodiments, R 1 However, C 1~3 Alkyl, C 4~11 A 6-7 membered heterocycline having a heteroatom selected from cycloalkyl, nitrogen, and oxygen, C 14 A 10-membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted. In some embodiments of the compound of formula (IIa) or its pharmaceutically acceptable salt, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted. In some embodiments, R 1 However, C 1~3 Alkyl, C 4~11 A 6-7 membered heterocycline having a heteroatom selected from cycloalkyl, nitrogen, and oxygen, C 10 A 10-membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0081] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIb) [ka] It is a compound of, Z 1 However, it is a non-substitution.

[0082] In some embodiments of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has one Z 1 Replaced by, Z 1 These independently produce cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, C 3~6 Cycloalkyl, -OZ 1A , -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl is unsubstituted. each Z 1A These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, or C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted.

[0083] In some embodiments of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has one Z 1 Replaced by, Z 1 These independently produce cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, -OZ 1A , -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl is unsubstituted. each Z 1A These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, or C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted.

[0084] In some embodiments of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~3 Alkyl, C 4~6 A cycloalkyl or nitrogen-containing 6-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline has one Z 1 Replaced by, Z 1 However, cyano, hydroxy, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OZ 1A , -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH2, C 6~10 A 6-10 membered heteroaryl having an aryl or nitrogen atom, where each alkyl, aryl, or heteroaryl is unsubstituted. each Z 1A C 1~3 The alkyl or phenyl group is unsubstituted.

[0085] In some embodiments of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~3 Alkyl, C 4~6 A cycloalkyl or nitrogen-containing 6-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline has one Z 1 Replaced by, Z 1 However, cyano, hydroxy, C 1~6 Alkyl, -OZ 1A , -NH(Z1A ), -C(O)-Z 1A -C(O)-NH2, C 6~10 A 6-10 membered heteroaryl having an aryl or nitrogen atom, where each alkyl, aryl, or heteroaryl is unsubstituted. each Z 1A C 1~3 The alkyl or phenyl group is unsubstituted.

[0086] In some embodiments of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] [ka] That is the case.

[0087] In some embodiments of the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] That is the case.

[0088] In some embodiments of the compounds of formula (I) or (IIb), or pharmaceutically acceptable salts thereof, the compound is of formula (IIIa) [ka] It is a compound of, Z 1A is unsubstituted. In some embodiments of the compound of formula (IIIa), or a pharmaceutically acceptable salt thereof, R 1 It is cyclohexyl, and Z 1A is unsubstituted C 1~3 It is alkyl or unsubstituted phenyl. In some embodiments, -R 1 -OZ 1A teeth, [ka] In some embodiments, -R 1 -OZ 1A teeth, [ka] That is the case.

[0089] In some embodiments of the compound of formula (I) or (IIb), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIIb), [ka] It is a compound of, Z 1A is unsubstituted. In some embodiments of the compound of formula (IIIb), or a pharmaceutically acceptable salt thereof, R 1 -CO-Z 1A teeth, [ka] In some embodiments of the compound of formula (IIIb), or a pharmaceutically acceptable salt thereof, -R 1 -CO-Z 1A teeth, [ka] That is the case.

[0090] In some embodiments of the compound of formula (I) or (IIb), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIIc) [ka] It is a compound of, Z 1A This is a non-substitution.

[0091] In some embodiments of the compound of formula (IIIc), or a pharmaceutically acceptable salt thereof, R 1 -NH-Z 1A teeth, [ka] That is the case.

[0092] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIc) [ka] It is a compound of, Z 1A This is a non-substitution.

[0093] In some embodiments of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has one Z 1 Replaced by, Z 1 However, cyano, hydroxy, oxo, halogen, C 1~6 Alkyl, -OZ 1A , -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 6-10 membered heteroaryl having an aryl, or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl has one Z 1A Replaced by, Z 1A These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, C 6~10 The alkyl, aryl, or heteroaryl group is an aryl group or a 6-10 membered heteroaryl group having 1-2 nitrogen atoms, and each alkyl, aryl, or heteroaryl group is unsubstituted.

[0094] In some embodiments of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has one Z 1 Replaced by, Z 1 However, cyano, hydroxy, oxo, halogen, C 1~6 Alkyl, -OZ 1A , -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 6-10 membered heteroaryl having an aryl, or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl has one Z 1A Replaced by, Z 1A These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, or C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted.

[0095] In some embodiments of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 A cycloalkyl, or an oxygen-containing 4-12 membered heterocyclyl, or a nitrogen-containing 6-10 membered heteroaryl, wherein each alkyl, cycloalkyl, or heterocyclyl contains one Z 1 Replaced by, Z 1 However, C 1~3 Alkyl, or C6~10 It is an aryl group, and each alkyl or aryl group has one Z 1A Replaced by, Z 1A However, cyano, hydroxy, halogen, C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted.

[0096] In some embodiments of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 A cycloalkyl, or an oxygen-containing 4-12 membered heterocyclyl, or a nitrogen-containing 6-10 membered heteroaryl, wherein each alkyl, cycloalkyl, or heterocyclyl contains one Z 1 Replaced by, Z 1 However, C 1~3 Alkyl, C 6~10 An aryl or a 6-10 membered heteroaryl having 1-2 nitrogen atoms, where each alkyl, aryl, or heteroaryl has 1 Z 1A Replaced by, Z 1A However, cyano, hydroxy, halogen, or C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted.

[0097] In some embodiments of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof, R 1 However, one Z 1 These are ethyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, pyrrolidyl, piperidyl, or tetrahydroquinolinyl, each substituted with the respective: Z 1 However, one Z 1A These are methyl, ethyl, or phenyl substituted with each other, Z 1A However, each of these is an unsubstituted cyano, hydroxy, chloro, fluorophenyl, pyrazolyl, pyridyl, or indazolyl compound.

[0098] In some embodiments of the compound of formula (IIc), or a pharmaceutically acceptable salt thereof, R 1 However, one Z 1 These are ethyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, or tetrahydroquinolinyl, each substituted with the respective, Z 1 However, one Z 1A These are methyl, ethyl, or phenyl substituted with each other, Z 1A These are, respectively, unsubstituted cyano, hydroxy, chloro, or phenyl.

[0099] In some embodiments of the compound of formula (IIc), or its pharmaceutically acceptable salt, -R 1 -Z 1 -Z 1A teeth, [ka] [ka] That is the case.

[0100] In some embodiments of the compound of formula (IIc), or its pharmaceutically acceptable salt, -R 1 -Z 1 -Z 1A teeth, [ka] That is the case.

[0101] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (IId) [ka] It is a compound of, Z 1B This is a non-substitution.

[0102] In some embodiments of the compound of formula (IId), or its pharmaceutically acceptable salt, -R1 -Z 1 -Z 1A -Z 1B teeth, [ka] That is the case.

[0103] In some embodiments of the compound of formula (IId), or its pharmaceutically acceptable salt, -R 1 -Z 1 -Z 1A -Z 1B teeth, [ka] That is the case.

[0104] In some embodiments of the compound of formula (I) or (IId), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIId) [ka] It is a compound of, Z 1B This is a non-substitution.

[0105] In some embodiments of the compound of formula (IIId), or a pharmaceutically acceptable salt thereof, -R 1 -C(O)-NH-Z 1A -Z 1B teeth, [ka] That is the case.

[0106] In some embodiments of compounds of formula (I) or (IId), or pharmaceutically acceptable salts thereof, the compound is of formula (IIIe) [ka] It is a compound of, Z 1B This is a non-substitution.

[0107] -R 1 -C(O)-OZ 1A -Z 1B but, [ka] The compound according to claim 31, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is of formula (IIe-1) [ka] It is a compound of, Z 1 This is a non-substitution.

[0109] In some embodiments of the compound of formula (IIe-1), or a pharmaceutically acceptable salt thereof, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has two Z atoms, which may be the same or different. 1 Replaced by, each Z 1 These independently produce cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, -C(O)-NH2, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl is unsubstituted.

[0110] In some embodiments of the compound of formula (IIe-1), or its pharmaceutically acceptable salt, R 1 These are two Zs, which may be the same or different. 1 C replaced by each 1~3Alkyl, cyclohexyl, oxaspiro[4.5]decanyl, and each Z 1 R is independently hydroxy, fluoro, unsubstituted methyl, or unsubstituted phenyl. In some embodiments of the compound of formula (IIe-1), or its pharmaceutically acceptable salt, R 1 These are two Zs, which may be the same or different. 1 C replaced by each 1~3 Alkyl or cyclohexyl, each Z 1 is independently a hydroxyl, fluoro, or unsubstituted phenyl. In some embodiments, -R 1 (Z 1 )2 is, [ka] In some embodiments, -R 1 (Z 1 )2 is, [ka] That is the case.

[0111] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is of formula (IIe-2) [ka] It is a compound of, Z 1 This is a non-substitution.

[0112] In some embodiments of the compound of formula (IIe-2), or a pharmaceutically acceptable salt, -R 1 (Z 1 )3 is 3 Z 1 Bicyclo[3.1.1]heptyl substituted with each Z 1 It is an unsubstituted methyl group.

[0113] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIf) [ka] It is a compound of, Z 1A This is a non-substitution.

[0114] In some embodiments of the compound of formula (IIf), or its pharmaceutically acceptable salt, R 1 However, C 1~6 Alkyl, C 3~12 4-12 membered heterocyclyl having heteroatoms selected from cycloalkyl, nitrogen, and oxygen, C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has two Z atoms, which may be the same or different. 1 Replaced by, each Z 1 These independently produce cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, -OZ 1A , -NH(Z 1A ), C(O)-Z 1A -C(O)-NH2, -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 6-10 membered heteroaryl having an aryl or heteroatom selected from nitrogen and oxygen, wherein each alkyl, aryl, or heteroaryl is optionally a Z 1A Replaced by, Z 1A These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, or C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted.

[0115] In some embodiments of the compound of formula (IIf), or a pharmaceutically acceptable salt thereof, R 1 methyl, phenyl, oxo, -C(O)O-CH3 and two Z selected from fluoro 1It is a piperidyl substituted with methyl, where methyl is substituted with phenyl. In some embodiments of the compound of formula (IIf), or its pharmaceutically acceptable salt, R 1 Two Z selected from methyl, oxo, and fluoro 1 It is a piperidyl substituted with methyl, and the methyl is substituted with phenyl. In some embodiments, -R 1 (Z 1 )(Z 1 -Z 1A )teeth [ka] In some embodiments, -R 1 (Z 1 )(Z 1 -Z 1A )teeth, [ka] That is the case.

[0116] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (IIg) [ka] It is a compound of, Z 1A This is a non-substitution.

[0117] In some embodiments of the compound of formula (IIg), or its pharmaceutically acceptable salt, -R 1 -Z 1 (Z 1A )3) is, [ka] That is the case.

[0118] In some embodiments of the compound of formula (IIg), or its pharmaceutically acceptable salt, R 1 teeth, [ka] That is the case.

[0119] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 is unsubstituted C 1~3 It is alkyl.

[0120] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 These are 1-2 Z which may be the same or different. 1 C is optionally replaced by 1~3 It is alkyl. Each Z 1 These independently form hydroxy, C 6~10 A 6-10 member heteroaryl having aryl or nitrogen, where each aryl is optionally associated with one Z 1A Replaced with Z 1A is a halogen. In some embodiments, R 1 These are 1-2 Z which may be the same or different. 1 The methyl, ethyl, or isopropyl compounds are optionally substituted with each Z. 1 Each is independently hydroxy, phenyl, indolyl, or tetrahydronaphthyl, and each phenyl is optionally one Z 1A Replaced with Z 1A However, it is chloro. In some embodiments, R 1 teeth, [ka] That is the case.

[0121] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 is unsubstituted C 4~6 It is a cycloalkyl group.

[0122] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 These are 1-2 Z which may be the same or different.1 C is optionally replaced by 4~6 It is a cycloalkyl compound. Each Z 1 These independently produce cyano, hydroxy, halogen, and C 1~6 Alkyl, -OZ 1A , -NH(Z 1A ), -C(O)-NH2, or C 6~10 It is an aryl group, and each alkyl or aryl group may be the same or different 1 to 3 Z 1A It is optionally replaced by each Z 1A These are independently cyano, hydroxy, halogen, and C 1~6 Alkyl, or C 6~10 It is an aryl group, and each alkyl or aryl group is unsubstituted. In some embodiments, R 1 These are 1-2 Z which may be the same or different. 1 Each of the following is a cyclobutyl, cyclopentyl, or cyclohexyl molecule optionally substituted with Z. 1 These independently produce cyano, hydroxy, fluoro, and C 1~4 Alkyl, -OZ 1A , -NH(Z 1A ), -C(O)-NH2, or phenyl, where each alkyl group may be the same or different 1 to 3 Z 1A It is optionally replaced by each Z 1A These are independently cyano, hydroxy, halogen, and C 1~3 It is an alkyl or phenyl, and each alkyl or phenyl is unsubstituted. In some embodiments, R 1 teeth, [ka] [ka] [ka] That is the case. In some embodiments, R 1 teeth, [ka] [ka] That is the case. In some embodiments, R 1 C 3~12 Cycloalkyls are bicyclic C 5~11 It is a cycloalkyl ring. In some embodiments, R 1 The biring C 5~11 The cycloalkyl ring is unsubstituted. In some embodiments, R 1 The biring C 5~11 The cycloalkyl ring is a crosslinked cycloalkyl ring. In some embodiments, R 1 These are bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl. In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, R 1 The biring C 5~11 Cycloalkyl is a spironicyclic ring. In some embodiments, R 1 is spiro[2.5]octyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, R 1 teeth, [ka] That is the case.

[0123] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 It is a 5- to 12-membered heterocycline having heteroatoms selected from nitrogen and oxygen, and the heterocycline is unsubstituted.

[0124] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 These are 1-2 Z which may be the same or different. 1 A 5-12 member heterocycline having heteroatoms selected from nitrogen and oxygen, which are optionally substituted with each Z 1 These are independent of oxo, halogen, and C. 1~6 Alkyl, -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH-(Z 1A ), -C(O)-OZ 1A , C 6~10 A 6-10 membered heteroaryl having an aryl or nitrogen atom, wherein each alkyl, aryl, or heteroaryl is optionally associated with one Z 1A Replaced with Z 1A is halogen, C 1~6 Alkyl, or C 6~10 It is an aryl, and each alkyl or aryl is one Z 1B It is optionally replaced by Z 1B is halogen or unsubstituted C 6~10 It is an arrow. In some embodiments, R 1 These are 1-2 Z which may be the same or different. 1 Pyrrolidil, piperidil, or tetrahydropyranil are optionally substituted with each Z 1 These are independently oxo, fluoro, and C 1~3 Alkyl, -NH(Z 1A ), -C(O)-Z 1A -C(O)-NH-(Z 1A ), -C(O)-OZ 1A, phenyl, or pyridyl, and each alkyl, phenyl, or pyridyl is optionally one Z 1A Replaced with Z 1A C 1~3 It is an alkyl or phenyl, and each alkyl or phenyl is one Z 1B It is optionally replaced by Z 1B is chloro or unsubstituted phenyl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 It is a biring ring. In some embodiments, R 1 It is a bridging biring ring. In some embodiments, R 1 is azabicyclo[2.2.1]heptanyl. In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, R 1 R is a spironicyclic ring. In some embodiments, R 1 is oxaspiro[3.5]nonanyl or oxaspiro[5.5]undecanyl. In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, R 1 teeth, [ka] That is the case.

[0125] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 is a 6-10 member aryl. In some embodiments, R 1The aryl group is unsubstituted. In some embodiments, R 1 The 6-10 membered aryl is a biring aryl ring. In some embodiments, R 1 The bicyclic aryl ring is tetrahydronaphthyl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0126] In some embodiments of compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, R 1 R is a 6-10 membered heteroaryl or heterocyclyl having heteroatoms selected from nitrogen and oxygen. In some embodiments, R 1 The 6-10 member heteroaryl or heterocyclyl is unsubstituted. In some embodiments, R 1 A 6-10 member heteroaryl or heterocyclyl is one Z 1 It is a biring ring that is optionally substituted with Z 1 is one Z 1A C is optionally replaced by 1~3 It is alkyl, Z 1A is unsubstituted C 6~10 It is an arrow. In some embodiments, R 1 A 6-10 member heteroaryl or heterocyclyl is one Z 1 A tetrahydroquinolinyl or chromanil optionally substituted with Z 1 is one Z 1A A methyl atom optionally substituted with Z 1A R is an unsubstituted phenyl compound. In some embodiments, R 1 teeth, [ka] That is the case.

[0127] In some embodiments of formula (I) or (Ia), or its pharmaceutically acceptable salts, each Z 1 These are independently cyano, hydroxy, oxo, halogen, and C 1~6 Alkyl, -OZ 1A ,-C(O)-Z 1A , -C(O)-NH2, -C(O)-NH(Z 1A ), -C(O)-OZ 1A , 6-10 membered aryl, or 5-10 membered heteroaryl having heteroatoms selected from nitrogen and oxygen. In some embodiments, each Z 1 These are independently cyano, hydroxy, oxo, fluoro, methyl, ethyl, propyl, n-butyl, and -OZ. 1A ,-C(O)-Z 1A , -C(O)-NH2, -C(O)-NH(Z 1A ), -C(O)-OZ 1A These are phenyl, pyridinyl, indolyl, tetrahydroquinolinyl, or chromanil. In some embodiments, Z 1 Each alkyl, aryl, and heteroaryl is unsubstituted. In some embodiments, each methyl, ethyl, propyl, n-butyl, phenyl, pyridinyl, indolyl, tetryhydroquinolinyl, or chromanil is unsubstituted.

[0128] In some embodiments of formula (I) or (Ia), or its pharmaceutically acceptable salts, each Z 1A These are independently hydroxy, halogen, and C 1~6 Alkyl or 6-10 membered aryl, where each alkyl or aryl is Z 1B It is optionally replaced by Z. In some embodiments, Z 1B is non-substitutable. In some embodiments, each Z 1AThese are independently hydroxy, fluoro, chloro, methyl, ethyl, propyl, and phenyl, and each methyl, ethyl, propyl, or phenyl is one Z 1B It is optionally substituted with. In some embodiments of formula (I) or (Ia), or its pharmaceutically acceptable salts, Z 1B This is a 6-10 member aryl. In some embodiments, Z 1B is phenyl. In some embodiments, Z 1B is a halogen. In some embodiments, Z 1B That is Chlorophyll.

[0129] In some embodiments of formula (I) or (Ia), or its pharmaceutically acceptable salts, R 2 It is hydrogen.

[0130] In some embodiments of formula (I) or (Ia), or its pharmaceutically acceptable salts, R 2 C 1~3 It is alkyl. In some embodiments, R 2 It is methyl.

[0131] In some embodiments, a compound of formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, a compound of formula (I) or (IIa), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, a compound of formula (I) or (IIb), or a pharmaceutically acceptable salt thereof, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, a compound of formula (I) or (IIb), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the compound of formula (I), (IIb), or (IIIa), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the compound of formula (I), (IIb), or (IIIa), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, a compound of formula (I), (IIb), or (IIIb), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, a compound of formula (I), (IIb), or (IIIb), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound of formula (I), (IIb), or (IIIc), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, a compound of formula (I) or (IIc), or a pharmaceutically acceptable salt thereof, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, a compound of formula (I) or (IIc), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, a compound of formula (I) or (IId), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, a compound of formula (I) or (IId), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, a compound of formula (I), (IId), or (IIId), or a pharmaceutically acceptable salt thereof, [ka] Alternatively, a selection is made from its pharmaceutically acceptable salts.

[0145] In some embodiments, a compound of formula (I), (IId), or (IIIe), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, a compound of formula (I) or (IIe-1), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, a compound of formula (I) or (IIe-1), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, a compound of formula (I) or (IIe-2), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

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

[0150] In some embodiments, a compound of formula (I) or (IIf), or a pharmaceutically acceptable salt thereof, [ka] or a pharmaceutically acceptable salt thereof.

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

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

[0153] Pharmaceutical composition and dosage form Furthermore, the present disclosure provides a pharmaceutical composition comprising, at least, one of the compounds of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier, as an active ingredient.

[0154] The pharmaceutical compositions of this disclosure may further comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0155] The composition is suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), intraocular (ophthalmic), intrapulmonary (nasal or buccal inhalation), or nasal administration, but the most suitable route in any given case depends on the characteristics and severity of the condition being treated and the characteristics of the active ingredient. The composition can be conveniently presented in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical field.

[0156] In practical use, the compounds of this disclosure can be combined as effective components in homogeneous admixtures with pharmaceutical carriers according to conventional pharmaceutical formulation techniques. The carriers can take a wide variety of forms depending on the desired form of the preparation for administration, e.g., oral or parenteral (including intravenous). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, for example, in the case of oral liquid preparations such as suspensions, elixirs, and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc., or in the case of oral solid preparations such as powders, hard capsules, soft capsules, and tablets, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants, and solid oral preparations are preferred over liquid preparations.

[0157] Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage forms, in which case solid drug carriers are used. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The proportion of the active compound in these compositions can, of course, vary and may conveniently range from about 2 percent to about 60 percent of the unit weight. The amount of the active compound in such therapeutically useful compositions is such that an effective dose is obtained. The active compound may also be administered intranasally, for example, as droplets or sprays.

[0158] Tablets, pills, capsules, etc., may also contain binders such as gum tragacan, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, or alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. If the unit dosage form is a capsule, in addition to the above types of materials, it may contain a liquid carrier such as fatty oil.

[0159] Various other materials may be present as coatings or to improve the physical shape of the unit dosage form. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, syrups or elixirs may contain sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavor.

[0160] In some embodiments, the compounds of the present disclosure can also be used as salts having various countercations to obtain orally usable formulations.

[0161] The compounds of this disclosure may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water, preferably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can be prepared in glycerol in oil, liquid polyethylene glycol, and mixtures thereof. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0162] Suitable pharmaceutical forms for use by injection include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid enough to be easily dispensed into a syringe. The form must be stable under manufacturing and storage conditions and must be protected from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0163] Any preferred route of administration may be used to deliver an effective dose of the compounds of this disclosure to mammals, particularly humans. For example, oral, rectal, topical, parenteral, intraocular, intrapulmonary, intranasal, etc. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of this disclosure are administered orally.

[0164] kit Kits comprising the compounds of the Disclosure herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and suitable packaging are also provided herein. In one embodiment, the kit further includes instructions for use. In one embodiment, the kit comprises the compounds of the Disclosure herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and labels and / or instructions for the use of the compounds in the treatment of indications including diseases or conditions described herein.

[0165] Products containing the compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, in suitable containers are also provided herein. The containers may be vials, wide-mouthed bottles, ampoules, filled syringes, and infusion bags.

[0166] Treatment methods and use This disclosure further relates to the use of the compound for the treatment and / or prevention of diseases and / or conditions through the binding and degradation of IKZF proteins (e.g., IKZF2 and / or IKZF4 proteins) by the compound. Furthermore, this disclosure relates to the use of the compound for the preparation of pharmaceuticals for the treatment and / or prevention of IKZF-related diseases and / or conditions through the binding and degradation of IKZF proteins (e.g., IKZF2 and / or IKZF4 proteins) by the compound. In some embodiments, IKZF-related diseases or conditions are mitigated by the selective degradation of IKZF2 protein. In some embodiments, IKZF-related diseases or conditions are mitigated by the degradation of IKZF2 protein. In some embodiments, IKZF-related diseases or conditions are mitigated by the degradation of IKZF2 protein and one or more additional IKZF proteins (e.g., IKZF1 and / or IKZF4 proteins). In some embodiments, IKZF-related diseases or conditions are mitigated by the degradation of the IKZF4 protein.

[0167] In some embodiments, the IKZF-related disease and / or condition is an IKZF2-related disease and / or condition. In some embodiments, the IKZF2-related disease or condition is mitigated by the selective degradation of the IKZF2 protein. In some embodiments, the IKZF2-related disease and / or condition is mitigated by the degradation of the IKZF2 protein and one or more additional IKZF proteins (e.g., IKZF1 and / or IKZF4 proteins).

[0168] The pharmaceuticals referred to herein may be prepared by conventional processes, which involve combinations of the compounds described herein with pharmaceutically acceptable carriers.

[0169] In some embodiments, methods for treating and / or preventing an IKZF protein (e.g., IKZF2 protein)-related disease or condition in a patient requiring treatment and / or prevention of said disease or condition are provided herein, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, methods for degrading IKZF proteins (e.g., IKZF2 proteins) are provided herein, the methods comprising administering to a patient in need (e.g., a patient with an IKZF2 protein-related disease or condition) a composition comprising a therapeutically effective amount of a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof, or a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, methods for reducing cell proliferation are provided herein, which include contacting cells with a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof, and reducing IKZF protein (e.g., IKZF2 protein) levels in the cells.

[0172] In some embodiments, IK ZF IKZF2 protein levels in patients (e.g., patients with IKZF2-related disease or condition) ZF A method for reducing protein levels is provided herein, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, IKZF protein (e.g., IKZF2 protein)-related diseases or conditions include cancer. In some embodiments, cancer is a hematological cancer. In some embodiments, cancer is a solid tumor. In some embodiments, cancer is a malignant tumor. In some embodiments, cancer includes metastatic cancer. In some embodiments, cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, more than 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "hot" cancer or tumors). In some embodiments, more than 1% and less than 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "warm" cancer or tumors). In some embodiments, less than 1% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancer or tumors).

[0174] In some embodiments, IKZF protein (e.g., IKZF2 protein)-related diseases or conditions are hematological cancers, e.g., leukemia (e.g., acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), anaplastic leukemia, lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), primary macroglobulinemia (WM)), and / or myeloma (e.g., multiple myeloma (MM)).

[0175] In some embodiments, IKZF protein (e.g., IKZF2 protein)-related diseases or conditions include epithelial tumors (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasm), tubular tumors (e.g., adenocarcinoma, adenoma, adenomyoma), mesenchymal tumors or soft tissue tumors (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, chondroma, chondrosarcoma, hydatidiform soft tissue sarcoma, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), and lymphoma.

[0176] In some embodiments, IKZF protein (e.g., IKZF2 protein)-related diseases or conditions include solid tumors in or arising from tissues or organs, for example, • 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, tendonoid, 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 sialadenoma, adenoid cystic carcinoma of the salivary gland, mucoepidermoid carcinoma of the salivary gland, Warthin's tumor of the salivary gland); • Esophagus (e.g., Barrett's esophagus, dysplasia, and adenocarcinoma); • The gastrointestinal tract (including the stomach (e.g., gastric adenoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposition, 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); • Pancreatic (e.g., serous neoplasms (including microcystic or macrocystic serous cystadenoma, solid serous cystoma, von Hippel-Lindau (VHL)-associated serous cystic neoplasm, serous cystadenoma); mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), intraductal tubular neoplasm, cystic acinar neoplasm (including acinar cell cystadenoma, acinar cell cystadenoma, pancreatic adenocarcinoma), invasive ductal adenocarcinoma (tubular adenocarcinoma, adenoplasty); (Including epithelial carcinoma), mucinous carcinoma, medullary carcinoma, hepatocarcinoid carcinoma, signet ring cell carcinoma, anaplastic carcinoma, anaplastic carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenoma, neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs) (including small cell or large cell NECs), islet cell adenoma, gastrin-producing tumors, glucagon-producing tumors, serotonin-producing NETs, ​​somatostatin-producing tumors, VIP-producing tumors, solid pseudopapillary tumors (SPNs), pancreatic blastoma; • Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic bile duct cancer); • Neuroendocrine conditions (e.g., adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma); • Thyroid gland (e.g., poorly differentiated (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma); • Liver (e.g., adenoma, mixed type of hepatocellular carcinoma and cholangiocarcinoma, lamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal tumor, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, cystic 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, chromophobic renal cell carcinoma, clear cell carcinoma, clear cell sarcoma, metanephrocytoma, metanephrocytoma, mucinous tubular spindle cell carcinoma, renal tumor, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); • Breast (for example, invasive ductal carcinoma (including, but not limited to, acinar cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell carcinoma, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, malignant palloid cell carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma); lobular carcinoma (including, but not limited to, pleomorphic cell carcinoma, signet ring cell carcinoma); • Peritoneal tissue (e.g., mesothelioma; primary peritoneal cancer); • Ovaries (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous carcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Müller's tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., cervical cancer, endometrial polyps, endometrial hyperplasia, carcinoma in situ (EIC)), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, trophoblastic tumors) Female reproductive tissue, including squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasms), leiomyomas (e.g., endometrial stromal nodules, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibrilloma, carcinoma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma MMMT)), endometrial stromal tumors, malignant Müllerian ductal mixed tumors of the endometrium, choriocarcinoma of pregnancy (partial hydatidiform mole, complete hydatidiform mole, invasive hydatidiform mole, placental attachment tumor)), vulva, and vagina; • Male reproductive organs, including the prostate, testes (e.g., germ cell tumors, spermatocyte seminomas), and penis; • Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); • Brain (e.g., gliomas (e.g., astrocytoma (non-invasive, low-grade, poorly differentiated, glioblastoma; oligodendroglioma, ependymoma), meningioma, ganglioglioma, schwannoma, craniopharyngioma, chordoma, non-Hodgkin lymphoma (NHL), slow non-Hodgkin lymphoma (iNHL), refractory iNHL, pituitary tumors; • Eyes (e.g., retinocytoma, retinoblastoma, intraocular melanoma, posterior uveal melanoma, iris hamartoma); • Head and neck (e.g., nasopharyngeal cancer, endolymphatic sac tumor (ELST), epidermal carcinoma, laryngeal cancer (including squamous cell carcinoma (SCC) (e.g., glottic cancer, supraglottic cancer, subglottic cancer, combined laryngeal cancer), in situ carcinoma, wart-like, spindle cell, and basal SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal sarcoma)), head and neck paraganglioma (e.g., carotid body, paraganglioma, vagus nerve); • Thymus (e.g., thymoma); • The heart (e.g., cardiac myxoma); • Lung (for example, small cell carcinoma (SCLC), non-small cell lung cancer (NSCLC) (including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, and pleuropulmonary blastoma); Lymphoma (including, for example, lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), painless non-Hodgkin lymphoma (iNHL), refractory iNHL), Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (B-cell lymphoma and T-cell lymphoma (including, for example, Burkitt lymphoma); large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, slow B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large B-cell lymphoma; primary humoral 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)); lymphangioleiomyomatosis); Central nervous system (CNS) (e.g., gliomas (astrocytomas (e.g., pilocytic astrocytoma, pilocytic myxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrous astrocytoma, large round cell astrocytoma, protoplasmic astrocytoma, undifferentiated astrocytoma) cell tumors, glioblastomas (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and gliomatosis cerebri), oligodendrogliomas (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., Subependymal tumors, myxopapillary ependymomas, ependymomas (e.g., cell, papillary, clear cell, elongated ependymal cell), poorly differentiated ependymomas), optic gliomas, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal / glial cell tumors, pineal tumors, germ cell tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paravertebral nerve tumors, stellate region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, neuroblastoma group tumors (neuroblastoma, ganglioblastoma, gangliomas), trisomia 19 ependymomas, etc.); • Neuroendocrine tissue (e.g., preganglionic system including adrenal medulla (pheochromocytoma) and extraadrenal paraganglioma); • Skin (including, for example, clear cell hidradenoma, benign cutaneous fibrous histiocytoma, cystoma, hidradenoma, melanoma (cutaneous melanoma, mucosal melanoma), pilomatoma, Spitz tumor); and • Soft tissue (e.g., invasive angiomyxoma, alveolar rhabdomyosarcoma, hydatidiform soft tissue sarcoma, angiofibroma, hemangiomatous fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, fibroplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's sarcoma / neuroectodermal tumor (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paravertebral sarcoma, inflammatory myofibroblastoma, lipoblasts) The patient has a solid tumor arising from a tissue or organ selected from the group consisting of tumor, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant soft tissue melanoma, myoepithelial carcinoma, myoepithelioma, myxin inflammatory fibroblast sarcoma, undifferentiated sarcoma, perivascular cell tumor, rhabdomyosarcoma, nonrhabdomyosarcoma, soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, and well-differentiated liposarcoma.

[0177] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-related 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.

[0178] In some embodiments, the IKZF protein (e.g., IKZF2 protein)-related disease or condition is a cancer selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, and gastrointestinal stromal tumor (GIST). In some embodiments, the cancer is metastatic.

[0179] Dosage The effective dose of the active ingredient used may vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such doses can be easily determined by those skilled in the art.

[0180] When treating or preventing IKZF protein (e.g., IKZF2 protein)-related diseases or conditions requiring the compounds of this disclosure, generally satisfactory results are obtained when the compounds are administered at a daily dose of approximately 0.1 milligrams to approximately 300 milligrams per kilogram of animal body weight. In some embodiments, the compounds of this disclosure are administered as a single daily dose, in 2 to 6 divided doses per day, or in a sustained-release form. For most large mammals, the total daily dose is approximately 1 milligram to approximately 1000 milligrams, or approximately 1 milligram to approximately 50 milligrams. For a 70 kg adult human, the total daily dose is generally approximately 0.1 milligrams to approximately 200 milligrams. This dosage regimen can be adjusted to provide an optimal therapeutic response. In some embodiments, the total daily dose is approximately 1 milligram to 900 milligrams, approximately 1 milligram to 800 milligrams, approximately 1 milligram to 700 milligrams, approximately 1 milligram to 600 milligrams, approximately 1 milligram to 400 milligrams, approximately 1 milligram to 300 milligrams, approximately 1 milligram to 200 milligrams, approximately 1 milligram to 100 milligrams, approximately 1 milligram to 50 milligrams, approximately 1 milligram to 20 milligrams, or approximately 1 milligram to 10 milligrams.

[0181] The compounds or compositions thereof of this application may be administered once, twice, three times, or four times daily using any preferred form described above. Administration or treatment with the compounds may be continued for several days; for example, treatment will typically last for at least 7, 14, or 28 days for one treatment cycle. Treatment cycles alternate periodically with rest periods of approximately 1 to 28 days, usually about 7 or 14 days, between cycles. Treatment cycles may also be continuous in other embodiments.

[0182] In some embodiments, the method comprises administering an initial daily dose of about 1 to 800 mg of the compound described herein, and increasing the dose incrementally until clinical efficacy is achieved. The dose can be increased using increments of about 5, 10, 25, 50, or 100 mg. The dose can be increased daily, every other day, twice a week, or once a week.

[0183] combination In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are four additional therapeutic agents.

[0184] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0185] In some embodiments, one or more additional therapeutic agents include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulant immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antineoplastic agents, antiproliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapy agents, therapeutic antigen-binding molecules (e.g., monospecific and multispecific antibodies of any form, and their fragments, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, etc.), bispecific antibodies, non-immunoglobulin antibody mimics (e.g., adonectin, afibody molecules, affin, affimer, afitin, alphabody, antikalin, peptide aptamers, armadillo repeat proteins (ARM), atrimers, avimers, designed ankyrin repeat proteins) Examples include proteins (including DARPin®), finomers, Nottin, Knitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editing agents, cells containing chimeric antigen receptors (CARs), modified T cell receptors (TCR-T) including T cell immunotherapy agents, NK cell immunotherapy agents, or macrophage immunotherapy agents, or any combination thereof.

[0186] Exemplary target In some embodiments, one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modulators, stimulants, blockers, activators, or suppressors of targets (e.g., polypeptides or polynucleotides), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI gene ID: 25); and Absent-in melanoma 2 (AIM2; NCBI gene ID: 9447). ;Acetyl-CoA acyltransferase 2 (ACAA2; NCBI gene ID: 10499); Acid phosphatase 3 (ACP3; NCBI gene ID: 55); Adenosine deaminase (ADA, ADA1; NCBI gene ID: 100); Adenosine receptor (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI gene ID: 134, 135, 136, 137); AKT serine / thre Onion kinase 1 (AKT1, AKT, PKB; NCBI gene ID: 207); alanylaminopeptidase, membrane (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 oxidase (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI gene IDs: 26, 314, 8639) Androgen receptor (AR; NCBI gene ID: 367); Angiopoietin (ANGPT1, ANGPT2; NCBI gene IDs: 284, 285); Angiotensin II receptor type 1 (AGTR1, NCBI gene ID: 185); Angiotensinogen (AGT; NCBI gene ID: 183); Apolipoprotein A1 (APOA1; NCBI gene ID: 335); Apoptosis-inducing factor mitochondrial-related 1 (AIFM1, AIF; NCBI gene ID: 9131);Arachidonic acid 5-lipoxygenase (ALOX5; NCBI gene ID: 240); asparaginase (ASPG; NCBI gene ID: 374569); Astalade 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-related (BTLA, CD272; NCBI gene ID: 151888); Baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (Survivin); NCBI gene IDs: 329, 330, 331, 332); Basidine (Ok blood group) (BSG, CD147; NCBI gene ID: 68 2); B-cell lymphoma 2 (BCL2; NCBI gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; NCBI gene ID: 27113); BCL2-like (e.g., BcCLL1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI gene ID: 598, 10018); Beta-3-adrenergic receptor (ADRB3; NCBI gene ID: 155); Bone gamma-carboxyglutamate protein (BGLAP; NCBI gene ID: 632); Bone morphogenesis 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 regions (BCR; NCBI gene ID: 613); bromodomain and extradomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI gene ID: 695);Cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI gene IDs: 1001, 1004); cancer / testicular 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 (CHST15; NCBI gene ID: 51363); carbonic anhydrase (CA1, CA2, CA3, CA4, CA5A, CA5 B, 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, 377677); carcinoembryonic antigen-associated cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK 2);NCBI gene IDs: 1452, 1457);Caspase (e.g., CASP3, CASP7, CASP8;NCBI gene IDs: 836, 840, 841, 864);Catenin β1 (CTNNB1;NCBI gene ID: 1499);Cathepsin G (CTSG;NCBI gene ID: 1511);Cbl proto-oncogene B (CBLB, Cbl-b;NCBI gene ID: 868);CC motif chemokine ligand 21 (CCL21;NCBI gene ID: 6366);CC motif chemokine receptor 2 (CCR2;NCBI gene ID: 7292 30); 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 (CEBPA, CEBP; NCBI gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI gene ID: 23705); cell division cycle 7 (CDC7; NCBI gene ID: 8317); cell communication network factor 2 (CCN2; NCBI gene ID: 1490);Cerebron (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 (CSH1; NCBI gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI gene IDs: 9074, 51208); differentiation marker clusters —(For example, CD1A, CD1C, CD1D, CD1E, CD2, CD3 Alpha (TRA), CD Beta (TRB), CD Gamma (TRG), CD Delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 ( BLAST1), CD52, CD55(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CS F1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2) R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902 , 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI gene IDs: 2155, 2159); collagen type IV alpha chains (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily members -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 (COPS5; NCBI gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD3 71); CD371; NCBI gene IDs: 160364, 170482, 283420); CXC motif chemokine ligand 12 (CXCL12; NCBI gene ID: 6387); CXC 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, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); Cyclin G1 (CCNG1; NCBI gene ID: 900); Cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); Cytochrome P450 redox reactions; Enzymes (POR; NCBI gene ID: 5447); cytokine-inducible SH2-containing proteins (CISH; NCBI gene ID: 1154); cytotoxic T lymphocyte-associated proteins 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); diabetic IAP-binding mitochondrial proteins ( DIABLO, SMAC; NCBI gene ID: 56616); diacylglycerol kinase (e.g., DGKA, DGKZ; NCBI gene ID: 1606, 8525); dickkopfWNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI gene ID: 22943, 27122); dihydrofolate reductase (DHFR; NCBI gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI gene ID: 1803); DISCO Idin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI gene IDs: 780, 4921); DNA-dependent protein kinases (PRKDC; NCBI gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI gene IDs: 7150, 7153, 7155, 7156, 8940); Dopachrome tautomers (DCT; NCBI gene ID: 1638); Dopamine receptor D2 (DRD2; NCBI gene ID: 1318) ;DOT1-like histone lysine methyltransferase (DOT1L; NCBI gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI gene ID: 5169); EMAP-like 4 (EML4; NCBI gene ID: 27436); endoglin (ENG; NCBI gene ID: 2022); endoplasmic reticulum aminopeptidase (e.g., ERAP1, ERAP2; NCBI gene IDs: 51752, 64167); zeste2 polycomb repression complex 2 subunit enhancer (EZH2;NCBI gene ID: 2146); Ephrin receptor (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); Ephrin (e.g., EFNA1, EFNA4, EFNB2; NCBI gene IDs: 1942, 1945, 1948); Epidermal growth factor receptor (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), E RBB3 (HER3), ERBB4 (HER4) NCBI gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI gene ID: 4072); epithelial mitotic factor (EPGN; NCBI gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI gene IDs: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI gene IDs: 1973, 1984); exopolitin-1 (XPO1; NCBI gene ID: 7514); fal Nesoid 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); Ig receptor Fc fragment (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI gene ID: 9971); Gene ID: 83416); Fibroblast-activating protein α (FAP; NCBI gene ID: 2191); Fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI gene IDs: 2260, 2261, 2263, 2264); Fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI gene IDs: 2246, 2247, 2249, 2250); Fibronectin 1 (FN1, MSF;NCBI gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI gene IDs: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI gene ID: 2346); folate receptor 1 (FOLR1; NCBI gene ID: 2 348); 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); Galectin (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI gene ID: 3958, 3964, 3965); Glucocorticoid receptor (NR3C1, GR; NCBI gene ID: 2908); Glucuronidase β (GUSB; NCBI gene ID: 2990); Gluta Transaminase receptor 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 (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); G PNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI gene ID: 10457); growth and differentiation factor 2 (GDF2, BMP9; NCBI gene ID: 2658); growth factor receptor binding protein 2 (GRB2, ASH; NCBI gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL; NCBI gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK;NCBI gene ID: 3055); Heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), 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 cell receptor 2 (HAVCR2, TIM3, CD366; NCBI gene ID: 84868); Liver growth factor (HGF; NCBI gene ID: 3082); HERV-H LTR-related genes 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 oncogenes, GTPases (HRAS; NCBI gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI gene IDs: 3551, 3553); IKAROS family zinc fingers (IKZF1 (LYF1), IKZF3; NCBI gene IDs: 10320, 22806); immunosuppressants Epidemic globulin superfamily member 11 (IGSF11; NCBI gene ID: 152404); indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI gene ID: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI gene ID: 3480, 3482); insulin-like growth factor (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 IDs: 3678, 3685, 3688, 3695, 3698); cell adhesion molecule 1 (ICAM1, CD54; NCBI gene ID: 3383); interleukin-1 receptor-related kinase 4 (IRAK4; NCBI gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122) ), IL2RG(CD132), IL3RA, IL6R, IL13RA2(CD213A2), IL22RA1; NCBI gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6(HGF), IL7, IL8(CXCL8), IL10(TGIF), 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 ID: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI gene ID: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI gene ID: 354); killer cell immunoglobulin-like receptor, Ig domer In 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 insertion domain receptors (KDR, CD309, VEGFR2; NCBI gene ID: 3791); kinesin family member 11 (KIF11; NCBI gene ID: 3832); KiSS-1 transpossession suppressor (KISS1; NC; BI gene ID:3814); KIT oncogene, receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI gene ID:3815); KRAS oncogene, GTPase (KRAS; NCBI gene ID:3845); lactotransferrin (LTF; NCBI gene ID:4057); LCK oncogene, Src family tyrosine kinase (LCK; NCBI gene ID:3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI gene ID:4 035); Leucine-rich repeat-containing 15 (LRRC15; NCBI gene ID: 131578); Leukocyte immunoglobulin-like receptor (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI gene ID: 10288, 10859); Leukotriene A4 hydrolase (LTA4H; NCBI gene ID: 4048); Linker for T cell activation (LAT; NCBI gene ID: 27040); Luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NC BI gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI gene ID: 27076); Lymphocyte activation 3 (LAG3; CD223; NCBI gene ID: 3902); Lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI gene IDs: 4063, 17076); LYN oncogene, Src family tyrosine kinase (LYN; NCBI gene ID: 4067); Lymphocyte cytosolic protein 2 (LCP2; NCBI gene ID: 3937); Zindemethylase 1A (KDM1A; NCBI gene ID: 23028); Lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI gene ID: 1902); Lysyl oxidase (LOX; NCBI gene ID: 4015); Lysyl oxidase-like receptor 2 (LOXL2, NCBI gene ID: 4017); Macrophage migration inhibitor (MIF, GIF; NCBI gene ID: 4282); Macrophage-stimulating receptor 1 (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 complexes (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI gene IDs: 3105, 3133) , 3134, 3135); Major vault protein (MVP, VAULT1, NCBI gene ID: 9961); MALT1 paracaspase (MALT1; NCBI gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI gene ID: 9261); MAPK-interacting serine / threonine kinase (e.g., MKNK1, MKNK2; NCBI gene IDs: 2872, 8569); Matrix metallopeptidase (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11) MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCB I gene ID: 4170); MDM2 oncogene (MDM2; NCBI gene ID: 4193); p53 MDM4 regulator (MDM4; BMFS6; NCBI gene ID: 4194); Mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI gene ID: 2475); Melan-A (MLANA; NCBI gene ID: 2315); Melanocortin receptor (MC1R, MC2R; NCBI gene ID: 4157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI gene ID: 10461); Mesoserine (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 sequences (e.g., MICA, MICB; NCBI gene IDs: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI gene IDs: 5594, 5595, 559 9, 5600, 5601, 5602, 819251); Mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2), NCBI gene IDs: 4217, 1326); Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184); Mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI gene IDs: 5604, 5605, 5609); MPL oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI gene ID: 4352); mucin (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 oncogene, bHLH transcription factor (MYC; NCBI gene ID: 4609); myostatin (MSTN, GDF8; NCBI gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI gene ID: 4883); natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI gene ID: 374383); nexin, MAGE family member (NDN; NCBI gene ID: 4692);Nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI gene IDs: 5819, 81607); Neuronal cell adhesion molecule 1 (NCAM1, CD56; NCBI gene ID: 4684); Neuropilin (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI gene IDs: 8828, 8829); Neurotrophic 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 3 (NLRP3, NALP3; NCBI gene ID: 114548); Notch receptor (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 (NF KB1, NFKB2; NCBI gene ID: 4790, 4791); Nuclear factor, erythrocyte-like 2 (NFE2L2; NRF2; NCBI gene ID: 4780); Nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI gene ID: 3164); Nucleolin (NCL; NCBI gene ID: 4691); Nucleophosmin 1 (NPM1; NCBI gene ID: 4869); Nucleotide-binding oligomerized domain-containing 2 (NOD2; NCBI gene ID: 64127); Nudix hydrolase 1 (NUDT1; NCBI gene ID: 45 21); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI gene ID: 4255); opioid receptor delta-1 (OPRD1; NCBI gene ID: 4985); ornithine decarboxylase 1 (ODC1; NCBI gene ID: 4953); oxoglutarate dehydrogenase (OGDH; NCBI gene ID: 4967); parathyroid hormone (PTH; NCBI gene ID: 5741); PD-L1 (CD274; NCBI gene ID: 29126); periostin (POSTN; NCBI gene ID: 10631);Peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI gene IDs: 5465, 5467, 5468); phosphatases and tensin homologs (PTEN; NCBI gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA (PI3KA) PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G2 G15; NCBI gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogene, serine / threonine kinase (e.g., PIM1, PIM2, PIM3; NCBI gene IDs: 5292, 11040, 415116); placental growth factor (PGF); NCBI gene ID: 5228); plasma Nogen activator, urokinase (PLAU, u-PA, ATF; NCBI gene ID: 5328); platelet-derived growth factor receptor (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI gene ID: 5156, 5159); plexin B1 (PLXNB1; NCBI gene ID: 5364); poliovirus receptor (poliovirus Cell adhesion molecule (PVR, CD155; NCBI gene ID: 5817); Pollo-like kinase 1 (PLK1; NCBI gene ID: 5347); Poly(ADP-ribose) polymerase (e.g., PARP1, PARP2, PARP3; NCBI gene ID: 142, 10038, 10039); Polycomb protein EED (EED; NCBI gene ID: 8726); Polcupin O-acyltransferase (PORCN; NCBI gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI gene ID: 23532); Premelanosome protein (PMEL;NCBI gene ID: 6490); progesterone receptor (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); propi; Osin (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 ID: 5742, 5743); Proteasome 20S subunit beta-9 (PSMB9; NCBI gene ID: 5698); Protein Arginine methyltransferase (e.g., PRMT1, PRMT5; NCBI gene ID: 3276, 10419); protein kinase N3 (PKN3; NCBI gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NC BI gene ID: 5787, 5788); Prothymosin α (PTMA; NCBI gene ID: 5757); Purine nucleoside phosphorylase (PNP; NCBI gene ID: 4860); Purinergic receptor P2X7 (P2RX7; NCBI gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI gene ID: 79037); Raf-1 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 transcription corepressor 1 (RB1; NCBI gene ID: 5925); receptor interaction serine / threonine protein kinase 1 (RIPK1; NCBI gene ID: 8737); ret proto-oncogene (ret proto-oncogene, RET; NCBI gene ID: 5979); retinoic acid early transcript (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-related coiled-coil-containing protein kinases (e.g., ROCK1, ROCK2; NCBI gene IDs: 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 cancer precursor Gene 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); Secretory Fritzl-Related Protein 2 (SFRP2; NCBI gene ID: 6423); Secretory Phosphoprotein 1 (SPP1; NCBI gene ID: 6696); Secretoglobin Family 1 A member 1 (SCGB1A1; NCBI gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI gene IDs: 6401, 6402, 6403); semaphorin 4D (semaphorin, SEMA4D; CD100; NCBI gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI gene IDs: 27036, 27180, 89790); signal regulatory protein alpha ( SIRPA, CD172A; NCBI gene ID: 140885); signal transducers and transcription activators (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI gene ID: 23410); signal transduction lymphocyte activating molecules (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9;NCBI gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI gene ID: 84189); Smooth, fritz-like 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), SLC 44A4; NCBI gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI gene IDs: 6751, 6752, 6753, 6754, 6755); ultrasonic hedgehog signaling molecules (SHH; NCBI gene ID: 6469); Sp1 transcription factors (SP1; NCBI gene ID: 6667); sphingosine kinases (e.g., SPHK1, SPHK2; NCBI gene ID: 88 77, 56848); Sphingosine-1-phosphate receptor 1 (S1PR1, CD363; NCBI gene ID: 1901); Spleen-associated tyrosine kinase (SYK; NCBI gene ID: 6850); Splicing factor 3B 1 (SF3B1; NCBI gene ID: 23451); SRC 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); Interferon response cGAMP interactor stimulator 1 (STING1; NCBI gene ID: 340061); Superoxide dismutase 1 (SOD1, ALS1; NCBI gene ID: 6647); Cytokine signaling inhibitors (SOCS1 (CISH1), SOCS3 (CISH3); NCBI gene ID: 8651, 9021); 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 immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); Tachykinin receptor (e.g., TACR1, TACR3; NCBI gene IDs: 6869, 6870); Tank binding Kinase 1 (TBK1, NCBI gene ID: 29110); Tankirase (TNKS, NCBI gene ID: 8658); TATA box-binding protein-related factor, RNA polymerase I subunit B (TAF1B; NCBI gene ID: 9014); T-box transcription factor T (TBXT, NCBI gene ID: 6862); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI gene ID: 25976); Lymphocyte-specific Protein tyrosine kinase (TEC); NCBI gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI gene ID: 7010); human telomerase reverse transcriptase (TERT; NCBI gene ID: 7015); tenascin C (TNC; NCBI gene ID: 3371); 3-prime repair exonuclease (e.g., TREX1, TREX2; NCBI gene IDs: 11277, 11219); thrombomodulin ( THBD, CD141; NCBI gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI gene ID: 1890); thymidylate synthase (TYMS; NCBI gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI gene ID: 7606, 7608); thyroid-stimulating hormone receptor (TSHR; NCBI gene ID: 7253);TNF Super Family 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); transf Transferrin (TF; NCBI gene ID: 7018); Transferrin receptor (TFRC, CD71; NCBI gene ID: 7037); Transforming growth factors (e.g., 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: 9 333); Transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI gene ID: 7442); Transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H, IGPR1; NCBI gene ID: 126259); Trigger receptors expressed in bone marrow 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 signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); tumor necrosis factor (TNF; NCBI gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD1; 37, 4-1BB), TNFRSF10A(CD261), TNFRSF10B(TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B(OPG), TNFRSF12A, TNFRSF13B, TNFR1 NCBI genetic Child 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 (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); Tyrosina -ase (TYR; NCBI gene ID: 7299); tyrosine hydroxylase (TH; NCBI gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI gene ID: 7075); tyrosine protein phosphatase, non-receptor type 11 (PTPN11, SHP2; NCBI gene ID: 5781); ubiquitin-conjugating enzyme E2I (UBE2I, UBC9; NCBI gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI gene ID: 51377); ubiquitin-specific peptide Tidase 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); balocin-containing proteins (VCP, CDC48; NCBI gene ID: 7415); vascular cell adhesion molecules 1 (VCAM1, CD106; NCBI gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI gene IDs: 7422, 7423);Vimentin (VIM; NCBI gene ID: 7431); Vitamin D receptor (VDR; NCBI gene ID: 7421); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7-H4; NCBI gene ID: 79679); V-set immunomodulatory receptor (VSIR, VISTA, B7-H5; NCBI gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI gene ID: 7465); WRNRecQ-like helicase (WRN; RECQ3; NCBI gene ID: 7486); WT1 conversion transcription factor (WT1; NCBI gene ID: 7490); 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-related transcription regulator (YAP1; NCBI gene ID: 10413); or zeta chain-related protein kinase 70 (ZAP70; NCBI gene ID: 7535).

[0187] In some embodiments, one or more additional therapeutic agents may include drugs that target, for example, 5'-nucleotidase ectopropyl alcohol (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Receptor (ADORA2A; NCBI gene ID: 135); adenosine A 2BReceptor (ADORA2B; NCBI gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI gene ID: 1154); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI gene ID: 1606); fms-like tyrosine kinase 3 (FLT3, CD135; NCBI gene ID: 2322); integrin-related 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 1 (MAP4K1) (also called hematopoietic progenitor kinase 1 (HPK1), NCBI gene ID: 11184); myeloid 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 cell death ligand 1 (PD-L1, CD274; NCBI gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI gene ID: 29126); Child 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 immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); trigger receptor expressed on bone marrow cell 1 (TREM1; NCBI gene ID: 54210); trigger receptor expressed on bone marrow cell 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); WRNRecQ-like helicase (WRN; NCBI gene ID: 7486); or zinc finger protein Helios (IKZF2; NCBI gene ID: 22807).

[0188] Exemplary mechanism of action Immune checkpoint modulator In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulants, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune evasion of cancer cells in the tumor environment. Activation or stimulation of stimulating immune checkpoints can enhance the effects of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., as outlined in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T cells (Tregs) or Treg depletion may reduce the suppression of the antitumor immune response and have an anticancer effect (see, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0189] Examples of immune checkpoint proteins or receptors that can be combined with the compounds provided herein, or their pharmaceutically acceptable salts, 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 cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-related 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-related (BTLA), NCBI gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFSF13B (BAFF; NCBI gene ID: 10673); TNFRSF18 (GITR; NCBI gene ID: 8784), TNFSF18 (GITRL; NCBI gene ID: 8995); MHC class I polypeptide related sequence A (MICA; NCBI gene ID: 100507436); MHC class I polypeptide related sequence B (MICB; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI gene ID :5133); Cytotoxic T lymphocyte-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); Contains PVR-associated immunoglobulin domain (PVRI G, CD112R; NCBI gene ID: 79037); T cell immune receptor with Ig and ITIM domain (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 3 (LAG3, CD223; NCBI gene ID: 3902);Signal transduction 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 (U LBP2; NCBI gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI gene ID: 79465); retinoic acid initial transcript 1E (RAET1E; ULBP4; NCBI gene ID: 135250); retinoic acid initial transcript 1G (RAET1G; ULBP5; NCBI gene ID: 353091); retinoic acid initial transcript 1L (RAET1L; ULBP6; NCBI gene ID: 154064); killer cell immunoglobulin-like receptor, 3 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: 8302); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI gene ID: 3802); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI gene ID: 3803); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3; NCBI gene ID: 3804);Examples include killer cell immunoglobulin-like receptors, three Ig domains, and a long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1; NCBI gene ID: 3824); killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI gene ID: 10219); sialic acid-binding Ig-like lectin 7 (SIGLEC7; NCBI gene ID: 27036); and sialic acid-binding Ig-like lectin 9 (SIGLEC9; NCBI gene ID: 27180).

[0190] In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Examples of T cell inhibitory immune checkpoint proteins or receptors include: CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-related (BTLA)); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); Ig and ITIM domain T cell immune receptors with I-1 (TIGIT); lymphocyte activator 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1).In some embodiments, the compounds or pharmaceutically acceptable salts provided herein are administered together with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors. Examples of T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecules (ICOS, CD278); inducible T cell costimulatory molecule ligands (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). For example, see Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0191] In some embodiments, compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with one or more blockers or inhibitors of one or more NK cell-inhibitory immune checkpoint proteins or receptors. Examples of NK cell inhibitory immune checkpoint proteins or receptors include: killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 Examples include (KIR2DL3); killer cell immunoglobulin-like receptor, with three Ig domains and a 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-bound Ig-like lectin 7 (SIGLEC7); and sialic acid-bound Ig-like lectin 9 (SIGLEC9). In some embodiments, the compounds or pharmaceutically acceptable salts provided herein are administered together with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulated immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7).See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0192] In some embodiments, one or more immune checkpoint inhibitors include a protein-based (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include a protein-based inhibitor of LAG3 (e.g., antibody or fragment thereof, or antibody mimetic).

[0193] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zarifremab (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. Examples include 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).

[0194] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, semiprimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosiberimab (CK-301), sasamrimab (PF-06801591), tislerizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS- 1003, HLX-10, Retifan Limab (MGA-012), BI-754091, Valstilimab (AGEN-2034), AMG-404, Tripalimab (JS-001), Cetrelimab (JNJ-63723283), Genolimuzumab (CBT-501), LZM-009, Prorugolimab (BCD-100), Rhodapolimab (LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, Buzigalimab (ABBV-181), PD1-PIK, BAT-1306, Avelumab (MSB0010718) C), CX-072, CBT-502, Dostallimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, Embafolimab (KN-035), Syntilimab (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, Zimbererimab (AB12 2) Spartalizumab (PDR-001), and compounds described in International Publication No. 2018 / 195321, International Publication No. 2020 / 014643, International Publication No. 2019 / 160882, or International Publication No. 2018 / 195321, 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), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), RG7769(PD-1 / TIM-3), TA K-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-15 Examples include 5 (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 razertinib (GNS-1480; PD-L1 / EGFR).

[0195] Examples of TIGIT inhibitors that may be co-administered include tiragolumab (RG-6058), vivostrimab, domvanarimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigirimab.

[0196] An example of a LAG3 inhibitor that can be co-administered is relamirimab (LAG525).

[0197] Inhibition of regulatory T cell (Treg) activity or Treg depletion can mitigate the suppression of the antitumor immune response and may have an anticancer effect. 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, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof provided herein, are administered in combination with one or more inhibitors of Treg activity or Treg depleting agents. Treg inhibition or depletion can enhance the effects of immune checkpoint inhibitors in cancer treatment.

[0198] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are administered together with one or more Treg inhibitors. In some embodiments, Treg inhibitors can suppress the migration of Tregs into the tumor microenvironment. In some embodiments, Treg inhibitors can reduce the immunosuppressive function of Tregs. In some embodiments, Treg inhibitors can modulate the cellular phenotype and induce the production of inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists, as well as 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).

[0199] Examples of Helios-degrading agents that may be co-administered are not limited to the following: Examples include compounds disclosed in I-57 (Novartis) and International Publication Nos. 2019 / 038717, 2020 / 012334, 2020 / 0117759, and 2021 / 101919.

[0200] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are administered together with one or more Treg depletion agents. In some embodiments, the Treg depletion agent is an antibody. In some embodiments, the Treg depletion antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg depletion antibody is an antibody-drug conjugate (ADC). Examples of Treg depletion 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).

[0201] In some embodiments, Treg inhibitors or Treg depletors that may be administered concurrently include CC-motif chemokine receptor 4 (CCR4), CC-motif chemokine receptor 7 (CCR7), CC-motif chemokine receptor 8 (CCR8), CXC-motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), and cells. 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), neuronal cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin The product contains antibodies or antigen-binding fragments thereof that selectively bind to cell surface receptors selected from the following: β-unit αE (ITGAE; CD103), interleukin-7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat-containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulator (ICOS; CD278), lymphocyte activator 3 (LAG3; CD223), transforming growth factor β1 (TGFB1), hepatitis A virus cell receptor 2 (HAVCR2; CD366; TIM3), T cell immune receptor having Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), and combinations thereof.

[0202] Examples of Treg depletion anti-CCR8 antibodies that may 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 Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in International Publication Nos. 2021 / 163064, 2020 / 138489, and 2021 / 152186.

[0203] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0204] Inhibition, depletion, or reprogramming of non-stimulated myeloid cells in the tumor microenvironment can enhance the anti-cancer immune response (see, e.g., Binnewies et al., Nat. Med.:2018)24(5):541-550, International Publication No. 2016 / 049641). Exemplary targets for depleting or reprogramming non-stimulated myeloid cells include the trigger receptors TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209), which are expressed on myeloid cells. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are administered together with one or more myeloid depletion or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; antibody disclosed in International Publication No. 2019 / 032624) or an anti-TREM-2 antibody (e.g., PY314; antibody disclosed in International Publication No. 2019 / 118513).

[0205] Cluster of differentiation agonists or activators In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with agents that target clusters of differentiation (CD) markers. Examples of CD marker targeters that may be co-administered include, but are not limited to, A6, AD-IL24, neratinib, and tucatinib (ONT 380), Mobocertinib (TAK-788), Tesevatinib, Trastuzumab (HERCEPTIN®), Trastuzumab Biosimimer (HLX-02), Margetuximab, BAT-8001, Pertuzumab (Perjeta), Pegfilgrastim, RG6264, Zanidatamab (ZW25), Cavatak, AIC-100, Tagraxofusp (SL-401), HLA-A240 2 / HLA-A0201 restriction epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene ovadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivative, AGX-73, levastinib, NMS-088, lucitanib hydrochloride, midostaurin, cedilanib, dovitinib, citravaginib Tinib, tivozanib, masitinib, regorafenib, olberen batinib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and International Publication No. 2016 / 196388, International Publication No. 2 International Publication No. 016 / 033570, International Publication No. 2015 / 157386, International Publication No. 1992 / 03459, International Publication No. 1992 / 21766, International Publication No. 2004 / 080462, International Publication No. 2005 / 020921, International Publication No. 2006 / 009755, International Publication No. 2007 / 078034, International Publication No. 2007 / 092403, International Publication No. 2007 / 127317, International Publication No. 2008 / 005877,International Publication Nos. 2012 / 154480, 2014 / 100620, 2014 / 039714, 2015 / 134536, 2017 / 167182, 2018 / 112136, 2018 / 112140, 2019 / 155067, 2020 / 076105, International Application PCT / US2019 / 063091, International Publication No. 1917 / 3692 International Publication No. 2016 / 179517, International Publication No. 2017 / 096179, International Publication No. 2017 / 096182, International Publication No. 2017 / 096281, International Publication No. 2018 / 089628, International Publication No. 2017 / 096179, International Publication No. 2018 / 089628, International Publication No. 2018 / 195321, International Publication No. 2020 / 014643, International Publication No. 2019 / 160882, International Publication No. 2018 / 195321, Country International Publication No. 2001 / 40307, ​​International Publication No. 2002 / 092784, International Publication No. 2007 / 133811, International Publication No. 2009 / 046541, International Publication No. 2010 / 083253, International Publication No. 2011 / 076781, International Publication No. 2013 / 056352, International Publication No. 2015 / 138600, International Publication No. 2016 / 179399, International Publication No. 2016 / 205042, International Publication No. 2017 / 178653, International Publication International Publication No. 2018 / 026600, International Publication No. 2018 / 057669, International Publication No. 2018 / 107058, International Publication No. 2018 / 190719, International Publication No. 2018 / 210793, International Publication No. 2019 / 023347, International Publication No. 2019 / 042470, International Publication No. 2019 / 175218, International Publication No. 2019 / 183266, International Publication No. 2020 / 013170, International Publication No. 2020 / 068752, Cancer Examples of compounds disclosed include those in 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).

[0206] In some embodiments, small molecule inhibitors, such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), logalatinib (BAY-1163877), AZD4547, robritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, and BLU-263 may be co-administered as CD marker targeting agents. Examples include CD117-ADC, AZD3229, teratinib, bororanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavolixafor (X4P-001-IO), plerixafor, CTX-5861, and REGN-5678 (PSMA / CD28).

[0207] In some embodiments, CD marker targeting agents that may be co-administered include small molecule agonists, such as interleukin-2 receptor subunit gamma, eltrombopag, rintatolimod, polyICLC (NSC-301463), riboxone, apoxime, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, and motorimo. This includes d, resikimod, selgantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, covitlimod, chilsotrimod, litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatrimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0208] In some embodiments, CD marker targeting agents that can be co-administered include antibodies such as tafacitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), valrirumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otreltuzumab (TRU-016), isatuximab, ferzaltamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, and sericrelumab (R G7876), APX-005M, ABBV-428, ABBV-927, Mitazarimab (JNJ-64457107), Dzylma, Alemtuzumab, Emactuzumab, AMG-820, FPA-008 (Kabilarizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), Verantamab Fodotin (GSK-2857916), AFM26 (BCMA / CD16A), Simlukafusp Alpha alfa)(RG7461), urerumab, utomirumab (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, relatrimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enserimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20).5) MEDI-9447 (oleculumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, Rituximab (IPH-2102), Lactamab (IPH-4102), Monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), Iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, INBRX-109 Examples include antibodies that target clusters of differentiation markers, such as GEN-1029, pepinemab (VX-15), voplaterimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and compounds published in International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628.

[0209] In some embodiments, CD marker targeting agents that can be co-administered include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, l iso-cel, lisocabtagene maraleucel (JCAR-017), axicaptagene siroleucel (KTE-C19, Yescarta®), axicaptagene siroleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), tisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt expressing T cells, and CD19 / 4-1BBL armored CAR T-cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T-cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silent IL-6 expression, cancer, 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-CD20CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecroucell-T, CART-19, tisagenlecroucell (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 This includes MODULATOR, KD-045, PD-L1 t-HANK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, and therapies disclosed in International Publication No. 2012 / 079000 or International Publication No. 2017 / 049166.

[0210] Surface antigen classification 47 (CD47) inhibitorsIn some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with CD47 inhibitors (IAP, MER6, OA3; NCBI gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include CC-90002, maglorimab (Hu5F9-G4), AO-176 (Vx-1004), retaprimab (IBI-188), remzoparlimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, and GenS. ci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or International Publication No. 1997 / 27873, International Publication No. 1999 / 40940, International Publication No. 2002 / 092784, International Publication No. 2005 / 044857, International Publication No. 200 International Publication No. 9 / 046541, International Publication No. 2010 / 070047, International Publication No. 2011 / 143624, International Publication No. 2012 / 170250, International Publication No. 2013 / 109752, International Publication No. 2013 / 119714, International Publication No. 2014 / 087248, International Publication No. 2015 / 191861, International Publication No. 2016 / 022971, International Publication Publication No. 2016 / 023040, International Publication No. 2016 / 024021, International Publication No. 2016 / 081423, International Publication No. 2016 / 109415, International Publication No. 2016 / 141328, International Publication No. 2016 / 188449, International Publication No. 2017 / 027422, International Publication No. 2017 / 049251, International Publication No. 2017053423,International Publication Nos. 2017 / 121771, 2017194634, 2017 / 196793, 2017 / 215585, 2018 / 075857, 2018 / 075960, 2018 / 089508, 2018 / 0954 Issue 28, International Publication No. 2018 / 137705, International Publication No. 2018 / 233575, International Publication No. 2019 / 027903, International Publication No. 2019 / 034895, International Publication No. 2019 / 042119, International Publication No. 2019 / 042285, International Publication No. 2019 / 042470, International Publication No. 2019 Examples of compounds disclosed in International Publication No. 086573, International Publication No. 2019 / 108733, International Publication No. 2019 / 138367, International Publication No. 2019 / 144895, International Publication No. 2019 / 157843, International Publication No. 2019 / 179366, International Publication No. 2019 / 184912, International Publication No. 2019 / 185717, International Publication No. 2019 / 201236, International Publication No. 2019 / 238012, International Publication No. 2019 / 241732, International Publication No. 2020 / 019135, International Publication No. 2020 / 036977, International Publication No. 2020 / 043188, and International Publication No. 2020 / 009725. 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 maglorimab.

[0211] In some embodiments, the CD47 inhibitors are 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 These are bispecific antibodies that target 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.

[0212] SIRPα targeting agent In some embodiments, the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are antibodies or antigen-binding fragments thereof that conjugate to a SIRPα targeter (NCBI gene ID: 140885; UniProt P78324). Examples of SIRPα-targeting agents that can 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 used include, for example, International Publication Nos. 2001 / 40307, ​​2002 / 092784, 2007 / 133811, 2009 / 046541, 2010 / 083253, 2011 / 076781, 2013 / 056352, 2015 / 138600, 2016 / 179399, 2016 / 205042, and 2017 / 1 This information is contained in International Publication No. 78653, International Publication No. 2018 / 026600, International Publication No. 2018 / 057669, International Publication No. 2018 / 107058, International Publication No. 2018 / 190719, International Publication No. 2018 / 210793, International Publication No. 2019 / 023347, International Publication No. 2019 / 042470, International Publication No. 2019 / 175218, International Publication No. 2019 / 183266, International Publication No. 2020 / 013170, and International Publication No. 2020 / 068752.

[0213] FLT3R Agonist In some embodiments, the compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with an FLT3R agonist. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are administered together with an FLT3 ligand. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are administered together with, for example, the FLT3L-Fc fusion protein described in International Publication No. 2020 / 263830. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are administered together with GS-3583 or CDX-301. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are administered together with GS-3583.

[0214] Agonists or activators of members of the TNF receptor superfamily (TNFRSF). In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are agonists of one or more members of the TNF receptor superfamily (TNFRSF), 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, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAI LR2 (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 (CD26 8. It is further combined with one or more agonists from among NCBI gene ID; 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID; 608), TNFRSF18 (GITR, CD357, NCBI gene ID; 8784), TNFRSF19 (NCBI gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI gene ID; 27242), and TNFRSF25 (DR3, NCBI gene ID; 8718).

[0215] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tavorixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in International Publication Nos. 2016 / 179517, 2017 / 096179, 2017 / 096182, 2017 / 096281, and 2018 / 089628.

[0216] Exemplary anti-TNFRSF5 (CD40) antibodies that can be administered concurrently include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0217] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is co-administered.

[0218] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be administered concurrently include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0219] In some embodiments, the anti-TNFRSF17(BCMA) antibody GSK-2857916 is co-administered.

[0220] Examples of anti-TNFRSF18(GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4(OX40) and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0221] Examples of bispecific antibodies targeting TNFRSF family members that can be administered concurrently 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).

[0222] TGFβ antagonist In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with a TGFβ antagonist. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. The TGFβ-specific antibody may be prepared and characterized using methods known to those skilled in the art, for example, those described in PCT International Publication No. 2018 / 129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist binds to a TGFβ latent-associated peptide (LAP), for example, 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. Patent No. 8,198,412 or U.S. Patent No. 10,017,567. In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-independent manner (e.g., independently of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) localized in the extracellular matrix, for example, in the connective tissue of the liver. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) localized in the thymus, lymph nodes, or tumor microenvironment (e.g., in patients with liver cancer). In some embodiments, TGFβ antagonists block the activation of latent TGFβ (e.g., latent TGFβ1) by latent TGFβ binding protein (LTBP).In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) by Glycoprotein-A Repetitions Predominant protein (GARP), as described, for example, in U.S. Patent 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-latent related peptide (LAP) antibody that specifically binds to the LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in the extracellular matrix (ECM), for example, in connective tissue within the liver. 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 comprising a TGFβ receptor that may be useful in relation to the compositions and methods provided herein are described, for example, in PCT International Publications 2019 / 113123(A1) and 2019 / 113464(A1).

[0223] Bispecific T cell engagers In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with a bispecific T cell engager (e.g., one without Fc) or an anti-CD3 bispecific antibody (e.g., one with Fc). Examples of anti-CD3 bispecific antibodies or BiTEs that can be administered concurrently 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), and odronexutamab (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 / CD 3), AMG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), AMG-211 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY97 4(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-18087 (SSTR2 / CD3)), JNJ-63709178 (CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20) Examples include tidutamab (XmAb-18087; SSTR2 / CD3), catumakisomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosnetuzumab (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). The anti-CD3 binding bispecific molecule may or may not have an Fc, as needed. Exemplary bispecific T-cell engagers that may be co-administered include those containing CD3 and tumor-associated antigens described herein (e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565);It targets 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).

[0224] Bispecific and tripspecific natural killer (NK) cell engagers In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) described herein, or pharmaceutically acceptable salts thereof, are bispecific NK cell promoters (BiKE) or trispecific NK cell promoters (tri-specific NK-cell promoters). The agent is administered with an engager (TriKE) (e.g., without Fc), or a bispecific antibody against NK cell activating receptors (e.g., with Fc), such as CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), innate cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell type C lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediates antibody-dependent 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). Examples of co-administered anti-CD16 bispecific antibodies, BiKEs, or TriKEs include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). The anti-CD16 binding bispecific molecule may or may not have an Fc, as required. Exemplary co-administered bispecific NK cell engagers target CD16 and one or more tumor-associated antigens described herein (e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKEs and TriKEs are described, for example, Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

[0225] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with MCL1 apoptosis regulators or inhibitors of BCL2 family members (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in International Publication Nos. 2018 / 183418, 2016 / 033486, and 2017 / 147410.

[0226] SHP2 inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors of protein tyrosine phosphatase nonreceptor 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 International Publication Nos. 2018 / 172984 and International Publication Nos. 2017 / 211303.

[0227] Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors and degrading agents In some embodiments, compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an inhibitor of mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of hematopoietic progenitor cell kinase 1 (HPK1) inhibitors include International Publication Nos. 2020 / 092621, 2018 / 183956, 2018 / 183964, 2018 / 167147, 2018 / 049152, 2020 / 092528, and 2016 / 205942. This includes, but is not limited to, the information contained in International Publication Nos. 2016 / 090300, 2018 / 049214, 2018 / 049200, 2018 / 049191, 2018 / 102366, 2018 / 049152, and 2016 / 090300.

[0228] Apoptosis signal-regulated kinase (ASK) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with ASK inhibitors, such as mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors are described in International Publication No. 2011 / 008709 (Gilead Sciences) and International Publication No. 2013 / 112741 (Gilead Sciences).

[0229] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with Bruton's tyrosine kinase inhibitors (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebralutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0230] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are 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 It is administered together with an inhibitor of cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI gene ID: 1019), cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI gene ID: 1021), cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI gene ID: 1022), or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, arbocidicib (HMR-1275, flavopyridol), AT-7519, dinacyclib, Ibrance, FLX-925, LEE001, palbociclib, samuracyclib, ribociclib, rigosertib, selinexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milcilib, trilaciclib, simrosertib hydrate (TAK931), and TG-02.

[0231] Discoidine domain receptor (DDR) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI gene ID: 4921). Examples of DDR inhibitors include dasatinib, as well as those disclosed in International Publication No. 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), International Publication No. 2013 / 027802 (Chugai Pharmaceutical), and U.S. Patent Application Publication No. 2013 / 034933 (Imperial Innovations).

[0232] Targeted E3 ligase ligand conjugate In some embodiments, compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with a targeted E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and Survival) E3 ubiquitin ligase binding moiety, von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, cereblon E3 ubiquitin ligase binding moiety, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase the degradation of a targeted protein, for example, via the ubiquitin pathway. In some embodiments, a targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds to the proteins described herein, and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate includes a targeting or binding moiety that targets or binds to a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI gene ID: 868) and hypoxia-inducible factor 1 subunit α (HIF1A; NCBI gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate includes a kinase inhibitor (e.g., a small molecule kinase inhibitor of BTK and the E3 ligase ligand or binding moiety). See, for example, International Publication No. 2018 / 098280.In some embodiments, the targeted E3 ligase ligand conjugate includes interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); rapidly accelerating fibrosarcoma proteins (such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD proteins; and a binding site that targets or binds to the E3 ligase ligand or binding site. See, for example, International Publication Nos. 2019 / 099926, 2018 / 226542, 2018 / 119448, 2018 / 223909, and 2019 / 079701. Additional targeted E3 ligase ligand conjugates that may be administered concurrently are described, for example, in International Publication Nos. 2018 / 237026, 2019 / 084026, 2019 / 084030, 2019 / 067733, 2019 / 043217, 2019 / 043208, and 2018 / 144649.

[0233] Histone deacetylase (HDAC) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are further combined with histone deacetylase inhibitors, such as histone deacetylase 9 inhibitors (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include avexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, and entinostat.

[0234] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrhodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccines, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0235] Janus kinase (JAK) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restoltinib, momerotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0236] Lysyl oxidase-like protein (LOXL) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors of LOXL proteins, 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 antibodies described in International Publication No. 2009 / 017833 (Arresto Biosciences), International Publication No. 2009 / 035791 (Arresto Biosciences), and International Publication No. 2011 / 097513 (Gilead Biologics).

[0237] Matrix metalloproteinase (MMP) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are inhibitors of matrix metallopeptidases (MMPs), such as MMP1 (NCBI gene ID: 4312), MMP2 (NCBI gene ID: 4313), MMP3 (NCBI gene ID: 4314), MMP7 (NCBI gene ID: 4316), MMP8 (NCBI gene ID: 4317), MMP9 (NCBI gene ID: 4318); MMP10 (NCBI gene ID: 4319); MMP11 (NCBI gene ID: 4312); 20); Further combination with inhibitors of MMP12 (NCBI gene ID: 4321), MMP13 (NCBI gene ID: 4322), MMP14 (NCBI gene ID: 4323), MMP15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066), and / or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), cipestat (Ro 32-3555), GS-5745 (andecaliximab), and those described in International Publication No. 2012 / 027721 (Gilead Biologics).

[0238] RAS and RAS pathway inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are KRAS proto-oncogene, GTPase (KRAS); also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c- Ras inhibitors are administered along with inhibitors of the Ki-ras2 (NCBI gene ID: 3845) proto-oncogene, GTPase (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI gene ID: 4893) or the HRAS proto-oncogene, GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI gene ID: 3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of the following: EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Examples of K-Ras inhibitors that can be co-administered include sotrasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1(G12C), adaglasib (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.Examples of KRAS mRNA inhibitors include anti-KRAS U1 adapter, AZD-4785, siG12D-LODER®, and siG12D exosome. Examples of MEK inhibitors that may be co-administered include binimetinib, cobimetinib, PD-0325901, pimacertib, RG-7304, selumetinib, trametinib, and those described below and herein. Examples of Raf dimer inhibitors that may be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Examples of ERK inhibitors that may be co-administered include LTT-462, LY-3214996, MK-8353, labocertinib, and urixertinib. Examples of Ras GTPase inhibitors that can be administered concurrently include ligogocertib. Examples of PI3K inhibitors that can be administered concurrently include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Examples of AKT inhibitors that can be administered concurrently include capivacertib and GSK2141795. Examples of PI3K / mTOR inhibitors that may be co-administered include daptricib, omiparisib, boxalisib, gedatricib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanicertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), racemethyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatacertib (CC-223), SF-1126, and PQR-309 (vimiralisib). In some embodiments, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, for example, Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Additionally, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor neratinib.For example, see Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0239] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors 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 antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib + trametinib, PD-0325901, pimacerutib, LTT462, AS703988, CC-90003, and refametinib.

[0240] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha; NCBI gene). It can be further combined with inhibitors of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D; NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparisib (BKM120), BYL719 (alperisib), CH5132799, copanlisib (BAY80-6946), duverisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, and IPI-5. 49, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, Rigosertib, RP5090, RP6530, SRX3177, Taselicib, TG100115, TGR-1202 (Umbralicib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Waltmannin, ZSTK474, and International Publication No. 2005 / 113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Examples include compounds described in International Publication No. 2013 / 116562 (Gilead Calistoga), International Publication No. 2014 / 100765 (Gilead Calistoga), International Publication No. 2014 / 100767 (Gilead Calistoga), and International Publication No. 2014 / 201409 (Gilead Sciences).

[0241] Spleen tyrosine kinase (SYK) inhibitors In some embodiments, compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine, BAY-61-3606, celduratinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusatinib (ASN-002), and those described in U.S. Patent No. 8,450,321 (Gilead Connecticut), and those described in U.S. Patent Application Publication No. 2015 / 0175616.

[0242] Toll-like receptor (TLR) agonist In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are agonists of Toll-like receptors (TLRs), such as TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene I It is administered together with agonists of D:7097), TLR3 (NCBI gene ID:7098), TLR4 (NCBI gene ID:7099), TLR5 (NCBI gene ID:7100), TLR6 (NCBI gene ID:10333), TLR7 (NCBI gene ID:51284), TLR8 (NCBI gene ID:51311), TLR9 (NCBI gene ID:54106), and / or TLR10 (NCBI gene ID:81793). Examples of TLR7 agonists that can be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogues, LHC-165, TMX-101 (imiquimod), GSK-2245035, reciquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences). U.S. Patent Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent Publication No. 2014 / 0045849 (Janssen), U.S. Patent Publication No. 2014 / 0073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Publication No. 2014 / 0350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Publication No. 2008 / 0234251 (ArrayArray Biopharma, U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0118235 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Application Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 2014 / 0275167 (Novira Compounds disclosed in U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics) and other publications include those disclosed in U.S. Patent Application Publication No. 2014 / 0045849 (Janssen) and U.S. Patent Application Publication No. 2014 / 00736. 42 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 2014 / 0350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), US Patent Application Publication No. 2008 / 0234251 (Array Biopharma), US Patent Application Publication No. 2008 / 0306050 (Array Biopharma), US Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), US Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), US Patent Application Publication No. 2011 / 0118235 (VentirxExamples include compounds disclosed in U.S. Patent Publication No. 2012 / 0082658 (Ventirx Pharma), U.S. Patent Publication No. 2012 / 0219615 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0066432 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Patent Publication No. 2014 / 0275167 (Novira Therapeutics), and U.S. Patent Publication No. 2013 / 0251673 (Novira Therapeutics). Examples of TLR9 agonists that can be administered concurrently include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0243] Tyrosine kinase inhibitors (TKIs) In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with a tyrosine kinase inhibitor (TKI). The TKI may target the epidermal growth factor receptor (EGFR), as well as the receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cejiranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src Examples include, but are not limited to, lapatinib, restaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rosiletinib, sulfatinib (HMPL-012), sunitinib, famitinib, L-malate (MAC-4), tiboanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Examples of EGFR targeting agents include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, baritinib, avivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), rifilafenib (BGB-283), vectibix, razertinib (LECLAZA®), and compounds disclosed in Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotalocan (RM-1929), cerivanthumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0244] Chemotherapy agents In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with chemotherapeutic agents or antineoplastic agents.

[0245] As used herein, the terms “chemotherapeutic agent” or “chemotherapeutic agent” (or “chemotherapy” when referring to treatment with a chemotherapeutic agent) mean any non-proteinogenic (e.g., non-peptidogenic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., benzodepa, carboquan, metuledepa, and uredepa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemiloromelamine; acetogenins, e.g., bratacin and bratacinone; camptothecin, including the synthetic analog topotecan; bryostatin, callistatin; CC-1065, including adzeresin, karzeresin, and bizeresin synthetic analogs; and crypto Ficins, in particular cryptophycin 1 and cryptophycin 8; dorastatin; duocalmycin, including synthetic analogs KW-2189 and CBI-TMI; eryuterobin; 5-azacitidine; pancratistatin; sarcodictiin; spongstatin; nitrogen mustards, e.g., chlorambucil, chlornafadin, cyclophosphamide, gluphosphamide, evophosphamide, bendamustine, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitine, fenestrine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., carmustine, chlorozotosine, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as engine antibiotics (e.g., Calichemycin, especially Calichemycin γII and Calichemycin φI1), dinemycin containing dinemycin A, bisphosphonates such as clodronate, esperamycin, neocardinostatin chromophores and related chromoprotein engine antibiotic chromophores, acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin Detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenime Phosphates, dinostatins, and zolubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folate analogs, e.g., demopterin, methotrexate, pteropterin, and trimethrexate; purine analogs, e.g., cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; an Drogens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepithiostan, and testotractone; anti-adrenal drugs, e.g., aminoglutethimide, mitotane, and trilostane; folic acid supplements, e.g., floric acid; radiotherapy agents such as radium-223; trichothecenes, especially T-2 toxin, beraclin A, loridine A, and anguidin; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizabrin (Veru-111); platinum analogs, e.g., cisplatin and carboplatin, NC-6004 nanoplatin; acegraton; aldofhamide glycoside; aminolevulinic acid; enyluracil; amsacrin, hestrabucil; bisanthren; edatrexate; defofamine; demecoltin; diaziquan; elformutin; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea, lentinan; leucovorin; lonida Min; Maytansinoids, e.g., maytansine and anthamitosine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Fluoropyrimidine; Folic acid; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide K (PSK); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Trabectedin, Triadiquan; 2,2',2''-T Lichlorotriemylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobromane; gasitosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; bancristine; vinorelbine (N AVELBINE®); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DFMO); Retinoids, e.g., retinoic acid; Capecitabine; NUC-1031; FOLFOX (folic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folic acid, 5-fluorouracil, irinotecan);Examples include FOLFOXIRI (folic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folic acid, 5-fluorouracil, irinotecan, oxaliplatin), and any pharmaceutically acceptable salts, acids, or derivatives of the above. Such agents may be conjugated to an antibody or any targeting agent described herein to create an antibody-drug conjugate (ADC) or a targeted drug conjugate.

[0246] Anti-hormone drugs The definition of "chemotherapeutic agents" includes anti-hormonal agents such as anti-estrogen agents and selective estrogen receptor modulators (SERMs), enzyme aromatase inhibitors, anti-androgens, and any pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to modulate or inhibit the hormonal effects on tumors.

[0247] Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifen, droloxifen, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (FARESTON®).

[0248] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal gland. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestan, fadrozol, borozol (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0249] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enovotherm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antisense).

[0250] An example of a progesterone receptor antagonist is onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethindrone + ethinylestradiol), norgestimate + ethinylestradiol (Tri-Cyclen), and levonorgestrel.

[0251] Anti-angiogenic agents In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with anti-angiogenic agents. Anti-angiogenic agents that can be administered concurrently include retinoid acids and their derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, nexparanib, suramin, squalamine, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clepein), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, and thiapro. Examples include phosphorus, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin serum, metalloproteinase-3 chicken inhibitor (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagiline, sodium aurantithiomalate, d-penicillamine, β-1-anticollagenase serum, alpha-2-antiplasmin, bisanthren, lobenzalit disodium, n-2-carboxyphenyl-4-chloroantonylate disodium or "CCA", thalidomide, angiogenesis-inhibiting steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tascinimod.Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-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, falisimab, dirasimab (ABT-165;DLL4 / VEGF), or nabisixizumab (OMP-305B83);DLL4 / VEGF).

[0252] Antifibrotic agents In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with antifibrotic agents. Antifibrotic agents that may be co-administered include compounds such as beta-aminopropionitrile (BAPN), as well as compounds disclosed in U.S. Patent No. 4,965,288, relating to lysyl oxidase inhibitors and their use in the treatment of diseases and conditions associated with abnormal collagen deposition, and compounds disclosed in U.S. Patent No. 4,997,854, relating to compounds that inhibit LOX for the treatment of various pathological fibrous conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Patents 4,943,593, 5,021,456, 5,059,714, 5,120,764, and 5,182,297 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Patent 5,252,608 relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication 2004 / 0248871, which are incorporated herein by reference.

[0253] Examples of antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that, after binding to carbonyl, produce a resonance-stabilized product, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazides 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 ​​lactones.

[0254] Other antifibrotic agents are copper chelating agents that either penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that inhibit aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamins, particularly D-penicillamine and its analogues, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate, and sodium-4-mercaptobutane sulfinate trihydrate.

[0255] Anti-inflammatory drugs In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with an anti-inflammatory agent. Examples of anti-inflammatory agents include arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA1 Examples include, but are not limited to, inhibitors of one or more of the following: 4 (NCBI gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI gene ID: 1326). In some embodiments, the inhibitor is a biinhibitor, such as a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, or COX-2 / 5-LOX biinhibitor.

[0256] Examples of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) inhibitors that can be co-administered include mofezolac, GLY-230, and TRK-700.

[0257] Examples of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743) inhibitors that can be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maesoshri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, lutecarpine, chilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that can be administered concurrently include HP-5000, lornoxicam, ketrolactromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be administered concurrently include polmacoxib and imurecoxib.

[0258] Examples of co-administered inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES; gene ID: 9536) include LY3023703, GRC27864, and international publications 2015 / 158204, 2013 / 024898, 2006 / 063466, 2007 / 059610, 2007 / 124589, and 2010 / 100. International Publication No. 249, International Publication No. 2010 / 034796, International Publication No. 2010 / 034797, International Publication No. 2012 / 022793, International Publication No. 2012 / 076673, International Publication No. 2012 / 076672, International Publication No. 2010 / 034798, International Publication No. 2010 / 034799, International Publication No. 2012 / 022792, International Publication No. 2009 / 103778, International Publication No. 2011 / 048004, International Publication No. 201 International Publication No. 2 / 087771, International Publication No. 2012 / 161965, International Publication No. 2013 / 118071, International Publication No. 2013 / 072825, International Publication No. 2014 / 167444, International Publication No. 2009 / 138376, International Publication No. 2011 / 023812, International Publication No. 2012 / 110860, International Publication No. 2013 / 153535, International Publication No. 2009 / 130242, International Publication No. 2009 / 146696, International Publication Examples of compounds include those described in International Publication No. 2013 / 186692, International Publication No. 2015 / 059618, International Publication No. 2016 / 069376, International Publication No. 2016 / 069374, International Publication No. 2009 / 117985, International Publication No. 2009 / 064250, International Publication No. 2009 / 064251, International Publication No. 2009 / 082347, International Publication No. 2009 / 117987, and International Publication No. 2008 / 071173. Furthermore, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be administered co-administered. See, for example, Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):282 35-46.

[0259] Carbonic anhydrases that can be administered simultaneously (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 for one or more of the following: 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), and CA14 (NCBI gene ID: 23632) include acetazolamide, metazolamide, dorzolamide, zonisamide, brinzolamide, and diclofenamide. CG100649 is an example of a COX-2 / CA1 / CA2 dual inhibitor that can be co-administered.

[0260] Examples of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) inhibitors that can be co-administered include meclofenamate sodium and dilauton.

[0261] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) that can be co-administered include compounds described in International Publication No. 2015 / 148954. Examples of co-administered COX-2 / SEH dual inhibitors include compounds described in International Publication No. 2012 / 082647. Examples of co-administered SEH and fatty acid amide hydrolase dual inhibitors (FAAH; NCBI gene ID: 2166) include compounds described in International Publication No. 2017 / 160861.

[0262] Examples of mitogen-activated protein kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI gene ID: 1326) that can be co-administered include GS-4875, GS-5290, BHM-078, and, for example, International Publication Nos. 2006 / 124944, 2006 / 124692, 2014 / 064215, 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al. This includes the findings described in al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0263] Tumor oxygenation agent In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered together with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Examples of co-administered agents include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, such as PT-2977, PT-2385; VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding proteins (HNOX)), such as OMX-302 and HNOX proteins described in, for example, International Publication Nos. 2007 / 137767, 2007 / 139791, 2014 / 107171, and 2016 / 149562.

[0264] Immunotherapy agents In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with an immunotherapy agent. In some embodiments, the immunotherapy agent is an antibody.Examples of immunotherapies that can be co-administered include avagovomab, AB308, ABP-980, adecatumumab, aftumumab, alemtuzumab, artumomab, amatuximab, anatumomab, alsitunomab, atezolizumab, bavituximab, vectumomab, bevacizumab, vibatuzumab, blinatumumab, brentuximab, camidanlumab, cantuzumab, catumakisomab, CC49, cetuximab, sitatuzumab, xixtumumab, cribatuzumab, conatumumab, dacetuzumab, darotuzumab, daratuzumab, detumomab. Dinutuximab, dombanarimab, dorodizumab, durigotumab, dusigitumab, eclomeximab, elotuzumab, emibetuzumab, encituzumab, erzumakisomab, etalacizumab, falletuzumab, ficratuzumab, figitumumab, frambotuzumab, futuximab, ganituzumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igobomab, imugatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-73) 4016, and MDX-101), iratumumab, rabetuzumab, lexatumumab, lintuzumab, rorbotuzumab, lucatumumab, mapatumumab, matsuzumab, milatuzumab, minretuzumab, mitumomab, mogamulitsumab, moxetumomab, naptumomab, narunatumab, nesitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, okalatuzumab, ofatumumab, oraratuzumab, onarutuzumab, oporutuzumab, olegobomab, panitumumab, pulsatuzumab, pasdotox, patrizumab, pemutz Examples include momab, pertuzumab, pintumomab, pritumumab, lacosumomab, radretumumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samarizumab, saturomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, takatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucosumab, ubirituximab, bertuzumab, borsetuzumab, botumumab, zaltumumab, zimbererimab, and 3F8.Rituximab can be used to treat slow chronic B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0265] The exemplified therapeutic antibodies may be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y cribatuzumab), or iodine-131.

[0266] In some embodiments, the immunotherapeutic agent that may be co-administered is an antibody-drug conjugate (ADC). Exemplary co-administered ADCs include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics targeting proteins or antigens listed above and herein. Examples of co-administered ADCs include gemtuzumab, brentuximab, brentuximab (e.g., verantamab mafodotin), camidanrumab (e.g., camidanrumab tesirin), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetuzumab, and mirbetuxizumab (mirve Tuximab (e.g., milbetuxizumab sobatansine), depatuxizumab, vadasotuximab, rabetsuzumab, radilatuzumab (e.g., radilatuzumab vedotin), roncatuximab (e.g., roncatuximab tesrin), sacituzumab (e.g., sacituzumab govitecan), datopotamab (e.g., datopotamab deruxtecan; DS-1062;Dato-DXd), patritumab (e.g., patritumab deruxtecan), rifazutuzumab, indusatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitamab brilsodotin), indatuximab, milatuzumab, Robalpituzumab (e.g., lovalpituzumab tesirin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab tansine), disitamab (e.g., disitamab vedotin), terisotuzumab vedotin (ABBV-399), AGS-16C3F, ASG- 22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IM GN289, IMGN151, IMGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203(BMS936561), MEDI-5 Examples include 47, PF-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. Co-administered ADCs 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.

[0267] Examples of drug-conjugated antibodies, fragments thereof, or exemplary therapeutic agents (e.g., anticancer or antitumor agents) that can be conjugated mimetically include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, mytansine or its analogues (e.g., meltansine / emtansine (DM1), ravtansine / solavtansine (DM4)), anthracyclines (e.g., Examples include doxorubicin, daunorubicin, epirubicin, idarubicin, pyrrolobenzodiazepine (PBD) DNA crosslinking agent SC-DR002 (D6.5), duocalmycin, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epotilone), pyrrolobenzodiazepine (PBD) or its dimers, duocalmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antineoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to a 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 anticancer or antineoplastic agent) that can be conjugated to a drug-conjugated antibody, a fragment thereof, or an antibody mimetic includes immune checkpoint inhibitors. 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 includes BPI-002.

[0268] In some embodiments, the co-administered ADC may include antibody-targeted tumor-associated calcium signaling molecule 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Examples of anti-TROP-2 antibodies include TROP2-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 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP2-TRACTr (Janux Therapeutics), and LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius). BioTech), LIV-2008b (LivTech / 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 (MediterraneaTheranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and International Publication No. 2020 / 016662 (Abmart), International Publication No. 2020 / 249063 (Bio-Thera Solutions), US Patent Application Publication No. 2019 / 0048095 (Bio-Thera Solutions), International Publication No. 2013 / 077458 (LivTech / Chiome), European Patent Application Publication No. 2011 / 0783675 (Chiome), International Publication No. 2015 / 098099 (Daiichi Sankyo), International Publication No. 2017 / 002776 (Daiichi Sankyo), International Publication No. 2020 / 130125 (Daiichi Sankyo), International Publication No. 2020 / 240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021 / 093730 (Daiichi Sankyo), U.S. Patent Application Publication No. 9850312 (DaiichiSankyo, Chinese Patent No. 112321715 (Biosion), US Patent Application Publication No. 2006 / 193865 (Immunomedics / Gilead), International Publication No. 2011 / 068845 (Immunomedics / Gilead), US Patent Application Publication No. 2016 / 296633 (Immunomedics / Gilead), US Patent Application Publication No. 2017 / 021017 (Immunomedics / Gilead), US Patent Application Publication No. 2017 / 209594 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017 / 274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018 / 271992 (Immunomedics / Gilead), International Publication No. 2018 / 217227 (Immunomed Immunomedics / Gilead), U.S. Patent Application Publication No. 2019 / 248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021 / 093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021 / 069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent No. 843 Patent No. 5529 (Immunomedics / Gilead), U.S. Patent No. 9,492,566 (Immunomedics / Gilead), International Publication No. 2003 / 074566 (Gilead), International Publication No. 2020 / 257648 (Gilead), U.S. Patent Application Publication No. 2013 / 039861 (Gilead), International Publication No. 2014 / 163684 (Gilead), U.S. Patent No. 9,427,464 (LivTech / Chiome), U.S. Patent No. 1,0501,555 (Abruzzo Theranostic / Oncoxx), International Publication No. 2018 / 036428 (Sichuan KelunExamples include, but are not limited to, those described in International Publication No. 2013 / 068946 (Pfizer), International Publication No. 2007 / 095749 (Roche), and International Publication No. 2020 / 094670 (SynAffix). 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, hRS7 is as disclosed in U.S. Patents 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody conjugated by a linker and an anticancer agent. In some embodiments, the linker is as disclosed in U.S. Patent No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug portion of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholino-doxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, ruthecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanmycin, ansamycin, and epotilon. In some embodiments, the chemotherapeutic portion is SN-38. In some embodiments, the antibody and / or fusion protein provided herein is administered together with sacituzumab govitecan.

[0269] In some embodiments, the co-administered ADC comprises an antibody targeting carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1; CD66a; NCBI gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in International Publication No. 1996 / 011013). In some embodiments, the CEACAM1-ADC is as described in International Publication No. 2010 / 093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein is administered together with CEACAM1-ADC IMMU-130.

[0270] In some embodiments, the co-administered ADC comprises an antibody that targets MHC class II cell surface receptors encoded by human leukocyte antigen complexes (HLA-DRs). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in International Publication No. 2006 / 094192). In some embodiments, the HLA-DR-ADC is as described in International Publication No. 2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein is administered together with HLA-DR-ADC IMMU-140.

[0271] Cancer gene therapy and cell therapy In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include: insertion of normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; genetic approaches to directly kill cancer cells, for example, injection of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response against cancer cells, or to activate the patient's own immune system (T cells or natural killer cells) to kill or detect and kill cancer cells; and genetic approaches to modify cell activity to further alter the intrinsic immune responsiveness to cancer.

[0272] cell therapy In some embodiments, compounds of formulas (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe-1), (IIe-2), (IIf), (IIg), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more cell therapies. Exemplary cell therapies include, but are not limited to, the co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor-infiltrating lymphocytes (TILs), and / or dendritic cells (DCs). In some embodiments, cell therapy involves co-administration of T cell therapy, such as populations of α / βTCR T cells, γ / δTCR T cells, regulatory T (Treg) cells, and / or TRuC® T cells. In some embodiments, cell therapy involves co-administration of NK cell therapy, such as NK-92 cells. If necessary, cell therapy may involve co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0273] 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 includes a tumor antigen-binding domain. In T cell therapy, the T cell receptor (TCR) is engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0274] Regarding the structure of CAR, in some embodiments, CAR includes an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain includes a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain includes the signaling functional domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0275] In some embodiments, the co-stimulatory domain is a ligand that specifically binds to CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD 4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 9 12), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL 1. It contains one or more functional domains of proteins selected from the group consisting of 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.

[0276] In some embodiments, the transmembrane domain is the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, 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, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E It contains a transmembrane domain of a protein selected from the group consisting of 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.

[0277] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapy agent described herein (e.g., monospecific or multispecific antibodies or their antigen-binding fragments or antibody mimetic) binds to tumor-associated antigens (TAAs). In some embodiments, tumor-associated antigens are selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); type C lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); 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 (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit α-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor α (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testicin or PR SS21); Vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; Platelet-derived growth factor receptor β (PDGFR-β); Stage-specific fetal antigen-4 (SSEA-4); CD20; Delta-like 3 (DLL3); Folate receptor α; Receptor tyrosine protein kinase, ERBB2 (Her2 / neu); Mucin 1, cell surface binding (MUC1); Epidermal growth factor receptor (EGFR); Neuronal cell adhesion molecule (NCAM); Prostase; Prostatic acid phosphatase (PAP); Elongation factor 2 variant (ELF2M); Ephrin B2; Fibroblast-activating protein α (FAP);Insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, β type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of cleavage cluster region (BCR) and Abelson mouse leukemia virus oncogene homolog 1 (abl) (bcr-abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); prostate I Six transmembrane epithelial antigens (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 antigen 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3); panexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ Alternative Reading Frame Protein (TARP); Wilms Tumor Protein (WT1); Cancer / Testicular Antigen 1 (NY-ESO-1); Cancer / Testicular Antigen 2 (LAGE-la); Melanoma-Associated Antigen 1 (MAGE-A1); ETS Translocation Variant Gene 6 (ETV6-AML) located on chromosome 12p; Sperm Protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); Angiopoietin-Binding Cell Surface Receptor 2 (Tie2); Melanoma Cancer Testicular Antigen-1 (MADCT-1); Melanoma Cancer Testicular Antigen-2 (MADCT-2); Fos-Associated Antigen 1; Tumor Protein p53 (p53); p53 Variant; Prostein; Sulbibin; Telomerase;Prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma apoptosis inhibitor (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 virus 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 (a sibling of BORIS or an imprint site regulator), squamous cell carcinoma antigen 3 (SART3) recognized by T cells; 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-break point 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous protein 1 (RUI); renal ubiquitous protein 2 (RU2); regmine; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); enteric carboxylesterase; heat shock protein 70-2 variant (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of tumor-associated antigen presented to the MHC.

[0278] In some embodiments, the tumor antigens are 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-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1(DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-binding receptor, α-fetoprotein (AFP), angiogenic factor, exogenous allobinding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (C The following antigens are selected: EA), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate-binding protein, gp100, hepatitis B surface antigen, κ chain, κ light chain, kdr, λ chain, livin, melanoma-associated antigen, mesoserin, mouse double micro2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrotic antigen, fetal cancer antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenacin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0279] 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-testicular antigen. In some embodiments, cancer testicular antigens include 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 anchor 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, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI gene ID: 8852), ATPase family AAA domain-containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI gene ID: 29028), and kinetochore scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI gene ID: 84519). Gene ID: 57082), Centrosole Protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI gene ID: 55165), Cancer / Testicular Antigen 1A (CTAG1A; ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1; NCBI gene ID: 246100), Cancer / Testicular Antigen 1B (CTAG1B; CT6.1, CTAG, CTAG1, E SO1, LAGE-2, LAGE2B, NY-ESO-1 (NCBI gene ID: 1485), cancer / testicular 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), Cathenin α2 (CTNNA2;CAP-R, CAPR, CDCBM9, CT114, CTNR;NCBI gene ID:1496), Cancer / Testicular Antigen 83 (CT83;CXorf61, KK-LC-1, KKLC1;NCBI gene ID:203413), Cyclin A1 (CCNA1;CT146;NCBI gene ID:8900), Dead-box type helicase 43 (DDX43;CT13, HAGE;NCBI gene ID:55510) ), developmental pluripotency-related 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI gene ID: 151871), fetal and adult testicular expression 1 (FATE1; CT43, FATE; NCBI gene ID: 89885), FMR1 adjacency (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 (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 D2 (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), NDC80 kinetochore complex NUF2 component (NUF2; CDCA1, CT106, NUF2R; NCBI gene ID: 83540), Nuclear extranucleotide RNA transport factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI gene ID: 5600) 1) PAS domain-containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI gene ID: 139135), 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 preferential expression antigen (PRAME; CT130, MAPE, OIP-4, OIP4; NCBI Gene ID: 23532), sperm-associated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI gene ID: 9043), nuclear X-binding 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, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757) The group is selected from the following: synaptonema structural protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI gene ID: 50511), testicular expression 14 intercellular bridge formation factors (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). TCR-like antibodies that bind to the epitopes of cancer-testis antigens presented on T cell receptors (TCRs) and major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasms are summarized, for example, in Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and in the CT database website at cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to the NY-ESO-1 epitope presented on MHC are, for example, Stewart-Jones, et al.,Proc Natl Acad Sci USA.This is described in International Publications 2009 Apr 7;106(14):5784-8; International Publications 2005 / 113595, 2006 / 031221, 2010 / 106431, 2016 / 177339, 2016 / 210365, 2017 / 044661, 2017 / 076308, 2017 / 109496, 2018 / 132739, 2019 / 084538, 2019 / 162043, 2020 / 086158, and 2020 / 086647. Exemplary TCRs and TCR-like antibodies that bind to the epitopes of PRAME presented on MHC are described, for example, in International Publications 2011 / 062634, 2016 / 142783, 2016 / 191246, 2018 / 172533, 2018 / 234319, and 2019 / 109821. Exemplary TCRs and TCR-like antibodies that bind to the epitopes of MAGE variants presented on MHC are described, for example, in International Publications 2007 / 032255, 2012 / 054825, 2013 / 039889, 2013 / 041865, 2014 / 118236, and 2016 / 055785. These are described in International Publication Nos. 2017 / 174822, 2017 / 174823, 2017 / 174824, 2017 / 175006, 2018 / 097951, 2018 / 170338, 2018 / 225732, and 2019 / 204683. Exemplary TCRs and TCR-like antibodies that bind to the epitope of alpha-fetoprotein (AFP) presented on MHC are described, for example, in International Publication No. 2015 / 011450. Exemplary TCRs and TCR-like antibodies that bind to the epitope of SSX2 presented on MHC are described, for example, in International Publication No. 2020 / 063488. Exemplary TCRs and TCR-like antibodies that bind to the KK-LC-1(CT83) epitope presented on MHC are described, for example, in International Publication No. 2017189254.

[0280] Examples of cell therapies include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogen Recurcel (US Patent No. 9089520, International Publication No. 2016 / 100236), AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Imi Recrucel-T, Baltaluce-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 transducer huCART-mesocells, CART-22 cells, EGFRt / 19-28z / 4-1BBL Examples 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.

[0281] In some embodiments, one or more additional co-administered therapeutic agents may be classified into the following groups, for example, based on their mechanism of action: • Drugs that target adenosine deaminase, such as pentostatin or cladribine; • Drugs that target ATMs, such as AZD1390; MET-targeting drugs such as servotinib, capmatinib, tetoponitib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; Antroquinonol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mildametinib (PD-0325901), pimacertib, refametinib or International Publication No. 2011 / 008709, International Publication No. 2013 / 112741, International Publication No. 2006 / 124944, International Publication No. 2006 / 124692, International Publication No. 2014 / 064215, International Publication No. 2018 / 005435, 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 Drugs targeting mitogen-activated protein kinases, such as compounds disclosed in 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; Drugs that target thymidine kinases, such as agratimazine besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk); Drugs that target the interleukin pathway, such as pegylodecaquin (AM-0010) (PEGylated IL-10) and CA-4948 (IRAK4 inhibitor); Drugs that target cytochrome P450 family members, such as letrozole, anastrozole, aminoglutethimide, medystrol acetate (MEGACE®), exemestane, formestan, fadrozole, borozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); CD73-targeting drugs such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 drugs (e.g., oleculumab); • Drugs that target DKK3, such as MTG-201; • Drugs that target EEF1A2, such as platidisin; • Drugs that target EIF4A1, such as rohinitib; • Endoglin-targeting drugs such as TRC105 (inflotuximab); • Drugs that target exopolitin-1, such as ertanexor; • Drugs that target fatty acid amide hydrolases, such as compounds disclosed in International Publication No. 2017 / 160861; • Drugs that target heat shock protein 90-beta family member 1, such as anlotinib; • Drugs that target lactoferrin, such as ruxotemitide (LTX-315); Drugs that target lysyl oxidase, such as compounds disclosed in U.S. Patent Nos. 4,965,288, 4,997,854, 4,943,593, 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608, or U.S. Patent Publication No. 2004 / 0248871; Drugs that target MAGE family members such as KITE-718, MAGE-A10C796T, or MAGE-A10TCR; MDM2-targeting agents such as ALRN-6924, CMG-097, mirademethane monotosylate monohydrate (DS-3032b), or AMG-232; • Drugs that target MDM4, such as ALRN-6924; • Drugs targeting Melan-A, such as MART-1 F5 TCR-operated PBMCs; • Drugs that target mesothelin, such as CSG-MESO or TC-210; • METAP2-targeting drugs such as M8891 or APL-1202; • Drugs that target NLRP3, such as BMS-986299; Drugs that target oxoglutarate dehydrogenase, such as devimistat (CPI-613); • Drugs that target placental growth factors, such as aflibercept; Drugs targeting SLC10A3, such as compounds disclosed in International Publication No. 2015 / 148954, International Publication No. 2012 / 082647, or International Publication No. 2017 / 160861; • Drugs targeting transforming growth factor alpha (TGFα), such as compounds disclosed in International Publication No. 2019 / 103203; Drugs that target the tumor protein p53, such as kevetrin (a stimulating agent); • Drugs that target vascular endothelial growth factor A, such as aflibercept; • Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250; • VISTA-targeting drugs such as CA-170 or HMBD-002; • Drugs targeting WEE1, such as adavosertib (AZD-1775); • Small molecule inhibitors targeting ABL1, such as imatinib, levatinib, aciminib, and ponatinib (ICLUSIG®); • Small molecule antagonists that target adenosine receptors, such as CPI-444, AZD-4635, preradiant, etrumandent (AB928), or PBF-509; • Small molecule inhibitors that target arachidonic acid 5-lipoxygenase, such as sodium meclofenamate or diloton; • Small molecule inhibitors targeting ATR serine / threonine kinases, such as BAY-937, ceraracertib (AZD6738), AZD6783, VX-803, or VX-970 (belzocertib); • Small molecule inhibitors targeting AXL receptor tyrosine kinases, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); ·(S)-6-amino-9-(1-(buto-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posertinib (HM71224), ibrutinib (Imbruvica), M Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as -2951 (evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebralutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; • Small molecule inhibitors that target neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195); • Small molecule inhibitors targeting ROS proto-oncogene 1 receptor tyrosine kinases, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; • Small molecule inhibitors targeting SRC proto-oncogene nonreceptor tyrosine kinases, such as VAL-201, tilvanibrin (KX2-391), or irginatinib maleate (NS-018); • Small molecule inhibitors targeting B-cell lymphoma II, such as Navitoclax (ABT-263), Venetoclax (ABT-199, RG-7601), and AT-101 (Gossypol); Small molecule inhibitors targeting bromodomain and extracellular domain (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), mibeblesib, 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 metazolamide; • Small molecule inhibitors targeting catenin beta 1, such as CWP-291 or PRI-724; • Small molecule antagonists that target CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Bicribiroc); • Bilixafortide, a small molecule antagonist that targets CXC-motif chemokine receptors (e.g., CXCR4); • Small molecule inhibitors targeting cereblon, such as abbamide (CC-122), CC-92480, CC-90009, or iverdamide; • Small molecule inhibitors that target checkpoint kinase 1, such as SRA737; • Small molecule inhibitors that target complement components, such as Imprime PGG (Biothera Pharmaceuticals); • Small molecule inhibitors that target CXC motif chemokine ligands (such as CXCL12), including olaptesed pegol (NOX-A12); • Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, ceviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; • Small molecule inhibitors that target deadbox helicase 5, such as spinoxin (RX-5902); • Small molecule inhibitors targeting DGKα, such as those described in International Publication No. 2021 / 130638; • Small molecule inhibitors targeting Diablo IAP-binding mitochondrial protein, e.g., 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 that target MARCKS, such as BIO-11006; • Small molecule inhibitors targeting RIPK1, such as GSK-3145094; • Small molecule inhibitors targeting Rho-related coiled-coil protein kinases such as AT13148 or KD025; • Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecan pegol, or amrubicin; • Small molecule inhibitors that target dopamine receptor D2, such as ONC-201; • Small molecule inhibitors that target DOT1, such as histone lysine methyltransferase (EPZ-5676), etc. • Small molecule inhibitors targeting EZH2, such as tazemethostat, CPI-1205, or PF-06821497; • Small molecule inhibitors that target fatty acid synthases, such as TVB-2640 (Sagimet Biosciences); • Small molecule inhibitors that target fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144); • Small molecule inhibitors targeting focal adhesion kinases (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; • Small molecule inhibitors that target folate receptor 1, such as pralatrexate; • Small molecule inhibitors that target FOXM1, such as thiostrepton; • Small molecule inhibitors that target galectin-3, such as belapectin (GR-MD-02); • Small molecule antagonists that target glucocorticoid receptors, such as relacorilant (CORT-125134); Small molecule inhibitors targeting glutaminase, including but not limited to CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazole-2-yl)ethyl sulfide (BPTES); • Small molecule inhibitors that target GNRHR, such as elagolyx, relugolix, or degarelix; • Small molecule inhibitors targeting EPAS1, such as verzutifan (PT-2977 (Merck & Co.)); • Restricted small molecule inhibitors that target isocitrate dehydrogenase (NADP(+)), such as ivosidenib (AG-120), boracidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221). • Small molecule inhibitors that target lysine demethylase 1A, such as CC-90011; • Small molecule inhibitors that target MAPK-interacting serine / threonine kinases, such as tomibosertib (eFT-508); • Small molecule inhibitors that target Notch receptors, such as AL-101 (BMS-906024); • Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as borasertib or onvancertib; • Small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), lucaparib, 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 that target Polycomb protein EEDs such as MAK683; • Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974; • Small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as HP-5000, lofecoxib, ketrolactromethamine, bromfenac sodium, Otenaproxil (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, re-prescription celecoxib (DRGT-46), AAT-076, Meisoshri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, firocoxib, lofecoxib, lutecarpine, chilmacoxib, zaltoprofen, or imurecoxib; • Small molecule inhibitors that target 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 International Publication No. 2018 / 172984 or International Publication No. 2017 / 211303; • Small molecule antagonists that target retinoic acid receptors, for example, tamibarotene (SY-1425), • Small molecule inhibitors that target ribosomal protein S6 kinase B1, such as MSC2363318A; • Small molecule inhibitors that target S100 calcium-binding protein A9, such as tascinimod; • Small molecule inhibitors that target selectin E, such as uproleselan sodium (GMI-1271); • Small molecule inhibitors that target SF3B1, such as H3B-8800; • Small molecule inhibitors that target sirtuin-3, such as YC8-02; • Small molecule inhibitors targeting SMOs, such as soni-degib (Odomzo®, formerly LDE-225), bismodegib (GDC-0449), glassdegib (PF-04449913), itraconazole, or patidegib and taladegib; • Small molecule antagonists that target somatostatin receptors, such as OPS-201; • Small molecule inhibitors that target sphingosine kinase 2, such as opaganib (Yeliva®, ABC294640); • Small molecule inhibitors that target STAT3, such as napabucasin (BBI-608); • Tankyrase-targeting small molecule inhibitors such as G007-LK or stenoparib (2X-121(e-7499)); • Small molecule inhibitors targeting TFGBR1, such as garnicertib and PF-06952229; • Small molecule inhibitors that target thymidylate synthase, such as idetrexed (ONX-0801); • Small molecule inhibitors that target the oncoprotein p53, such as CMG-097; • Small molecule inhibitors that target balocin-containing proteins such as CB-5083; • Small molecule inhibitors targeting WT1, such as ombipepimut-S (DSP-7888); • Small molecule agonists that target adenosine receptors, such as namodenoson (CF102); • Small molecule agonists that target asparaginases such as chrysanthaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), graspargase pegol, or pegaspargase; • Small molecule agonists that target CCAAT enhancer-binding protein alpha, such as MTL-501; • Small molecule agonists that target the cytochrome P450 family, such as mitotane; • Small molecule agonists that target DExD / H-box helicase 58, such as RGT-100; • Small molecule agonists targeting GNRHR, such as leuprorelin acetate, leuprorelin acetate sustained-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate; • Small molecule agonists that target GRB2, such as plexijebersen (BP1001); • Small molecule agonists that target NFE2L2, such as omaveloxolone (RTA-408); • Small molecule agonists that target NOD2, such as mifamultide (liposome); • Small molecule agonists that target RAR-related orphan receptor gamma, such as cintirorgon (LYC-55716); • Small molecule agonists that target retinoic acid receptors (RARs), 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 diAMP; • Small molecule agonists that target thyroid hormone receptor beta, such as levothyroxine sodium; • Small molecule agonists that target tumor necrosis factors, such as tasonelmin; • Antisense agents targeting baculovirus IAP repeats, including EZN-3042 and others; • Antisense agents that target GRB2, such as plexidjebersen; • Antisense agents that target heat shock protein 27, such as apatorcene; • Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx); • Gene therapy targeting CC motif chemokine receptors such as SB-728-T; Gene therapy targeting interleukins 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 clodicimab; • Antibodies that target clatherin, such as AB-16B5; • Antibodies that target complement components, such as ravulizumab (ALXN-1210); Antibodies targeting CXC motif chemokine ligands such as BMS-986253 (HuMax-Inflam); • Antibodies targeting delta-like standard notch ligand 4 (DLL4), such as demcizumab and nabixixizumab (DLL4 / VEGF); • Antibodies targeting EPH receptor A3, such as fibatuzumab (KB-004); • Antibodies that target epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); • Antibodies targeting fibroblast growth factors such as GAL-F2 and B-701 (bofatamab); • Antibodies that target hepatocyte growth factors, such as MP-0250; Antibodies targeting interleukins, such as canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), siltuximab, or tocilizumab; • Antibodies targeting LRRC15, such as ABBV-085 or xatuzumab (ARGX-110); • Antibodies targeting mesoserine, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; • Antibodies targeting myostatin, such as landogrozumab; • Antibodies that target the Notch receptor, such as tarectumab; Antibodies targeting TGFB1 (TGFβ1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089, or compounds disclosed in International Publication No. 2019 / 103203; • Vaccines targeting fms-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201 restriction epitope peptide vaccines. • Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); • IO-120 + IO-103 (PD-L1 / PD-L2 vaccine) or PD-L1 targeting vaccines such as IO-103; • Vaccines that target oncoprotein p53, such as MVA-p53; • Vaccines targeting WT1, such as WT-1 analog peptide vaccines (WT1-CTL); • Cell therapies targeting baculovirus IAP repeats, such as dendritic cell vaccines loaded with tumor lysates / MUC1 / Survivin PepTivator; • Cell therapies targeting carbonic anhydrase, such as DC-Ad-GMCAIX; • Cell therapy targeting CC motif chemokine receptors such as CCR5-SBC-728-HSPC; • Cell therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN; • Cell therapies targeting GSTP1, such as CPG3-CAR (GLYCAR); • Cell therapy targeting HLA-A such as FH-MCVA2TCR or NeoTCR-P1; • Cell therapies targeting interleukins such as CST-101; • Cell therapies targeting KRAS, such as anti-KRAS G12D mTCR PBL; • Cell therapies targeting METs, such as anti-cMet RNA CAR T; • Cell therapies targeting MUC16, such as JCAR-020; • PD-1-targeted cell therapies such as PD-1 knockout T-cell therapy (esophageal cancer / NSCLC); • Cell therapies targeting PRAME, such as BPX-701; • Cell therapy targeting transformed protein E7 such as KITE-439; Cell therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016.

[0282] Exemplary combination therapy Lymphoma or leukemia combination therapy Some chemotherapy agents are suitable for treating lymphoma or leukemia. These include aldezleukin, arbocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, β-aretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), briostatin 1, brusulfan, campas-1H, carboplatin, and carfilzomib (Kyprol). is(registered trademark)), 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-diffitox, dexamethasone, docetaxel, dorastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone) (Doxanthrone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), Enzastaurin, epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopyridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (superfractionated cyclophosphamide, vincristi) (doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon α-2b, ixabepyrone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafingadolinium, mycophenolate mofetil,Nelarabine, ovatocrax (GX15-070), oblimersen, octreotide acetate, ω-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab Examples include rituximab and FCM, R-ICE (rituximab and ICE), R-MCP (rituximab and MCP), R-roscovitine (cericiclib, CYC202), salglamostim, sildenafil citrate, simvastatin, sirolimus, styrylsulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, allogeneic lymphocytes for therapeutic use, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberanililohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

[0283] One improved approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies, but not limited to, include iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

[0284] The above treatments may be supplemented with or combined with stem cell transplantation or therapy. Treatment options include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow resection with stem cell support, in vitro processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myelectomy allogeneic hematopoietic stem cell transplantation.

[0285] Combination therapy for non-Hodgkin lymphoma Treatment for non-Hodgkin lymphoma (NHL), particularly B-cell origin lymphoma, 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, and prednisolone), all of which may include rituximab®), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

[0286] Examples of non-conjugate monoclonal antibodies for the treatment of NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-associated apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0287] Examples of experimental antibody drugs used to treat NHL / B-cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0288] 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.

[0289] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[0290] Combination therapy for mantle cell lymphoma Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapy regimens, such as CHOP, hyperCVAD, and FCM. These regimens may be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies may be combined with stem cell transplantation or ICE to treat MCL.

[0291] An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines such as GTOP-99, which are based on the genetic structure of the individual patient's tumor.

[0292] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential therapy with CHOP.

[0293] Other approaches to treating MCL include autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administration of anti-angiogenic agents such as thalidomide, particularly in combination with rituximab.

[0294] Another treatment approach involves administering drugs that, in combination with other chemotherapeutic agents, induce the degradation of the Bcl-2 protein, thereby increasing the sensitivity of cancer cells to chemotherapy, such as oblimersen.

[0295] Further therapeutic approaches include the administration of mTOR inhibitors, which can inhibit cell proliferation and even induce cell death. Non-limiting examples include sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (vimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0296] Other recent therapies for MCL have been disclosed. Examples include flavopyridol, palbociclib (PD0332991), R-roscovitine (celiciclib, CYC202), styrylsulfone, ovatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).

[0297] Adjunctive therapy for Waldenström-type macroglobulinemia Waldenstrom's type macroglobulinemiaTherapeutic agents used to treat macroglobulinemia (WM) include aldezleukin, alemtuzumab, arbocidib, 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, β-aretin, bortezomib (VELCADE®), briostatin 1, busulfan, campas-1H, carboplatin, and carmustin. Caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin difutitox, dexamethasone, docetaxel, dorastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin α, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 toxin Momab, irinotecan hydrochloride, ixabepirone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (e.g., tisagenlecroicel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafingadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pentos Tatin, Perifosin, Prednisone, Recombinant FLT3 Ligand, Recombinant Human Thrombopoietin, Recombinant Interferon α, Recombinant Interleukin-11, Recombinant Interleukin-12, Rituximab, Salgramostim, Sildenafil Citrate (VIAGRA®), Simvastatin, Sirolimus, Tacrolimus, Tanespimycin, Thalidomide, Allogeneic Lymphocytes for Therapy, Thiotepa, Tipifarnib, Tositumomab, Urocuplumab, Vertuzumab, Vincristine Sulfate, Vinorelbine Tartrate, Vorinostat, WT1Examples include 126-134 peptide vaccines, WT-1 analog peptide vaccines, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0298] Examples of treatments used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole-body radiation therapy, stem cell infusion, bone marrow resection with stem cell support, in vitro processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma-ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myelectomyable allogeneic hematopoietic stem cell transplantation.

[0299] 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 drugs listed for WM, as well as any combination of them, 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 (Treanda®)), gemcitabine, oxyplatin, oxaliplatin, tafacitamab, polatuzumab, cyclophosphamide, or combinations thereof.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 + lenalom...

Claims

1. Compound of formula (I), 【Chemistry 134】 or a pharmaceutically acceptable salt thereof R １ However, C ３～１５ A cycloalkyl or 4-14 membered heterocyclil having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl or heterocyclil may be unsubstituted, the same, or different, and 1-4 Z １ Replaced by, R ２ is hydrogen or C １～３ It is alkyl, X １ and X ２ However, each is independently hydrogen, fluoro, or chloro. Y is hydrogen or deuterium, Each Z １ is independently cyano, hydroxy, oxo, imino, halogen, C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl having 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, C ６～１０ aryl, 5- to 10-membered heteroaryl having 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, -O-Z １Ａ , -C(O)-Z １Ａ , -C(O)O-Z １Ａ 、-C(O)-NH ２ 、-C(O)-NH(Z １Ａ )、-C(O)-N(Z １Ａ ) ２ 、-NH ２ 、-NH(Z １Ａ )、 -N(Z １Ａ ) ２ 、-NHC(O)-Z １Ａ 、-N(Z １Ａ )C(O)-Z １Ａ 、-NHC(O)O-Z １Ａ 、-N(Z １Ａ )C(O)O-Z １Ａ 、 -NHC(O)N(Z) １Ａ ) ２ 、-N(Z １Ａ )C(O)NH(Z １Ａ )、-NHC(O)NH(Z １Ａ ) -N(Z １Ａ )C(O)N(Z １Ａ ) ２ 、-NHS(O) ２ (Z １Ａ )、-N(Z １Ａ )S(O) ２ (Z １Ａ )、-NHS(O) ２ N(Z １Ａ ) ２ 、 -NHS(O) ２ NH(Z １Ａ )、-N(Z １Ａ )S(O) ２ NH(Z １Ａ )、-N(Z １Ａ )S(O) ２ NH ２ 、 -N(Z １Ａ )S(O) ２ N(Z １Ａ ) ２ 、-NHS(O) ２ O(Z １Ａ )、-N(Z １Ａ )S(O) ２ O(Z １Ａ )、-OC(O)-Z １Ａ 、 -OC(O)O-Z １Ａ 、-OC(O)-NH ２ 、-OC(O)-NH(Z １Ａ )、-OC(O)-N(Z １Ａ ) ２ 、-S-Z １Ａ 、 -S(O)-Z １Ａ , -S(O)(NH)-Z １Ａ , -S(O) ２ Z １Ａ , -S(O) ２ N(Z １Ａ ) ２ , or -S(O)(Z １Ａ ) ２ And each Z １Ａ However, they may be the same or different, and each Z １ The imino, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl in the above may be unsubstituted, the same, or different, and there are 1 to 4 Z １Ａ Replaced by, Each Z １Ａ These independently comprise hydroxyl, halogen, oxo, cyano, and C. １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ A 4-10 membered heterocyclyl having one or two heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C ６～１０ 6-10 membered heteroaryls having 1-2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur, -O-Z １Ｂ , -C(O)-Z １Ｂ , -C(O)O-Z １Ｂ 、-C(O)-NH ２ 、-C(O)-NH(Z １Ｂ )、-C(O)-N(Z １Ｂ ) ２ 、-NH ２ 、-NH(Z １Ｂ )、 -N(Z １Ｂ ) ２ 、-NHC(O)-Z １Ｂ 、-N(Z １Ｂ )C(O)-Z １Ｂ 、-NHC(O)O-Z １Ｂ 、-N(Z １Ｂ )C(O)O-Z １Ｂ 、 -N(Z １Ｂ )C(O)N(Z １Ｂ ) ２ 、-NHC(O)N(Z １Ｂ ) ２ 、-N(Z １Ｂ )C(O)NH(Z １Ｂ )、-NHS(O) ２ (Z １Ｂ )、 -N(Z １Ｂ )S(O) ２ (Z １Ｂ )、-NHS(O) ２ N(Z １Ｂ ) ２ 、-N(Z １Ｂ )S(O) ２ NH(Z １Ｂ )、-NHS(O) ２ NH(Z １Ｂ )、 -N(Z １Ｂ )S(O) ２ N(Z １Ｂ ) ２ 、-N(Z １Ａ )S(O) ２ NH ２ 、-N(Z １Ｂ )S(O) ２ O(Z １Ｂ )、 -NHS(O) ２ O(Z １Ｂ )、-OC(O)Z １Ｂ 、-OC(O)O-Z １Ｂ 、-OC(O)-N(Z １Ｂ ) ２ 、 -OC(O)-NH(Z １Ｂ )、-OC(O)-NH ２ 、-S-Z １Ｂ 、-S(O)Z １Ｂ 、-S(O)(NH)Z １Ｂ 、 -S(O) ２ Z １Ｂ , -S(O) ２ N(Z １Ｂ ) ２ , -S(O) ２ NH(Z １Ｂ ), or -S(O)(NZ １Ｂ ) Z １Ｂ And each Z １Ａ However, they may be the same or different, and each Z １Ａ The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups of the above may be unsubstituted, the same, or different from 1 to 4 Z groups. １Ｂ Replaced by, Each Z １Ｂ These independently comprise hydroxyl, halogen, oxo, cyano, and C. １～９ Alkyl, C １～９ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１０ A 4-10 membered heterocyclyl having one or two heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C ６～１０ 6-10 membered heteroaryls having 1-2 heteroatoms selected from aryl, nitrogen, oxygen, and sulfur, -CO ２－ R ＸＸＡ , -NH ２ , -SH, -O-R ＸＸＡ , -NH-R ＸＸＡ , -N(R ＸＸＡ ) (Caution ＸＸＢ ), -C(O)-R ＸＸＡ , -C(O)O-R ＸＸＡ , -C(O)N(R ＸＸＡ ) (Caution ＸＸＢ ), -N(R ＸＸＡ )C(O)(R ＸＸＢ ), -N(R ＸＸＡ )C(O)O(R ＸＸＢ )、-N(R ＸＸＡ )C(O)NH(R ＸＸＢ )、-N(R ＸＸＡ )S(O)(R ＸＸＢ )、 -S-R ＸＸＡ ,-S(O)N(R ＸＸＡ ) ２ ,-S(O)(R ＸＸＡ ), -S (O) ２ (R) ＸＸＡ ),-S (O)N (R ＸＸＡ )(R ＸＸＢ ), or -S(O) ２ N(R) ＸＸＡ ) (Caution ＸＸＢ ) and each R ＸＸＡ and R ＸＸＢ Hydrogen, C １～９ Alkyl, C １～９ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinil, C ３～１５ A 4-10 membered heterocyclyl having one or two heteroatoms selected from cycloalkyl, nitrogen, oxygen, and sulfur, C ６～１０ It is a 6-10 membered heteroaryl having aryl or 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. A compound, or a pharmaceutically acceptable salt thereof.

2. (i) The compound of formula (I) is the compound of formula (Ia) 【Chemistry 135】 It is; (ii) X １ and X ２ However, each is hydrogen; and / or (iii) R １ However, C ３～１２ A cycloalkyl or 4-12 membered heterocyclil having 1-2 heteroatoms selected from nitrogen and oxygen, wherein each cycloalkyl or heterocyclil may be unsubstituted, the same, or different, and 1-4 Z １ Replaced by, R ２ However, hydrogen or C １～３ It is alkyl, X １ and X ２ However, each is hydrogen, Y is hydrogen, Each Z １ These independently produce cyano, hydroxy, oxo, halogen, and C １～６ Alkyl, C ３～６ Cycloalkyl, -O-Z １Ａ ,-NH(Z １Ａ ), -C(O)-Z １Ａ , -C(O)-NH ２ , -C(O)-NH-(Z １Ａ ), -C(O)-O-Z １Ａ , C ６～１０ Aryl, or A 5-10 membered heteroaryl having 1-2 heteroatoms selected from nitrogen and oxygen, and 1-4 Z atoms, where each alkyl, aryl, or heteroaryl is unsubstituted, the same, or different. １Ａ Replaced by, Each Z １Ａ These independently produce cyano, hydroxy, halogen, and C １～６ Alkyl, C ６～１０ An aryl or a 6-10 membered heteroaryl having 1-2 nitrogen atoms, each alkyl, aryl, or heteroaryl may be unsubstituted, the same, or different, and each Z is one-four Z atoms. １Ｂ Replaced by, Z １Ｂ However, halogen or unsubstituted C ６～１０ It is Ariel. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) is (i) Compounds of formula (IIa) 【Transformation 136】 And, R in equation (IIa) １ However, this is the same as the case of non-substitution in the definition of claim 1; or (ii) Compounds of formula (IIb) 【Chemistry 139】 And, R1 in formula (IIb) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) of claim 1, and Z in formula (IIb) １ However, this is the same as the case of non-substitution in the definition of claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) or formula (IIb) is (i) Compounds of formula (IIIa) 【Chemistry 142】 And, R1 in formula (IIIa) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) of claim 1, and Z in formula (IIIa) １Ａ However, this is the same as the case of non-substitution in the definition of claim 1; or (ii) Compounds of formula (IIIb) 【Chemistry 145】 And, R1 in formula (IIIb) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) of claim 1, and Z in formula (IIIb) １Ａ However, this is the same as the case of non-substitution in the definition of claim 1; or Compound of formula (iii) (IIIc) 【Chemistry 148】 And, R1 in formula (IIIc) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) of claim 1, and Z in formula (IIIc) １Ａ However, this is the same as the case of non-substitution in the definition of claim 1. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) is (i) Compounds of formula (IIc) [Chemical 150] And, R1 in formula (IIc) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) in claim 1, Z1 in formula (IIc) is a divalent group obtained by removing one hydrogen atom from Z1 in formula (I) in claim 1, and Z in formula (IIc) １Ａ However, this is the same as the case of non-substitution in the definition of claim 1; (ii) Compounds of formula (IId) 【Chemistry 154】 And, R1 in formula (IId) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) in claim 1, Z1 in formula (IId) is a divalent group obtained by removing one hydrogen atom from Z1 in formula (I) in claim 1, Z1A in formula (IId) is a divalent group obtained by removing one hydrogen atom from Z1A in formula (I) in claim 1, and Z in formula (IId) １Ｂ However, this is the same as the case of non-substitution in the definition of claim 1; Compounds of formula (iii) (IIId) 【Chemistry 157】 And, R1 in formula (IIId) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) in claim 1, Z1A in formula (IIId) is a divalent group obtained by removing one hydrogen atom from Z1A in formula (I) in claim 1, and Z in formula (IIId) １Ｂ However, this is the same as the case of non-substitution in the definition of claim 1; (iv) Compounds of formula (IIIe) 【Chemistry 159】 And, R1 in formula (IIIe) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) of claim 1, Z1A in formula (IIIe) is a divalent group obtained by removing one hydrogen atom from Z1A in formula (I) of claim 1, and Z in formula (IIIe) １Ｂ However, this is the same as the case of non-substitution in the definition of claim 1; (v) Compounds of formula (IIe-1) 【Chemistry 161】 And, R1 in formula (IIe-1) is a trivalent group obtained by removing two hydrogen atoms from R1 in formula (I) of claim 1, and Z in formula (IIe-1) １ However, this is the same as the case of non-substitution in the definition of claim 1; (vi) Compounds of formula (IIe-2) 【Chemistry 164】 And, R1 in formula (IIe-2) is a tetravalent group obtained by removing three hydrogen atoms from R1 in formula (I) of claim 1, and Z in formula (IIe-2) １ However, this is the same as the case of non-substitution in the definition of claim 1; (vii) Compounds of formula (IIf) 【Chemistry 165】 And, R1 in formula (IIf) is a trivalent group obtained by removing two hydrogen atoms from R1 in formula (I) in claim 1, Z1* in formula (IIf) is a divalent group obtained by removing one hydrogen atom from Z1 in formula (I) in claim 1, Z1 in formula (IIf) is the same as the unsubstituted case in the definition of claim 1, and Z in formula (IIf) １Ａ However, this is the same as the case of non-substitution in the definition of claim 1; or Compound of formula (IIg) (viiii) 【Chemical 168】 And, R1 in formula (IIg) is a divalent group obtained by removing one hydrogen atom from R1 in formula (I) in claim 1, Z1 in formula (IIg) is a tetravalent group obtained by removing three hydrogen atoms from Z1 in formula (I) in claim 1, and Z in (IIg) １Ａ However, this is the same as the case of non-substitution in the definition of claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. (v) R １ However, non-substituted C ４～６ It is cycloalkyl; (vi)R １ However, one or two Z may be unsubstituted or may be the same or different. １ C replaced by ４～６ It is a cycloalkyl, Each Z １ These independently produce cyano, hydroxy, halogen, and C １～６ Alkyl, -O-Z １Ａ ,-NH(Z １Ａ ), -C(O)-NH ２ , or C ６～１０ 1 to 3 Z atoms, each alkyl or aryl atom may be unsubstituted, the same, or different. １Ａ Replaced by, Each Z １Ａ These independently produce cyano, hydroxy, halogen, and C １～６ Alkyl, or C ６～１０ It is an aryl group, and each alkyl or aryl group is unsubstituted; (vii)R １ However, each of the following may be non-substituted or may be the same or different Z. １ A cyclobutyl, cyclopentyl, or cyclohexyl substituted with, Each Z １ These independently produce cyano, hydroxy, fluoro, and C １～４ Alkyl, -O-Z １Ａ ,-NH(Z １Ａ ), -C(O)-NH ２ , or phenyl, each alkyl group may be unsubstituted or the same or different, 1 to 3 Z １Ａ Replaced by, Each Z １Ａ These independently produce cyano, hydroxy, halogen, and C １～３ Alkyl or phenyl, where each alkyl or phenyl is unsubstituted; (viiii)R １ However, the basis of the following equation: 【Chemistry 172】 【Chemistry 173】 【Chemistry 174】 It is; (ix)R １ However, the basis of the following equation: 【Chemistry 175】 【Chemistry 176】 It is; (x)R １ However, the double-ring type C ５～１１ It is a cycloalkyl ring; (xi)R １ However, non-substitutive biring C ５～１１ It is a cycloalkyl ring; (xi)R １ However, the double-ring bridge type C ５～１１ It is a cycloalkyl ring; (xiii)R １ However, these are bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl; (xiv)R １ However, the basis of the following equation: 【Chemistry 177】 It is; (xv)R １ However, the basis of the following equation: 【Chemistry 178】 It is; (xvi)R １ However, spironic ring C ５～１１ It is cycloalkyl; (xvii)R １ However, these are spiro[2.5]octyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, or spiro[5.5]undenyl; (xviiii)R １ However, the basis of the following equation: 【Chemistry 179】 That is (xix)R １ However, the basis of the following equation: 【Chemistry 180】 It is; (xx)R １ However, the heterocyclil is a 5-12 membered heterocyclil, bicyclic heterocyclil, or spiro-bicyclic heterocyclil having one or two heteroatoms selected from nitrogen and oxygen, wherein the heterocyclil is unsubstituted; (xxi)R １ However, one or two Z may be unsubstituted or may be the same or different. １ A 5-12 membered heterocyclil, bicyclic heterocyclil, or spiro-bicyclic heterocyclil, which is substituted with and has one or two heteroatoms selected from nitrogen and oxygen, Each Z １ These are independently oxo, halogen, and C １～６ Alkyl, -NH(Z １Ａ ), -C(O)-Z １Ａ , -C(O)-NH-(Z １Ａ ), -C(O)-O-Z １Ａ , C ６～１０ An aryl or a 6-10 membered heteroaryl having 1-2 nitrogen atoms, wherein each alkyl, aryl, or heteroaryl is unsubstituted or has one Z １Ａ Replaced by, Z １Ａ However, halogen, C １～６ Alkyl, or C ６～１０ It is an aryl group, and each alkyl or aryl is unsubstituted or has one Z. １Ｂ Replaced by, Z １Ｂ However, halogen or unsubstituted C ６～１０ It is an allele; (xxii)R １ However, one or two Z may be unsubstituted or may be the same or different. １ Pyrrolidyl, piperidyl, or tetrahydropyranil substituted with Each Z １ These are independently oxo, fluoro, and C １～３ Alkyl, -NH(Z １Ａ ), -C(O)-Z １Ａ , -C(O)-NH-(Z １Ａ ), -C(O)-O-Z １Ａ The alkyl group is phenyl or pyridyl, and each alkyl group, phenyl, or pyridyl is unsubstituted or one Z group is present. １Ａ Replaced by, Z １Ａ However, C １～３ The alkyl or phenyl is either unsubstituted or has one Z. １Ｂ Replaced by, Z １Ｂ However, it is chloro or unsubstituted phenyl; (xxiii)R １ However, the basis of the following equation: 【Chemistry 181】 【Chemistry 182】 It is; (xxiv)R １ However, the basis of the following equation: 【Chemistry 183】 It is; (xxv)R １ However, it is azabicyclo[2.2.1]heptanyl; (xxvi)R １ However, the basis of the following equation: 【Chemistry 184】 It is; (xxvii)R １ However, it is oxaspiro[3.5]nonanyl, oxaspiro[4.5]decanyl, or oxaspiro[5.5]undecanyl; or (xxviiii)R １ However, the basis of the following equation: 【Chemistry 185】 That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. (i) Each Z １ These independently produce cyano, hydroxy, oxo, halogen, and C １～６ Alkyl, -O-Z １Ａ , -C(O)-Z １Ａ , -C(O)-NH ２ , -C(O)-NH(Z １Ａ ), -C(O)-O-Z １Ａ , a 6-10 membered aryl, or a 5-10 membered heteroaryl having 1-2 heteroatoms selected from nitrogen and oxygen; (ii) Each Z １Ａ These independently produce hydroxyl, halogen, and C １～６ Alkyl or 6-10 membered aryl, where each alkyl is unsubstituted or Z １Ｂ Replaced with Z １Ｂ However, it is a non-substitution; (iii) Z １Ｂ However, they are unsubstituted 6- to 10-membered aryl compounds; (iv) Z １Ｂ However, it is a halogen; (v) R ２ However, it is hydrogen; (vi)R ２ However, C １～３ It is alkyl; or (vii)R ２ However, it is methyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. The aforementioned compound, (i) The compound shown below: 【Chemistry 190】 【Chemistry 191】 It is; (ii) The compound shown below: 【Chemistry 192】 It is; (iii) Compounds of the following form: 【Chemistry 193】 【Chemistry 194】 It is; (iv) The compound shown below: 【Chemistry 195】 It is; (v) The compound shown below: 【Chemistry 196】 It is; (vi) Compounds of the following form: 【Chemistry 197】 It is; (vii) Compounds of the following form: 【Chemistry 198】 It is; (viiii) Compounds of the following form: 【Chemistry 199】 It is; (ix) Compounds of the following form: 【Chemistry 200】 It is; (x) Compounds shown below: 【Chemical Engineering 201】 【Chemical Engineering 202】 It is; (xi) Compounds of the following form: 【Chemical 203】 It is; (xi) Compounds of the following form: 【Chemical 204】 It is; (xiiii) Compounds of the following formula: 【Chemical 205】 It is; (xiv) Compounds shown in the following formula: 【Chemical 206】 It is; (xv) Compounds of the following form: 【Chemical 207】 It is; (xvi) Compounds of the following form: 【Chemical 208】 It is; (xvii) Compounds of the following form: 【Chemical Engineering 209】 It is; (xviiii) Compounds of the following form: 【Chemical 210】 It is; (xix) Compounds of the following form: 【Chemistry 211】 It is; (xx) Compounds of the following formula: 【Chemical Engineering 212】 It is; (xxi) Compounds of the following formula: 【Chemistry 213】 is; or, (xxii) Compounds of the following formula: 【Chemical 214】 That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

10. The pharmaceutical composition according to claim 9, further comprising an additional therapeutic agent.

11. A composition for use in a method for treating an IKZF2 protein-related disease or condition, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the composition to a patient in need of treatment, wherein the IKZF2 protein-related disease or condition is cancer.

12. The aforementioned cancer, (i) a hematological cancer selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), anaplastic leukemia, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), primary macroglobulinemia (WM), and multiple myeloma (MM); or (ii) A solid tumor selected from lung cancer, colorectal cancer, stomach cancer, kidney cancer, ovarian cancer, testicular cancer, uterine cancer, bladder cancer, breast cancer, prostate cancer, cervical cancer, pancreatic cancer, and head and neck cancer. The composition according to claim 11.

13. The composition according to claim 11, characterized in that the composition is administered in combination with an additional therapeutic agent or mode of treatment.

14. (i) The additional therapeutic agent or additional therapeutic mode comprises one, two, three, or four additional therapeutic agents and / or therapeutic modes; or (ii) The additional therapeutic agent or mode of treatment is an immune checkpoint modulator, an antibody-drug conjugate (ADC), an anti-apoptotic agent, a targeted anticancer drug, a chemotherapeutic agent, surgery, radiotherapy, or a combination thereof. The pharmaceutical composition according to claim 10 or the composition according to claim 13.

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