Prmt5 inhibitors and uses thereof

Abstract

The present disclosure relates generally to compounds that inhibit PRMT5. The present disclosure further relates to the use of these compounds for the manufacture of a medicament for the treatment of a disease and / or disorder by inhibiting PRMT5. The present disclosure further relates to the use of these compounds for the treatment of a disease or disorder associated with loss of chromosome 9p21 or MTAP inactivation. The present disclosure further relates to the use of these compounds for the treatment of cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 595,941, filed November 3, 2023, and U.S. Provisional Application No. 63 / 665,858, filed June 28, 2024, the full text of which is incorporated herein by reference for all purposes. Technical Field

[0003] This disclosure relates to compounds that inhibit PRMT5. This disclosure further relates to the use of these compounds in response to PRMT5 inhibition to treat and / or prevent diseases and / or conditions. Background Technology

[0004] Protein arginine methyltransferases (PRMTs) catalyze the methylation of arginine residues on proteins involved in chromatin organization, gene expression, RNA splicing, protein translation, and signal transduction. PRMTs in various sub-states are located in a variety of subcellular compartments, including the nucleus, nucleolus, and cytosol, making many biological processes essential for mammalian cell function and survival.

[0005] Of the nine members of the PRMT family, PRMT5 is responsible for generating most of the symmetrical dimethylarginine residues on protein substrates. PRMT5 methylation is distributed, meaning that PRMT5 generates and releases monomethylarginine residues prior to the second methylation event. PRMT5 functions as a homotetramer complex with the MEP50 / WDR77 protein. MEP50 / WDR77 is essential for PRMT5 enzyme activity, substrate recognition, and interactions with many binding partners (S. Antonysamy et al., PNAS 109, 2012).

[0006] PRMT5 expression is frequently upregulated in leukemia, lymphoma, and solid tumors, and its expression may be negatively correlated with patient survival (Greenblatt et al., Exp. Hematol. 2016; Chen, H. et al., Oncogene 2016; Lattouf et al., Oncotarget, 2019). In normal tissues, PRMT5 is essential for hematopoiesis and enhances hematopoietic stem cell pluripotency and progenitor cell proliferation, suggesting that its inhibition may have a myelosuppressive effect (Liu et al., J. Clin. Invest., 2015).

[0007] Over the past few years, several PRMT5 inhibitors have entered clinical trials to treat tumors that are addicted to PRMT5 activity and / or particularly sensitive to PRMT5 inhibition. Narrow therapeutic windows and myelosuppression have been consistently observed in patients enrolled in these trials, suggesting that PRMT5 inhibition in normal tissues is undesirable. Inhibition of PRMT5 activity in tumors, although it does not harm normal cells, is presumably intended to mitigate the adverse effects of these first-generation PRMT5 inhibitors.

[0008] Human cancers frequently acquire homozygous deletions of the chromosomal locus 9p21, which carries the tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A). The MTAP (methylthioadenosine phosphorylase) gene, located near CDKN2A, is deleted in 90% of tumors with CDKN2A loss. It is estimated that 10-15% of all cancers carry homozygous deletions of the MTAP gene. Pancreatic cancer, bladder cancer, NSCLC, head and neck cancer, esophageal cancer, and glioblastoma are cancers with a significant proportion of patients exhibiting MTAP loss.

[0009] Loss / inactivation / absence of MTAP leads to the accumulation of its substrate, methylthioadenosine (MTA), which is structurally similar to SAM (S-adenosine-L-methionine), utilized by PRMT5 as a methyl-donating cofactor for catalyzing arginine dimethylation. In MTAP-deficient cancer cells, accumulated MTA competes with SAM for binding to the catalytic site of PRMT5 and partially inhibits its enzymatic activity. Tumor cells growing under the stress of reduced PRMT5 activity become particularly susceptible to further loss of PRMT5, such as through knockdown with shRNA or siRNA.

[0010] The accumulation of the PRMT5-MTA complex in MTAP-deficient cancers can be therapeutically utilized. Designing MTA-co-inhibiting small molecule inhibitors of PRMT5 is attractive, as these would selectively induce inhibition of PRMT5 in cancer cells with elevated MTA levels and MTA-bound PRMT5 accumulation.

[0011] There is still a need for PRMT5 inhibitors with the desired selectivity, potency, metabolic stability, or reduced harmful effects. Summary of the Invention

[0012] This disclosure provides compounds that can be used as PRMT5 inhibitors. This disclosure further relates to the use of the compounds for treating and / or preventing diseases and / or conditions by inhibiting PRMT5 through said compounds. This disclosure further relates to the use of the compounds for treating and / or preventing diseases and / or conditions by inhibiting PRMT5 in tumors associated with MTAP insensitivity or chromosome 9p21 deletion through said compounds.

[0013] In one embodiment, compounds of formula (I) are provided herein:

[0014] (I)

[0015] Or its pharmaceutically acceptable salt, wherein:

[0016] It can be a single bond or a double bond;

[0017] Ring A is C 5-7 Cycloalkyl, phenyl, 5- to 7-membered heterocyclic, or 5- or 6-membered heteroaryl; the cycloalkyl, phenyl, heterocyclic, or heteroaryl group of ring A is optionally surrounded by one to four R groups. 6 Replace, R 6 They can be the same or different;

[0018] Each R 6 Independently, it can be a halogenated group, -OH, -OCH3, oxo group, -CN, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0019] X is N or CR 7 ;

[0020] R 7 H, halogroup, CN, halomethyl, -CH3, -C2H5, -OCH3, ethynyl or cyclopropyl; R 7 Cyclopropyl is optionally surrounded by 1 to 3 Z-terminal groups. 7 Replace, Z 7 Can be the same or different; each Z 7 Independently CN, F, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0021] R 1 and R 2 Together with the N attached to them, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups; wherein R 1 and R 2 The heterocyclic groups formed together with the N attached to them are optionally surrounded by one to four Z. 1 Replace, Z 1 They can be the same or different, where R is the only one. 1 and R 2 The resulting heterocyclic group has 0 to 3 additional heteroatoms, each of which is independently N, O or S;

[0022] Or R 1 and R 2 Together with the N to which they are attached, they do not form heterocyclic groups, and R 1 C 10-14 Tricyclic aryl, and R2 C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; wherein R 1 The aryl group is optionally divided by 1 to 4 Z groups. 2 Replace, Z 2 They can be the same or different;

[0023] Each Z 1 or Z 2 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -SF5, -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R)12b ) or -S(O)(NR 12a )R 12b ; where each Z 1 or Z 2 The alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally bounded by 1 to 4 Z-terminal groups. 1a Replace, Z 1a They can be the same or different;

[0024] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a-S(O)2N(R) 12a (R) 12b ) or -S(O)(NR 12a )R 12b Z 1a The alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally bounded by 1 to 4 Z-terminal groups. 1b Replace, Z 1b They can be the same or different;

[0025] Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2; wherein Z 1b The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally bounded by one to three Cs. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 Alkyl), or -S(O)2N(C 1-9 Alkyl)2-substituted; and

[0026] Each R 12a R 12b or R 12c H and C independently 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl; wherein R12a R 12b or R 12c Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally bounded by 1 to 4 Z-groups. 1b Replace, Z 1b They can be the same or different;

[0027] Unless otherwise specified, each heteroaryl group in the compounds of formula (I) is a 5- to 14-membered heteroaryl group;

[0028] Unless otherwise specified, each heterocyclic group in the compounds of formula (I) is 3 to 20 heterocyclic groups;

[0029] Unless otherwise specified, each heteroaryl or heterocyclic group of the compound of formula (I) has one to four heteroatoms that are independently N, O or S.

[0030] In some embodiments, pharmaceutical compositions are provided herein comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0031] In some embodiments, the pharmaceutical compositions provided herein further comprise 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 compositions further comprise a therapeutically effective amount of 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.

[0032] In some embodiments, this disclosure provides methods for inhibiting PRMT5 in a subject in need, methods comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie)) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.

[0033] In some embodiments, this disclosure provides methods for treating patients with conditions associated with chromosome 9p21 deletion or MTAP ineffectiveness, methods comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie)) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein. Detailed Implementation

[0034] This disclosure relates to inhibitors of PRMT5. This disclosure also relates to compositions and methods in connection with PRMT5 inhibitors, and the use of such compounds for the treatment and / or prevention of diseases and conditions. This disclosure further relates to compositions and methods for the treatment and / or prevention of cancer or viral infections, comprising a combination of a PRMT5 inhibitor with one or more additional therapeutic agents.

[0035] Definitions and general parameters

[0036] It should be understood in the following description that this disclosure is considered illustrative 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 provided for convenience and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that, as used herein and in the appended claims, the singular forms “an,” “a,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes a plurality of such compounds, and reference to “determination” includes reference to one or more determinations and their equivalents known to one of ordinary skill in the art, and so on.

[0038] As used in this specification, the following terms and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0039] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -CONH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted without one or more dashes without losing its general meaning. A wavy line drawn through a line in the structure indicates the attachment point of a group. The order in which chemical groups are written or named does not indicate or imply directionality unless required by chemistry or structure. A solid line extending from the center of the ring indicates that the attachment point of a substituent on the ring can be at any ring atom. For example, R in the following structure... a It can be attached to any one of the five carbon ring atoms, or R a Hydrogen atoms that can be substituted for those attached to nitrogen ring atoms:

[0040] .

[0041] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6"Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "xy-membered" ring (where x and y are numerical ranges, such as "3 to 12-membered heterocyclic group") refers to a ring containing xy atoms (e.g., 3-12), of which up to 80% may be heteroatoms such as N, O, S, P, and the remaining atoms are carbon.

[0042] Furthermore, certain commonly used alternative chemical names may or may not be used. For example, divalent groups (such as divalent "alkyl" groups, divalent "aryl" groups, etc.) may also be referred to as "alkylene" groups or "aryene" groups, respectively.

[0043] The terms "compounds disclosed herein," "compounds disclosed herein," "compounds provided herein," or "compounds described herein" refer to compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie). Specific compounds from the embodiments provided herein are also included.

[0044] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In some other embodiments, the term "about" includes an indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Moreover, unless the context clearly specifies otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "compound" includes a variety of such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0045] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 8 carbon atoms (i.e., C64) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups, 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl group or 1 to 3 carbon atoms (i.e., C46) 1-3Alkyl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by its chemical name or identified by its molecular formula, it may encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0046] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl group or 2 to 4 carbon atoms (i.e., C44) 2-4 Alkenyl groups are aliphatic groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0047] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkynyl group), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0048] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these can be optionally substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0049] "Alkoxy" refers to an alkyl group having an oxygen atom attached to the alkyl group at the attachment point: alkyl-O-. Like alkyl groups, alkoxy groups will have any suitable number of carbon atoms, such as C... 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups may be further substituted by various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0050] "Alkoxyalkyl" refers to an alkoxy group attached to an alkyl group, which is then attached to the remainder of the compound. Alkoxyalkyl groups have any suitable number of carbons, such as 2 to 6 (C6+12+12+12+12+12+12+12+12+12+12+12+12+12+12+12+13 ...3+12+13+13+12+13+13+12+13+13+13+12+13+13+13+13+14+13+13+13+14+13+13+13+14+13+13+14+13+13+13+14+13+ 2-6 alkoxyalkyl), 2 to 5 (C 2-5 alkoxyalkyl), 2 to 4 (C 2-4 alkoxyalkyl), or 2 to 3 (C 2-3 Alkoxyalkyl. The number of carbons refers to the total number of carbons in the alkoxy group and the alkyl group. For example, in some embodiments, C6 alkoxyalkyl means ethoxy (C2 alkoxy) linked to butyl (C4 alkyl) and in other embodiments, n-propoxy (C3 alkoxy) linked to isopropyl (C3 alkyl). Alkoxy and alkyl are as defined above, wherein the alkyl group is divalent and may include, but is not limited to, methoxymethyl (CH3OCH2-), methoxyethyl (CH3OCH2CH2-), etc.

[0051] "Amino" refers to the -NR group. y R z , where R y and R z Independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each of which may optionally be substituted.

[0052] As used herein, “aryl” refers to a single all-carbon aromatic ring or a polycyclic all-carbon ring system, wherein at least one ring 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. Aryl groups include phenyl radicals. Aryl groups also include polycyclic systems (e.g., systems comprising 2, 3, or 4 rings) having 9 to 20 carbon atoms (e.g., 9 to 16 carbon atoms), wherein at least one ring is aromatic and the other ring may be aromatic or non-aromatic (i.e., a carbon ring). Such polycyclic systems may optionally have one or more (e.g., 1, 2, or 3) oxo groups substituted on any carbon ring portion of the polycyclic system. When valence requirements permit, the rings of a polycyclic system may be linked to each other via fusion, spirocyclic, and bridging bonds. It should also be understood that when referring to a range of aryl groups (e.g., 6-10 aryl groups), the range of atoms refers to the total number of ring atoms in that aryl group. For example, a 6-membered aryl group would include a phenyl group, and a 10-membered aryl group would include a naphthyl group and a 1,2,3,4-tetrahydronaphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthraceneyl, etc.

[0053] "Cyano" or "formonitrile" refers to the -CN group.

[0054] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C64 carbon atoms). 3-20 cycloalkyl groups, 3 to 12 cyclic carbon atoms (i.e., C12) 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C145-C ... 3-10 cycloalkyl groups, 3 to 8 cyclic carbon atoms (i.e., C1464) 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0055] "Fusing" refers to the bonding of one ring with an adjacent ring. In some embodiments, the fused ring system is a heterocyclic group. In some embodiments, the fused ring system is an oxabiscyclohexyl group. In some embodiments, the fused ring system is... or .

[0056] "Bridged" refers to ring fusion in which non-adjacent atoms on the ring are linked by a divalent substituent (such as an alkylene group, an alkylene group containing one or two heteroatoms) or a single heteroatom. Quinine cycloyl and adamantyl are examples of bridged ring systems. In some embodiments, the bridged ring is a bicyclopentyl (e.g., bicyclo[1.1.1]pentyl), a bicycloheptyl (e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl), or a bicyclooctyl (e.g., bicyclo[2.2.2]octyl). In some embodiments, the bridged ring... , , , or .

[0057] "Spiro" refers to a cyclic substituent linked by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein cyclopentane and piperidine are spiro-substituents, respectively. In some embodiments, the spiro-substituent is spiropentyl (spiropentyl), spirohexyl, spiroheptyl, spiroctyl (e.g., spiro[2.5]octyl), spirononyl (e.g., spiro[3.5]nonyl), spirdecyl (e.g., spiro[4.5]decyl), or spiroundecyl (e.g., spiro[5.5]undecyl). In some embodiments, the spiro-substituent is... , , or .

[0058] "Halogen" or "halogenated group" includes fluorine, chlorine, bromine and iodine.

[0059] As used herein, “haloalkyl” means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a halosubstituent, which may be the same or different. For example, C 1-4 The alkyl halide is C 1-4 Alkyl, wherein C 1-4 One or more hydrogen atoms in the alkyl group have been replaced by a halogenated substituent. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0060] "Haloalkoxy" refers to an alkoxy group in which some or all of its hydrogen atoms are replaced by halogen atoms. Regarding alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as C0... 1-6 The alkoxy group can be replaced by one, two, three or more halogens. When all hydrogens are replaced by a halogen (e.g., fluorine), the compound is fully substituted, such as perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

[0061] As used herein, the term "heteroaryl" refers to a single aromatic ring or a bicyclic ring. This term includes monoaryl rings having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided the ring is aromatic. Such rings include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. The term also includes polycyclic ring systems (e.g., ring systems containing 2 or 3 rings) in which a heteroaryl group as defined above may be fused with one or more heteroaryl groups (e.g., naphthidyl), carbocyclic rings (e.g., 5,6,7,8-tetrahydroquinolinyl), or aryl groups (e.g., indazole) to form a polycyclic ring. Such polycyclic rings may optionally be substituted by one or more (e.g., 1, 2, or 3) oxo groups on the carbocyclic portion of the polycyclic ring. It should be understood that the attachment point of the ring in a heteroaryl polycyclic ring as defined above can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portion of the ring. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inazolyl, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, and thionyl.

[0062] As used herein, “heterocyclic group” or “heterocycle” refers to a monosaturated or partially unsaturated ring or a polycyclic ring. This term includes monosaturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) containing 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. Such rings include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydrofuranyl, or piperidinyl. This term also includes polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which a heterocyclic group (as defined above) can be attached to two adjacent atoms via one or more heterocycles (e.g., decahydronaphthidyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthidyl), carbocyclic (e.g., decahydroquinolinyl), or aryl (fused heterocycle). When valence requirements permit, the rings of a polycyclic ring system can be connected to each other via fusion, spirocyclic, and bridging bonds. It should be understood that the attachment point of the ring in a heterocyclic polycyclic system as defined above can be at any position on the ring, including the heterocyclic, heteroaryl, aryl, or carbocyclic moiety of the ring. Exemplary heterocycles include, but are not limited to, aziridinyl, aziridine, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, benzodihydropyranyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxanepentyl, and 1,4-benzodioxyl. Exemplary fused bicyclic heterocycles include, but are not limited to, […].

[0063] , , , , , , , , , , , , , , , , .

[0064] "Hydroxy group" refers to the -OH group.

[0065] "Oxide group" refers to a group (=O) or (O).

[0066] "Sulfonyl" refers to the group -S(O)2R c , where R cIt can be alkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0067] Unless otherwise stated, whenever the graphical representation of a group terminates at a single-bonded nitrogen atom, the group represents an -NH2 group. Similarly, unless otherwise expressed, hydrogen atoms are implied and assumed to be present where necessary, based on knowledge of valence or to provide stability by those skilled in the art.

[0068] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. Furthermore, the term “optionally substituted” means that any one or more hydrogen atoms on the specified atom or group may be substituted with portions other than hydrogen, or may not be substituted with portions other than hydrogen.

[0069] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidine, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of further substituents (e.g., substituted aryl groups with substituted alkyl groups, which themselves are substituted by substituted aryl groups, which are further substituted by substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)-substituted aryl)-substituted aryl. Similarly, the above definition is 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 chemical groups, the term "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise stated, groups are described as optionally substituted, and any substituted elements of these groups are themselves unsubstituted.

[0070] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, CN, haloyl, amino, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents, including alkyl, haloalkyl, CN, cycloalkyl, heterocyclic, aryl, heteroaryl, amino, alkoxy, haloyl, oxo, and hydroxyl; "substituted heterocyclic" refers to a heterocyclic group having one or more substituents, including alkyl, amino, haloalkyl, CN, heterocyclic, cycloalkyl, aryl, heteroaryl, alkoxy, haloyl, oxo, and hydroxyl; "substituted aryl" refers to a group having one or more substituents. The aryl group, wherein the one or more substituents include halogroup, alkyl, amino, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, alkoxy, and cyano; “substituted heteroaryl” refers to a heteroaryl group having one or more substituents, including halogroup, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkoxy, and cyano, and “substituted sulfonyl” refers to the group -S(O)2R, wherein R is substituted by one or more substituents, including alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted by halogroup, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted by halogroup, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is not substituted.

[0071] In some embodiments, the substituted cycloalkyl, substituted heterocyclic, substituted aryl, and / or substituted heteroaryl groups comprise cycloalkyl, heterocyclic, aryl, and / or heteroaryl groups having substituents on the ring atom, which are attached to the remainder of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group:

[0072] .

[0073] The disclosure described illustratively herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be understood broadly and without limitation. Furthermore, the terminology and expressions used herein have been used descriptively rather than restrictively, and are not intended to exclude any equivalents or portions thereof of the features shown and described, but it should be recognized that various modifications are possible within the scope of this claimed disclosure.

[0074] 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 alkali or acid (including inorganic bases or inorganic acids and organic bases or organic acids). Where the compounds of this disclosure contain one or more acidic or basic groups, this disclosure also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly those that are pharmaceutically usable. Thus, compounds of this disclosure containing acidic groups may be present on these groups and may be used according to this disclosure as, for example, alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts containing ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine), amino acids, or other bases known to those skilled in the art. Compounds of this disclosure containing one or more basic groups (i.e., protonable groups) may exist in the form of addition salts of inorganic or organic acids and may be used according to this disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimecrolic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0075] If the compounds of this disclosure contain both acidic and basic groups in their molecules, then in addition to the salt forms mentioned, this disclosure also includes internal salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0076] This disclosure also includes all salts of the compounds disclosed herein, which are not directly applicable to pharmaceuticals due to low physiological compatibility, but may be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases that can be used to react with the compounds below 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 compounds below (after disclosure) are known to those skilled in the art and disclosed, for example, in Berge et al., Journal of Pharmaceutical Science, January 1977, Vol. 66, No. 1, and other sources.

[0077] Furthermore, the compounds disclosed herein are susceptible to tautomerism. Where tautomerism (e.g., keto-enol tautomerism) is possible in the compound or its prodrug, individual forms (e.g., keto and enol forms) and mixtures thereof in any ratio are within the scope of this disclosure. This also applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformational isomers, etc.

[0078] The term "protecting group" refers to a part of a compound that masks or alters the properties of functional groups or the properties of the compound as a whole. Chemical protecting groups and strategies used 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 mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. The term "deprotection" refers to the removal of the protecting group.

[0079] Those skilled in the art will understand that when a list of alternative substituents includes members that cannot be used to substitute for a particular group due to their valence requirements or other reasons, the list is intended to be interpreted by those skilled in the art as including only those members suitable for substituting for a particular group.

[0080] Furthermore, the compounds disclosed herein may exist in the form of solvates, such as those including water as a solvate, or pharmaceutically acceptable solvates, such as alcohols, particularly ethanol. A “solvate” is formed through the interaction of a solvent and a compound.

[0081] In some embodiments, optical isomers, racemates, or other mixtures thereof (e.g., non-racemate mixtures) of the compounds described herein or their pharmaceutically acceptable salts or mixtures thereof are provided. If desired, the isomers can be separated by methods well known in the art, such as liquid chromatography. In these cases, the single enantiomer or diastereomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolution. For example, resolution can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column.

[0082] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are mirror images of each other that cannot be superimposed. "Diabeta-isomeric" are stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Unless otherwise specified, this specification is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th Edition, J. March, John Wiley and Sons, New York, 1992).

[0083] In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or for amino acids as (D)- or (L)-. Some embodiments include all such possible isomers as well as their racemic, non-racemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included. When a compound is represented in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomeric or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a “non-racemic mixture” is a mixture of stereoisomers in a ratio not equal to 1:1.

[0084] The compositions provided herein, including the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof, may comprise racemic mixtures or mixtures containing an enantiomer in excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomers of these compounds are expressly included herein as if each and every isomer were specifically and individually listed.

[0085] Any formula or structure given herein is intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 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 I. Various isotope-labeled compounds disclosed herein, such as those in which radioactive isotopes such as 3 H, 13 C and 14 C is incorporated. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including the determination of tissue distribution of drugs or substrates, or for radiation therapy of patients. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents in the formulations or procedures disclosed in the examples and formulations described below.

[0086] This disclosure also includes “deuterated analogues” of the compounds disclosed herein, wherein one to n hydrogen atoms attached to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds may exhibit increased resistance to metabolism and are therefore used to extend 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 methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0087] The deuterium-labeled or substituted therapeutic compounds disclosed herein may possess beneficial DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies.

[0088] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0089] In addition, this disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient, and a pharmaceutically acceptable carrier.

[0090] "Pharmaceutical composition" means one or more active ingredients, one or more inert ingredients constituting a carrier, and any product obtained directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions disclosed herein may cover any composition prepared by mixing at least one compound of this disclosure with a pharmaceutically acceptable carrier.

[0091] As used herein, “pharmaceutically acceptable carriers” include excipients or reagents that are harmless to the disclosed compound or its intended use, such as solvents, diluents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption-retarding agents, etc. Compositions for preparing pharmaceutically active substances using such carriers and reagents are well known in the art (see, for example, “Remington’s Pharmaceutical Sciences,” Mace Publishing Co., Philadelphia, PA, 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GSBanker and CTRhodes).

[0092] IC 50 "or "EC" 50 "This refers to the inhibitory concentration required to achieve 50% of the maximum desired effect."

[0093] "Treatment" is a method for achieving a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or attenuating the severity of the disease or condition); b) slowing or preventing the development 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 its spread (e.g., metastasis of the disease or condition); and / or c) alleviating the disease, i.e., resulting in the resolution of clinical symptoms (e.g., improving the disease state, providing partial or overall relief of the disease or condition, enhancing the effect of another medication, delaying the progression of the disease, increasing quality of life, and / or prolonging survival). In some embodiments, the term "treatment" means administering a compound or pharmaceutically acceptable salt of formula (I) for the purpose of: (i) delaying the onset of the disease, i.e., preventing or delaying the development of clinical symptoms of the disease; (ii) suppressing the disease, i.e., preventing the development of clinical symptoms; and / or (iii) alleviating the disease, i.e., resulting in the resolution of clinical symptoms or their severity.

[0094] "Prevention" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0095] "Subject" refers to an animal, such as a mammal (including humans), which has been or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human therapeutic and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0096] The term "therapeutic effective amount" or "effective amount" refers to an amount sufficient to achieve a therapeutic effect when administered to a subject, providing a therapeutic benefit such as improvement of symptoms or slowing disease progression. For example, a therapeutic effective amount may be an amount sufficient to alleviate symptoms of a disease or condition in response to a PRMT5 inhibitor. Therapeutic effective amounts can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the route of administration, which can be readily determined by those skilled in the art.

[0097] List of abbreviations and acronyms

[0098]

[0099]

[0100] compound

[0101] In one embodiment, this disclosure provides a compound of formula (I):

[0102] (I)

[0103] Or its pharmaceutically acceptable salt, wherein:

[0104] It can be a single bond or a double bond;

[0105] Ring A is C 5-7 Cycloalkyl, phenyl, 5- to 7-membered heterocyclic, or 5- or 6-membered heteroaryl; the cycloalkyl, phenyl, heterocyclic, or heteroaryl group of ring A is optionally surrounded by one to four R groups. 6 Replace, R 6 They can be the same or different;

[0106] Each R 6 Independently, it can be a halogenated group, -OH, -OCH3, oxo group, -CN, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0107] X is N or CR 7 ;

[0108] R 7 H, halogroup, CN, halomethyl, -CH3, -C2H5, -OCH3, ethynyl or cyclopropyl; R 7 Cyclopropyl is optionally surrounded by 1 to 3 Z-terminal groups. 7 Replace, Z 7 Can be the same or different; each Z 7 Independently CN, F, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0109] R 1 and R 2 Together with the N attached to them, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups; wherein R 1 and R 2 The heterocyclic groups formed together with the N attached to them are optionally surrounded by one to four Z. 1 Replace, Z 1 They can be the same or different, where R is the only one. 1 and R 2 The resulting heterocyclic group has 0 to 3 additional heteroatoms, each of which is independently N, O or S;

[0110] Or R 1 and R 2Together with the N to which they are attached, they do not form heterocyclic groups, and R 1 C 10-14 Tricyclic aryl, and R 2 C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; wherein R 1 The aryl group is optionally divided by 1 to 4 Z groups. 2 Replace, Z 2 They can be the same or different;

[0111] Each Z 1 or Z 2 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -SF5, -S(O)R 12a -S(O)(NH)R12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ) or -S(O)(NR 12a )R 12b ; where each Z 1 or Z 2 The alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally bounded by 1 to 4 Z-terminal groups. 1a Replace, Z 1a They can be the same or different;

[0112] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a-S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ) or -S(O)(NR 12a )R 12b Z 1a The alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally bounded by 1 to 4 Z-terminal groups. 1b Replace, Z 1b They can be the same or different;

[0113] Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2; wherein Z 1b The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally bounded by one to three Cs. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 Alkyl), or -S(O)2N(C 1-9 Alkyl)2-substituted; and

[0114] Each R 12a R 12b or R 12cH and C independently 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl; wherein R 12a R 12b or R 12c Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally bounded by 1 to 4 Z-groups. 1b Replace, Z 1b They can be the same or different;

[0115] Unless otherwise specified, each heteroaryl group in the compounds of formula (I) is a 5- to 14-membered heteroaryl group;

[0116] Unless otherwise specified, each heterocyclic group in the compounds of formula (I) is a 3- to 20-membered heterocyclic group;

[0117] Unless otherwise specified, each heteroaryl or heterocyclic group of the compound of formula (I) has one to four heteroatoms that are independently N, O or S.

[0118] In some embodiments, the compound of formula (I) is the compound of formula (Ia).

[0119] (Ia)

[0120] Or its pharmaceutically acceptable salt.

[0121] In some embodiments, the compound of formula (I) is a compound of formula (Ib).

[0122] (Ib)

[0123] Or its pharmaceutically acceptable salt.

[0124] In some embodiments, the compound of formula (I) is the compound of formula (Ic).

[0125] (Ic)

[0126] Or its pharmaceutically acceptable salt.

[0127] In some embodiments, the compound of formula (I) is the compound of formula (Id).

[0128] (Id)

[0129] Or its pharmaceutically acceptable salt.

[0130] In some embodiments, the compound of formula (I) is a compound of formula (Ie).

[0131] (Ie)

[0132] Or its pharmaceutically acceptable salt.

[0133] In some embodiments, the compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt thereof, is a compound in which X is N. In some embodiments, X is CR. 7 In some implementations, R 7 It can be H, CH3, F, Cl, or CN. In some implementations, R 7 It can be H, CH3, or F. In some implementations, R 7 To be arbitrarily divided by 1 to 3 Z 7 Substituted cyclopropyl, Z 7 Can be the same or different; each Z 7 F and C independently 1-3 Alkyl or C 1-3 Halogenated alkyl groups. In some embodiments, each Z... 7 X can be F, CH3, CHF2, or CF3 independently. In some embodiments, X is -CF. In some embodiments, X is -CH.

[0134] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 1 To be arbitrarily divided by 1 to 4 Z 2 Replacement Z 2 They can be the same or different. In some implementations, R 1 yes .

[0135] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 2 Independent of halogenated group, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, C 6-10 Aryl or 4- to 10-membered heterocyclic groups; Z 2 The alkyl, alkynyl, cycloalkyl, heteroaryl, aryl, or heterocyclic group is optionally surrounded by 1 to 3 Z-terminal groups. 1a Replace, each Z 1aIndependent of halogenated group, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, C 6-10 Aryl or 5 to 10-membered heterocyclic groups, of which Z 1a Each alkyl, alkynyl, cycloalkyl, heteroaryl, aryl, or heterocyclic group is optionally surrounded by one to three groups selected from halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Cycloalkyl substituents. In some embodiments, each Z... 2 Independently halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyclopropyl, CN, or -OH. In some embodiments, Z 2 It is -CF3.

[0136] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 2 C 1-3 alkyl.

[0137] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 1 and R 2 Together with the N atoms to which they are attached, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups; any two connected rings of the tricyclic or tetracyclic heterocyclic group can be fused or bridged; and are composed of R 1 and R 2 The heterocyclic groups formed together with the attached N can optionally be surrounded by 1 to 4 Z groups. 1 replace.

[0138] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 1 and R 2 Together with the N atoms to which they are attached, they form 11 to 20-membered tricyclic heterocyclic groups; any two connected rings of the tricyclic or tetracyclic heterocyclic group can be fused or bridged; and are composed of R 1and R 2 The heterocyclic groups formed together with the attached N can optionally be surrounded by 1 to 4 Z groups. 1 replace.

[0139] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 1 and R 2 Together with the N attached to them, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups;

[0140] Any two linked rings of a tricyclic or tetracyclic heterocyclic group are fused or helical; and are composed of R 1 and R 2 The heterocyclic groups formed together with the attached N can optionally be surrounded by 1 to 4 Z groups. 1 replace.

[0141] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 1 and R 2 Together with the N atoms to which they are attached, they form 11 to 20-membered tricyclic heterocyclic groups; any two connected rings of the tricyclic heterocyclic group are fused or spiral; and are composed of R 1 and R 2 The heterocyclic groups formed together with the attached N can optionally be surrounded by 1 to 4 Z groups. 1 replace.

[0142] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein R 1 and R 2 Together with the N attached to them, they form 10 to 15-membered tricyclic heterocyclic groups; wherein R 1 and R 2 The heterocyclic groups formed together with the N attached to them are optionally surrounded by one to four Z. 1 Replace, Z 1 They can be the same or different.

[0143] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0144] -NR 1 R 2 yes ;

[0145] Q, Q1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the range do not exceed N;

[0146] X 4 To be arbitrarily determined by one or two Z 1 Replaced CH2;

[0147] X 6 For bond, O, -CH2-, -CH2O- or -CH2CH2-, where X 6 Each of CH2, CH2CH2, and OCH2 is optionally divided by one or two Z. 1 replace;

[0148] X 7 For the key or optionally by one or two Z 1 Replaced CH2;

[0149] X 8 For bonds, CH2 or CH2O, where X 8 Each of CH2 and CH2O is optionally separated by one or two ZnO. 1 Replace; and

[0150] X 9 For bonds, CH2, CH2O or CH2CH2, where X 9 Each of CH2, CH2O, and CH2CH2 is optionally divided by one or two Z. 1 replace.

[0151] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0152] -NR 1 R 2 yes ;

[0153] Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the range do not exceed N;

[0154] X 1It is -OCF2-, -OCH2-, -CH2-, -CH2CH2-, -OCH2CH2-, -CF2-, or -CH2NR. 1b -; where R 1b C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxetane, -C(O)-R 12a -S(O)R 12a Or C 3-6 cycloalkyl;

[0155] X 2 It can be O, -OCH2-, -CF2-, -CH2CH2-, or -CH2-;

[0156] X 3 For the key, -CF2- or -CH2-; and

[0157] q is 0, 1, or 2.

[0158] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for .

[0159] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for In some implementations, -NR 1 R 2 for In some implementations, -NR 1 R 2 for In some implementations, -NR 1 R 2 for .

[0160] In some embodiments, the compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt thereof, is a compound in which q is 0. In some embodiments, q is 1.

[0161] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0162] -NR1 R 2 for or heterocyclic groups, wherein -NR 1 R 2 The heterocyclic group is optionally surrounded by 1 to 4 Z groups. 1 Replace, Z 1 They can be the same or different;

[0163] Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the middle do not exceed N; and

[0164] X 5 It is -OCH2-, -CH2-, -CH2CH2-, or -CF2-.

[0165] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for And n is 0, 1, or 2.

[0166] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for In some implementations, -NR 1 R 2 for .

[0167] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0168] -NR 1 R 2 yes or ;

[0169] Y 7 For O, -OCH2-, -CH2, or -CH2CH2-; Y 7 Each of -OCH2-, -CH2-, and -CH2CH2- is optionally construed by one or two Z-terminals.1 replace;

[0170] Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the middle do not exceed N; and

[0171] m can be 0, 1, or 2.

[0172] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein Q 3 For N, CH or CZ 1 And Q, Q 1 Or Q 2 Each independently is CH or CZ 1 .

[0173] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein Q 3 Let N be the number of elements in the array.

[0174] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein Q, Q 1 Q 2 and Q 3 One of them is CZ 1 .

[0175] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein Q, Q 1 Or Q 3 Each of them is CH; and Q 2 For CZ 1 .

[0176] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein Q, Q 1 Q 2 and Q 3 Each of them is CH or CZ 1 .

[0177] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 Independently for C 1-6 Alkyl, -OH, CN, halogroup, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkynyl group, C 3-15 Cycloalkyl, 3-18 membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)-R 12a -C(O)OR 12a ; wherein the alkyl, alkynyl, cycloalkyl, heterocyclic or heteroaryl groups are optionally surrounded by one to four Z groups. 1a Replace, Z 1a Can be the same or different; each Z 1a Independently -OH, CN, C 1-6 Alkyl, Halogenated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, 5-18 membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to four Z groups. 1b Replace, Z 1b Can be the same or different; each Z 1b Independently, CN, -OH, C 1-6 Alkyl, Halogenated, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups; and each R 12a H and C independently 1-6 Alkyl or C 3-10 Cycloalkyl.

[0178] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 Independently -OH, CN, C 1-6 Alkyl, Halogenated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein Z 1 The phenyl or heteroaryl group is optionally surrounded by 1 to 3 Z-terminal groups. 1a Replace, Z 1aCan be the same or different; each Z 1a Independently, it is a halogenated group or C 1-6 Halogenated alkyl groups.

[0179] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 Independently for C 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, phenyl, or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one to three groups independently selected from the halogroup and C. 1-3 Substituents of haloalkyl groups.

[0180] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 Independently for C 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, phenyl, or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one to three groups independently selected from the halogroup and C. 1-3 Substituents of haloalkyl groups.

[0181] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 It can be independently -CF3, -OCF3, -CH3, -OCHF2, F, Cl, or Br.

[0182] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 It can be -CH3, CF3, F or Br independently.

[0183] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein X 2 It can be O, -OCH2-, -CH2CH2-, or -CH2-.

[0184] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0185] -NR 1 R 2 yes ;

[0186] Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 N is defined as having no more than one of the following.

[0187] X 2 It is O or -CH2-;

[0188] X 10 It is O or -CH2-; and

[0189] r is 0, 1, or 2.

[0190] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0191] -NR 1 R 2 yes ;

[0192] X 2 It is O or -CH2-;

[0193] X 10 It is O or -CH2-;

[0194] Each Z 1b Independently H or Z 1 ;and

[0195] r is 0, 1, or 2.

[0196] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0197] -NR 1 R 2 for ;

[0198] X 2 It is O or -CH2-;

[0199] X 10 It is O or -CH2-; and

[0200] Each Z 1b Independently H or Z 1 .

[0201] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0202] -NR 1 R 2 yes, ,or;

[0203] X 2 It is O or -CH2-;

[0204] X 10 It is O or -CH2-; and

[0205] Each Z 1b Independently H or Z 1 .

[0206] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0207] -NR 1 R 2 for ;

[0208] X 2 It is O or -CH2-;

[0209] X 10 It is O or -CH2-;

[0210] Each Z 1b Independently H or Z 1 ;and

[0211] r is 0, 1, or 2.

[0212] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0213] -NR 1 R 2 yes ;and

[0214] p is 1 or 2.

[0215] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds that are: wherein

[0216] -NR 1 R 2 yes .

[0217] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 F and C independently 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0218] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1 It can be F, -CH3, -CF3, -C2F5, or -OCF3 independently.

[0219] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein each Z 1b Independently, it is either H or F.

[0220] In some embodiments, the compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt thereof, is a compound in which at least one Z 1b It is F.

[0221] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein X 2 It is O; and X 10 It is -CH2-.

[0222] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in the following form: wherein X 2 It is -CH2-; and X 10 It is O.

[0223] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for

[0224] , , , , , or .

[0225] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for

[0226] , , or .

[0227] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for .

[0228] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for

[0229] or .

[0230] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1 R 2 for

[0231] or .

[0232] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or their pharmaceutically acceptable salts, are compounds in which -NR 1R 2 for

[0233] or In some implementations, -NR 1 R 2 for

[0234] or .

[0235] In some embodiments, this disclosure provides the compounds in Table 1 or their pharmaceutically acceptable salts.

[0236] In some embodiments, this disclosure provides racemic mixtures comprising compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure provides racemic mixtures comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure provides non-racemic mixtures comprising compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure provides non-racemic mixtures comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof.

[0237] Those skilled in the art will know that the groups disclosed herein (e.g., R) 1 Each embodiment of ) can be combined with the remaining group (e.g., R) 2 Z 1 Z 2 Any other combination of embodiments of each of the following can be used to produce a complete compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) or any of the formulas described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein each is considered to be within the scope of this disclosure.

[0238] Pharmaceutical Compositions and Administration Methods

[0239] In addition, this disclosure provides pharmaceutical compositions comprising at least one compound of this disclosure as an active ingredient, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0240] In some embodiments, the pharmaceutical compositions disclosed herein may additionally comprise one or more other compounds, such as prodrug compounds or other enzyme inhibitors, as active ingredients.

[0241] In some embodiments, the pharmaceutical compositions of this disclosure may comprise additional therapeutic agents or therapeutic modalities. In some embodiments, the additional therapeutic agents include one, two, three, or four additional therapeutic agents and / or therapeutic modalities. In some embodiments, the additional therapeutic agents or therapeutic modalities are selected from immune checkpoint modulators, antibody-drug conjugates (ADCs), anti-apoptotic agents, targeted anticancer therapies, chemotherapy agents, surgery, or radiotherapy. In some embodiments, the immune checkpoint modulators are selected from anti-PD-(L)1 antibodies, anti-TIGIT antibodies, anti-CTLA4 antibodies, anti-CCR8 antibodies, anti-TREM1 antibodies, anti-TREM2 antibodies, CD47 inhibitors, DGKα inhibitors, HPK1 inhibitors, FLT3 agonists, adenosine pathway inhibitors, and CAR-T cell therapy.

[0242] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most appropriate route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They are readily available in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical field.

[0243] In practical use, the compounds of this disclosure can be tightly blended with drug carriers as active ingredients using conventional drug formulation techniques. Depending on the desired formulation form, such as oral or parenteral (including intravenous) administration, the carrier can take various forms. When preparing compositions for oral dosage forms, any commonly used drug medium can be used. In the case of oral liquid formulations (e.g., suspensions, elixirs, and solutions), carriers such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used; or in the case of oral solid formulations (e.g., powders, hard capsules, soft capsules, and tablets), carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., are preferred over liquid formulations.

[0244] Because of their ease of application, tablets and capsules represent the most advantageous form of oral dosage unit, in which case a solid drug carrier is used. If desired, tablets can be coated using standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of the active compound in these compositions can vary and is conveniently between about 2% and about 60% per unit weight. The amount of the active compound in the composition useful for such treatment ensures an effective dose. The active compound can also be administered, for example, as drops or nasal sprays.

[0245] Tablets, pills, capsules, etc., may also contain binders such as gum arabic, gum arabic, 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. When the dosage unit is in capsule form, in addition to the above-mentioned materials, it may also contain a liquid carrier such as fatty oil.

[0246] Various other materials may exist as coatings or alter the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, syrups or elixirs may also contain sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings (such as cherry or orange flavorings).

[0247] In some embodiments, the compounds disclosed herein can also be used as salts having various countercations to produce orally available formulations.

[0248] The compounds disclosed herein can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water appropriately mixed with a surfactant, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0249] Suitable drug forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be a fluid readily injectable. It must be stable under manufacturing and storage conditions and must be protected against 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.

[0250] Any suitable route of administration may be used to deliver an effective dose of the disclosed compound to mammals, particularly humans. For example, it may be administered orally, rectally, topically, parenterally, ocularly, pulmonaryly, or nasally. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the disclosed compound is administered orally.

[0251] Reagent test kit

[0252] This document also provides kits comprising the compounds of this disclosure or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and suitable packaging. In one embodiment, the kit further includes instructions for use. In one aspect, the kit comprises the compounds of this disclosure, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and a label and / or instructions for use of the compound in a therapeutic indication, including the diseases or conditions described herein.

[0253] This document also provides articles comprising the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof in suitable containers. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, and intravenous bags.

[0254] Treatment methods and uses

[0255] This disclosure further relates to the use of the compounds disclosed herein for treating and / or preventing diseases and / or conditions by inhibiting PRMT5 through said compounds. This disclosure further relates to the use of the compounds disclosed herein for treating and / or preventing diseases and / or conditions by inhibiting PRMT5 through said compounds. This disclosure further relates to the use of the compounds disclosed herein for treating and / or preventing diseases and / or conditions by inhibiting PRMT5 in MTAP-ineffective cells through said compounds. Furthermore, this disclosure relates to the use of said compounds in the preparation of medicaments for treating and / or preventing diseases and / or conditions related to chromosome 9p21 deletion or MTAP ineffectiveness by inhibiting PRMT5 in MTAP-ineffective cells through said compounds. In some embodiments, inhibiting PRMT5 in MTAP-ineffective cells alleviates diseases or conditions related to chromosome 9p21 deletion or MTAP ineffectiveness.

[0256] The drugs referred to herein can be prepared by conventional methods, including combinations of compounds according to this disclosure and pharmaceutically acceptable carriers.

[0257] In some embodiments, this document provides a method for treating and / or preventing MTAP ineffectiveness or chromosome 9p21 deletion-related diseases or conditions in patients in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) or a pharmaceutically acceptable salt thereof.

[0258] In some implementations, diseases or conditions associated with chromosome 9p21 deletion or MTAP invalidity include solid tumors in or originating from tissues or organs, such as:

[0259] • Skeletal tissue (e.g., amelomas, aneurysmal bone cysts, angiosarcomas, chondroblastomas, chondromas, chondromycinous fibromas, chondrosarcomas, chordomas, dedifferentiated chondrosarcomas, enchondromas, epithelioid hemangioendotheliomas, fibrous dysplasia of bone, giant cell tumors of bone, hemangiomas and related lesions, osteoblastomas, osteochondromas, osteosarcomas, osteoid osteomas, osteomas, periosteal chondromas, desmoid tumors, Ewing sarcomas);

[0260] • Lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Worcesteroma);

[0261] •Esophagus (e.g., Barrett's esophagus, developmental abnormalities, and adenocarcinoma);

[0262] • The gastrointestinal tract, including the stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric cancer, gastric sarcoma, neuroendocrine carcinoma, primary squamous cell carcinoma of the stomach, gastric adenoacanthoma), intestine and smooth muscle (e.g., intravenous leiomyoma), colon (e.g., colorectal adenocarcinoma), rectum and anus;

[0263] • Pancreas (e.g., serous tumors, including microcystic or macrocystic serous cystadenomas, solid serous cystadenomas, Von) Hippel-Landau (VHL) associated serous cystic tumors, serous cystadenocarcinomas; mucinous cystic tumors (MCN), intraductal papillary mucinous tumors (IPMN), intraductal eosinophilic papillary tumors (IOPN), intraductal tubular tumors, cystic acinar tumors (including acinar cell cystadenomas and acinar cell cystadenocarcinomas), pancreatic cancer, invasive pancreatic ductal adenocarcinomas (including tubular adenocarcinomas and adenosquamous carcinomas), colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenomas, neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC) (including small cell or large cell NEC), insulinomas, gastrinomas, glucagonomas, serotonin-producing NETs, ​​somatostatinomas, VIPomas, solid pseudopapillary tumors (SPN), pancreatoblastomas);

[0264] • Gallbladder (e.g., gallbladder cancer and extrahepatic bile duct and intrahepatic bile duct cancer);

[0265] • Neuroendocrine glands (e.g., adrenocortical carcinoma, carcinoid, pheochromocytoma, pituitary adenoma);

[0266] • Thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, eosinophilic cell tumor, papillary carcinoma, adenocarcinoma);

[0267] • Liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastic carcinoma, hepatocellular carcinoma, mesenchymal nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cyst adenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibroma, teratoma, yolk sac tumor, carcinosarcoma, rhabdomyosarcoma);

[0268] • Kidney (e.g., ALK rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephrotic adenoma, metanephrotic adenofibroma, mucinous tubular and spindle cell carcinoma, renal adenoma, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal eosinophilic tumor, renal cell carcinoma, succinate dehydrogenase deficient renal cell carcinoma, collecting duct carcinoma);

[0269] • Breast cancer (e.g., invasive ductal carcinoma, including but not limited to acinar cell carcinoma, adenoid cystic carcinoma, apocrine gland carcinoma, cribriform carcinoma, glycogen-rich / clear cell inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, eosinophilic cell carcinoma, papillary carcinoma, sebaceous gland carcinoma, secretory breast cancer, tubular carcinoma; lobular carcinoma, including but not limited to pleomorphic carcinoma, signet ring cell carcinoma);

[0270] • Peritoneum (e.g., mesothelioma; primary peritoneal carcinoma);

[0271] • Female sex organ tissues, including the ovaries (e.g., choriocarcinoma, epithelial cell carcinoma, germ cell carcinoma, sex cord-stromal tumor), fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Müllerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell carcinoma, choriocarcinoma, trophoblastoma), uterus (e.g., cervical cancer, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma). Mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal tumor), leiomyomas (e.g., endometrial stromal nodules, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinoma fibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, malignant mixed Miller tumors of the endometrium, gestational trophoblastic tumors (partial vesicular mass, complete vesicular mass, invasive vesicular mass, placental site tumors)), vulva, vagina;

[0272] • Male sex organ tissues, including the prostate, testes (e.g., germ cell tumors, spermatogenic seminoma), and penis;

[0273] • Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma);

[0274] • Brain tumors (e.g., gliomas (e.g., astrocytomas (including non-invasive, low-grade, anaplastic), glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, Schwannomas (neuromas), craniopharyngiomas, chordomas, non-Hodgkin lymphomas (NHL), chronic non-Hodgkin lymphomas (iNHL), refractory iNHL, pituitary tumors);

[0275] • Eyes (e.g., retinoblastoma, retinoblastoma, ocular melanoma, choroidal malignant melanoma, iris hamartoma);

[0276] • Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal carcinoma (including squamous cell carcinoma (SCC)) (e.g., glottic carcinoma, supraglottic laryngeal carcinoma, subglottic laryngeal carcinoma, transglottic carcinoma), carcinoma in situ, verrucous hemangioma, spindle cell and basal cell SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal tumor), head and neck paraganglioma (e.g., carotid body tumor, tympanic cavity tumor, vagus neuroma);

[0277] • Thymus (e.g., thymoma);

[0278] • The heart (e.g., cardiac myxoma);

[0279] • Lung cancer (e.g., small cell carcinoma (SCLC), non-small cell lung cancer (NSCLC) (including squamous cell carcinoma (SCC)), adenocarcinoma, and large cell carcinoma), carcinoid tumor (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, pleural pulmonary blastoma);

[0280] • Lymphomas (e.g., lymphomas including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), chronic non-Hodgkin's lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative disorders, including B-cell lymphomas and T-cell lymphomas (e.g., Burkitt's lymphoma; large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, chronic B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary exudative lymphoma; plasmablastic lymphoma; nasal extranodal NK / T-cell lymphoma; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma), lymphangioleiomyomatosis).

[0281] • Central nervous system (CNS) tumors (e.g., gliomas, including astrocytic tumors such as pilocytic astrocytoma, hexoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrous astrocytoma, chubby cell astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma), glioblastomas (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and gliomatosis), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), ependymal tumors, etc. Tumors (e.g., subventricular ependymoma, myxopapillary ependymoma, ependymoma (e.g., cellular, papillary, clear cell, elongated cell), anaplastic ependymoma), optic nerve gliomas and non-glial tumors (e.g., choroid plexus tumors, neuronal and mixed neuron-glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, skull and paravertebral nerve tumors, stellate region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, peripheral neuroblastomas (including but not limited to neuroblastomas, ganglioblastomas, gangliomas), trisomy 19 cell ependymomas);

[0282] • Neuroendocrine tissues (e.g., the paraganglionic system, including adrenal medullaris (pheochromocytoma) and extra-adrenal paraganglioma).

[0283] • Skin conditions (e.g., clear cell hidradenoma, benign fibrous histiocytoma of the skin, cylindrica, hidradenoma, melanoma (including cutaneous melanoma and mucosal melanoma), pilomatoma, Spitz tumor); and

[0284] • Soft tissue tumors (e.g., invasive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, angiofibroma, hemangioma-like fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastic fibroma, embryonal rhabdomyosarcoma, Ewing's tumor / primitive neuroectodermal tumor (PNET), extraosseous myxoid chondrosarcoma, extraosseous osteosarcoma, paravertebral sarcoma) Tumors, inflammatory fibroblastic tumors, lipoblastic tumors, lipomas, chondroid lipomas, liposarcomas / malignant lipomas, liposarcomas, myxoid liposarcomas, fibromyxoid sarcomas, lymphangiomyomas, malignant myoepitheliomas, soft tissue malignant melanomas, myoepithelial carcinomas, myoepitheliomas, myxoid inflammatory fibroblastic sarcomas, undifferentiated sarcomas, peridermoid cell tumors, rhabdomyosarcomas, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), soft tissue leiomyosarcomas, undifferentiated sarcomas, well-differentiated liposarcomas.

[0285] In some implementations, the disease or condition associated with chromosome 9p21 deletion or MTAP invalidation is cancer selected from the following: lung cancer, urothelial carcinoma, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell tumor, head and neck cancer, bile duct cancer, esophageal cancer, glioblastoma, gastric cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, kidney cancer, colorectal cancer, prostate cancer, leukemia, and cervical cancer.

[0286] In some implementations, the disease or condition associated with chromosome 9p21 deletion or MTAP invalidity is cancer selected from the following: ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, and bladder cancer.

[0287] dose

[0288] The effective dosage of the active ingredient used can vary depending on the specific compound used, the administration method, the condition being treated, and the severity of the condition. Such dosages can be readily determined by those skilled in the art.

[0289] When treating or preventing diseases or conditions related to chromosome 9p21 deletion or MTAP ineffectiveness to which the compounds of this disclosure are applicable, satisfactory results are generally obtained when the compounds of this disclosure are administered at a daily dose of about 0.1 mg to about 300 mg per kilogram of animal body weight. In some embodiments, the compounds of this disclosure are administered in a single daily dose or in divided doses two to six times daily or in a sustained-release form. For most large mammals, the total daily dose is about 1 mg to about 1000 mg, or about 1 mg to about 50 mg. In the case of a 70 kg adult, the total daily dose will typically be about 0.1 mg to about 200 mg. This dosage regimen may be adjusted to provide the best therapeutic response. In some embodiments, the total daily dose is about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, or about 1 mg to about 10 mg.

[0290] The compounds or compositions thereof of this application may be administered once, twice, three times, or four times daily using any of the suitable modes described above. Furthermore, administration of the compound or treatment may continue for multiple days; for example, for a treatment cycle, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles typically alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0291] In some implementations, the method provided herein involves administering an initial daily dose of about 1 mg to 800 mg of the compound described herein to a subject, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0292] combination

[0293] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more adjunctive therapeutic agents to treat or prevent the diseases or conditions disclosed herein. In some embodiments, the one or more adjunctive therapeutic agents are one, two, three, or four adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are one adjunctive therapeutic agent. In some embodiments, the one or more adjunctive therapeutic agents are two adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are three adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are four adjunctive therapeutic agents.

[0294] In some embodiments, the pharmaceutical compositions provided herein have a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) 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.

[0295] In some embodiments, the one or more additional therapeutic agents include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulating immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antitumor agents, antiproliferative agents, antiangiogenic agents, anti-inflammatory agents, immunotherapeutic agents, and therapeutic antigen-binding molecules (e.g., monospecific and multispecific antibodies or fragments thereof in any form, such as DART). ® Duobody ® BiTE ® BiKE, TriKE, XmAb ® TandAb ® scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimics (e.g., including adnectin, affinity, affilin, affimer, affitin, alphabet, anticalin, peptide aptamers, armadillo repeat protein (ARM), atrimer, avimer, and designed ankylosing repeat protein (DARPin)). ®(fynomer, knottin, Kunitz domain peptide, monoclonal antibody and nanoCLAMP), antibody-drug conjugate (ADC), antibody-peptide conjugate), oncolytic virus, gene modifier or gene editor, cells containing chimeric antigen receptor (CAR) (e.g., including T cell immunotherapies, NK cell immunotherapies or macrophage immunotherapies), cells containing engineered T cell receptor (TCR-T), or any combination thereof.

[0296] Indicative targets

[0297] In some embodiments, one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modulators, stimulants, blockers, activators, or suppressors of targets such as: 2'-5'-oligoadenylate synthase (OAS1; NCBI gene ID: 4938); 5'-3' exonuclease 1 (XRN1; NCBI gene ID: 54464); 5'-exonuclease (NT5E, CD73; NCBI gene ID: 4907); ABL proto-oncogene 1; and non-receptor tyrosine kinases (ABL1, BCR-ABL, c-ABL, v-ABL; N... NCBI gene ID: 25); melanoma deficiency factor 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 / threonine kinase 1 (AKT1, AKT, PKB; N NCBI gene ID: 207); Alanine aminopeptidase (membrane) (ANPEP, CD13; NCBI gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI gene ID: 238); Alpha-fetoprotein (AFP; NCBI gene ID: 174); Copper-containing amine oxidases (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI gene ID: 26, 314, 8639); Androgen receptor (AR; NCBI gene ID: 367); Angiopoietin (ANGPT1, ANGPT2; NCBI gene ID: 284, 285); Angiotensin II receptor type 1 (AGTR1; NCBI gene ID: 207); Due to ID: 185); angiotensinogen (AGT; NCBI gene ID: 183); apolipoprotein A1 (APOA1; NCBI gene ID: 335); mitochondrial-associated apoptosis-inducing factor 1 (AIFM1, AIF; NCBI gene ID: 9131); arachidonic acid 5-lipoxygenase (ALOX5; NCBI gene ID: 240); asparaginase (ASPG; NCBI gene ID: 374569); astrocyte homologue 1 (ASTE1; NCBI gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI gene ID: 472); ATP-binding box subfamily B member 1 (ABCB1, CD243, GP170);NCBI gene ID: 5243); ATP-dependent Clp protease (CLPP; NCBI gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI gene ID: 558); B and T lymphocyte-associated proteins (BTLA, CD272; NCBI gene ID: 151888); proteins containing baculovirus IAP repeats (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI gene ID: 329, 330, 331, 332); ba Sigin (OK blood type) (BSG, CD147; NCBI gene ID: 682); B-cell lymphoma 2 (BCL2; NCBI gene ID: 596); BCL2 binding component 3 (BBC3, PUMA; NCBI gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI gene ID: 598, 10018); β3-adrenergic receptor (ADRB3; NCBI gene ID: 155); Bone γ-carboxyglutamate protein (BGLAP; NCBI gene ID: 632); Bone morphogenetic protein-10 ligand (BMP10; NCB I gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI gene ID: 623, 624); B-RAF (BRAF; NCBI gene ID: 273); breakpoint cluster regions (BCR; NCBI gene ID: 613); proteins containing bromo domains and external (BET) bromo domains (e.g., BRD2, BRD3, BRD4, BRDT; NCBI gene ID: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI gene ID: 695); cadherin (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin)). (e.g., CTAG1A, CTAG1B, CTAG2; NCBI gene ID: 1001, 1004); Cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI gene ID: 1485, 30848, 246100); Cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI gene ID: 1268, 1269); Carbohydrate sulfonyltransferase 15 (CHST15; NCBI gene ID: 51363); Carbonic anhydrases (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14);NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 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 (CK2); NCBI gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI gene ID: 836, 840, 841, 864); catechol-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: 8366). Gene ID: 729230); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein α (CEBPA, CEBP; NCBI gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI gene ID: 23705); cell cycle 7 (CDC7; NCBI gene ID: 8317); cell communication network Correlation factor 2 (CCN2; NCBI gene ID: 1490); cereblon (CRBN; NCBI gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI gene ID: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI gene ID: 887); human chorionic gonadotropin 1 (CSH1; NCBI gene ID: 1442); blocking proteins (e.g., CLDN6, CLDN18; NCBI gene ID: 9074, 51208).Differentiation cluster markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3α (TRA), CDβ (TRB), CDγ (TRG), CDδ (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD55 (DAF), CD58 (LFA3) ), CD74, CD79a, CD79b, CD80 (B7-1), CD84, CD86 (B7-2), CD96 (TACTILE), CD99 (MIC2), CD115 (CSF1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 ( IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), C D194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2R), CD223 (LAG3), CD226 (DNAM1), CD244, CD247, CD248, CD276 (B7-H3), CD331 (FGFR1), CD332 (FGFR2), CD333 (FGFR3), CD334 (FGFR4); NCBI gene ID: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 9 53, 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); Cluster protein (CLU; NCBI gene ID: 1191);Coagulation factors (e.g., F7, FXA; NCBI gene ID: 2155, 2159); collagen type IV α chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI gene ID: 1282, 1284, 1285, 1286, 1287); collagen lectin subfamily member 10 (COLEC10; NCBI gene ID: 10584); colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI gene ID: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI gene ID: 7). 18, 727); COP9 signaling subunit 5 (COPS5; NCBI gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI gene ID: 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-1)). 0R), 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 P4 Family 50 members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductases (POR; NCBI gene ID: 5447); cytokine-inducible SH2-containing proteins (CISH; NCBI gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI gene ID: 1493); DEAD box helicases (e.g., DDX5, DDX6, DDX58);NCBI gene IDs: 1655, 1656, 23586); delta-like classical Notch ligands (e.g., DLL3, DLL4; NCBI gene IDs: 10683, 54567); Diablo IAP-binding mitochondrial proteins (DIABLO, SMAC; NCBI gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI gene IDs: 1606, 8525); dickkopf Inhibitors of the WNT signaling pathway (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); discoid domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI gene ID: 780, 4921); DNA-dependent protein kinases (PRKDC; N NCBI gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI gene ID: 7150, 7153, 7155, 7156, 8940); Dopachrome tautomerase (DCT; NCBI gene ID: 1638); Dopamine receptor D2 (DRD2; NCBI gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI gene ID: 84444); Exonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3) CD203c; NCBI gene ID: 5169); EMAP-like 4 (EML4; NCBI gene ID: 27436); endothelial glycoprotein (ENG; NCBI gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI gene ID: 51752, 64167); zeste homolog enhancer 2 multicomb repressor complex 2 subunit (EZH2; NCBI gene ID: 2146); hepatic ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPH...). A5, EPHA7, EPHB4; NCBI gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050; liver glycoproteins (e.g., EFNA1, EFNA4, EFNB2; NCBI gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4);NCBI gene IDs: 1956, 2064, 2065, 2066); Epithelial cell adhesion molecule (EPCAM; NCBI gene ID: 4072); Epithelial mitogen (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); Export protein-1 (XPO1; NCBI gene ID: 7514); Farnesol X receptor (NR1H4, FXR; NCBI gene ID: 9971); Fas ligand (FAS) LG, FASL, CD95L, CD178, TNFSF6; NCBI gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI gene ID: 2194); Fc fragments of Ig receptors (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI gene ID: 83416); fibroblast activation protein α (FAP; NCBI gene ID: 2191); fibroblast growth factor receptors (e.g., FG FR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI gene IDs: 2260, 2261, 2263, 2264; fibroblast growth factors (e.g., FGF1 (FGFα), FGF2 (FGFβ), 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); NC NCBI gene IDs: 2321, 2322, 2324); fms-associated receptor tyrosine kinase 3 ligand (FLT3LG; NCBI gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI gene ID: 2346); folate receptor 1 (FOLR1; NCBI gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI gene ID: 2305); furin protease (FURIN, PACE; NCBI gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI gene ID: 2534);Gastrin (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI gene ID: 3958, 3964, 3965); glucocorticoid receptors (NR3C1, GR; NCBI gene ID: 2908); glucuronidase β (GUSB; NCBI gene ID: 2990); glutamate metabolite receptor 1 (GRM1; NCBI gene ID: 2911); glutaminase (GLS; NCBI gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI gene ID: 2990). 2950); Glycogen synthase kinase 3β (GSK3B; NCBI gene ID: 2932); Phosphatidylinositol polysaccharide 3 (GPC3; NCBI gene ID: 2719); Gonadotropin-releasing hormone 1 (GNRH1; NCBI gene ID: 2796); Gonadotropin-releasing hormone receptor (GNRHR; NCBI gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI gene ID: 10457); Growth differentiation factor 2 (GDF2, BMP9; NCBI gene ID: ... Glycogen synthase kinase 3β (GPC3; NCBI gene ID: 2719); Gonadotropin-releasing hormone 1 (GNRH1; NCBI gene ID: 2796); Gonadotropin-releasing hormone receptor (GNRHR; NCBI gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI gene ID: 10457); Growth differentiation factor 2 (GDF2, BMP9 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); maternal expression transcripts of H19 imprinted genes (H19; NCBI gene ID: 283120); HCK proto-oncogene Src family tyrosine kinases (HCK; NCBI gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB) 1 (HSP27), HSP90B1 (GP96); NCBI gene ID: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI gene ID: 3162, 3163); heparinase (HPSE; NCBI gene ID: 10855); hepatitis A virus cell receptor 2 (HAVCR2, TIM3, CD366; NCBI gene ID: 84868); hepatocyte growth factor (HGF; NCBI gene ID: 3082); HERV-H LTR-related 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 ID: 3065, 9734, 51564); HRAs proto-oncogene GTPases (HRAS; NCBI gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1)).NCBI gene IDs: 2034, 3091); I-κ-B kinase (IKKβ; NCBI gene IDs: 3551, 3553); IKAROS family zinc fingers (IKZF1 (LYF1), IKZF3; NCBI gene IDs: 10320, 22806); Immunoglobulin superfamily member 11 (IGSF11; NCBI gene ID: 152404); Indoleamine 2,3-dioxygenases (e.g., IDO1, IDO2; NCBI gene IDs: 3620, 169355); Inducible T cell co-stimulatory factors (ICOS, CD278; NCBI gene ID: 29851); Inducible T cell co-stimulatory factor ligands (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 ID: 3678, 3685, 3688, 3695, 369 8); Intercellular adhesion molecule 1 (ICAM1, CD54; NCBI gene ID: 3383); Interleukin 1 receptor-associated kinase 4 (IRAK4; NCBI gene ID: 51135); Interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); Interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8). (CXCL8), IL10 (TGIF), IL12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-29 (IFNL1); NCBI gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618; isocitrate dehydrogenase (NADP(+)1) (e.g., IDH1, IDH2; NCBI gene IDs: 3417, 3418); Janus kinases (e.g., JAK1, JAK2, JAK3);NCBI gene IDs: 3716, 3717, 3718; kallikrein-associated peptidase 3 (KLK3; NCBI gene ID: 354); cytotoxic cell immunoglobulin-like receptor Ig domains and long cytoplasmic tails (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI gene ID: 3 802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285; cytotoxic lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI gene ID: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insertion domain receptors (KDR, CD309, VEGFR2; NCBI gene ID: 3791); kinin family Member 11 (KIF11; NCBI gene ID: 3832); KiSS-1 metastasis inhibitor (KISS1; NCBI gene ID: 3814); KIT proto-oncogene receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI gene ID: 3815); KRAS proto-oncogene GTPase (KRAS; NCBI gene ID: 3845); lactoferrin (LTF; NCBI gene ID: 4057); LCK proto-oncogene Src family tyrosine kinase (LCK; NCBI gene ID: 3932); LDL receptor-associated protein 1 (LRP1, CD91, IGFBP3R; NCBI gene ID: 4035); rich in Leucine repeat protein 15 (LRRC15; NCBI gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D; NCBI gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI gene ID: 4048); adaptors for T cell activation (LAT; NCBI gene ID: 27040); luteinizing hormone / human chorionic gonadotropin receptor (LHCGR; NCBI gene ID: 3973); protein 3 containing the LY6 / PLAUR domain (LYPD3; NCBI gene ID: 27076).Lymphocyte activation gene 3 (LAG3; CD223; NCBI gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI gene ID: 4063, 17076); LYN proto-oncogene Src family tyrosine kinase (LYN; NCBI gene ID: 4067); lymphocyte cytoplasmic protein 2 (LCP2; NCBI gene ID: 3937); lysine demethylase 1A (KDM1A; NCBI gene ID: 23028); lysophosphatidyl receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI gene ID: 1 902); Lysyl oxidase (LOX; NCBI gene ID: 4015); Lysyl oxidase-like protein 2 (LOXL2; NCBI gene ID: 4017); Macrophage migration inhibitory factor (MIF, GIF; NCBI gene ID: 4282); Macrophage stimulating factor 1 receptor (MST1R, CD136; NCBI gene ID: 4486); MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAG). ED1, 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); main fornix proteins (MVP, VAULT1; NCBI gene ID: 9961); MALT1 paracaspase (MALT1; NCBI gene ID: 1 0892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI gene ID: 2872, 8569); matrix metallopeptides (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; NCBI gene ID: 4170); MDM2 proto-oncogene (MDM2; NCBI gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI gene ID: 4194); rapamycin kinase Mechanistic targets (MTOR, FRAP1; NCBI gene ID: 2475); melanin-A (MLANA; NCBI gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI gene ID: 4157, 4148); MER proto-oncogene tyrosine kinase (MERTK; NCBI gene ID: 10461); mesothelin (MSLN; NCBI gene ID: 10232); MET proto-oncogene receptor tyrosine kinases (MET, c-Met, HGFR; NCBI gene ID: 4233); methionine aminopeptidase 2 (METAP2, MAP2; NCBI gene ID: 10988); MHC Class I polypeptide-related sequences (e.g., MICA, MICB; NCBI gene ID: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 β), MAPK12; NCBI gene ID: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI gene ID: 4217, 1326); mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184); mitogen-activated protein kinase kinases (e.g., MAP... 2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI gene IDs: 5604, 5605, 5609); MPL proto-oncogene thrombopoietin receptor (MPL; NCBI gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., including MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125); NCBI gene IDs: 4582, 4586, 94025);MYC proto-oncogene bHLH transcription factor (MYC; NCBI gene ID: 4609); myostatin (MSTN, GDF8; NCBI gene ID: 2660); myristylated alanine-rich protein kinase C substrate (MARCKS; NCBI gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI gene ID: 4883); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI gene ID: 374383); necdin, a member of the MAGE family (NDN; NCBI gene ID: 4692); nectin cell adhesion molecules (e.g., NECTIN2 (CD112)). PVRL2), NECTIN4 (PVRL4); NCBI gene ID: 5819, 81607); Neural cell adhesion molecule 1 (NCAM1, CD56; NCBI gene ID: 4684); Neurociliary proteins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI gene ID: 8828, 8829); Neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI gene ID: 4914, 4915, 4916); NFKB activator (NKAP; NCBI gene ID: 79 576); NIMA-associated kinase 9 (NEK9; NCBI gene ID: 91754); NLR family heat protein domain-containing protein 3 (NLRP3, NALP3; NCBI gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene GTPase (NRAS; NCBI gene ID: 4893); Nuclear factor κB (NFKB1, NFKB2; NCBI gene ID: 4790, 4791); Erythrocyte-derived nuclear factor 2-like protein 2 (NFE2L2; NRF2; N NCBI gene ID: 4780); Nuclear receptor subfamily 4A member 1 (NR4A1; NCBI gene ID: 3164); Nucleolin (NCL; NCBI gene ID: 4691); Nucleophosphoprotein 1 (NPM1; NCBI gene ID: 4869); Protein 2 containing nucleotide-binding oligomerization domain (NOD2; NCBI gene ID: 64127); Nudix hydrolase 1 (NUDT1; NCBI gene ID: 4521); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI gene ID: 4255); Opioid receptor δ1 (OPRD1; NCBI gene ID: 4985); Ornithine decarboxylase 1 (ODC1;NCBI gene ID: 4953); ketoglutarate dehydrogenase (OGDH; NCBI gene ID: 4967); parathyroid hormone (PTH; NCBI gene ID: 5741); PD-L1 (CD274; NCBI gene ID: 29126); periosteal protein (POSTN; NCBI gene ID: 10631); peroxisome proliferator-activated receptors (e.g., PPARA (PPARα), PPARD (PPARδ), PPARG (PPARγ)). NCBI gene IDs: 5465, 5467, 5468); phosphatases and tensin homologues (PTEN; NCBI gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinases (PIK3CA (PI3Kα), PIK3CB (PI3Kβ), PIK3CD (PI3Kδ), PIK3CG (PI3Kγ); NCBI gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2...). G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647; Pim proto-oncogene serine / threonine kinases (e.g., PIM1, PIM2, PIM3); NCBI gene IDs: 5292, 11040, 415116); placental growth factor (PGF; NCBI gene ID: 5228); plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1; NCBI gene IDs: 5156, 5159); plexin B1 (PLXNB1; NCBI gene ID: 5364); Poliovirus receptor (PVR) cell adhesion molecules (PVR, CD155; NCBI gene ID: 5817); Polo-like kinase 1 (PLK1; NCBI gene ID: 5347); Poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI gene ID: 142, 10038, 10039); Polycomb protein EED (EED; NCBI gene ID: 8726); Porcupine O-acyltransferase (PORCN; NCBI gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI gene ID: 23532); Premelanosome protein (PMEL;NCBI gene ID: 6490); progesterone receptor (PGR; NCBI gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI gene ID: 5133); programmed cell death protein 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); Prostaglandin-activated protein (PSAP; NCBI gene ID: 5660); Prostaglandin E receptor 4 (PTGER4; NCBI gene ID: 5734); Prostaglandin E synthase (PTGES; NCBI gene ID: 9536); Prostaglandin-endoperoxidase (PTGS1 (COX1), PTGS2 (COX2); NCBI gene ID: 5742, 5743); Proteasome 20S subunit β9 (PSMB9; NCBI gene ID: 5698) Protein arginine methyltransferases (e.g., PRMT1; NCBI gene ID: 3276); 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 receptors (PTPRB (PTPB), PTPRC (CD45R); NCBI gene IDs: 5787, 5788); prothymosin α (PTMA; NCBI gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI gene ID: 4860); purinergic receptor P2X 7 (P2RX7; NCBI gene ID: 5027); Contains PVR-associated immunoglobulin domains (PVRIG, CD112R; NCBI gene ID: 79037); Raf-1 proto-oncogene serine / threonine kinases (RAF1, c-Raf; NCBI gene ID: 5894); RAR-associated orphan receptor γ (RORC; NCBI gene ID: 6097); Ras homolog family member C (RHOC; NCBI gene ID: 389); mTORC1-binding Ras homolog (RHEB; NCBI gene ID: 6009); RB transcriptional co-repressor 1 (RB1; NCBI gene ID: 5925); Receptor-interacting serine / threonine protein kinase 1 (RIPK1; NCBI gene ID: 8737); ret proto-oncogene (RET; NCBI gene ID: 5979); Early retinoic acid transcripts (e.g., RAET1E, RAET1G, RAET1L);NCBI gene IDs: 135250, 154064, 353091); retinoic acid receptor α (e.g., RARA, RARG; NCBI gene IDs: 5914, 5916); retinoid X receptors (e.g., RXRA, RXRB, RXRG; NCBI gene IDs: 6256, 6257, 6258); protein kinases containing Rho-associated coiled helices (e.g., ROCK1, ROCK2; NCBI gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-β1; NCBI gene ID: 6198); ring finger protein 128 (RNF128, GRAIL; NCBI gene ID: 79 589); ROS proto-oncogene 1 receptor tyrosine kinase (ROS1; NCBI gene ID: 6098); island guide 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 coil-associated protein 2 (SFRP2; NCBI gene ID: 6423); secretory phosphoprotein 1 (SPP1; NCBI gene ID: 6696); secretory globin family 1A member 1 (SCGB1A1; NCBI gene ID: 7356); selectins (e.g., SELE, S... ELL (CD62L), SELP (CD62); NCBI gene ID: 6401, 6402, 6403); semaphore 4D (SEMA4D; CD100; NCBI gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI gene ID: 27036, 27180, 89790); signal regulatory protein α (SIRPA, CD172A; NCBI gene ID: 140885); signal transducers and transcription activators (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI gene ID: 140885); NCBI gene ID: 140885. D: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI gene ID: 23410); members of the signal transduction lymphocyte activation molecule (SLAM) family (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI gene ID: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI gene ID: 84189); smooth-curled class receptor (SMO; NCBI gene ID: 6608);Soluble epoxide hydrolase 2 (EPHX2; NCBI gene ID: 2053); members of the solute carrier family (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI gene IDs: 6751, 6752, 6753, 6754, 6755); sonic acid Hedgehog signaling molecules (SHH; NCBI gene ID: 6469); Sp1 transcription factor (SP1; NCBI gene ID: 6667); sphingosine kinases (e.g., SPHK1, SPHK2; NCBI gene ID: 8877, 56848); sphingosine-1-phosphate receptor 1 (S1PR1, CD363; NCBI gene ID: 1901); spleen-associated tyrosine kinase (SYK; NCBI gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI gene ID: 23451); SRC proto-oncogene non-receptor tyrosine kinase (SRC; NCBI gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI gene ID: 23166); STEAP family member 1 (STEAP1; NCBI gene ID: 26872); Steroid sulfatase (STS; NCBI gene ID: 412); Interferon response stimulator cGAMP interactor 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); Synaptic protein 3 (SYN3; NCBI gene ID: 23166); Due to ID: 8224); multiligand glycan 1 (SDC1, CD138, multiligand glycan; NCBI gene ID: 6382); synuclein α (SNCA, PARK1; NCBI gene ID: 6622); protein 4 containing T cell immunoglobulin and mucin domains (TIMD4, SMUCKLER; NCBI gene ID: 91937); T cell immune receptors with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI gene ID: 6869, 6870); TANK-binding kinase 1 (TBK1; NCBI gene ID: 29110);Terminal anchor polymerase (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); TEC protein tyrosine kinase (TEC; NCBI gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI gene ID: 7010); Telomerase reverse transcriptase (TERT; NCBI gene ID: 7015) Tenosynovin C (TNC; NCBI gene ID: 3371); three major repair exonucleases (e.g., TREX1, TREX2; NCBI gene ID: 11277, 11219); thrombomodulin (THBD, CD141; NCBI gene ID: 7056); thymidine kinases (e.g., TK1, TK2; NCBI gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI gene ID: 1890); thymidine synthase (TYMS; NCBI gene ID: 7298); thyroid hormone receptors (THRA, THRB; NCBI gene ID: 7606, 7608); thyroid-stimulating hormone receptor (TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), T NFSF18 (GITRL); NCBI gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995; Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793);Transferrin (TF; NCBI gene ID: 7018); Transferrin receptors (TFRC, CD71; NCBI gene ID: 7037); Transforming growth factor (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: 9333); Transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1); NCBI gene ID: 7442); transmembrane and immunoglobulin domain-containing proteins 2 (TMIGD2, CD28H, IGPR1; NCBI gene ID: 126259); trigger receptors expressed on 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 hydroxylases (e.g., TPH1, TPH2). ; NCBI gene ID: 7166, 121278); Tumor-associated calcium signal transducers 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); Tumor necrosis factor (TNF; NCBI gene ID: 7124); Members of the tumor necrosis factor (TNF) receptor superfamily (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD13) 7, 4-1BB), TNFRSF10A (CD261), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRSF12A, TNFRSF13B, TN FR13C (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25;NCBI gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504; tumor protein p53 (TP53; NCBI gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (TUSC2; NCBI gene ID: 11334) TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI gene ID: 7301); tyrosinase (TYR; NCBI gene ID: 7299); tyrosine hydroxylase (TH; NCBI gene ID: 7054); tyrosine kinase 1 with immunoglobulin-like and EGF-like domains (e.g., TIE1, TIE1; NCBI gene ID: 7075); tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2; NCBI gene ID: 5781); ubiquitin-coupled enzyme E2 I (UBE2I, UBC9; NCBI gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI gene ID: 7874); ubiquitin-like modifier activator 1 (UBA1; NCBI gene ID: 7317); UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI gene ID: 79465, 80328, 80328); valine-containing proteins (VCP, CDC48; NCBI gene ID: 7415); vascular cell adhesion components VCAM1, CD106; NCBI gene ID: 7412; Vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI gene ID: 7422, 7423); Vimentin (VIM; NCBI gene ID: 7431); Vitamin D receptor (VDR; NCBI gene ID: 7421); V-set domain-containing T cell activation inhibitors 1 (VTCN1, B7-H4; NCBI gene ID: 79679); V-set immunomodulatory receptors (VSIR, VISTA, B7-H5; NCBI gene ID: 64115); WEE1 G2 checkpoint kinase (WEE1; NCBI gene ID: 7465); WRN RecQ-like helicase (WRN; RECQ3; NCBI gene ID: 7486); WT1 transcription factor (WT1; NCBI gene ID: 7490); WW domain-containing transcriptional regulator 1 (WWTR1; TAZ; NCBI gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI gene ID: 6375);XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI gene ID: 2829); Yes1-associated transcriptional regulator (YAP1; NCBI gene ID: 10413); or ζ chain-associated protein kinase 70 (ZAP70; NCBI gene ID: 7535).

[0298] In some implementations, one or more additional therapeutic agents include, for example, agents targeting: 5'-extracellular nucleotidases (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Receptor (ADORA2A; NCBI gene ID: 135); Adenosine A 2BReceptors (ADORA2B; NCBI gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); Cytokine-inducible SH2-containing proteins (CISH; NCBI gene ID: 1154); Diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI gene ID: 1606); fms-like tyrosine kinase 3 (FLT3, CD135; NCBI gene ID: 2322); Integrin-associated proteins (IAP, CD47; NCBI gene ID: 961); Interleukin-2 (IL2; NCBI gene ID: 3558); Interleukin 2 receptors (IL2RA, IL2RB, IL2RG; NCBI gene ID: 3559, 3560, 3561); Kirsten rat sarcoma virus (KRAS; NCBI gene ID: 3845; including mutations such as KRAS) G12C or G12D); mitogen-activated protein kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor cell 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 δ (PIK3CD; NCBI gene ID: 5293); programmed death ligand 1 (PD-L1, CD274; NCBI gene ID 29126); programmed cell death protein 1 (PD-1, CD279; NCBI gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI gene ID: 3815); signal regulatory protein α (SIRPA, CD172A; NCBI gene ID: 140885); TCDD-induced poly(ADP-ribose) polymerase (TIPARP, PARP) 7; NCBI gene ID: 25976); T-cell immune receptors with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); Trigger receptor 1 expressed on bone marrow cells (TREM1; NCBI gene ID: 54210); Trigger receptor 2 expressed on bone marrow cells (TREM2; NCBI gene ID: 54209); Tumor-associated calcium signaling transducers 2 (TACSTD2, TROP2, EGP1; NCBI gene ID: 4070); Tumor necrosis factor receptor superfamily member 4 (TNFRSF4, CD134, OX40; NCBI gene ID: 7293); Tumor necrosis factor receptor superfamily member 9 (TNFRSF9, 4-1BB, CD137; NCBI gene ID: 3604); Tumor necrosis factor receptor superfamily member 18 (TNFRSF18, CD357, GITR; NCBI gene ID: 8784).WRN RecQ-like helicase (WRN; NCBI gene ID: 7486); or zinc finger protein Helios (IKZF2; NCBI gene ID: 22807).

[0299] Exemplary mechanism of action

[0300] Immune checkpoint modulators

[0301] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) 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 with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape of cancer cells within the tumor microenvironment. Activation or stimulation of stimulating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in cancer treatment. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In some implementations, immune checkpoint proteins or receptors modulate NK cell responses (e.g., in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671–688). Suppression of regulatory T cells (Tregs) or depletion of Tregs can alleviate their inhibition of antitumor immune responses and have anticancer effects (e.g., reviewed in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459–77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140–1146).

[0302] Examples of immune checkpoint proteins or receptors that can bind to 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), CD2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H; NCBI gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI gene ID: 8832), and CD96 (NCBI gene ID: 102). 25) CD160 (NCBI gene ID: 11126), MS4A1 (CD20; NCBI gene ID: 931), CD244 (SLAMF4; NCBI gene ID: 51744); CD276 (B7H3; NCBI gene ID: 80381); T cell activation inhibitors containing V-set domains 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA; NCBI gene ID: 64115); Immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI gene ID: 152404); Natural killer cell 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 costimulatory factors (ICOS, CD278; NCBI gene ID: 29851); Inducible T cell costimulatory factor ligands (ICOSLG, B7H2; NCBI gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI gene ID: 7292); TNFRSF8 (CD30; NCBI gene ID: 943) TNFSF8 (CD30L; NCBI gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI gene ID: 8797), TNFRSF9 (CD137; NCBI gene ID: 3604), TNFSF9 (CD137L; NCBI gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI gene ID: 8795), TNFRSF10 (TRAIL; NCBI gene ID: 8743); TNFRSF14 (HVEM, CD270);NCBI gene ID: 8764), TNFSF14 (HVEML; NCBI gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA); NCBI gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFSF13B (BAFF; NCBI gene ID: 10673); TNFRSF18 (GITR; NCBI gene ID: 8784), TNFSF18 (GITRL; NCBI gene ID: 8995); MHC class I peptide-associated sequence A (MICA; NCBI gene ID: 100507436); MHC Class I polypeptide-related sequences 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 ( ...4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI gene ID: 4277); CD274 (CD274, PDL1, PD-L1; 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); containing PVR-associated immunoglobulin domains (PVRIG, CD112R; NCBI gene ID: 79037); T cells with Ig and ITIM domains Cellular immune receptor (TIGIT; NCBI gene ID: 201633); 4 containing T cell immunoglobulin and mucin domains (TIMD4; TIM4; NCBI gene ID: 91937); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3; NCBI gene ID: 84868); Galactagogue 9 (LGALS9; NCBI gene ID: 3965); Lymphocyte activation gene 3 (LAG3, CD223; NCBI gene ID: 3902); Member 1 of the signaling lymphocyte activation molecule family (SLAMF1, SLAM, CD150; NCBI gene ID: 6504); Lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); Member 6 of the SLAM family (SLAMF6, CD352; NCBI gene ID: 114836); Member 7 of the SLAM family (SLAMF7, CD319; NCBI gene ID: 57823); UL16 binding protein 1 (ULBP1;NCBI gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI gene ID: 154064); cytotoxic cell immunoglobulin-like Receptors, three Ig domains, and a long cytoplasmic tail 1 (KIR, CD158E1; NCBI gene ID: 3811, e.g., lirelurumab (IPH-2102, IPH-4102)); cytotoxic lectin-like receptor C1 (KLRC1, NKG2A, CD159A; NCBI gene ID: 3821); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI gene ID: 22914); cytotoxic lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI gene ID: 3822); cytotoxic Cytokine-like lectin receptor C3 (KLRC3, NKG2E; NCBI gene ID: 3823); Cytokine-like lectin receptor C4 (KLRC4, NKG2F; NCBI gene ID: 8302); Cytokine-like immunoglobulin receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1; NCBI gene ID: 3802); Cytokine-like immunoglobulin receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2; NCBI gene ID: 3803); Cytokine-like immunoglobulin receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3) (NCBI gene ID: 3804); cytotoxic cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor D1 (KLRD1; NCBI gene ID: 3824); cytotoxic 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).

[0303] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with one or more blockers or inhibitors of one or more T-cell suppressive immune checkpoint proteins or receptors. Exemplary T-cell suppressor immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-containing immunoglobulin... Protein domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered together with one or more agonists or activators of one or more T-cell-stimulating immune checkpoint proteins or receptors.Exemplary T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulators (ICOS, CD278); inducible T-cell costimulator 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). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0304] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) 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. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors; and cytotoxic cell immunoglobulin-like receptors. Cellular immunoglobulin-like receptors, three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic lectin-like receptors C1 (KLRC1, NKG2A, CD159A); cytotoxic lectin-like receptors D1 (KLRD1, CD94); cytotoxic lectin-like receptors G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-binding Ig-like lectin 7 (SIGLEC7); and sialic acid-binding Ig-like lectin 9 (SIGLEC9). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof 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-stimulating immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); cytotoxic 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.

[0305] In some embodiments, one or more immune checkpoint inhibitors comprise inhibitors of proteins (e.g., antibodies or fragments thereof or antibody mimics) of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors comprise small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors comprise inhibitors of proteins (e.g., antibodies or fragments thereof or antibody mimics) of LAG3.

[0306] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (an ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, and HBM- 4003, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and 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).

[0307] Examples of co-administerable PD-L1 (CD274) or PD-1 (PDCD1) inhibitors include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, and cosibelimab (CK). -301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ) -63723283), Genolimzumab (CBT-501), LZM-009, Prolgolimab (BCD-100), Lodapolimab (LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, Bulgarimab (ABBV-181), PD1-PIK, BAT-1306, Avelumab (MSB0010718C), CX-072, CBT-502, Dotalilimumab Dostarlimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), Envafolimab (KN-035), Sintilismab (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, MAX10181The compounds disclosed in zimberrelimab (AB122), spartazolizumab (PDR-001), and WO2018195321, WO2020014643, WO2019160882 or WO2018195321, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 ( PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), TAK-252 (PD-1 / OX40L), Xm Ab-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), Bintrafusp α (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor, such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0308] Examples of TIGIT inhibitors that can be co-administered include tirelimumab (RG-6058), vimbrolizumab, dunnilumab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or atelimumab.

[0309] Examples of LAG3 inhibitors that can be co-administered include, but are not limited to, erralizumab (LAG525).

[0310] Inhibition of regulatory T cell (Treg) activity or Treg depletion can reduce their suppression of antitumor immune responses and have anticancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with one or more Treg activity inhibitors or Treg depletion agents. Treg inhibition or depletion can enhance the effects of immune checkpoint inhibitors in cancer therapeutics.

[0311] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are administered together with one or more Treg inhibitors. In some embodiments, the Treg inhibitors inhibit Treg migration into the tumor microenvironment. In some embodiments, the Treg inhibitors reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitors modulate cell phenotype and induce the production of pro-inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists and Ikaros zinc finger protein degraders (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).

[0312] Examples of Helios degrading agents that can be co-applied include, but are not limited to, I-57 (Novartis) and the compounds disclosed in WO2019038717, WO2020012334, WO20200117759 and WO2021101919.

[0313] 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 cytotoxic (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc-engineered to have enhanced ADCC activity. In some embodiments, the Treg depletion antibody is an antibody-drug conjugate (ADC). Indicative targets 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).

[0314] In some implementations, the co-administerable Treg inhibitors or Treg depletion agents comprise antibodies or antigen-binding fragments thereof that selectively bind to cell surface receptors selected from the group consisting of: 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), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialylated Lewis... x (CD15s), CD27, extracellular nucleotide triphosphate diphosphate hydrolase 1 (ENTPD1; CD39), C-type protein tyrosine phosphatase receptor (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit αE (ITGAE; CD103), interleukin-7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), containing leucine-rich repeat sequences The following are considered as a whole: LRRC32 (GARP), IKAROS family zinc finger 2 (IKZF2 (HELIOS), inducible T cell co-stimulatory factor (ICOS (CD278), lymphocyte activation 3 (LAG3 (CD223), transforming growth factor β1 (TGFB1), hepatitis A virus cell receptor 2 (HAVCR2 (CD366 (TIM3), T cell immune receptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b (TNFR2), IL2RA (CD25), or combinations thereof.

[0315] Examples of applicable Treg-depleted anti-CCR8 antibodies 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 the antibodies disclosed in WO 2021163064, WO 2020138489, and WO 2021152186.

[0316] Examples of administerable Treg-depleted anti-CCR4 antibodies include moglicillinumab.

[0317] Suppressing, depleting, or reprogramming non-stimulated myeloid cells in the tumor microenvironment can enhance anticancer immune responses (see, for example, Binnewies et al., Nat. Med. (2018) 24(5): 541-550; WO2016049641). Exemplary targets for depleting or reprogramming non-stimulated myeloid cells include trigger receptors expressed on myeloid cells, TREM-1 (CD354, NCBI gene ID: 54210), and TREM-2 (NCBI gene ID: 54209). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are administered together with one or more myeloid cell depletion or reprogramming agents such as anti-TREM-1 antibodies (e.g., the antibody disclosed in PY159; WO2019032624) or anti-TREM-2 antibodies (e.g., the antibody disclosed in PY314; WO2019118513).

[0318] Differentiation cluster agonists or activators

[0319] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered co-administered with an agent targeting a cluster of differentiation (CD) biomarker. Exemplary co-administered CD biomarker targets include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, and trastuzumab (HERCEPTIN). ®Trastuzumab biosimilar (HLX-02), Margetuximab, BAT-8001, Pertuzumab (Perjeta), Pegfilgrastim, RG6264, Zanidatamab (ZW25), Cavasta, AIC-100, Tagraxofusp (SL-401), HLA-A2402 / HLA-A0201 restricted epitope peptide vaccine, Dasatinib, Imatinib, Nilotinib, Sorafenib, Lenvatinib Mesylate, Ofranergene Obadenovec, Cabozantinib Malate malate), AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivative, AGX-73, rebastinib, NMS-088, lucitinib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverembatinib Dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asunercept (APG-101), APO-010,and WO2016196388, WO2016033570, WO2015157386, WO199203459, WO199221766, WO2004080462, WO2005020921, W O2006009755, WO2007078034, WO2007092403, WO2007127317, WO2008005877, WO2012154480, WO2014100620, WO 2014039714, WO2015134536, WO2017167182, WO2018112136, WO2018112140, WO2019155067, WO2020076105, PCT / US2019 / 063091、WO19173692、WO2016179517、WO2017096179、WO2017096182、WO2017096281、WO2018089628、W O2017096179, WO2018089628, WO2018195321, WO2020014643, WO2019160882, WO2018195321, WO200140307, ​​WO2 002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO20 16179399, WO2016205042, WO2017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO201 8210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170, WO2020068752, Cancer Discov. January 9, 2019 (1):8; and Gariepy J. et al., compounds disclosed at the 106th Annu Meet Am Assoc Immunologists (AAI) (May 9–13, San Diego, 2019, Abst 71.5).

[0320] In some implementations, agents targeting CD biomarkers that can be co-administered include small molecule inhibitors such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, roblitinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, and JSP-19. 1. BLU-263, CD117-ADC, AZD3229, Tiratitinib, Voronanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, Motixafortide (BL-8040), LY2510924, Burixafor (TG-0054), X4P-002, Mavorixafor (X4P-001-IO), Plerixafor, CTX-5861, and REGN-5678 (PSMA / CD28).

[0321] In some implementations, co-administerable CD marker targets include small molecule agonists such as interleukin-2 receptor subunit γ, eltrombopag, rapamod, polyICLC (NSC-301463), Riboxxon, Apoxxim, and RIBOXXIM. ® MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, requimide, selgantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0322] In some implementations, co-administerable CD biomarker targets include antibodies such as tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzartamab (MOR-202), TAK-079, TAK573, and daratumumab (DARZALEX). ®TTX-030, selicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazalimab (JNJ-64457107), lenzilumab, alemtuzuma, emactuzumab, AMG-820, FPA-008 (cabiralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simlukafusp α alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatlimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, encelimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20).5) MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, lirilumab (IPH-2102), lacutamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM) 5 / 6), Iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavolixizumab)), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, Compounds disclosed in GWN-323, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, cobolimab (TSR-022), MBG-453, INCAGN-2390, and WO2017096179, WO2017096276, WO2017096189, and WO2018089628.

[0323] In some implementations, co-administerable CD marker targets include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, lisocabtagenemaraleucel (JCAR-017), and axicabtageneciloleucel (KTE-C19, Yescarta). ®), Akylenza (KTE-X19), US7741465, US6319494, UCART-19, Tabelecleucel (EBV-CTL), T tisagenlecleucel-T (CTL019), T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, CD19 / 4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζ T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T cell therapy (B-cell acute lymphoblastic leukemia, National University of Malaysia), anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silencing IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20 CAR T-cell therapy (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), Tn / mem expressing CD19CAR-CD28-CD3ζ-EGFRt, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tesajinlut-T, CART-19, tesajinlut (CTL-019)), anti-CD20 CAR T-cell therapy (non-Hodgkin's lymphoma), MB-CART2019.1. (CD19 / CD20), WZTL-002 Dual Anti-CD19 / Anti-CD20 CAR-T Cell Therapy, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR, CD33, CD33CAR, Dual Anti-BCMA / Anti-CD38 CAR T Cell Therapy, CAR-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 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, CAR-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D ligand modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CAR, and therapies disclosed in WO2012079000 or WO2017049166.

[0324] Differentiation cluster 47 (CD47) inhibitors

[0325] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an inhibitor of CD47 (IAP, MER6, OA3; NCBI gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (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.Other exemplary anti-CD47 antibodies include CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), letaplimab (IBI-188), lemzoparlimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX- 148. AK-117, TTI-621, TTI-622, or WO199727873, WO199940940, WO2002092784, WO2005044857, WO2009046541, WO2010070047, WO2011143624, W O2012170250, WO2013109752, WO2013119714, WO2014087248, WO2015191861, WO2016022971, WO2016023040, WO2016024021, WO2016081423, WO 2016109415, WO2016141328, WO2016188449, WO2017027422, WO2017049251, WO2017053423, WO2017121771, WO2017194634, WO2017196793, WO2 017215585, WO2018075857, WO2018075960, WO2018089508, WO2018095428, WO2018137705, WO2018233575, WO2019027903, WO2019034895, WO20 Compounds disclosed in WO2019042119, WO2019042285, WO2019042470, WO2019086573, WO2019108733, WO2019138367, WO2019144895, WO2019157843, WO2019179366, WO2019184912, WO2019185717, WO2019201236, WO2019238012, WO2019241732, WO2020019135, WO2020036977, WO2020043188 and WO2020009725.In some implementations, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some implementations, the CD47 inhibitor is molotovicillin.

[0326] In some implementations, CD47 inhibitors are bispecific antibodies targeting CD47, such as IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), and IMM-26011 (CD47 / FLT). 3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM- 2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801.

[0327] SIRP α Targeted agents

[0328] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with a SIRPα target (NCBI gene ID: 140885; UniProt P78324). Examples of SIRPα targets 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)). The additional SIRPα targeting agents used are described, for example, in the following literature: WO200140307, ​​WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO2016179399, WO2016205042, W O2017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170 and WO2020068752.

[0329] FLT3R agonists

[0330] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with an FLT3R agonist. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, is administered together with an FLT3 ligand. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, is administered together with an FLT3L-Fc fusion protein, for example, as described in WO2020263830. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, is administered together with GS-3583 or CDX-301. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, is administered together with GS-3583.

[0331] TNF receptor superfamily (TNFRSF) agonists or activators

[0332] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is administered co-administered with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such agonists as one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 7293), TNFRSF1A (OX40, CD134; NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 7293), TNFRSF1B (CD134, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40, CD134; NCBI gene ID: 7293), TNFRSF1B (CD134, CD134; TNFRSF1B (CD134, CD134; TNFRSF1B (CD134)); TNFRSF1B (CD134, CD134 ... D: 958), TNFRSF6 (FAS, NCBI gene ID: 355), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFR SF10C (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 (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 (CD264 ... 68, 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).

[0333] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include MEDI6469, MEDI6383, tavorizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO 2016179517, WO 2017096179, WO 2017096182, WO 2017096281 and WO 2018089628.

[0334] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0335] In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

[0336] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include urinumab, urinumab (PF-05082566), AGEN-2373, and ADG-106.

[0337] In some implementations, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0338] Examples of co-administerable anti-TNFRSF18 (GITR) antibodies include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0339] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronextamab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), plamotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20).

[0340] TGFβ antagonists

[0341] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is combined with TGF. β Antagonists are administered together. In some implementations, TGF-β is used. β The antagonist is TGF β - Specific antibodies. TGF can be prepared and characterized using methods known to those skilled in the art, such as those described in PCT International Application Publication WO 2018 / 129329 and U.S. Patent 9,518,112. β - Specific antibodies. In some implementations, TGF... β Antagonists and TGF β Potentially related peptides (LAPs) (e.g., TGF) β 1-LAP) binding. TGF can be prepared and characterized using methods known to those skilled in the art, such as those described in U.S. Patent No. 8,198,412 or U.S. Patent No. 10,017,567. β 1-LAP-specific antibody. In some implementations, TGF... β Antagonists work in an environment-dependent manner (e.g., with TGF). β (It is unrelated to the expression in specific tissues or organs) and is associated with TGF. β (e.g., TGF) β 1) Combination. In some implementation schemes, TGF β Antagonists interact with TGF in an environment-dependent manner. β (e.g., TGF) β 1) Combination. In some implementation schemes, TGF βAntagonists block potential TGF located in the extracellular matrix (e.g., connective tissue of the liver). β (e.g., potential TGF) β 1) Activation. In some implementations, TGF β Antagonists block potential TGF located in the thymus, lymph nodes, or tumor microenvironment (e.g., in patients with liver cancer). β (e.g., potential TGF) β 1) Activation. In some implementations, TGF β Antagonists via potential TGF β Blocking potential TGF-binding protein (LTBP) β (e.g., potential TGF) β 1) Activation. In some implementations, TGF β Antagonists block potential TGF through glycoprotein-A repeat major protein (GARP). β (e.g., potential TGF) β 1) Activation, such as that described in U.S. Patent No. 10,000,572. In some embodiments, TGF β The antagonist is ARGX-115. In some implementations, TGF... β The antagonist is SK-181. In some implementations, TGF... β Antagonists are associated with LAP-TGF β Anti-Latent Related Peptide (LAP) antibodies that specifically bind to the complex. In some embodiments, the anti-LAP antibody binds to LAP-TGF in, for example, the extracellular matrix (ECM) of connective tissue in the liver. β The complex binds specifically. In some embodiments, the anti-LAP antibody binds to the surface of certain immunosuppressive cell types such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived suppressor cells (e.g., in the tumor microenvironment) and LAP-TGF. β The complex binds specifically. In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody binds to LAP-TGF in any environment. β The complex binds specifically. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, TGF... β Antagonists include TGF β Receptors. In some implementations, TGF... β The antagonist is TGF β Receptor-Fc fusion protein. In some implementations, TGF... β Antagonists are those containing TGF βAntibodies against receptors. For example, TGF-containing compounds that can be used in conjunction with the compositions and methods provided herein have been described in PCT International Publications WO 2019 / 113123 A1 and WO 2019 / 113464 A1. β TGF receptor β Antagonist.

[0342] Bispecific T cell adaptor

[0343] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with a bispecific T-cell adaptor (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortxizumab (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 onitrile. Tumumab (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673 (CD33 / CD3), AM G-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), Titumumab (XmAb-18087;SSTR2 / CD3, catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33). Depending on the situation, anti-CD3 binding bispecific molecules may or may not have an Fc. Exemplary bispecific T-cell adaptors that can be co-administered target CD3 and tumor-associated antigens as described herein, including, for example, CD19 (e.g., bonnetumab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil et al., Oncoimmunology. (2017) May 17; 6(7):e1326437); PD-L1 (Horn et al., Oncotarget. 2017 Aug 3; 8(35):57964-57980); and EGFRvIII (Yang et al., CancerLett. 2017 Sep 10; 403:224-230).

[0344] Bispecific and trispecific natural killer (NK) cell adaptors

[0345] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with a bispecific NK cell adjuvant (BiKE) or a trispecific NK cell adjuvant (TriKE) (e.g., without Fc) or a bispecific antibody against: NK cell activation receptors, such as CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, ...). NKG2E / H and NKG2F), natural cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIRs) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Depending on the situation, anti-CD16 binding bispecific molecules may or may not have an Fc. Exemplary bispecific NK cell adaptors that can be co-administered target CD16 and one or more tumor-associated antigens as described herein, including, for example, CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54.

[0346] MCL1 is a regulator of cell apoptosis and an inhibitor of the BCL2 family member (MCL1).

[0347] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with an inhibitor of the following: members of the BCL2 family of MCL1 apoptosis regulators (MCL1,TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO2018183418, WO2016033486, and WO2017147410.

[0348] SHP2 inhibitors

[0349] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an inhibitor of non-receptor protein tyrosine phosphatase 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO2018172984 and WO2017211303.

[0350] Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors and degraders

[0351] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with an inhibitor of mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of hematopoietic progenitor cell kinase 1 (HPK1) inhibitors include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300.

[0352] Inhibitors of apoptosis signal-regulated kinase (ASK)

[0353] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an ASK inhibitor, such as mitogen-activated protein kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO 2013112741 (Gilead Sciences).

[0354] Bruton's tyrosine kinase (BTK) inhibitors

[0355] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, and M-2951 (ibrutinib). Evobrutinib, M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0356] Cyclin-dependent kinase (CDK) inhibitors

[0357] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors of: cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; p34CDC2; NCBI gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 3 (CDK2, CDC28A; p34CDC2; NCBI gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 3 (CDKN2 ... Enzyme 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 CDK 1, 2, 3, 4, 6, 7 and / or 9 include abemaciclib, alvocidib (HMR-1275, flovipridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, samuraciclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, simurosertib hydrate (TAK931), and TG-02.

[0358] Discoid domain receptor (DDR) inhibitors

[0359] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with inhibitors of: discoid domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI gene ID: 780); and / or discoid domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO2013 / 034933 (Imperial Innovations).

[0360] Targeting E3 ligase ligand conjugates

[0361] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with E3-targeting ligand conjugates. Such conjugates have a target protein binding moiety and an E3 ligand binding moiety (e.g., inhibitors of apoptosis proteins (IAPs) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin) E3 ubiquitin ligand binding moiety, Von Hippel-Lindau E3 ubiquitin ligand (VHL) binding moiety, cereblon E3 ubiquitin ligand binding moiety, mouse bismin 2 homolog (MDM2) E3 ubiquitin ligand binding moiety), and can be used, for example, to promote or increase the degradation of the target protein via the ubiquitin pathway. In some embodiments, the E3-targeting ligand conjugate comprises: a targeting or binding moiety that targets or binds to the protein described herein, and an E3 ligand ligand or binding moiety. In some embodiments, the E3 ligase-targeting conjugate comprises 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 E3 ligase-targeting conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor, such as BTK, and a small molecule kinase inhibitor of the E3 ligase ligand or binding moiety). See, for example, WO2018098280. In some embodiments, the E3 ligase-targeting conjugate comprises: a binding moiety that targets or binds to interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4); a rapidly accelerating fibrosarcoma (RAF, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and an E3 ligase ligand or binding moiety. See, for example, WO2019099926, WO2018226542, WO2018119448, WO2018223909, and WO2019079701. Co-application of additional targeting E3 ligase ligand conjugates is described, for example, in WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649.

[0362] Histone deacetylase (HDAC) inhibitors

[0363] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an inhibitor of histone deacetylases, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitana, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0364] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0365] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), resminostat, SBLK-200802 and shIDO-ST, EOS-200271, KHK-2455 and LY-3381916.

[0366] Janus kinase (JAK) inhibitors

[0367] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or their pharmaceutically acceptable salts, 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), lestaurtinib, momelotinib (CYT0387), igratinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib citrate), INCB052793, and XL019.

[0368] Lysyl oxidase-like protein (LOXL) inhibitors

[0369] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) 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 WO 2009017833 (Arresto Biosciences), WO 2009035791 (Arresto Biosciences), and WO 2011097513 (Gilead Biologics).

[0370] Matrix metalloproteinase (MMP) inhibitors

[0371] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie), (Ia), (Ib), or (Ic) provided herein, or pharmaceutically acceptable salts thereof, are administered together with inhibitors of matrix metalloproteinases (MMPs), such as inhibitors of the following: MMP1 (NCBI gene ID: 4312), MMP2 (NCBI gene ID: 4313), MMP3 (NCBI gene ID: 4314), MMP7 (NCBI gene ID: 4316), MMP8 (NCBI gene ID: 4317), MMP9 (NCBI gene ID: 4318), MMP10 (NCBI gene ID: 4319), MMP11 (NCBI gene ID: 4320), and MMP12 (NCBI gene ID: 4320). 1) 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 marimastastat (BB-2516), simmastastat (Ro 32-3555), GS-5745 (andadecaliximab), and those described in WO 2012027721 (Gilead Biologics).

[0372] RAS and RAS pathway inhibitors

[0373] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with an inhibitor of: KRAS proto-oncogene GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI gene ID: 3845); NR Ras proto-oncogene GTPases (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI gene ID: 4893) or HRAS proto-oncogene GTPases (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 the polynucleotide (e.g., transcription inhibitors) or peptide (e.g., GTPase inhibitors) level. In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, such as inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that can be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adagrasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and selective K-Ras (G12D) inhibitory peptides, including KRpep-2 and KRpep-2d. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 aptamers, AZD-4785, and siG12D-LODER. ™And siG12D exosomes. Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include ligoteb. Indicative PI3K inhibitors that can be co-administered include edrelixib (Zydelig). ® Avocadoliximab, bupaliximab, pictilisib, inavolisib (RG6114), and ASN-003 are examples of AKT inhibitors that can be co-administered. Examples of PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, GSK-2126458, enoxacillin (RG6114), sapanisertib, ME-344, sirolimus (oral nanoamorphous formulation, for cancer), racemic tyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), and tamsilimus (TORISEL). ® , CCI-779), CC-115, onatasertib (CC-223), SF-1126 and PQR-309 (bimiralisib). In some implementations, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be suppressed by co-administration of the MEK inhibitor selmetinib and the CDK4 / 6 inhibitor pebocilib. See, for example, Zhou et al., Cancer Lett. 2017 Nov 1; 408:130-137. Moreover, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor lenatatinib. See, for example, Booth et al., Cancer Biol Ther. 2018 Feb 1; 19(2):132-137.

[0374] Mitogen-activated protein kinase (MEK) inhibitors

[0375] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinonol, bimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimatetinib, LTT462, AS703988, CC-90003, and refametinib.

[0376] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0377] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with an inhibitor of the substance: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI gene ID: 5290); 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, P110DELTA, PI3K, p110D; NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, and idelalisib (Zydelig). ®INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Wollman penicillin, ZSTK474, and WO2005113556 (ICOS), WO The compounds described in 2013 / 052699 (Gilead Calistoga), WO2013116562 (Gilead Calistoga), WO2014100765 (Gilead Calistoga), WO2014100767 (Gilead Calistoga) and WO2014201409 (Gilead Sciences).

[0378] Spleen tyrosine kinase (SYK) inhibitors

[0379] In some implementations, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or their pharmaceutically acceptable salts, 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]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in US8450321 (Gilead Connecticut) and US 20150175616.

[0380] Toll-like receptor (TLR) agonists

[0381] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with an agonist of a Toll-like receptor (TLR), such as an agonist of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793).Exemplary TLR7 agonists that can be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, 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 US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014056953 (Janssen), WO2014076221 (Ja nssen), WO2014128189 (Janssen), US20140350031 (Janssen), WO2014023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx The compounds disclosed in US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics) are included. A co-administerable TLR7 / TLR8 agonist is NKTR-262.Exemplary TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Jans sen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Examples of TLR9 agonists that can be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, literimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include retalimod, polyICLC, and RIBOXXON. ® Apoxxim, RIBOXXIM ® IPH-33, MCT-465, MCT-475 and ND-1.1.

[0382] Tyrosine kinase inhibitors (TKIs)

[0383] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with a tyrosine kinase inhibitor (TKI). The TKI targets the epidermal growth factor receptor (EGFR) as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, sildenafil, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), and others. Patinib, Lentatinib, Lenvatinib, Midotaurin, Nintedanib, ODM-203, Osimertinib (AZD-9291), Ponatinib, Poziotinib, Quizartinib, Radotinib, Rociletinib, Sulfatinib (HMPL-012), Sunitinib, Famitinib L-malate (MAC-4), Tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeting agents include neratinib, taucatinib (ONT-380), tervatinib, mobotinib (TAK-788), DZD-9008, vallitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, and lazertinib (LECLAZA).® ) and compounds disclosed in the following literature: 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), seribantumab, neximetumab, depatuxizumab mafodotin (ABT-414), tomuzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0384] Chemotherapy

[0385] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with chemotherapeutic agents or antitumor agents.

[0386] As used herein, the terms "chemotherapy agent" or "chemotherapeutic agent" (or "chemotherapy" in the context of treatment with a chemotherapy agent) are intended to cover any non-protein (e.g., non-peptide) compound that can be used to treat cancer. Examples of chemotherapy agents include, but are not limited to: alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN). ®); alkyl sulfonates, such as busulfan, indomethacin, and piperosulfan; azacyclopropanes, such as benzothiopena, carboquinone, metopepane, and urotepipe; ethylene imines and methyl melamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; lactones, such as brassic acid and brassanoic acid; camptothecin, including the synthetic analog topotecan; bryophyll, callus inhibin; CC-1065, including its synthetic analogs adolexin, calcexin, and bicelenexin; nostocin, especially nostocin 1 and nostocin 8; salicylate; pyromycin, including the synthetic analog KW -2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, naphthylambucil, cyclophosphamide, glucosamine, levomycinamide, bendamustine, estradiol, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine hydrochloride, melphalan, neo-embezzin, benzylmustine, prednimustine, trelophosphamide, and uracil mustard; nitrosourea, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ramustine; antibiotics, such as Enadenyllium antibiotics (e.g., chachiin, especially chachiin γII and chachiin φI1), danendomycin (including danendomycin A), bisphosphonates (such as clophosphonates), esperamycin, neocarcinogen chromophores and related pigment proteins, enadenyllium antibiotic chromophores, aclarubicin, actinomycin, atrazosin, diazoserine, bleomycin, actinomycin C, carabicin, carrninomycin, carzinophilin, chromomycin, actinomycin D, donomycin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin (including morpholino) - Doxorubicin, cyanomorpholine-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, isopycin, idarubicin, mesorcinol, mitomycin such as mitomycin C, mycophenolic acid, nogamycin, olivomycin, pepromycin, pofibromycin, puromycin, quelamycin, rodorubicin, streptomycin, streptozotocin, tuberculin, ubenmex, fenestrated statin and zolrubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as norpterin, methotrexate, pteroxate and trimethoprim; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thioimidazoline and thioguanine.Pyrimidine analogues, such as ancitabine, azacitidine, 6-azouridine, carmoflu, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, and fluorouridine; androgens, such as capprotestone, drotalonone propionate, cyclothionol, meandrolone, and testrolide; antiadrenergics, such as aminoglutethimide, mitotane, and trilosterone; folic acid supplements, such as folinic acid; radiotherapy agents, such as radium-223; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxanes, such as paclitaxel (TAXOL); ® ), albumin-bound paclitaxel (abraxane), docetaxel (TAXOTERE) ® Cabazitaxel, BIND-014, Testacoxetine; sabizabulin (Veru-111); platinum analogs, such as cisplatin and carboplatin, NC-6004 nanoplatinum; glucuronolactone; aldehyde phosphoramide glycoside; aminolevulinic acid; emuramicin; acridine; hestrabucil; pyrimethanil; edatrazine; desphosphonamide; colchicine; desaccharin; elformthine; eletine; epothilone; etogluconol; gallium nitrate; hydroxyurea; lentinan; formyltetrahydrofolate; chlordamine; maytansine alkaloids, such as maytansine and anthraquinone; Mitoguanidine hydrazone; Mitoantrone; Mopiperazine; Diaminonitroacetyl; Pentostatin; Methionine mustard; Pirarubicin; Loxoantrone; Fluoropyrimidine; Leucovorin; Podophyllin; 2-Ethylhydrazide; Procarbazine; Polysaccharide-K (PSK); Razosen; Rhizomycin; Cizonan; Germonylspiramine; Alternaria ketoacid; Trabectedin, Triaminoquinone; 2,2',2''-Trichlorotrimethylamine; Carbamate; Vinpocetine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromoeugenol; Piperobromide; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Chlorobutacid; Gemcitabine ® ); 6-Thioguanine; mercaptopurine; methotrexate; vincristine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE) ®); Norsoxim; Teniposide; Idatroxa; Donomycin; Amistetine; Xeoloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DFMO); Retinoids, such as retinoic acid; Capecitabine; NUC-1031; FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin); FOLFIRI (leucovorin, 5-fluorouracil, irinotecan); FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing substances. Such agents may be conjugated to antibodies or any of the targeting agents described herein to form antibody-drug conjugates (ADCs) or targeted drug conjugates.

[0387] Anti-hormone agents

[0388] The definition of “chemotherapy agents” also includes anti-hormonal agents, such as anti-estrogens and selective estrogen receptor modulators (SERMs), aromatase inhibitors, anti-androgens, and any pharmaceutically acceptable salts, acids, or derivatives of the above substances, which are used to regulate or inhibit the effects of hormones on tumors.

[0389] Examples of anti-estrogens and SERMs include tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trivoxifen, raloxifene hydrochloride, LY117018, onanasone, and toremifene (FARESTON). ® ).

[0390] Inhibitors of aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, and megestrol acetate (MEGACE). ® Exemestane, Formexane, Fazodazole, Vorcicloazole (RIVISOR) ® Letrozole (FEMARA) ® ) and anastrozole (ARIMIDEX) ® ).

[0391] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, gluconate, nilumet, bicalutamide, leuprorelin, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antense).

[0392] Examples of progesterone receptor antagonists include onassidone. Additional progesterone-targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestrol + ethinyl estradiol (Tri-Cyclen), and levonorgestrel.

[0393] Anti-angiogenic agents

[0394] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include retinoic acid and its derivatives, 2-methoxyestradiol, and ANGIOSTATIN. ® ENDOSTATIN ®Regorafenib, necuparanib, suramin, squalamine, tissue inhibitors of metalloproteinase-1 and 2, plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2, chondroitin inhibitors, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (herring protamine), sulfated chitin derivatives (prepared from the shell of the grey-eyed snow crab), sulfated polysaccharide-peptide-polysaccharide complex (sp-pg), astrocytocin, matrix metabolism regulators (including proline analogs such as L-azacyclobutane-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, and thioproline), α,α'-dipyridyl, β-Aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken metalloproteinase inhibitor-3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecyl sulfate, eponemycin, fumonisin, sodium gold thiomalate, d-penicillamine, β-1-anticollagenase-serum, α-2-antifibrinolytic enzyme, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroaminoanisole disodium or "CCA", thalidomide, angiogenesis inhibitory steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, S100A9 inhibitors such as taquimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isotypes, VEGF-C, HGF / SF, and Ang-1 / Ang-2. Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, dilpacimab (ABT-165; DLL4 / VEGF), or navicixizumab (OMP-305B83; DLL4 / VEGF).

[0395] Anti-fibrotic agent

[0396] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an antifibrotic agent. Antifibrotic agents that may be administered together include compounds such as β-aminopropionitrile (BAPN), as well as compounds disclosed in US4965288 relating to lysyl oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition, and compounds disclosed in US4997854 relating to the inhibition of LOX to treat various pathological fibrotic states, which are incorporated herein by reference. Other exemplary inhibitors are described in US4943593, which relates to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; and in US5021456, US5059714, US5120764, US5182297, US5252608, and US20040248871, which relate to 2-(1-naphthoxymethyl)-3-fluoroallylamine, and are incorporated herein by reference.

[0397] Exemplary antifibrotic agents also include primary amines that react with the carbonyl group at the active site of lysyl oxidase, and more specifically, those that, upon binding with the carbonyl group, produce a product stabilized by resonance, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine and their derivatives; aminourea 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 selenocysteine ​​lactone.

[0398] Other antifibrotic agents are copper chelators, whether they penetrate cells or not. Exemplary compounds include indirect inhibitors that block aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiol amines (particularly D-penicillamine) and analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetaminoethyl)dithio)butyric acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butyric acid, sodium 4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetaminoethyl-2-acetaminoethylthiol sulfate, and sodium 4-mercaptobutanesulfinate trihydrate.

[0399] anti-inflammatory agents

[0400] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with an anti-inflammatory agent. Examples of anti-inflammatory agents include, but are not limited to, inhibitors of one or more of the following substances: arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), C A12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632)), prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin-endoperoxidase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secretory 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 8 (MAP3K8, TPL2; NCBI gene ID: 1326). In some implementations, the inhibitor is a dual inhibitor, such as a dual inhibitor of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, or COX-2 / 5-LOX.

[0401] Examples of prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742) inhibitors that can be co-administered include monoxazolidine, GLY-230, and TRK-700.

[0402] Examples of prostaglandin-endoperoxidase 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, mesosulide, romecoxib, meloxicam, vardicoxib, zaltoprofen, nimesulide, anizafen, alicoxib, cimicoxib, delacoxib, flumicazole, feroximateb, malvacoxib, NS-398, pamigre, parecoxib, robecoxib, rofecoxib, evodiamine, temoxib, and zaltoprofen. Examples of co-administerable dual COX1 / COX2 inhibitors include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of co-administerable dual COX-2 / carbonic anhydrase (CA) inhibitors include pomacoxib and ericoxib.

[0403] Examples of co-administerable inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES; gene ID: 9536) include LY3023703 and GRC. 27864, and WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589, WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673, WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778, WO2011048004, WO2012087771, WO2012161965, WO2013 The compounds described in WO2013072825, WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535, WO2009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376, WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347, WO2009117987 and WO2008071173. Metformin was also found to inhibit the COX2 / PGE2 / STAT3 axis and to be co-administered with metformin. See, for example, Tong et al., Cancer Lett. (2017) 389:23-32; and Liu et al., Oncotarget. (2016) 7(19):28235-46.

[0404] Examples of co-administerable carbonic anhydrase inhibitors (e.g., one or more of CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632)) include acetazolamide, metronidazole, dazolamide, zonisamide, brinzolamide, and dichlorobenzylsulfonamide. Dual COX-2 / CA1 / CA2 inhibitors that can be administered together include CG100649.

[0405] Examples of co-administerable inhibitors of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) include sodium meclofenamic acid and zileuton.

[0406] Co-administerable dual inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) include the compounds described in WO2015148954. Co-administerable dual inhibitors of COX-2 / SEH include the compounds described in WO2012082647. Co-administerable dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166) include the compounds described in WO2017160861.

[0407] Examples of co-administerable inhibitors of mitogen-activated protein kinase kinase 8 (MAP3K8, tumor progression locus-2, TPL2; NCBI gene ID: 1326) include GS-4875, GS-5290, BHM-078, and those described in the following literature: WO2006124944, WO2006124692, WO2014064215, WO2018005435; Teli et al., JEnzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0408] Tumor oxygenation

[0409] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or their pharmaceutically acceptable salts, are administered together with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor 1α (HIF-1α) inhibitors, such as PT-2977 and PT-2385; VEGF inhibitors, such as bevacizumab, IMC-3C5, GNR-011, tenibiruzumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding protein (HNOX)), such as OMX-302 and HNOX proteins as described in WO2007137767, WO2007139791, WO2014107171, and WO2016149562.

[0410] Immunotherapy agents

[0411] In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered together with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody. Exemplary immunotherapeutic agents that may be administered co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutuzumab, alenmab, altumomab, amatuximab, anatumomab, acitumomab, atezolizumab, bavituximab, bectumomab, and bevacizumab. Bevacizumab, bivatuzumab, belintouzumab, bentoxicumab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumab, cilibutumab, conatumumab, dacetuzumab, darotoxab tuzumab, daratumumab, detumomab, dinutuximab, domvanalimab, drozitumab, duligotuzumab, dusigitumab, ecromoximab, elotuzumab, emibetuzumab, ensituximab, ertuxomab (ertumaxomab), edaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomabIgovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, and YERVOY are all effective treatments for various ailments. ® MDX-010, BMS-734016, and MDX-101, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucarumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab zumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab ®), ritumumab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumumab Rituximab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, zimberelimab, and 3F8, are used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy is particularly effective.

[0412] The illustrated therapeutic antibodies can be further labeled or bound to radioactive isotope particles such as indium-111, yttrium-90 (90Y-crituzumab), or iodine-131.

[0413] In some implementations, the co-administerable immunotherapeutic agents are antibody-drug conjugates (ADCs). Exemplary co-administerable ADCs include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimics targeting the proteins or antigens listed above and herein. Exemplary co-administerable ADCs include gemtuzumab, belantamarab, belantamarab (e.g., belantamarab mofostatin), camidanlumab (e.g., camidanlumab teslin), trastuzumab (e.g., trastuzumab-drutecan; trastuzumab-mettansine), olibutuzumab, glembarumab, anetumab, and mirvetuximab (e.g., succedanemisulmibutrazol). Soravtansine), Depatuxizumab, Vadastuximab, Labezil, Ladiratuzumab (e.g., Ladiratuzumab vedotin), Loncastuximab (e.g., Loncastuximab teslin), Sacituzumab (e.g., Sacituzumab govitecan), Datopotamumab (e.g., Datopotamumab derutecan; DS-1062);Dato-DXd), pertratuzumab (e.g., pertratuzumab derutecan), lifatuzumab, indusatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., resorcinol upifitamab) rilsodotin), Indanexici, mirtuzumab, rofulpizumab (e.g., rofulpizumab teslin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab lavanten), disitamab (e.g., disitamab vedotin), territorizumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK28 57916, Humax-TF-ADC, IMGN289, IMGN151, IMGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, P F-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-administerable 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.

[0414] Exemplary therapeutic agents (e.g., anticancer or antitumor agents) that can be conjugated to drugs, their fragments, or antibody mimics include, but are not limited to, methylreoxetine E (MMAE), methylreoxetine F (MMAF), chachiin, anserine, maytansine, or analogues thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM1)). M4), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinking agent SC-DR002 (D6.5), pyroximin, microtubule inhibitors (MTIs) (e.g., taxane, vinca alkaloids, epothilone), pyrrolobenzodiazepine (PBD) or its dimer, pyroximin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antitumor agents described herein. In some embodiments, the therapeutic agent conjugated to the drug with an antibody is a topoisomerase I inhibitor (e.g., camptothecin analogues, such as irinotecan or its active metabolite SN38). In some embodiments, therapeutic agents (e.g., anticancer or antitumor agents) conjugated to antibodies, fragments thereof, or antibody mimics that can be conjugated to drugs include immune checkpoint inhibitors. In some embodiments, the conjugated immune checkpoint inhibitor is a small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the 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 small molecule inhibitor of CTLA4 includes BPI-002.

[0415] In some implementations, co-administerable ADCs include antibodies that target tumor-associated calcium signaling transducer 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Exemplary anti-TROP-2 antibodies include, but are not limited to, 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). HenliusBioTech), 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 EscugenBiotechnology, TOT Biopharma), Anti-Trop2 Antibody-CLB-SN-38 Conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / KlusPharma), 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)Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and WO2020016662 (Abmart), WO2020249063 (Bio-TheraSolutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech / Chiome), EP20110783675 (Chiome), WO2015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), WO2020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi)Sankyo)、CN112321715(Biosion)、US2006193865(Immunomedics / Gilead)、WO2011068845(Immunomedics / Gilead)、US2016296633(Immunomedics / Gilead)、US2017021017(Immunomedics / Gilead)、US2017209594(Immunomedics / Gilead)、US2017274093(Immunomedics / Gilead)、US2018110772(Immunomedics / Gilead)、US2018185351(Immunomedics / Gilead)、US2018271992(Immunomedics / Gilead)、WO2018217227(Immunomedics / Gilead)、US2019248917(Immunomedics / Gilead)、CN111534585(Immunomedics / Gilead)、US2021093730(Immunomedics / Gilead)、US2021069343(Immunomedics / Gilead)、US8435539(Immunomedics / Gilead)、US8435529(Immunomedics / Gilead)、US9492566(Immunomedics / Gilead)、WO2003074566(Gilead)、WO2020257648(Gilead)、US2013039861(Gilead)、WO2014163684(Gilead)、US9427464(LivTech / Chiome)、US10501555(AbruzzoTheranostic / Oncoxx)、WO2018036428(Sichuan KelunThe anti-Trop-2 antibody is selected from those described in Pharma, WO2013068946 (Pfizer), WO2007095749 (Roche), and WO2020094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Patent Nos. 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 and an anticancer agent linked by a linker. In some embodiments, the linker includes the linker disclosed in USPN 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the pharmaceutical 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-pyrrolinyl-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lurtotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldmycin, ansarmycin, and epothilone. In some embodiments, the chemotherapeutic component is SN-38. In some embodiments, the antibody and / or fusion protein provided herein are administered together with sacitrus tuzumab-glavotecan.

[0416] In some embodiments, the co-administerable ADC includes an antibody targeting carcinoembryonic antigen-associated cell adhesion molecule 5 (CEACAM5; CD66a; NCBI gene ID: 634). In some embodiments, the CEACAM5 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the CEACAM5-ADC is as described in WO 2010093395 (anti-CEACAM-5-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein are administered together with the CEACAM5-ADC IMMU-130.

[0417] In some embodiments, the co-administerable ADC includes an antibody targeting an MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibody and / or fusion protein provided herein are administered together with the HLA-DR-ADC IMMU-140.

[0418] Cancer gene therapy and cell therapy

[0419] In some implementations, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or pharmaceutically acceptable salts thereof, are administered in conjunction with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modifications to silence mutated genes; genetic methods to directly kill cancer cells; infusions 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 cancer cells, or to locate and kill cancer cells; and genetic methods to alter cellular activity to further modify the endogenous immune response against cancer.

[0420] Cell therapy

[0421] In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more cell therapies. Exemplary cell therapies include, but are not limited to, co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor-infiltrating lymphocytes (TILs), and / or dendritic cells (DCs). In some embodiments, the cell therapy requires T cell therapy, such as co-administration of α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TruC cells. ™ A population of T cells. In some implementations, cell therapy requires NK cell therapy, such as co-administration of NK-92 cells. Depending on the circumstances, cell therapy may require co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0422] In some implementations, cell therapy requires the co-administration of cells containing a chimeric antigen receptor (CAR). In such therapies, a population of immune effector cells is engineered to express the CAR, which contains a tumor antigen-binding domain. In T-cell therapy, T-cell receptors (TCRs) are engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0423] Regarding the structure of the CAR, in some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a co-stimulatory domain, or both a primary signaling domain and a co-stimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of: CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (Fcε Rlb), CD79a, CD79b, Fcγ RIIa, DAP10, and DAP12.

[0424] In some implementations, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of: CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NK p80 (KLRFI), CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, I TGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI Gene ID: 911), CD1D (NCBI Gene ID: 912), CD1E (NCBI Gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTA M, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46 and NKG2D.

[0425] In some implementations, the transmembrane domain includes the transmembrane domain of a protein selected from the group consisting of: α, β, or ζ chains 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, CD 1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD1 8), 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, CD15 0, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C.

[0426] In some implementations, the TCR or CAR antigen-binding domain or the immunotherapeutic agent described herein (e.g., a monospecific or multispecific antibody or its antigen-binding fragment or antibody mimic) binds to a tumor-associated antigen (TAA). In some implementations, tumor-associated antigens are selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)βDGIcp(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 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor β (PDGFR-β); stage-specific embryonic antigen-4 ( SSEA-4); CD20; δ-like 3 (DLL3); folate receptor α; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); cell surface-associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostate enzymes; prostatic acid phosphatase (PAP); mutant elongation factor 2 (ELF2M); liver ligand B2; fibroblast activating protein α (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (Macropain) subunit β-type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein composed of the split cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase;Hepatic glycoside A receptor 2 (EphA2); fucose GM1; sialylated 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-associated (TEM7R); prostatic six-transmembrane epithelial antigen I (STEAP1); blocking protein 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C5 member D (GPRCS) D); Chromosome X open reading frame 61 (CXORF61); CD97; CD179a; Anaplastic lymphoma kinase (ALK); Polysialic acid; Placenta-specific 1 (PLAC1); Hexasaccharide moiety of globoH glycoceramide (GloboH); Breast differentiation antigen (NY-BR-1); Uroplakin 2 (UPK2); Hepatitis A virus cell receptor 1 (HAVCR1); Adrenal receptor β3 (ADRB3); Pantothecin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, locus K 9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ alternating reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); spermin 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-associated antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galactagogue 8), melanoma antigen recognized by T cell 1 (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma Tumor translocation breakpoint; melanoma cell apoptosis inhibitor (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosamine transferase V (NA17); pairing 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-associated protein 2 (TRP-2).Cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (BORIS or imprinted site regulator sibling factor), squamous cell carcinoma antigen 3 (SART3) recognized by T cells; pairing box protein Pax-5 (PAX5); proapocrine-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchoring protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal insufficiency protein 1 (RUI); renal insufficiency protein 2 (RU2); pod protein; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; mutant heat shock protein 70-2 (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 2 containing mucin-like hormone receptor-like structure (EMR2); lymphocyte antigen 75 (LY75); phosphatidylinositol polysaccharide-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen presented in the MHC.

[0427] In some implementations, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, C D80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, 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-coupled receptor, alpha-fetoprotein (AFP), angiogenesis factor, exogenous homologous binding molecule (ExoCBM), oncogene products, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1) Liver glycoprotein 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, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tendinin, P2-Microgiobuin, Fc receptor-like protein 5 (FcRL5).

[0428] In some embodiments, the antigen-binding domain binds to an epitope of a target or tumor-associated antigen (TAA) presented in the major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer testis antigen. In some embodiments, the cancer testis antigen is selected from the group consisting of: sperm headgranulin-binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI gene ID: 84519), alpha fetal protein (AFP; AFPD, FETA, HPAFP; NCBI gene ID: 174); and A kinase-anchored protein 4 (AKAP4; AKAP). 82, 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), centromere scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI gene ID: 57082), centrosome protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI gene ID: 55165), cancer / testis antigen 1 A (CTAG1A; ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1; NCBI gene ID: 246100), Cancer / Testis Antigen 1B (CTAG1B; CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI gene ID: 1485), Cancer / Testis Antigen 2 (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), catechol α2 (CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI gene ID: 1496), cancer / testis antigen 83 (CT83; CXorf61, KK-LC-1, KKLC1; NCBI gene ID: 203413), cyclin A1 (CCNA1; CT146; NCBI gene ID: 8900), DEAD-box helicase 43 (DDX43; CT13, HAGE; NCBI gene ID: 55510), Developmental pluripotency-associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI gene ID: 151871), 1 expressed in fetal and adult testes (FATE1; CT43, FATE; NCBI gene ID: 89885), FMR1 neighbors (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI gene ID: 158521), 1 containing the HORMA domain (HORMAD1; CT46, NOHMA; NCBI gene ID: 84072), and 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), swirling spermatogenesis transposon silencer (MAEL; CT128, SPATA35; NCBI gene ID: 84944), MAGE family member A1 (MAGEA1; CT 1.1 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; N NCBI gene ID: 9585), NUF2 component of the NDC80 centromere complex (NUF2; CDCA1, CT106, NUF2R; NCBI gene ID: 83540), nuclear RNA export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI gene ID: 56001), PAS domain-containing repressor protein 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), and nuclear-associated spermin X-linked family member A1 (SPANXA1; CT11.1, CT11.3, NAP-X, S... PAN-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), synaptic filament complex protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI gene ID: 50511), 14 intercellular bridging proteins expressed in the testes. Factors such as TEX14, CT113, SPGF23, and NCBI gene ID 56155, transcription factor Dp family member 3 (TFDP3, CT30, DP4, HCA661, and NCBI gene ID 51270), serine protease 50 (PRSS50, CT20, TSP50, and NCBI gene ID 29122), TTK protein kinases (TTK, CT96, ESK, MPH1, MPS1, MPS1L1, PYT, and NCBI gene ID 7272), and zinc finger protein 165 (ZNF165, CT53, LD65, and ZSCAN7, and NCBI gene ID 7718) are included. T-cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer testis antigens presented in the major histocompatibility complex (MHC) molecule are known in the art and can be used in the heterodimers described herein. Cancer testicular antigens associated with tumor formation are summarized, for example, in Gibbs et al., Trends Cancer; 2018 Oct; 4(10):701-712 and the CT database website cta.lncc.br / index.php. Exemplary TCRs and TCR-like antibodies that bind to epitopes of NY-ESO-1 presented in the MHC are described, for example, in Stewart-Jones et al., Proc Natl Acad Sci USA.April 7, 2009; 106(14):5784-8; WO2005113595, WO2006031221, WO2010106431, WO2016177339, WO2016210365, WO2017044661, WO2017076308, WO2017109496, WO2018132739, WO2019084538, WO2019162043, WO2020086158 and WO2020086647. Exemplary TCR and TCR-like antibodies that bind to epitopes of PRAME presented in the MHC are described, for example, in WO2011062634, WO2016142783, WO2016191246, WO2018172533, WO2018234319 and WO2019109821. Exemplary TCRs and TCR-like antibodies that bind to MAGE epitopes presented in the MHC are described, for example, in WO2007032255, WO2012054825, WO2013039889, WO2013041865, WO2014118236, WO2016055785, WO2017174822, WO2017174823, WO2017174824, WO2017175006, WO2018097951, WO2018170338, WO2018225732, and WO2019204683. Exemplary TCRs and TCR-like antibodies that bind to epitopes of alpha-fetoprotein (AFP) presented in the MHC are described, for example, in WO2015011450. Exemplary TCRs and TCR-like antibodies that bind to the epitope of SSX2 presented in the MHC are described, for example, in WO2020063488. Exemplary TCRs and TCR-like antibodies that bind to the epitope of KK-LC-1 (CT83) presented in the MHC are described, for example, in WO2017189254.

[0429] Examples of cell therapies include: Algenpantucel-L, Sipuleucel-T, (BPX-501) rivogenlecleucel (US9089520, WO2016100236), 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 Imilecl. Eucel-T, Baltaleucel-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, lentivirus-transferred huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602 and CSG-005.

[0430] In some implementations, one or more additional co-administered therapeutic agents may be classified into groups such as the following based on their mechanisms of action:

[0431] • Medications that target adenosine deaminase, such as pentostatin or cladribine;

[0432] • Targeted ATM drugs, such as AZD1390;

[0433] • Targeted MET agents, such as savolitinib, capmatinib, tepotinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115;

[0434] • Agents targeting mitogen-activated protein kinase, such as dactoquinol, bimetinib, cobimetinib, selmetinib, trametinib, euprometinib, mirdametinib (PD-0325901), pimatetinib, refatinib, or compounds disclosed in the following literature: WO2011008709, WO2013112741, WO2006124944, WO2006124692, WO2014064215, WO2018005435; Zhou et al., Cancer Lett. 2017 Nov 1, 408:130-137; Teli et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila et al., Bioorg Med Chem. (2007) 15(19):6425-42; or Hu et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61;

[0435] • Targeted agents for thymidine kinase, such as belamcine besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk).

[0436] • Drugs that target the interleukin pathway, such as Pegilodecakin (AM-0010) (pegylated IL10) and CA-4948 (IRAK4 inhibitor).

[0437] • Medications targeting members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, and megestrol acetate (MEGACE). ® Exemestane, Formestane, Fazodazole, Vorcicloazole (RIVISOR) ® Letrozole (FEMARA) ® ) or anastrozole (ARIMIDEX) ® );

[0438] • Targeting agents for CD73, such as CD73 inhibitors (e.g., quemliclustat (AB680)) or anti-CD73 antibodies (e.g., oleclumab).

[0439] • Targeting agents for DKK3, such as MTG-201;

[0440] • Drugs that target EEF1A2, such as priltein;

[0441] • Drugs that target EIF4A1, such as lorlatinib.

[0442] • Targeting agents that target endothelial glycoproteins, such as TRC105 (carotuximab).

[0443] • Targeting agents that target export protein 1, such as eltanexor.

[0444] • Agents that target fatty acid amide hydrolases, such as the compounds disclosed in WO2017160861;

[0445] • Drugs that target heat shock protein 90β family member 1, such as anlotinib.

[0446] • Medications that target lactotransferrin, such as ruxotemitide (LTX-315).

[0447] • Agents targeting lysyl oxidase, such as compounds disclosed in US4965288, US4997854, US4943593, US5021456, US5059714, US5120764, US5182297, US5252608 or US20040248871;

[0448] • Targeting agents that target members of the MAGE family, such as KITE-718, MAGE-A10C796T, or MAGE-A10 TCR;

[0449] • Targeted agents for MDM2, such as ALRN-6924, CMG-097, milademetan monotosylate monohydrate (DS-3032b), or AMG-232;

[0450] • Targeting agents for MDM4, such as ALRN-6924;

[0451] • Targeting agents for melanin A, such as MART-1 F5 TCR engineered PBMCs;

[0452] • Targeting agents for mesothelin, such as CSG-MESO or TC-210;

[0453] • Targeting agents for METAP2, such as M8891 or APL-1202;

[0454] • Medications that target NLRP3, such as BMS-986299;

[0455] • Medications that target ketoglutarate dehydrogenase, such as devimistat (CPI-613).

[0456] • Medications that target placental growth factors, such as aflibercept;

[0457] • Agents targeting SLC10A3, such as compounds disclosed in WO2015148954, WO2012082647 or WO2017160861;

[0458] • Agents that target transforming growth factor α (TGFα), such as the compounds disclosed in WO2019103203;

[0459] • Drugs that target the tumor protein p53, such as kevetrin (a stimulant).

[0460] • Medications that target vascular endothelial growth factor A, such as aflibercept;

[0461] • Drugs that target the vascular endothelial growth factor receptor, such as fruquintinib or MP0250;

[0462] • Targeted drugs for VISTA, such as CA-170 or HMBD-002;

[0463] • Medications that target WEE1, such as adavosertib (AZD-1775).

[0464] • Small molecule inhibitors targeting ABL1, such as imatinib, rebamitinib, aciminib, or ponatinib (ICLUSIG) ® );

[0465] • Small molecule antagonists that target adenosine receptors, such as CPI-444, AZD-4635, prednisolone, ectedinam (AB928), or PBF-509;

[0466] • Small molecule inhibitors that target arachidonic acid 5-lipoxygenase, such as sodium meclomethate or ziljubut;

[0467] • Small molecule inhibitors that target ATR serine / threonine kinases, such as BAY-937, ceralasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib).

[0468] • Small molecule inhibitors that target AXL receptor tyrosine kinase, such as bemcentinib (BGB-324), SLC-0211, or giretinib (Axl / Flt3).

[0469] • Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as (S)-6-amino-9-(1-(but-2-ethynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posabrutinib (HM71224), ibrutinib (Imbruvica), M-2951 (ivobrutinib), tilabrutinib (ONO-4059), rizanubrutinib (PRN-1008), spetinib (CC-292), vecalabtinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315;

[0470] • Small molecule inhibitors that target neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or selitrectinib (LOXO-195).

[0471] • Small molecule inhibitors that target the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib;

[0472] • Small molecule inhibitors that target non-receptor tyrosine kinases of the SRC proto-oncogene, such as VAL-201, tirbanibulin (KX2-391), or ilginatinib maleate (NS-018).

[0473] • Small molecule inhibitors targeting B-cell lymphoma 2, such as quintostoxetine (navitoclax) (ABT-263), venetoclax (ABT-199, RG-7601), or AT-101 (gossypol).

[0474] • Small molecule inhibitors that target proteins containing both the bromo domain and the outer bromo domain (BET), 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), mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829;

[0475] • Small molecule inhibitors that target carbohydrate sulfonyltransferase 15, such as STNM-01;

[0476] • Small molecule inhibitors that target carbonic anhydrase, such as pamacoxib, acetazolamide, or acetazolamide;

[0477] • Small molecule inhibitors that target catechol β1, such as CWP-291 or PRI-724;

[0478] • Small molecule antagonists that target the CC motif chemokine receptor, such as CCX-872, BMS-813160 (CCR2 / CCR5) or MK-7690 (Vivivor).

[0479] • Small molecule antagonists that target CXC motif chemokine receptors (e.g., CXCR4), such as blixafortide.

[0480] • Small molecule inhibitors that target cereblon, such as avadomide (CC-122), CC-92480, CC-90009 or iberdomide.

[0481] • Small molecule inhibitors that target checkpoint kinase 1, such as SRA737;

[0482] • Small molecule inhibitors that target complement components, such as Imprime PGG (Biothera Pharmaceuticals).

[0483] • Small molecule inhibitors that target CXC motif chemokine ligands (e.g., CXCL12), such as olaptesed pegol (NOX-A12).

[0484] • Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate;

[0485] • Small molecule inhibitors that target DEAD box helicase 5, such as supinoxin (RX-5902).

[0486] • Small molecule inhibitors that target DGKα, such as those described in WO2021130638;

[0487] • Small molecule inhibitors that target diablo IAP binding to mitochondrial proteins, such as BI-891065;

[0488] • Small molecule inhibitors that target dihydrofolate reductase, such as pralatrexate or pemetrexed disodium;

[0489] • Small molecule inhibitors that target DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastuxin;

[0490] • Small molecule inhibitors that target MARCKS, such as BIO-11006;

[0491] • Small molecule inhibitors targeting RIPK1, such as GSK-3145094;

[0492] • Small molecule inhibitors that target protein kinases containing Rho-associated coiled helices, such as AT13148 or KD025;

[0493] • Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, firtecanpegol, or amrubicin;

[0494] • Small molecule inhibitors that target dopamine receptor D2, such as ONC-201;

[0495] • Small molecule inhibitors that target DOT1-like histone lysine methyltransferases, such as pinometostat (EPZ-5676).

[0496] • Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497;

[0497] • Small molecule inhibitors that target fatty acid synthase, such as TVB-2640 (Sagimet Biosciences).

[0498] • Small molecule inhibitors that target fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144).

[0499] • Small molecule inhibitors that target focal adhesion kinases (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098;

[0500] • Small molecule inhibitors that target folate receptor 1, such as pralatrexate;

[0501] • Small molecule inhibitors that target FOXM1, such as thiosphingolipids;

[0502] • Small molecule inhibitors that target galactagogue 3, such as belapectin (GR-MD-02).

[0503] • Small molecule antagonists that target glucocorticoid receptors, such as relacorilant (CORT-125134).

[0504] • Small molecule inhibitors targeting glutaminase include, but are not limited to, CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES).

[0505] • Small molecule inhibitors that target GNRHR, such as ellagoc, relugolix, or degarelix;

[0506] • Small molecule inhibitors targeting EPAS1, such as belzutifan (PT-2977 (Merck & Co.));

[0507] • Small molecule inhibitors that target isocitrate dehydrogenase (NADP(+)), such as ivosidenib (AG-120), vorasidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221).

[0508] • Small molecule inhibitors that target lysine demethylase 1A, such as CC-90011;

[0509] • Small molecule inhibitors that target MAPK-interacting serine / threonine kinases, such as tomisetin (tomivosertib) (eFT-508).

[0510] • Small molecule inhibitors that target the notch receptor, such as AL-101 (BMS-906024).

[0511] • Small molecule inhibitors that target polo-like kinase 1 (PLK1), such as volasertib or onvansertib.

[0512] • Small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazoleparib (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121 (e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102;

[0513] • Small molecule inhibitors that target polycomb protein EED, such as MAK683;

[0514] • Small molecule inhibitors that target porcupine O-acyltransferase, such as WNT-974;

[0515] • Small molecule inhibitors targeting prostaglandin-endoperoxidase synthase, such as HP-5000, lornoxicam, ketorolac tromethorphan, bromfenac sodium, onnaproxetine (ATB-346), monoxazole, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, new formulation celecoxib (DRGT-46), AAT-076, mesosulide, romecoxib, meloxicam, vardicoxib, zaltoprofen, nimesulide, anizafen. (anitrazafen), apricoxib, cimicoxib, deracoxib, fluimidazole, firocoxib, mavacoxib, pamigrarel, parecoxib, robenacoxib, rofecoxib, evodiamine, tilmacoxib, zaltoprofen, or imrecoxib.

[0516] • Small molecule inhibitors that target protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715 or GSK3326595;

[0517] • Small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720) or compounds disclosed in WO2018172984 or WO2017211303;

[0518] • Small molecule antagonists that target retinoic acid receptors, such as tamibarbitine (SY-1425).

[0519] • Small molecule inhibitors that target ribosomal protein S6 kinase B1, such as MSC2363318A;

[0520] • Small molecule inhibitors that target S100 calcium-binding protein A9, such as taquimod;

[0521] • Small molecule inhibitors that target selectin E, such as uproleselan sodium (GMI-1271).

[0522] • Small molecule inhibitors targeting SF3B1, such as H3B-8800;

[0523] • Small molecule inhibitors targeting Sirtuin-3, such as YC8-02;

[0524] • Small molecule inhibitors targeting SMO, such as sodegib (Odomzo) ® (formerly known as LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, patidegib, or taladegib.

[0525] • Small molecule antagonists that target the somatostatin receptor, such as OPS-201;

[0526] • Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva) ® (ABC294640)

[0527] • Small molecule inhibitors that target STAT3, such as napabucasin (BBI-608).

[0528] • Small molecule inhibitors that target end-anchored polymerases, such as G007-LK or stenoparib (2X-121 (e-7499)).

[0529] • Small molecule inhibitors targeting TGFBR1, such as galunisertib and PF-06952229;

[0530] • Small molecule inhibitors that target thymidine synthase, such as idetrexed (ONX-0801).

[0531] • Small molecule inhibitors that target the tumor protein p53, such as CMG-097;

[0532] • Small molecule inhibitors that target valine-containing proteins, such as CB-5083;

[0533] • Small molecule inhibitors targeting WT1, such as ombipepimut-S (DSP-7888).

[0534] • Small molecule agonists that target adenosine receptors, such as namodenoson (CF102).

[0535] • Small molecule agonists that target asparaginases, such as crisantaspase (Erwinase) ® ), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegargase;

[0536] • Small molecule agonists that target CCAAT enhancer-binding protein α, such as MTL-501;

[0537] • Small molecule agonists that target the cytochrome P450 family, such as mitotane;

[0538] • Small molecule agonists that target DExD / H box helicase 58, such as RGT-100;

[0539] • Small molecule agonists that target GNRHR, such as leuprorelin acetate, leuprorelin acetate extended-release reservoir (ATRIGEL), triptorelin dihydroxynaphthyl acetate, or goserelin acetate;

[0540] • Small molecule agonists that target GRB2, such as prexigebersen (BP1001).

[0541] • Small molecule agonists that target NFE2L2, such as omaveloxolone (RTA-408).

[0542] • Small molecule agonists that target NOD2, such as mifamotide (liposomes).

[0543] • Small molecule agonists that target the RAR-associated orphan receptor γ, such as Sindrog (LYC-55716).

[0544] • Small molecule agonists that target the retinoic acid receptor (RAR), such as retinoic acid;

[0545] • Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic-GAMP (cGAMP), or cyclic-di-AMP;

[0546] • Small molecule agonists that target thyroid hormone receptor β, such as levothyroxine sodium;

[0547] • Small molecule agonists that target tumor necrosis factor, such as tasonamin;

[0548] • Antisense agents targeting protein 5 of the baculovirus IAP repeat sequence, such as EZN-3042;

[0549] • Antisense agents targeting GRB2, such as prexigebersen.

[0550] • Antisense agents that target heat shock protein 27, such as apatorsen;

[0551] • Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx);

[0552] • Gene therapies targeting CC motif chemokine receptors, such as SB-728-T;

[0553] • Gene therapies targeting interleukins, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55;

[0554] • Antibodies that target claudin 18, such as claudiximab.

[0555] • Antibodies that target cluster proteins, such as AB-16B5;

[0556] • Antibodies that target complement components, such as ravulizumab (ALXN-1210).

[0557] • Antibodies that target CXC motif chemokine ligands, such as BMS-986253 (HuMax-Inflam).

[0558] • Antibodies that target delta-like classical Notch ligand 4 (DLL4), such as demcizumab and navexizumab (DLL4 / VEGF).

[0559] • Antibodies that target EPH receptor A3, such as fibatuzumab (KB-004).

[0560] • Antibodies that target epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845).

[0561] • Antibodies that target fibroblast growth factors, such as GAL-F2 and B-701 (vofatamab).

[0562] • Antibodies that target hepatocyte growth factors, such as MP-0250;

[0563] • Antibodies targeting interleukins, such as canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), stetoxicumab, or tocilizumab;

[0564] • Antibodies that target LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110).

[0565] • Antibodies that target mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE;

[0566] • Antibodies that target myostatin, such as landogrozumab.

[0567] • Antibodies that target the notch receptor, such as tarextumab.

[0568] • Targeting TGFB1 (TGF) β1Antibodies such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089 or compounds disclosed in WO2019103203;

[0569] • Vaccines targeting FMS-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201 restricted epitope peptide vaccines;

[0570] • Vaccines that target heat shock protein 27, such as PSV-AML (PhosphoSynVax).

[0571] • Vaccines targeting PD-L1, such as IO-120 + IO-103 (PD-L1 / PD-L2 vaccine) or IO-103;

[0572] • Vaccines that target the tumor protein p53, such as MVA-p53;

[0573] • Vaccines that target WT1, such as WT-1 analog peptide vaccines (WT1-CTL).

[0574] • Cell therapies targeting baculovirus IAP repeat sequence protein 5, such as tumor lysate / MUC1 / survivin PepTivator loaded dendritic cell vaccines;

[0575] • Cellular therapies targeting carbonic anhydrase, such as DC-Ad-GMCAIX;

[0576] • Cell therapies targeting CC motif chemokine receptors, such as CCR5-SBC-728-HSPC;

[0577] • Cell therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN;

[0578] • Cell therapies targeting GSTP1, such as CPG3-CAR (GLYCAR).

[0579] • Cell therapies targeting HLA-A, such as FH-MCVA2TCR or NeoTCR-P1;

[0580] • Cellular therapies targeting interleukins, such as CST-101;

[0581] • Cellular therapies targeting KRAS, such as anti-KRAS G12D mTCR PBL;

[0582] • Cellular therapies targeting MET, such as anti-cMet RNA CAR T;

[0583] • Cell therapies targeting MUC16, such as JCAR-020;

[0584] • Cell therapies targeting PD-1, such as PD-1 knockout T-cell therapy (esophageal cancer / NSCLC).

[0585] • Cell therapies targeting PRAME, such as BPX-701;

[0586] • Cell therapies targeting the converting protein E7, such as KITE-439;

[0587] • Cell therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016.

[0588] Example of combination therapy

[0589] Combination therapy for lymphoma or leukemia

[0590] Some chemotherapy agents are used to treat lymphoma or leukemia. These agents include interleukin, avocidib, amifostine trihydrate, aminocamptothecin, antitumor ketone A10, antitumor ketone AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541, and bortezomib (VELCADE). ® ), bortezomib (VELCADE) ® PS-341), lichenin 1, bulsulfan, campath-1H, carboplatin, carfilzomib (Kyprolis) ®Carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, scabraxine 10, doxorubicin, doxorubicin hydrochloride, DT-PACE ( Dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzatolin, epoetinalfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, frapinol, fludarabine, FR (fludarabine and rituximab), gerdemycin (17 AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixaprilone, lenalidomide (REVLIMID) ®CC-5013), lymphokine-activated killer cells, MCPs (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafen gadolinium, mycophenolate mofetil, nerabine, obatoclax (GX15-070), oblimersen, octreotide acetate, ω-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, taxanes Alcohol, pabuxirib (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 and FCM), R-ICE (rituximab and ICE), and R MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), saxaglastine, sildenafil citrate, simvastatin, sirolimus, styrene sulfone, tacrolimus, tanespimycin, tesimolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tepifenafil, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf) ® ), Vinetok (ABT-199).

[0591] One modified approach is radioimmunotherapy, in which a monoclonal antibody binds to radioactive isotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tosimomab (BEXXAR). ® Yttrium-90 tivamumab (ZEVALIN) ® ) and BEXXAR ® With CHOP.

[0592] The above-mentioned therapies can be supplemented or combined with stem cell transplantation or treatment. Treatment procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole-body irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo 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-myeloablative allogeneic hematopoietic stem cell transplantation.

[0593] Combination therapy for non-Hodgkin's lymphoma

[0594] Treatment for non-Hodgkin lymphoma (NHL) (especially those of B-cell origin) includes the use of monoclonal antibodies, standard chemotherapy regimens (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, and prednisolone), all optionally including rituximab®, etc.), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

[0595] Examples of unconjugated monoclonal antibodies used to treat NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0596] Examples of experimental antibody agents used to treat NHL / B-cell cancer include ofatumumab, ha20, PRO131921, alemtumab, galiximab, SGN-40, CHIR-12.12, epazolizumab, phenmiclimab, apolizumab, milatuzumab, and bevacizumab.

[0597] 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.

[0598] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 tivamomab (ZEVALIN). ® ) and iodine-131 tosimomab (BEXXAR)® ).

[0599] Combination therapy for mantle cell lymphoma

[0600] Therapeutic treatment for mantle cell lymphoma (MCL) includes combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0601] Alternative treatments for MCL include immunotherapy. One type of immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor.

[0602] A modified treatment for MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles (such as iodine-131 tosimomumab (BEXXAR)). ® ) and yttrium-90 tivamumab (ZEVALIN) ® ) combined. In another example, BEXXAR ® Used in conjunction with CHOP sequence treatment.

[0603] Other treatments for MCL include autologous stem cell transplantation combined with high-dose chemotherapy, and administration of proteasome inhibitors such as bortezomib (VELCADE). ® Or PS-341) or administer anti-angiogenic agents such as thalidomide, especially in combination with rituximab.

[0604] Another treatment approach is to combine a drug with other chemotherapy agents to cause the degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as Olimerson.

[0605] Another treatment option involves administering mTOR inhibitors, which can lead to inhibition of cell growth or even cell death. Non-limiting examples include sirolimus and tesilolimus (TORISEL). ® CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and RITUXAN ® VELCADE ® Tesirolimus in combination with other chemotherapeutic agents.

[0606] Other recent MCL therapies have been disclosed. Examples include frappindo, palbociclib (PD0332991), R-roscovitine (celecoxib, CYC202), styrenesulfone, omeprazole (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, and tesirobolimus (TORISEL). ® CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID) ® (CC-5013) and geldromycin (17 AAG).

[0607] Combination therapy for Waldenström macroglobulinemia

[0608] Therapeutic agents used to treat Waldenström macroglobulinemia (WM) include interleukin, alenmab, avocetide, amifostine trihydrate, aminocamptothecin, antitumor ketone A10, antitumor ketone AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-aritin, and bortezomib (VELCADE). ® ), lichenin 1, busulfan, Campasz-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarapine, cyclophosphamide, cyclosporine, cytarabine, diphenhydramine, dexamethasone, docetaxel, scabra 10, doxorubicin hydrochloride, DT-PACE, enzatolin, eportin afa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenivelamine, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride Contains various antibiotics including: ixaspirin, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibodies against CD19 (such as texazinlu-T, CART-19, CTL-019), monoclonal antibodies against CD20, motexafen gadolinium, mycophenolate mofetil, nerabine, olimol, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, pentostatin, perifoxetine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon-α, recombinant interleukin-11, recombinant interleukin-12, rituximab, saxaglastine, and sildenafil citrate (VIAGRA). ®Simvastatin, sirolimus, tacrolimus, spiramycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tepifenabil, tosimomab, urorubumab, vetuzumab, vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 tepifemumab, yttrium-90 humanized epazolizumab, and any combination thereof.

[0609] Examples of treatment procedures for 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 irradiation, stem cell infusion, bone marrow ablation with stem cell support, peripheral blood stem cell transplantation with in vitro treatment, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-bone marrow ablation allogeneic hematopoietic stem cell transplantation.

[0610] Diffuse large B-cell lymphoma (DLBCL) combination therapy

[0611] Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many agents listed in the WM (Wide Motion) list, and any combinations thereof, such as ICE and RICE. In some implementations, therapeutic agents for treating DLBCL include rituximab. ® ), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin) ® Prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, boratuzumab, vitolidine, piiq, bendamustine, cupanidix, lenalidomide (Revlimid) ® Dexamethasone, cytarabine, cisplatin, Yescarta ® Kymriah ® Polivy ® (Polaroiduzumab / Vidodine), BR (bendamustine / Treanda) ® Rituximab, oxaliplatin, tafacitinib, boratuzumab, cyclophosphamide, or combinations thereof. In some implementations, therapeutic agents for treating DLBCL include R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovinyl chloride)). ®R-ICE (rituximab + ifosfamide + carboplatin + etoposide), R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy ® (Polaroiduzumab / Vidodine) + BR (Bendamustine / Treanda) ® ) and rituximab (Rituxan ® R-GemOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafacitazumab + lenalidomide), Tafacitazumab + Revlimid ® 1. Polatozumab + Bendamustine, 2. Gemcitabine + Oxaliplatin, 3. R-EPOCH (Rituximab + Etoposide Phosphate + Prednisone + Vincristine Sulfate) ® ) + cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) or CHOP (cyclophosphamide + doxorubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin) ® (+prednisone). In some implementations, therapeutic agents for treating DLBCL include tafacitinib, glofitamab, epcoritamab, Lonca-T (teruntuximab), Debio-1562, boratuzumab, Yescarta, JCAR017, ADCT-402, bentuximab vitoline, MT-3724, onatuzumab, Auto-03, Allo-501A, or TAK-007.

[0612] Combination therapy for chronic lymphocytic leukemia

[0613] Treatment agents for chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[0614] High-risk myelodysplastic syndrome (HR MDS) combination therapy

[0615] Treatment agents used to treat HR MDS include azacitidine (Vidaza). ® ), decitabine (Dacogen) ® lenalidomide (Revlimid) ®), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, combinations include cytarabine + daunorubicin and cytarabine + idarubicin. In some embodiments, therapeutic agents for treating HR MDS include pervorisstat, venetoclax, sabatolimab, guarditabine, ligoroteb, evanib, ensididipine, celiniso, BGB324, DSP-7888, or SNS-301.

[0616] Low-risk myelodysplastic syndrome (LR MDS) combination therapy

[0617] Treatment agents for LR MDS include lenalidomide, azacytidine, and combinations thereof. In some embodiments, treatment agents for LR MDS include roxadustat, luspatercept, imestastat, LB-100, or ligoteb.

[0618] Combination therapy for acute myeloid leukemia (AML)

[0619] Therapeutic agents used to treat AML include cytarabine, idarubicin, daunorubicin, and midostaurin. ® Venetoclax, Azacitidine, Ivertinib, Gefitinib, Enxidipine, Low-dose Cytarabine (LoDAC), Mitoxantrone, Fludarabine, Granulocyte Colony-Stimulating Factor, Idarubicin, Gefitinib (Xospata) ® ), Ensidipine (Idhifa) ® Tibsovo ® ), decitabine (Dacogen) ® ), mitoxantrone, etoposide, gemtuzumab olzomircin (Mylotargin) ® ), Daurismo ® (and combinations thereof). In some embodiments, therapeutic agents for treating AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte colony-stimulating factor (G-CSF), and idarubicin), cytarabine + idarubicin, cytarabine + daunorubicin + midotaurine, venetoclax + azacitidine, cytarabine + daunorubicin, or MEC (mitoxantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents for treating AML include pervornistat, venetoclax, sabatolimab, eprenetapopt, or leszolizumab.

[0620] Combination therapy for multiple myeloma (MM)

[0621] Treatment agents used to treat multiple myeloma (MM) include lenalidomide, bortezomib, dexamethasone, and daratumumab (Darzalex). ® Pomalidomide, cyclophosphamide, carfilzomib (Kyprolis) ® ), erlotinib (Empliciti), and combinations thereof. In some embodiments, therapeutic agents for treating MM include RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide plus dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib plus dexamethasone), or PomDex (pomalidomide + low-dose dexamethasone). In some embodiments, therapeutic agents for treating MM include JCARH125, TAK-573, belantasumab (mofotin), and ide-cel (CAR-T).

[0622] Breast Cancer Combination Therapy

[0623] Therapeutic agents for the treatment of breast cancer include albumin-bound paclitaxel, anastrozole, atezolizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixaprilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents for the treatment of breast cancer (e.g., HR+ / - / HER2+ / -) include trastuzumab (Herceptin). ® Pertuzumab (Perjeta) ® Docetaxel, Carboplatin, Pebocili (Ibrance) ® Letrozole, Trastuzumab-Mestane (Kadcyla) ® ), fulvestrant (Faslodex) ® ), Lynparza ® ), eribulin, tocardinib, capecitabine, lapatinib, everolimus (Afinitor) ® ), exemestane, elebulin mesylate (Halaven) ®) and combinations thereof. In some embodiments, therapeutic agents for treating breast cancer include trastuzumab + pertuzumab + docetaxel, trastuzumab + pertuzumab + docetaxel + carboplatin, pebocilib + letrozole, tacardinib + capecitabine, lapatinib + capecitabine, pebocilib + fulvestrant, or everolimus + exemestane. In some embodiments, therapeutic agents for treating breast cancer include trastuzumab-drutecan, datopotecan / drutecan (DS-1062), enfutumab / vitoltin (Padcev) ® ), balixafortide, ellastrin, or combinations thereof. In some embodiments, therapeutic agents for treating breast cancer include balixafortide + ellastrin.

[0624] Triple-negative breast cancer (TNBC) combination therapy

[0625] Treatment agents for TNBC include atezolizumab, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, treatment agents for TNBC include olaparib (Lynparza). ® Atezolizumab (Tecentriq) ® ), paclitaxel (Abraxane) ® Halaven, bevacizumab (Avastin), carboplatin, gemcitabine, and elebulin mesylate (Halaven) ® ), saxitozumab-glavotecan (Trodelvy) ® Pembrolizumab (Keytruda) ® In some embodiments, the therapeutic agents for treating TNBC include atezolizumab + paclitaxel, bevacizumab + paclitaxel, carboplatin + paclitaxel, carboplatin + gemcitabine, or paclitaxel + gemcitabine. In some embodiments, the therapeutic agents for treating TNBC include eryaspase, capapasetinib, abolixib, rucapaib + nivolumab, atezolizumab + paclitaxel + gemcitabine + capecitabine + carboplatin, parsetzide + paclitaxel, latetuzumab + vedotin + pembrolizumab, durvalumab + DS-8201a, trelacizide + gemcitabine + carboplatin. In some embodiments, the therapeutic agents for treating TNBC include trastuzumab-druticon (Enheritance). ® ), datopotetan (druticon) (DS-1062), envtu (vedotin) (Padcev) ® ), balisafopeptide, adagloxad simolenin, nelipepimut-s (NeuVax ®Nivolumab (Opdivo) ® ), rucapranib, toripalimab (Tuoyi ® Camrelizumab, capapasetinib, durvalumab (Imfinzi) ® ), and combinations thereof. In some implementations, therapeutic agents for treating TNBC include nivolumab + rucapapanebine, bevacizumab (Avastin), and combinations thereof. ® () + chemotherapy, toripalimab + paclitaxel, toripalimab + albumin-bound paclitaxel, camrelizumab + chemotherapy, pembrolizumab + chemotherapy, balisafotetide + eribulin, durvalumab + trastuzumab-druticon, durvalumab + paclitaxel, or capapasetinib + paclitaxel.

[0626] Bladder cancer combination therapy

[0627] Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062) and trastuzumab deruxtecan (Enheritance). ® ), erdatinib, eganelisib, lenvatinib, beempegaldesleukin (NKTR-214), or combinations thereof. In some implementations, therapeutic agents for treating bladder cancer include eganelisib + nivolumab, pembrolizumab (Keytruda), etc. ® ) + Enftu monoclonal antibody Vidotin (Padcev) ® Nivolumab + ipilimumab, durvalumab + trimelimumab, lenvatinib + pembrolizumab, envitumab + vedotin (Padcev) ® ) + Pembrolizumab and bempegaldesleukin + Nivolumab.

[0628] Combination therapy for colorectal cancer (CRC)

[0629] Treatment agents for CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, aflibercept, and any combination thereof. In some embodiments, treatment agents for CRC include bevacizumab (Avastin). ® ), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda) ®FOLFIRI, Regorafenib (Stivarga) ® ), Zaltrap ® ), cetuximab (Erbitux) ® ), Lonsurf (Orcantas) ® Bevacizumab, XELOX, FOLFOXIRI, or combinations thereof are used to treat CRC. In some embodiments, the therapeutic agents for treating CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, the therapeutic agents for treating CRC include bimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, nabucascin + FOLFIRI + bevacizumab, and nivolumab + ipilimumab.

[0630] Combination therapy for esophageal and esophagogastric junction cancer

[0631] Therapeutic agents for treating esophageal and esophagogastric junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. In some embodiments, therapeutic agents for treating gastroesophageal junction cancer (GEJ) include Herceptin, cisplatin, 5-FU, ramucirumab, or paclitaxel. In some embodiments, therapeutic agents for treating GEJ cancer include ALX-148, AO-176, or IBI-188.

[0632] Combination therapy for gastric cancer

[0633] Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

[0634] Head and neck cancer combination therapy

[0635] Therapeutic agents used to treat head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0636] Treatment agents used to treat head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, and cetuximab (Erbitux). ® ), cisplatin, nivolumab (Opdivo) ® (and combinations thereof). In some embodiments, therapeutic agents for treating HNSCC include pembrolizumab + carboplatin + 5-FU, cetuximab + cisplatin + 5-FU, cetuximab + carboplatin + 5-FU, cisplatin + 5-FU, and carboplatin + 5-FU. In some embodiments, therapeutic agents for treating HNSCC include durvalumab, durvalumab + trimemumab, nivolumab + ipilimumab, rovaluecel, pembrolizumab, pembrolizumab + icocadorstat, GSK3359609 + pembrolizumab, lenvatinib + pembrolizumab, refulimab, refulimab + enobituzumab, ADU-S100 + pembrolizumab, icocadorstat + nivolumab + ipilimumab / lirerutumab.

[0637] Non-small cell lung cancer combination therapy

[0638] Therapeutic agents for the treatment of non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinorelbine, vinorelbine, and any combination thereof. In some implementations, the therapeutic agent for the treatment of NSCLC includes alectinib (alecensa). ® Tafinlar ® Trametinib (Mekinist) ® Osimertinib (Tagrisso) ® ), entrectinib (Tarceva) ® ), Crizotinib (Xalkori) ® Pembrolizumab (Keytruda) ® Carboplatin, Pemetrexed (Alimta) ® ), Nabothian paclitaxel (Abraxane) ® ), ramucirumab (Cyramza ® Docetaxel, bevacizumab (Avastin) ® ), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif) ®Nivolumab (Opdivo) ® ), Gefitinib (Iressa) ® ) and combinations thereof. In some implementations, therapeutic agents for treating NSCLC include dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + nabutaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + nabutaxel, cisplatin + gemcitabine, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nabutaxel, or pemetrexed + cisplatin + carboplatin. In some implementations, therapeutic agents for treating NSCLC include datopotane (DS-1062) and trastuzumab (Enheritan). ® ), Enftu monoclonal antibody vedotin (Padcev) ® ( ), durvalumab, cananulumab, cimiprimab, noglucan interleukin-alpha, avelumab, tisrelimumab, dunalimumab, vimbrolizumab, osperimab, or combinations thereof. In some implementations, therapeutic agents for the treatment of NSCLC include dattapotramab / drutecan + pembrolizumab, dattapotramab / drutecan + durvalumab, durvalumab + trimemumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, noglucan interleukin-alpha (N-803) + pembrolizumab, tisrelimumab + atezolizumab, vimbrolizumab + pembrolizumab, or osperimab + tisrelimumab.

[0639] Small cell lung cancer combination therapy

[0640] Therapeutic agents for the treatment of small cell lung cancer (SCLC) include atezolizumab, bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents for the treatment of SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, triprazine, or combinations thereof. In some embodiments, therapeutic agents for the treatment of SCLC include atezolizumab + carboplatin + etoposide, atezolizumab + carboplatin, atezolizumab + etoposide, or carboplatin + paclitaxel.

[0641] Ovarian cancer combination therapy

[0642] Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, hexamethylmelamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

[0643] Combination therapy for pancreatic cancer

[0644] Treatment agents used to treat pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, and nab-paclitaxel. ® ), FOLFIRINOX, and combi...

Claims

1. A compound of formula (I) (I) Or its pharmaceutically acceptable salt, wherein: It can be a single bond or a double bond; Ring A is C 5-7 Cycloalkyl, phenyl, 5- to 7-membered heterocyclic, or 5- or 6-membered heteroaryl; the cycloalkyl, phenyl, heterocyclic, or heteroaryl group of ring A is optionally surrounded by one to four R groups. 6 Instead, the R 6 They can be the same or different; Each R 6 Independently, it can be a halogenated group, -OH, -OCH3, oxo group, -CN, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl; X is N or CR 7 ; R 7 H, halogroup, CN, halomethyl, -CH3, -C2H5, -OCH3, ethynyl or cyclopropyl; R 7 The cyclopropyl group is optionally surrounded by 1 to 3 Z groups. 7 Instead, the Z 7 Can be the same or different; each Z 7 Independently CN, F, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; R 1 and R 2 Together with the N attached to them, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups; wherein R 1 and R 2 The heterocyclic groups formed together with the N to which they are attached are optionally surrounded by one to four Z. 1 Instead, the Z 1 They can be the same or different, where R is the only one. 1 and R 2 The formed heterocyclic group has 0 to 3 additional heteroatoms, each of which is independently N, O or S; Or R 1 and R 2 Together with the N to which they are attached, they do not form heterocyclic groups, and R 1 C 10-14 Tricyclic aryl, and R 2 C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; wherein R 1 The aryl group is optionally surrounded by 1 to 4 Z groups. 2 Instead, the Z 2 They can be the same or different; Each Z 1 or Z 2 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -SF5, -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ) or -S(O)(NR 12a )R 12b ; where each Z 1 or Z 2 The alkyl group, the haloalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group are each optionally surrounded by 1 to 4 Z-terminals. 1a Instead, the Z 1a They can be the same or different; Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ) or -S(O)(NR 12a )R 12b Z 1a The alkyl group, the haloalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group are each optionally surrounded by 1 to 4 Z-terminals. 1b Instead, the Z 1b They can be the same or different; Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2; wherein Z 1b The alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 Alkyl), or -S(O)2N(C 1-9 Alkyl)2-substituted; and Each R 12a R 12b or R 12c H and C independently 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl; wherein R 12a R 12b or R 12c Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally surrounded by 1 to 4 Z-terminal groups. 1b Instead, the Z 1b They can be the same or different; Unless otherwise specified, each heteroaryl group of the compounds of formula (I) is a 5- to 14-membered heteroaryl group; Unless otherwise specified, each heterocyclic group of the compound of formula (I) is a 3- to 20-membered heterocyclic group; Unless otherwise specified, each heteroaryl or heterocyclic group of the compound of formula (I) has one to four heteroatoms that are independently N, O or S.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structure of formula (Ia). (It)。 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof has the structure of formula (Ib). (Ib).

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof has the structure of formula (Ic). (Ic)。 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof has the structure of formula (Id). (Id)。 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof has the structure of formula (Ie). (Ie)。 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X is N.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X is a CR 7 And R 7 It can be H, CH3, F, Cl, or CN.

9. The compound according to any one of claims 1 to 6 and 8, or a pharmaceutically acceptable salt thereof, wherein X is a CR 7 ;R 7 It can be H, CH3, or F.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, 8 and 9, wherein X is -CF.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, 8 and 9, wherein X is -CH.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily divided by 1 to 4 Z 2 Replacement The Z 2 They can be the same or different.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 1 for .

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each Z 2 Independent of halogenated group, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, C 6-10 Aryl or 4- to 10-membered heterocyclic groups; Z 2 The alkyl, alkynyl, cycloalkyl, heteroaryl, aryl, or heterocyclic group is optionally surrounded by 1 to 3 Z-terminal groups. 1a Replace, each Z 1a Independent of halogenated group, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, C 6-10 Aryl or 5 to 10-membered heterocyclic groups, of which Z 1a Each alkyl, alkynyl, cycloalkyl, heteroaryl, aryl, or heterocyclic group is optionally surrounded by one to three groups selected from halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Substitution of cycloalkyl groups.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each Z 2 Independently halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyclopropyl, CN or -OH.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Z 2 It is -CF3.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-3 alkyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -CH3.

19. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N attached to them, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups; Any two connected rings of the tricyclic or tetracyclic heterocyclic group can be fused or bridged; and By R 1 and R 2 The heterocyclic groups formed together with the N to which they are attached can optionally be surrounded by 1 to 4 Z groups. 1 replace.

20. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N attached to them, they form 11 to 20-membered tricyclic or tetracyclic heterocyclic groups; Any two connected rings of the tricyclic or tetracyclic heterocyclic group are fused or helical; and By R 1 and R 2 The heterocyclic groups formed together with the N to which they are attached can optionally be surrounded by 1 to 4 Z groups. 1 replace.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, wherein R 1 and R 2 Together with the N to which they are attached, they form 11 to 15-membered tricyclic heterocyclic groups; wherein R 1 and R 2 The heterocyclic groups formed together with the N to which they are attached are optionally surrounded by one to four Z. 1 Instead, the Z 1 They can be the same or different.

22. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 yes ; Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the range do not exceed N; X 4 To be arbitrarily determined by one or two Z 1 Replaced CH2; X 6 For bond, O, -CH2-, -CH2O- or -CH2CH2-, where X 6 Each of CH2, CH2CH2, and OCH2 is optionally divided by one or two Z. 1 replace; X 7 For the key or optionally by one or two Z 1 Replaced CH2; X 8 For bonds, CH2 or CH2O, where X 8 Each of CH2 and CH2O is optionally separated by one or two ZnO. 1 Replace; and X 9 For bonds, CH2, CH2O or CH2CH2, where X 9 Each of CH2, CH2O, and CH2CH2 is optionally divided by one or two Z. 1 replace.

23. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 yes ; Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the range do not exceed N; X 1 It is -OCF2-, -OCH2-, -CH2-, -CH2CH2-, -OCH2CH2-, -CF2-, or -CH2NR. 1b -; where R 1b C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxetane, -C(O)-R 12a -S(O)R 12a Or C 3-6 cycloalkyl; X 2 It can be O, -OCH2-, -CF2-, -CH2CH2-, or -CH2-; X 3 For the key, -CF2- or -CH2-; and q is 0, 1, or 2.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes .

25. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes .

26. The compound according to any one of claims 23 to 25, or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes .

27. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes .

28. The compound according to any one of claims 23, 24 and 27, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 yes .

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 28, wherein q is 0.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 28, wherein q is 1.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, 19 and 21, wherein -NR 1 R 2 for or heterocyclic groups, wherein -NR 1 R 2 The heterocyclic group is optionally surrounded by 1 to 4 Zn groups. 1 Instead, the Z 1 They can be the same or different; Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the middle do not exceed N; and X 5 It is -OCH2-, -CH2-, -CH2CH2-, or -CF2-.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes ;and n is 0, 1, or 2.

33. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes .

34. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein... -NR 1 R 2 yes or ; Y 7 For O, -OCH2-, -CH2, or -CH2CH2-; Y 7 Each of -OCH2-, -CH2-, and -CH2CH2- is optionally construed by one or two Z-terminals. 1 replace; Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 The two numbers in the middle do not exceed N; and m can be 0, 1, or 2.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 22 to 34, wherein... Q 3 For N, CH or CZ 1 ;and Q, Q 1 Or Q 2 Each independently is CH or CZ 1 .

36. The compound according to any one of claims 22 to 34, or a pharmaceutically acceptable salt thereof, wherein Q 3 Let N be the number of elements in the array.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 22 to 34, wherein Q, Q 1 Q 2 and Q 3 One of them is CZ 1 .

38. The compound according to any one of claims 22 to 34, or a pharmaceutically acceptable salt thereof, wherein Q, Q 1 Or Q 3 Each of them is CH; and Q 2 For CZ 1 .

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 22 to 34, wherein Q, Q 1 Q 2 and Q 3 Each of them is CH or CZ 1 .

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 39, wherein Each Z 1 Independently for C 1-6 Alkyl, -OH, CN, halogroup, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkynyl group, C 3-15 Cycloalkyl, 3-18 membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)-R 12a -C(O)OR 12a The alkyl group, alkynyl group, cycloalkyl group, heterocyclic group, or heteroaryl group is optionally surrounded by one to four Z groups. 1a Instead, the Z 1a They can be the same or different; Each Z 1a Independently -OH, CN, C 1-6 Alkyl, Halogenated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, 5-18 membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, the heterocyclic, the aryl, or the heteroaryl is optionally divided by one to four Z. 1b Instead, the Z 1b They can be the same or different; Each Z 1b Independently, CN, -OH, C 1-6 Alkyl, Halogenated, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; and Each R 12a H and C independently 1-6 Alkyl or C 3-10 Cycloalkyl.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 39, wherein each Z 1 Independently -OH, CN, C 1-6 Alkyl, Halogenated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein Z 1 The phenyl or heteroaryl group is optionally surrounded by 1 to 3 Z groups. 1a Instead, the Z 1a Can be the same or different; each Z 1a Independently, it is a halogenated group or C 1-6 Halogenated alkyl groups.

42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 39, wherein each Z 1 Independently for C 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, phenyl, or pyridyl, wherein the phenyl or pyridyl group is optionally composed of one to three independently selected from halogenated groups and C. 1-3 Substituents of haloalkyl groups.

43. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 39, wherein each Z 1 It can be independently -CF3, -OCF3, -CH3, -OCHF2, F, Cl, or Br.

44. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 39, wherein each Z 1 It can be -CH3, CF3, F or Br independently.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 30 and 34 to 44, wherein X 2 It can be O, -OCH2-, -CH2CH2-, or -CH2-.

46. ​​The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein... -NR 1 R 2 yes ; Q, Q 1 Q 2 and Q 3 Each of them is independently N or optionally Z 1 The replacement of C is conditional on Q and Q'. 1 Q 2 and Q 3 N is a subset of N; and X 2 It is O or -CH2-; X 10 It is O or -CH2-; and r is 0, 1 or 2.

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein -NR 1 R 2 yes ; X 2 It is O or -CH2-; X 10 It is O or -CH2-; Each Z 1b Independently H or Z 1 ;and r is 0, 1, or 2.

48. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein -NR 1 R 2 for ; X 2 It is O or -CH2-; X 10 It is O or -CH2-; and Each Z 1b Independently H or Z 1 .

49. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein -NR 1 R 2 yes, ,or; X 2 It is O or -CH2-; X 10 It is O or -CH2-; and Each Z 1b Independently H or Z 1 .

50. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein... -NR 1 R 2 for ; X 2 It is O or -CH2-; X 10 It is O or -CH2-; Each Z 1b Independently H or Z 1 ;and r is 0, 1, or 2.

51. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein -NR 1 R 2 yes ;and p is 1 or 2.

52. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 21, wherein -NR 1 R 2 yes .

53. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 52, wherein each Z 1 F and C independently 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

54. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and 19 to 52, wherein each Z 1 It can be F, -CH3, -CF3, -C2F5, or -OCF3 independently.

55. The compound according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof, wherein each Z 1b It is either H or F.

56. The compound according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof, wherein at least one Z 1b It is F.

57. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 50 and 53 to 56, wherein X 2 It is O; and X 10 It is -CH2-.

58. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 46 to 50 and 53 to 56, wherein X 2 It is -CH2-; and X 10 It is O.

59. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 for , , , , , , , , , or .

60. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 for 。 61. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 for , , or .

62. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein -NR 1 R 2 for or .

63. A compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.

64. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

65. The pharmaceutical composition of claim 50, wherein the pharmaceutical composition further comprises an additional therapeutic agent.

66. A method for treating a disease or condition associated with chromosome 9p21 deletion, the method comprising administering to a patient in need a therapeutically effective amount of the compound of any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 64 or 65.

67. A method for treating a disease or condition associated with methylthioadenosine phosphorylase (MTAP) deficiency or any other MTAP loss-of-function event, said other MTAP loss-of-function event including but not limited to loss of mRNA expression, mRNA splicing defects, open reading frame stop codon or frameshift mutations, any mutation leading to enhanced degradation of the MTAP protein, said method comprising administering to a patient in need a therapeutically effective amount of the compound of any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claims 64 or 65.

68. A method of treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound according to claims 1 to 63 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 64 or 65.

69. The method according to claim 68, wherein the cancer is selected from lung cancer, urothelial carcinoma, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell tumor, non-Hodgkin's lymphoma, head and neck cancer, bile duct cancer, esophageal cancer, glioblastoma, gastric cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, kidney cancer, colorectal cancer, prostate cancer, leukemia, cervical cancer, endometrial cancer, and soft tissue cancer.

70. The method of claim 68, wherein the cancer is selected from ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, and bladder cancer.

71. The method according to any one of claims 68 to 70, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent or therapeutic modality.

72. The method of claim 71, wherein the additional therapeutic agent or additional therapeutic modality comprises one, two, three or four additional therapeutic agents and / or therapeutic modalities.

73. The pharmaceutical composition of claim 65 or the method of claim 71, wherein the additional therapeutic agent or therapeutic modality is selected from immune checkpoint modulators, antibody-drug conjugates (ADCs), anti-apoptotic agents, targeted anticancer therapeutic agents, chemotherapy agents, surgery, or radiotherapy.

74. The pharmaceutical composition or method according to claim 73, wherein the immune checkpoint modulator is selected from anti-PD-(L)1 antibody, anti-TIGIT antibody, anti-CTLA4 antibody, anti-CCR8 antibody, anti-TREM1 antibody, anti-TREM2 antibody, CD47 inhibitor, DGKα inhibitor, helios (IKZF2) degrader, HPK1 degrader, HPK1 inhibitor, FLT3 agonist, CD39 inhibitor, CD73 inhibitor, adenosine A2a and / or A2b receptor antagonist, natural killer cell adaptor, and CAR-T cell therapy.

75. The use of any compound of claims 1 to 63 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or condition associated with chromosome 9p21 deletion or any other MTAP deficiency.

76. Use of the compound according to claim 75, wherein the disease or condition is cancer.

77. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63, wherein the compound or a pharmaceutically acceptable salt thereof is used in a therapeutic manner.

78. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63, or the pharmaceutical composition according to claim 64 or 65, wherein the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is used in a method of treating a disease or condition, such as a disease or condition associated with chromosome 9p21 deletion or any other MTAP deficiency.

79. The compound, its pharmaceutically acceptable salt, or pharmaceutical composition used according to claim 78, wherein the disease or condition is cancer.

80. The compound, its pharmaceutically acceptable salt, or pharmaceutical composition used according to claim 78 or 79, wherein the compound or its pharmaceutically acceptable salt is administered in combination with an additional therapeutic agent or therapeutic modality.

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