PRMT5 inhibitors and their uses

Abstract

The present disclosure generally relates to compounds that inhibit PRMT5. The present disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of a disease and / or condition by inhibiting PRMT5. The present disclosure further relates to the use of the compounds for the treatment of a disease or condition associated with chromosome 9p21 deletion or MTAP null. The present disclosure further relates to the use of the compounds for the treatment of cancer. The present disclosure provides a method of inhibiting PRMT5 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 476,905, filed December 22, 2022, and U.S. Provisional Application No. 63 / 518,001, filed August 7, 2023, both of which are incorporated herein in their entirety for all purposes.

[0002] FIELD OF THE INVENTION The present disclosure relates to compounds that inhibit PRMT5. The present disclosure further relates to uses of the compounds for the treatment and / or prevention of diseases and / or conditions that respond to PRMT5 inhibition. [Background technology]

[0003] Protein arginine methyltransferase (PRMT) enzymes catalyze the methylation of arginine residues on proteins involved in chromatin organization, gene expression, RNA splicing, protein translation, and signal transduction. The diverse substrates for PRMTs are localized in various subcellular compartments, including the nucleus, nucleolus, and cytosol, enabling many biological processes important for mammalian cell function and survival.

[0004] Of the nine members of the PRMT family, PRMT5 is responsible for generating the majority of symmetric dimethylarginines on protein substrates. Methylation by PRMT5 is distributed, suggesting that PRMT5 generates and releases monomethylarginines before a second methylation event. PRMT5 functions as a homotetramer in a complex with the MEP50 / WDR77 protein homotetramer. MEP50 / WDR77 is essential for PRMT5 enzymatic activity, substrate recognition, and interaction with multiple binding partners (S. Antonysamy, et al. PNAS 109, 2012).

[0005] PRMT5 expression is frequently upregulated in leukemia, lymphoma, and solid tumors, and its expression can be inversely 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 required for hematopoiesis and enhances both hematopoietic stem cell pluripotency and progenitor cell expansion, suggesting that its inhibition may have myelosuppressive effects (Liu et al. J. Clin. Invest., 2015).

[0006] Over the past few years, several PRMT5 inhibitors have entered clinical trials with the goal of treating tumors dependent on PRMT5 activity and / or tumors particularly sensitive to PRMT5 inhibition. Narrow therapeutic windows and bone marrow suppression have consistently been observed in patients enrolled in these trials, suggesting that inhibition of PRMT5 in normal tissues is undesirable. Inhibition of PRMT5 activity in tumors could potentially alleviate the adverse effects of these first-generation PRMT5 inhibitors while sparing normal cells.

[0007] Human cancers frequently acquire homozygous deletions of the chromosome 9p21 locus harboring the tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A). The MTAP (methylthioadenosine phosphorylase) gene, located closely to CDKN2A, is co-deleted in 90% of tumors with CDKN2A loss. It is estimated that 10–15% of all cancers harbor homozygous deletions of the MTAP gene. Pancreatic cancer, bladder cancer, NSCLC, head and neck cancer, esophageal cancer, and glioblastoma harbor a significant proportion of patients with MTAP loss among cancers.

[0008] MTAP loss / null / deletion leads to the accumulation of its substrate, methylthioadenosine (MTA), which is structurally similar to S-adenosyl-L-methionine (SAM), which is utilized by PRMT5 as a methyl-donor cofactor to catalyze arginine dimethylation. MTA, which accumulates in MTAP-deficient cancer cells, competes with SAM for binding to the catalytic site of PRMT5, partially suppressing its enzymatic activity. Tumor cells growing under the pressure of reduced PRMT5 activity become particularly vulnerable to further PRMT5 loss, such as knockdown by shRNA or siRNA.

[0009] The accumulation of PRMT5-MTA complexes in MTAP-deficient cancers can be therapeutically exploited. It is attractive to design MTA-cooperative small molecule inhibitors of PRMT5 that selectively elicit their inhibitory effects in cancer cells with elevated MTA levels and accumulation of MTA-bound PRMT5. There remains a need for PRMT5 inhibitors with desirable selectivity, potency, metabolic stability, or reduced adverse effects. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Greenblatt,et al.Exp.Hematol.2016 [Non-patent document 2] Chen, H., et al. Oncogene 2016 [Non-patent document 3] Lattouf, et al. Oncotarget, 2019 [Non-patent document 4] Liu et al. J. Clin. Invest., 2015 Summary of the Invention [Means for solving the problem]

[0011] The present disclosure provides compounds useful as PRMT5 inhibitors. The present disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions by inhibiting PRMT5 with the compounds. The present disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions by inhibiting PRMT5 with the compounds in tumors associated with MTAP null or chromosome 9p21 deletion.

[0012] In one embodiment, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; [ka] is a single or double bond, Ring A is C 5~7 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, and the cycloalkyl, phenyl, heterocyclyl, or heteroaryl of ring A are each independently selected from 1 to 4 R 6 and optionally substituted with X is N or CR 7 and R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 1 each of the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 2 H, -CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~6 alkynyl, cyclopropyl, cyclobutyl, or oxetanyl; R2 alkyl, haloalkyl, alkoxyalkyl, alkynyl, cyclopropyl, or cyclobutyl, each of which may be the same or different, is selected from 1 to 4 Z 2 and each Z 2 But independently, C 2~6 Alkynyl, halo, -CN, -OR 2a , cyclopropyl, cyclobutyl, or oxetanyl, and R 2a But H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, or C 1~3 is alkyl, R 5 But H, C 1~3 Alkyl or C 1~3 Is it a haloalkyl? Or R 1 and R 2 together with the carbon to which they are attached, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, R 1 and R 2 wherein the cycloalkyl or heterocyclyl formed from 5 or optionally replaced by Or R 2 and R 5 together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, or oxetanyl, and R 2 and R 5 wherein the cyclopropyl or cyclobutyl formed from is optionally substituted with 1 to 4 halo; R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3a R 3b , -SO2R 3a , -SO2NR 3a R 3b , C 6~10 Aryl, C 3~10cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 3 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and optionally substituted with R 4 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 4 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 4 or optionally replaced by Or R 3 and R 4 together with the nitrogen to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, and R 3 and R 4 and the heterocyclyl or heteroaryl formed from the 9 and optionally substituted with R 3 and R 4 is a heterocyclyl having 0 to 3 additional heteroatoms, each independently being N, O, or S; and R 3 and R 4 is a heteroaryl having 0 to 3 additional heteroatoms, each independently being N, O, or S; Or R 2 and R 4 together with the atoms to which they are attached form a 5- to 10-membered heterocyclyl, and R 2 and R 4 The heterocyclyl formed from 8 and optionally substituted with Each R 6 are independently halo, -OH, -OCH3, oxo, -CN, C 1~3Alkyl, C 1~3 haloalkyl, or cyclopropyl; R 7 is H, halo, CN, halomethyl, -CH3, or -OCH3; each Z 1 , Z 3 , Z 4 , Z 5 , Z 8 , or Z 9 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, and each Z 1 , Z 3 , Z 4 , Z 5 , Z 8 , or Z 9 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -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)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a)S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3 and Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and Z 1b is a 5- to 10-membered heteroaryl; and Z 1b wherein the heterocyclyl is a 3- to 10-membered heterocyclyl; Each R 3a , R 3b , R 12a , R 12b , or R 12c However, independently, H, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5-10 heteroaryl, and each R 3a , R 3b , R 12a , R 12b , or R 12ceach of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein each heteroaryl or heterocyclyl in the compound has 1 to 3 heteroatoms, each independently being N, O, or S, unless otherwise specified.

[0013] In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0014] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0015] In some embodiments, the present disclosure provides a method of inhibiting PRMT5 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0016] In some embodiments, the present disclosure provides a method of treating a patient having a condition associated with a chromosome 9p21 deletion or MTAP null, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present disclosure relates to inhibitors of PRMT5. The present disclosure also relates to compositions and methods related to PRMT5 inhibitors and the use of such compounds for the treatment and / or prevention of diseases and conditions. The present disclosure also relates to compositions and methods for treating and / or preventing cancer or viral infections, comprising a PRMT5 inhibitor in combination with one or more additional therapeutic agents.

[0018] Definitions and general parameters The following description is made with the understanding that the present disclosure should be considered as an example of claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. It should be noted that as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art, etc.

[0020] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless a different meaning is suggested by the context in which they are used.

[0021] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. No directionality is indicated or implied by the order in which chemical groups are written or named, unless chemically or structurally required. A solid line projecting from the center of a ring indicates that the point of attachment of a substituent to that ring can be at any ring atom. For example, R in the following structure: a can be attached to any of the five carbon ring atoms, or the hydrogen attached to the nitrogen ring atom is R a can be replaced with: [ka]

[0022] "C u~v The prefix "" indicates that the following group has carbon atoms u through v. For example, "C 1~6"Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x- to y-membered" ring, where x and y are numerical ranges (e.g., "3- to 12-membered heterocyclyl") means a ring having x to y atoms (e.g., 3 to 12), up to 80% of which may be heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon.

[0023] Also, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, or alkylyl groups, "arylene" or "arylenyl" groups, or aryl groups, respectively.

[0024] "Compounds disclosed herein" or "compounds of the disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13). Also included are the specific compounds of Examples 1-52 provided herein.

[0025] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, for that term, "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0026] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), 1 to 4 carbon atoms (i.e., C 1~4 alkyl), or 1 to 3 carbon atoms (i.e., C 1~3 Examples of alkyl groups include methyl, ethyl, 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 group having a specific number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0027] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0028] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0029] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0030] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment (alkyl-O-). With respect to alkyl groups, alkoxy groups include C 1~6 Alkoxy groups may have any suitable number of carbon atoms, such as , ...

[0031] "Alkoxyalkyl" refers to an alkoxy group linked to an alkoxy group which is linked to the rest of the compound. The alkoxyalkyl has 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C 2~5 alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3The alkoxy and alkyl groups may have any suitable number of carbons, such as alkoxyalkyl. The number of carbons refers to the total number of carbons in the alkoxy and alkyl groups. For example, in some embodiments, Calkoxyalkyl refers to ethoxy (Calkoxy) linked to butyl (Calkyl), and in other embodiments, n-propoxy (Calkoxy) linked to isopropyl (Calkyl). Alkoxy and alkyl are as defined above, where alkyl is divalent and may include, but is not limited to, methoxymethyl (CHOCH-), methoxyethyl (CHOCHCH-), and the like.

[0032] "Amino" is -NR y R z refers to a group, wherein R y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which can be optionally substituted.

[0033] As used herein, "aryl" refers to an all-carbon aromatic monocyclic ring or an all-carbon polycyclic ring system in which at least one of the rings is aromatic. For example, in some embodiments, aryl groups have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such polycyclic ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the polycyclic ring system. The rings of a polycyclic ring system can be connected to each other through fused, spiro, and bridged bonds, where valence requirements allow. When referring to an aryl having a particular range of atom numbers (e.g., a 6- to 10-membered aryl), it is also understood that the atom range refers to the total ring atoms of the aryl. For example, a 6-membered aryl includes phenyl, and a 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0034] "Cyano" or "carbonitrile" refers to the group --CN.

[0035] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0036] "Fused" refers to a ring that is bonded to an adjacent ring. In some embodiments, the fused ring system is heterocyclyl. In some embodiments, the fused ring system is oxabicyclohexanyl. In some embodiments, the fused ring system is [ka] is.

[0037] "Bridged" refers to a ring fusion in which non-adjacent atoms on the ring are joined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems. In some embodiments, the bridged ring is bicyclopentyl (e.g., bicyclo[1.1.1]pentyl), bicycloheptyl (e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl), or bicyclooctyl (e.g., bicyclo[2.2.2]octyl). In some embodiments, the bridged ring is [ka] is.

[0038] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentanyl (spiro[ab]pentanyl), spirohexanyl, spiroheptanyl, spirooctyl (e.g., spiro[2.5]octyl), spirononanyl (e.g., spiro[3.5]nonanyl), spirodecanyl (e.g., spiro[4.5]decanyl), or spiroundecanyl (e.g., spiro[5.5]undecanyl). In some embodiments, the spiro substituent is [ka] is.

[0039] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0040] As used herein, "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by halo substituents, which may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 alkyl, C 1~4 One or more of the hydrogen atoms of the alkyl is replaced by a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0041] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to alkyl groups, a haloalkoxy group is 1~6The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3 or more halogens. When all hydrogen atoms are replaced with halogens, such as fluorine, the compound is persubstituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, etc.

[0042] The term "heteroaryl," as used herein, refers to a single aromatic ring or a polycyclic ring. This term includes aromatic monocyclic rings of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The sulfur and nitrogen atoms may be present in oxidized form, provided the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. This term also includes polycyclic ring systems (e.g., ring systems containing two or three rings), and heteroaryl groups may be fused to one or more heteroaryl (e.g., naphthyridinyl), carbocycles (e.g., 5,6,7,8-tetrahydroquinolyl), or aryl (e.g., indazolyl), as defined above, to form a polycyclic ring. Such polycyclic rings may be optionally substituted on the carbocyclic portion of the polycyclic ring with one or more (e.g., 1, 2, or 3) oxo groups. It is understood that the point of attachment of a heteroaryl polycyclic ring can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portions of the ring, as defined above. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, and thianaphthenyl.

[0043] "Heterocyclyl" or "heterocyclic ring" or "heterocycle," as used herein, refers to a single saturated or partially unsaturated ring or polycyclic ring. This term includes saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. The term also includes polycyclic ring systems (e.g., ring systems containing two or three rings) in which a heterocyclic group (defined above) can be linked to two adjacent atoms (fused heterocycles) with one or more heterocyclic (e.g., decahydronaphthyridinyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthyridinyl), carbocyclic (e.g., decahydroquinolyl), or aryl. It is understood that the point of attachment of a heterocyclic polycyclic ring can be at any position on the ring, including on the heterocyclic, heteroaryl, aryl, or carbocyclic portions of the ring, as defined above. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl. Exemplary fused bicyclic heterocycles include: [ka] These include, but are not limited to:

[0044] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0045] "Oxo" refers to the (=O) or (O) radical.

[0046] "Sulfonyl" is -S(O)R c refers to a group, wherein R c is alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0047] Whenever the graphical representation of a group ends in a singly bonded nitrogen atom, that group represents an —NH group unless otherwise indicated. Similarly, unless otherwise specified, hydrogen atoms are implied and considered to be present when needed to satisfy valence or provide stability, given the knowledge of one of ordinary skill in the art.

[0048] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not. Also, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0049] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanato, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining a substituent with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, if a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0050] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, CN, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, CN, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, CN, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano; and "substituted sulfonyl" refers to the group -S(O)R, wherein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0051] In some embodiments, the substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl includes a cycloalkyl, heterocyclyl, aryl, and / or heteroaryl having a substituent on a ring atom, where the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the remainder of the compound. For example, in the moiety below, the cyclopropyl is substituted with a methyl group: [ka]

[0052] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" should be read expansively and without limitation. In addition, the terms and expressions used herein are used as terms of description and not of limitation, and there is no intention to use such terms and expressions to exclude any equivalents of the features shown and described, or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure as claimed.

[0053] The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic and organic bases or acids. The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic and organic bases or acids. When a compound of the present disclosure contains one or more acidic or basic groups, the present disclosure also includes the corresponding pharmaceutically or toxicologically acceptable salts of the compound, particularly pharmaceutically acceptable salts of the compound. Thus, compounds of the present disclosure containing acidic groups may exist in these groups and can be used in accordance with the present disclosure, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to those skilled in the art. Compounds of the present disclosure that contain one or more basic groups, i.e., groups that can be protonated, may exist and may be used in the form of their addition salts with inorganic or organic acids in accordance with the present disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0054] When the compounds of the present disclosure simultaneously contain an acidic group and a basic group in the molecule, the present disclosure also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0055] The present disclosure also includes all salts of the compounds of the present disclosure that are not directly suitable for use in pharmaceuticals due to their poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reacting with the base compounds to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the base compounds (as disclosed) are known to those skilled in the art and are disclosed, for example, in Berge, et al., Journal of Pharmaceutical Science, January 1977, Vol. 66, No. 1, and other sources.

[0056] Furthermore, the compounds disclosed herein may be subject to tautomerism. Where tautomerism, e.g., keto-enol tautomerism, of the compounds or their prodrugs may occur, the individual forms, e.g., keto and enol forms, are each within the scope of the present disclosure, as are mixtures thereof in any ratio. The same applies to stereoisomers, e.g., enantiomers, cis / trans isomers, diastereomers, conformers, etc.

[0057] The term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions, e.g., to create and break chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0058] Those skilled in the art will understand that if the list of alternative substituents includes members that cannot be used to replace a particular group due to the valence requirements of the members or for other reasons, the list is intended to be read with the knowledge of one skilled in the art to include only those members of the list that are suitable to replace the particular group.

[0059] Additionally, compounds of the present disclosure may exist in the form of solvates, such as solvates that include pharmaceutically acceptable solvates such as water of solvation or alcohols, particularly ethanol. A "solvate" is formed by the interaction of a solvent and a compound.

[0060] In certain embodiments, optical isomers, racemates, or other mixtures thereof (e.g., scalenic mixtures) of the compounds described herein or pharmaceutically acceptable salts or mixtures thereof are provided. If desired, isomers can be separated by methods well known in the art, for example, liquid chromatography. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-pressure liquid chromatography (HPLC) column.

[0061] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different, non-interchangeable three-dimensional structures. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0062] The compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L)-. Some embodiments include all such possible isomers, as well as their racemic, scalenic, and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0063] Compositions provided herein containing the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, can include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer, or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0064] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14and those into which a radioactive isotope, such as C, is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation treatment of patients. Isotopically labeled compounds and prodrugs thereof of the present disclosure can generally be prepared by following the procedures disclosed in the schemes or in the examples and preparations described below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0065] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein, in which one to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and, therefore, may be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g., a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0066] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved drug metabolism and pharmacokinetic (DMPK) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18F-labeled compounds may be useful in PET or SPECT studies.

[0067] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0068] Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0069] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that constitute the carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure can encompass any composition made by mixing at least one compound of the present disclosure with a pharmaceutically acceptable carrier.

[0070] As used herein, "pharmaceutically acceptable carriers" includes excipients or agents, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are not deleterious to the disclosed compounds or their use. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0071] "I C 50 " or "EC 50 " refers to the inhibitory concentration required to achieve 50% of the maximum desired effect.

[0072] "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the severity of the disease or condition); b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving the quality of life of the patient). The therapeutic effects of certain compounds of formula (I), including but not limited to, ameliorating the condition of a disease or condition, providing partial or complete remission, enhancing the effect of another drug, slowing the progression of the disease, improving the quality of life, and / or prolonging survival. In some embodiments, the term "treatment" or "treating" refers to administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the purpose of (i) delaying the onset of the disease, i.e., preventing or delaying the onset of clinical symptoms of the disease, (ii) inhibiting the disease, i.e., preventing the onset of clinical symptoms, and / or (iii) relieving the disease, i.e., causing regression of clinical symptoms or their severity.

[0073] "Prevention" or "preventing" means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0074] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0075] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to effect treatment and provide a therapeutic benefit, such as amelioration of symptoms or slowing of disease progression, when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition in response to a PRMT5 inhibitor. A therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art. [Table 4] compound

[0076] In one embodiment, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, [ka] is a single or double bond, Ring A is C 5~7 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, and the cycloalkyl, phenyl, heterocyclyl, or heteroaryl of ring A are each independently selected from 1 to 4 R 6 and optionally substituted with X is N or CR 7 and R 1 But H, C 1~6Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 1 each of the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 2 H, -CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~6 alkynyl, cyclopropyl, cyclobutyl, or oxetanyl; R 2 alkyl, haloalkyl, alkoxyalkyl, alkynyl, cyclopropyl, or cyclobutyl, each of which may be the same or different, is selected from 1 to 4 Z 2 and each Z 2 But independently, C 2~6 Alkynyl, halo, -CN, -OR 2a , cyclopropyl, cyclobutyl, or oxetanyl, and R 2a But H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, or C 1~3 is alkyl, R 5 But H, C 1~3 Alkyl or C 1~3 Is it a haloalkyl? Or R 1 and R 2 together with the carbon to which they are attached, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, R 1 and R 2 wherein the cycloalkyl or heterocyclyl formed from 5 or optionally replaced by Or R 2 and R 5 together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, or oxetanyl, and R2 and R 5 wherein the cyclopropyl or cyclobutyl formed from is optionally substituted with 1 to 4 halo; R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3a R 3b , -SO2R 3a , -SO2NR 3a R 3b , C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 3 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and optionally substituted with R 4 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 4 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 4 or optionally replaced by Or R 3 and R 4 together with the nitrogen to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, and R 3 and R 4 and the heterocyclyl or heteroaryl formed from the 9 or optionally replaced by Or R 2 and R 4 together with the atoms to which they are attached form a 5- to 10-membered heterocyclyl, and R 2 and R 4The heterocyclyl formed from 8 and optionally substituted with Each R 6 are independently halo, -OH, -OCH3, oxo, -CN, C 1~3 Alkyl, C 1~3 haloalkyl, or cyclopropyl; R 7 is H, halo, CN, halomethyl, -CH3, or -OCH3; each Z 1 , Z 3 , Z 4 , Z 5 , Z 8 , or Z 9 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -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 12aS(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, and each Z 1 , Z 3 , Z 4 , Z 5 , Z 8 , or Z 9 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -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)O(R12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3 and Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and Z 1b is a 5- to 10-membered heteroaryl; and Z 1b wherein the heterocyclyl is a 3- to 10-membered heterocyclyl; Each R 3a , R 3b , R 12a , R 12b , or R 12c However, independently, H, C 1~6 Alkyl, C3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5-10 heteroaryl, and each R 3a , R 3b , R 12a , R 12b , or R 12c each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Provided are compounds or pharmaceutically acceptable salts thereof, wherein each heteroaryl or heterocyclyl has 1 to 3 heteroatoms, each independently N, O, or S.

[0077] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound, wherein: [ka] is a single or double bond, Ring A is C 5~7 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, and the cycloalkyl, phenyl, heterocyclyl, or heteroaryl of ring A are each independently selected from 1 to 4 R 6 and optionally substituted with X is N or CR 7 and R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 1 each of the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 2 H, -CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C2~6 alkynyl, cyclopropyl, cyclobutyl, or oxetanyl; R 2 alkyl, haloalkyl, alkoxyalkyl, alkynyl, cyclopropyl, or cyclobutyl, each of which may be the same or different, is selected from 1 to 4 Z 2 and each Z 2 But independently, C 2~6 Alkynyl, halo, -CN, -OR 2a , cyclopropyl, cyclobutyl, or oxetanyl, and R 2a But H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, or C 1~3 is alkyl, R 5 But H, C 1~3 Alkyl or C 1~3 Is it a haloalkyl? Or R 1 and R 2 together with the carbon to which they are attached, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, R 1 and R 2 wherein the cycloalkyl or heterocyclyl formed from 5 or optionally replaced by Or R 2 and R 5 together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, or oxetanyl, and R 2 and R 5 wherein the cyclopropyl or cyclobutyl formed from is optionally substituted with 1 to 4 halo; R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3a R 3b , -SO2R 3a , -SO2NR 3a R 3b , C 6~10 Aryl, C3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 3 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and optionally substituted with R 4 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 4 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 4 or optionally replaced by Or R 3 and R 4 together with the nitrogen to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, and R 3 and R 4 and the heterocyclyl or heteroaryl formed from the 9 and optionally substituted with R 3 and R 4 is a heterocyclyl having 0 to 3 additional heteroatoms, each independently being N, O, or S; and R 3 and R 4 is a heteroaryl having 0 to 3 additional heteroatoms, each independently being N, O, or S; Or R 2 and R 4 together with the atoms to which they are attached form a 5- to 10-membered heterocyclyl, and R 2 and R 4 The heterocyclyl formed from 8 and optionally substituted with Each R 6 are independently halo, -OH, -OCH3, oxo, -CN, C1~3 Alkyl, C 1~3 haloalkyl, or cyclopropyl; R 7 is H, halo, CN, halomethyl, -CH3, or -OCH3; each Z 1 , Z 3 , Z 4 , Z 5 , Z 8 , or Z 9 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -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 ), -SR12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, and each Z 1 , Z 3 , Z 4 , Z 5 , Z 8 , or Z 9 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1a and optionally substituted with each Z 1a But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -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)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3 and Z 1a alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be the same or different, is selected from 1 to 4 Z 1b and optionally substituted with each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and Z 1b alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15-cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and Z 1b is a 5- to 10-membered heteroaryl; and Z 1b wherein the heterocyclyl is a 3- to 10-membered heterocyclyl; Each R 3a , R 3b , R 12a , R 12b , or R 12c However, independently, H, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10aryl, or 5-10 heteroaryl, and each R 3a , R 3b , R 12a , R 12b , or R 12c each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1b and optionally substituted with Each heteroaryl or heterocyclyl in the compounds of formula (I) is a compound having 1 to 3 heteroatoms, each independently N, O, or S, unless otherwise specified.

[0078] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia): [ka] And, During the ceremony, each K and Q is independently N, CH, or CR 6 and Each J and L is independently CH or CR 6 is a compound.

[0079] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia-1): [ka] And, In the formula, each R 9 are independently H or R 6 is a compound.

[0080] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia-2): [ka] And, In the formula, each R 9 are independently H or R 6is a compound.

[0081] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia-3): [ka] And, In the formula, R 9 But H or R 6 is a compound.

[0082] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib): [ka] And, During the ceremony, Each L 1 , L 2 , and L 3 But independently, CR 9 , C.R. 9 R 9 ,O,S,N,NR 9 , or CO, Each dashed line represents each L 1 , L 2 , L 3 , and L 1 and L 3 represents an optional bond to satisfy the valence requirements of the two Cs bonded to Each R 9 are independently H or R 6 is a compound.

[0083] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-1): [ka] And, In the formula, each R 9 are independently H or R 6 is a compound.

[0084] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-2): [ka] And, In the formula, each R 9 are independently H or R 6 is a compound.

[0085] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-3): [ka] And, In the formula, each R 9 are independently H or R 6 is a compound.

[0086] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-4): [ka] And, In the formula, each R 9 are independently H or R 6 is a compound.

[0087] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-5): [ka] is.

[0088] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-6): [ka] is.

[0089] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-7): [ka] is.

[0090] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-8): [ka] is.

[0091] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-9): [ka] is.

[0092] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-10): [ka] is.

[0093] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-11): [ka] is.

[0094] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-12): [ka] is.

[0095] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-13): [ka] And, wherein q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2.

[0096] In some embodiments, the compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound wherein X is N. In some embodiments, X is CR 7 In some embodiments, R 7 is H, halo, CN, —CH, or halomethyl. In some embodiments, R 7 is halo. In some embodiments, R 7 is F. In some embodiments, R 7 is H.

[0097] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a substituted or unsubstituted aryl group, and ring B is a substituted or unsubstituted aryl group. 6 In some embodiments, ring A is a compound in which ring A is phenyl optionally substituted with 1 to 3 R 6 In some embodiments, ring A is a 5- or 6-membered heterocyclyl optionally substituted with 1 to 3 R 6 In some embodiments, ring A is a 5-7 membered heteroaryl optionally substituted with 1-3 R 6 In some embodiments, ring A is a 5-membered heteroaryl optionally substituted with 1 to 3 R 6 is a 6-membered heteroaryl optionally substituted with

[0098] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), or (Ib-4), or a pharmaceutically acceptable salt thereof, is a compound wherein each R 6 independently, halo, -OH, -CN, C 1~3 Alkyl or C 1~3 In some embodiments, each R 6 is independently F or Cl. In some embodiments, R 6 is -CH3.

[0099] In some embodiments, the compound of Formula (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), or (Ib-4), or a pharmaceutically acceptable salt thereof, is a compound having the formula: 9 is a compound where H is

[0100] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 5 is a compound where H is

[0101] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 2 But H, C 1~3 Alkyl or C 1~3 In some embodiments, R 2 is H.

[0102] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 is a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms, each independently being N, O, or S; R 1 wherein the heteroaryl is selected from the group consisting of 1 to 3 Z 1 In some embodiments, R 1 is 1 to 3 Z's which may be the same or different 1 In some embodiments, R is a monocyclic heteroaryl optionally substituted with 1 is 1 to 3 Z's which may be the same or different 1 In some embodiments, R is a bicyclic heteroaryl optionally substituted with 1 is a 5-6 membered heteroaryl containing one or two N, and R 1 The heteroaryl may have 1 to 3 Z 1 In some embodiments, R 1 teeth, [ka] and m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R 1 teeth, [ka] is.

[0103] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 1 to 3 Z's which may be the same or different 1 In some embodiments, R is a fused bicyclic heteroaryl optionally substituted with 1 is a [5,6] or [6,5] fused bicyclic heteroaryl containing 1 to 3 heteroatoms, each independently N, O, or S; R 1 The heteroaryl may have 1 to 3 Z 1 In some embodiments, R 1 is imidazopyridinyl, benzimidazolyl, pyrazolopyridinyl, benzothiazolyl, benzoxazolyl, benzothiophene, or benzothiadiazole; R 1 imidazopyridinyl, benzimidazolyl, pyrazolopyridinyl, benzothiazolyl, benzoxazolyl, benzothiophene, or benzothiadiazole may be substituted with 1 to 3 Z 1 In some embodiments, R 1 teeth, [ka] where n is 0, 1, or 2, and Z 1c is H or Z 1 In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, Z 1c is H.

[0104] In some embodiments, each Z 1 are independently halo, -CN, C 1~6 Alkyl, C 3~6Cycloalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 In some embodiments, each Z 1 are independently halo, -CN, C 1~6 Alkyl or C 1~6 In some embodiments, each Z 1 are independently halo or C 1~3 In some embodiments, Z is haloalkyl. 1 is -CF3.

[0105] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 but, [ka] is a compound.

[0106] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3b R 3b , -SO2R 3a , -SO2NR 3b R 3b , C 6~10 Aryl, C 3~10cycloalkyl, heterocyclyl, or heteroaryl; R 3 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and optionally substituted with R 4 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, heterocyclyl, or heteroaryl; R 4 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 4 is a compound optionally substituted with

[0107] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3b R 3b , C 6~10 Aryl, C 3~6 cycloalkyl, heterocyclyl, or heteroaryl; R 3 each of the aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and each R 3a and R 3b But C 1~6 Alkyl, C 6~10 aryl or heteroaryl, and R 3a each of the alkyl, aryl, or heteroaryl groups is selected from 1 to 4 Z 1b and each Z1b However, independently, halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 In some embodiments, each R 3a and R 3b independently, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl or heteroaryl, and R 3a The alkyl, cycloalkyl, aryl, or heteroaryl of 1b and each Z 1b are independently halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is haloalkoxy.

[0108] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , C 6~10 aryl or heteroaryl, and R 3 each of the aryl or heteroaryl groups is selected from 1 to 4 Z 3 and optionally substituted with R 3a But C 1~6 Alkyl, C 6~10 aryl or heteroaryl, and R 3a each of the alkyl, aryl, or heteroaryl groups is selected from 1 to 4 Z 1b and each Z 1bHowever, independently, halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 In some embodiments, R 3a is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl or heteroaryl, and R 3a The alkyl, cycloalkyl, aryl, or heteroaryl of 1b and each Z 1b are independently halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is haloalkoxy.

[0109] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 But, -COR 3a or -COOR 3a and R 3a But C 1~6 Alkyl, C 3~8 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and R 3a each of the alkyl, cycloalkyl, phenyl, or heteroaryl groups is selected from the group consisting of 1 to 3 Z 1b is a compound optionally substituted with

[0110] In some embodiments, R 3a is C 1~6 Alkyl or C 3~8 is cycloalkyl, and R 3a The alkyl or cycloalkyl in each group may be the same or different and may be substituted with 1 to 3 Z1b is optionally substituted with

[0111] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 But, -COR 3a and R 3a But C 1~3 Alkyl or C 3~6 cycloalkyl, and each R 3a each of the alkyl or cycloalkyl groups may be the same or different from 1 to 3 Z 1b In some embodiments, R 3 -COR 3a and R 3a is C 3~6 is cycloalkyl, and R 3a The cycloalkyl may be the same or different and may have 1 to 3 Z 1b In some embodiments, R is a fused bicyclic, bridged bicyclic, or spiro bicyclic ring optionally substituted with 3a The cycloalkyl may be the same or different and may have 1 to 4 Z 1b is a monocyclic optionally substituted with

[0112] In some embodiments, each Z 1b are independently halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, or C 1~6 It is an alkoxy.

[0113] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound wherein each Z 3 However, independently, halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, or C 1~6 It is a compound that is an alkoxy.

[0114] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 However, -COCH3, -COC2H5, -COOC2H5, [ka] is a compound.

[0115] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 4 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 6~10 Aryl, C 3~8 cycloalkyl, 5- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; R 4each of the aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 4 is a compound optionally substituted with

[0116] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 4 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, phenyl, C 3~8 cycloalkyl, or 5- or 6-membered heteroaryl; R 4 each of the phenyl, cycloalkyl, or heteroaryl groups is selected from 1 to 4 Z 4 is a compound optionally substituted with

[0117] In some embodiments, Z 4 are halo, -OH, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, or C 1~6 It is an alkoxy.

[0118] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 4 But H or C 1~3 It is a compound that is alkyl.

[0119] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 4 is a compound that is CD3.

[0120] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein [ka] but, [ka] is a compound.

[0121] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 and R 4 together with the nitrogen to which they are attached to form a 5- to 7-membered heterocyclyl, and R 3 and R 4 The heterocyclyl formed from 9 In some embodiments, R 3 and R 4 The heterocyclyl formed from 9is optionally substituted monocyclic with

[0122] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein [ka] but, [ka] and ring D is a ring having 1 to 3 Z 9 In some embodiments, ring D is a heterocyclyl optionally additionally substituted with 1 to 3 Z 9 is a monocyclic optionally additionally substituted with

[0123] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 and R 4 together with the nitrogen to which they are attached to form a 5- to 7-membered heterocyclyl, and R 3 and R 4 and the heterocyclyl formed from optionally has an additional heteroatom N, and R 3 and R 4 The heterocyclyl formed from 9 is a compound optionally substituted with

[0124] In some embodiments, each Z 9are independently oxo, halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, or C 1~6 In some embodiments, at least one Z 9 is oxo.

[0125] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein [ka] but, [ka] is a compound.

[0126] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 1 each of the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 2 H, -CN, C 1~5Alkyl, C 1~5 Haloalkyl, C 2~6 alkynyl, cyclopropyl, cyclobutyl, or oxetanyl; R 2 alkyl, haloalkyl, alkoxyalkyl, alkynyl, cyclopropyl, or cyclobutyl, each of which may be the same or different, is selected from 1 to 4 Z 2 and each Z 2 But independently, C 2~6 Alkynyl, halo, -CN, -OR 2a , cyclopropyl, cyclobutyl, or oxetanyl, and R 2a But H, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, or C 1~3 is alkyl, R 5 But H, C 1~3 Alkyl or C 1~3 A compound that is a haloalkyl.

[0127] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 1 each of the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 2 and R 5 together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, or oxetanyl, and R 2 and R5 wherein the cyclopropyl or cyclobutyl formed from is optionally substituted with 1 to 4 halo.

[0128] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 and R 2 together with the carbon to which they are attached, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, R 1 and R 2 wherein the cycloalkyl or heterocyclyl formed from 5 and optionally substituted with R 5 But H, C 1~3 Alkyl or C 1~3 A compound that is a haloalkyl.

[0129] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3a R 3b , -SO2R 3a , -SO2NR 3a R 3b , C 6~10 Aryl, C 3~10cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 3 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and optionally substituted with R 4 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 4 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 4 is a compound optionally substituted with

[0130] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 3 and R 4 together with the nitrogen to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, and R 3 and R 4 and the heterocyclyl or heteroaryl formed from the 9 and optionally substituted with R 3 and R 4 is a heterocyclyl having 0 to 2 additional heteroatoms, each independently being N, O, or S; and R 3 and R 4 wherein the heteroaryl formed from is a heteroaryl having 0 to 2 additional heteroatoms, each independently being N, O, or S.

[0131] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), or (Ib-11), or a pharmaceutically acceptable salt thereof, is a compound, wherein R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 1 each of the alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups is selected from the group consisting of 1 to 4 Z 1 and optionally substituted with R 5 But H, C 1~3 Alkyl or C 1~3 is haloalkyl, R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, -COR 3a , -COOR 3a , -CONR 3a R 3b , -SO2R 3a , -SO2NR 3a R 3b , C 6~10 Aryl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R 3 each of the alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl groups may be the same or different from one to four Z 3 and optionally substituted with R 2 and R 4 together with the atoms to which they are attached form a 5- to 10-membered heterocyclyl, and R 2 and R 4The heterocyclyl formed from 8 is a compound optionally substituted with

[0132] In some embodiments, the disclosure provides a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the present disclosure provides a racemic mixture comprising a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a racemic mixture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a scalemic mixture comprising a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a scalemic mixture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0134] Those skilled in the art will recognize the groups disclosed herein (e.g., R 1 ) each and every embodiment of the remaining groups (e.g., R 2 , R 3 , Z 1 , Z 3and the like) may be combined with any other embodiment of each of formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or any formula described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, each of which is considered to be within the scope of this disclosure. Pharmaceutical Compositions and Modes of Administration

[0135] The present disclosure further provides pharmaceutical compositions comprising, as an active ingredient, at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0136] In some embodiments, the pharmaceutical compositions of the present disclosure may additionally contain one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0137] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise an additional therapeutic agent or therapeutic modality. In some embodiments, the additional therapeutic agent comprises one, two, three, or four additional therapeutic agents and / or therapeutic modalities. In some embodiments, the additional therapeutic agent or therapeutic modality is selected from an immune checkpoint modulator, an antibody-drug conjugate (ADC), an anti-apoptotic agent, a targeted anti-cancer therapy, a chemotherapeutic agent, surgery, or radiation therapy. In some embodiments, the immune checkpoint modulator is selected from an anti-PD-(L)1 antibody, an anti-TIGIT antibody, an anti-CTLA4 antibody, an anti-CCR8 antibody, an anti-TREM1 antibody, an anti-TREM2 antibody, a CD47 inhibitor, a DGKα inhibitor, an HPK1 inhibitor, a FLT3 agonist, an adenosine pathway inhibitor, and a CAR-T cell therapy.

[0138] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (intranasal or buccal inhalation) or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts.

[0139] In practical use, the compounds of the present disclosure can be combined as active ingredients in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. for oral liquid preparations such as suspensions, elixirs, and solutions, or starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. for oral solid preparations such as powders, hard capsules, soft capsules, and tablets, and solid oral preparations are preferred over liquid preparations.

[0140] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of active compound in these compositions can, of course, be varied and may conveniently be from about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compound can also be administered intranasally, for example, as drops or spray.

[0141] Tablets, pills, capsules, etc. may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid, etc., lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0142] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0143] In some embodiments, the compounds of the present disclosure can also be used as salts with various counter cations to obtain orally available formulations.

[0144] The compounds of the present disclosure can also be administered parenterally.These active compounds can be prepared in water, suitably mixed with a surfactant such as hydroxypropylcellulose, in a solution or suspension.Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0145] Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0146] Any suitable route of administration can be used to provide an effective dose of a compound of the present disclosure to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compound of the present disclosure is administered orally. kit

[0147] Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0148] Also provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, in a suitable container, which can be a vial, bottle, ampoule, pre-filled syringe, and infusion bag. Treatment Methods and Uses

[0149] The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions by inhibiting PRMT5 with the compounds. The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions by inhibiting PRMT5 with the compounds. The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions by inhibiting PRMT5 in MTAP-null cells with the compounds. Furthermore, the present disclosure relates to the use of the compounds for the preparation of a medicament for the treatment and / or prevention of chromosome 9p21 deletion or MTAP-null associated diseases and / or conditions by inhibiting PRMT5 in MTAP-null cells with the compounds. In some embodiments, the chromosome 9p21 deletion or MTAP-null associated diseases or conditions are alleviated by inhibiting PRMT5 in MTAP-null cells.

[0150] The medicaments referred to herein can be prepared by conventional processes comprising combining a compound according to the present disclosure with a pharmaceutically acceptable carrier.

[0151] In some embodiments, provided herein are methods of treating and / or preventing an MTAP null or chromosome 9p21 deletion associated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), (Ib-13), (Ib-14), (Ib-15), (Ib-16), (Ib-17), (Ib-18), (Ib-19), (Ib-20), (Ib-21), (Ib-22), (Ib-23), (Ib-24), (Ib-25), (Ib-26), (Ib-27), (Ib-28), (Ib-29), (Ib-30), (Ib-31), (Ib-32), (Ib-33), (Ib-34), (Ib-35), (Ib-36), (Ib-37), (Ib-38), (Ib-39), (Ib-40), (Ib-41), (Ib-42), (Ib-43), (Ib-44), (Ib-45), (Ib-46), (Ib-47), (Ib-48), (Ib-49), (Ib-50), (Ib-51), (Ib-52), (Ib-53), (Ib-54), (Ib-55), (Ib-56), (Ib-57), (Ib-58), (Ib-59), (Ib-60), (Ib-61), (Ib-62), ( (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the chromosome 9p21 deletion or MTAP null associated disease or condition includes a solid tumor in a tissue or organ or arising from a tissue or organ, e.g., Bone (e.g., ameloblastoma, aneurysmal bone cyst, angiosarcoma, chondroblastoma, chondroma, chondromyxofibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid, osteoma, periosteal chondroma, desmoid, Ewing's sarcoma); Lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumor); Esophagus (e.g., Barrett's esophagus, dysplasia, and adenocarcinoma); Gastrointestinal tract (including stomach (e.g., gastric adenoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric carcinoid, gastric sarcoma, neuroendocrine carcinoma, primary gastric squamous cell carcinoma, gastric adenocarcinoma), small intestine and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, and anus); Pancreas (e.g., serous neoplasms (including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous cystic neoplasm, and serous cystadenocarcinoma); mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IPMN), and neoplasm (IOPN), intraductal tubular neoplasm, cystic acinar neoplasm (including acinar cell cystadenoma, acinar cell cystadenocarcinoma, and pancreatic adenocarcinoma), invasive pancreatic ductal adenocarcinoma (including tubular adenocarcinoma and adenosquamous carcinoma), mucinous carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinic cell carcinoma, neuroendocrine tumor, neuroendocrine microadenoma, neuroendocrine tumor (NET), neuroendocrine carcinoma (NEC) (including small cell or large cell NEC), islet cell adenoma, gastrinoma, glucagonoma, serotoninoma, somatostatinoma, VIPoma, solid-pseudopapillary neoplasm (SPN), and pancreatoblastoma; Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic bile duct cancer); Neuroendocrine (e.g., adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma); Thyroid gland (e.g., poorly differentiated (anaplastic) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma); Liver (e.g., adenoma, mixed hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal tumor, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, cholangiocyst adenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor); Kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, renal clear cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, renal mucinous tubular spindle cell carcinoma, renal neoplasm, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); Breast (e.g., invasive ductal carcinoma (including but not limited to acinic cell carcinoma, adenoid cystic carcinoma, apocrine adenocarcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, malignant oncocytoma, papillary carcinoma, sebaceous carcinoma, secretory carcinoma, tubular carcinoma); lobular carcinoma, including but not limited to pleomorphic carcinoma and signet-ring cell carcinoma; · Peritoneum (e.g., mesothelioma; primary peritoneal cancer); Ovarian (e.g., choriocarcinoma, epithelial tumor, germ cell tumor, sex cord-stromal tumor), Fallopian tube (e.g., serous adenocarcinoma, mucinous carcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblastic tumor), uterus (e.g., cervical cancer, endometrial polyp, endometrial hyperplasia, intraepithelial carcinoma (EIC)), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasm), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma) female genital tissues, including epithelial and mesenchymal tumors (e.g., adenofibroma, carcinoma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma, MMMT)), endometrial stromal tumor, malignant mixed Müllerian tumor of the endometrium, gestational trophoblastic tumor (partial hydatidiform mole, complete hydatidiform mole, invasive hydatidiform mole, placenta enthesal tumor), vulva, vagina; Male reproductive tissues, including the prostate, testes (e.g., germ cell tumors, spermatocytic seminomas), and penis; Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); Brain (e.g., gliomas (e.g., astrocytomas (including non-invasive, low-grade, poorly differentiated, glioblastomas; oligodendrogliomas, and ependymomas)), meningiomas, gangliogliomas, schwannomas (neurinomas), craniopharyngiomas, chordomas, non-Hodgkin's lymphomas (NHL), indolent non-Hodgkin's lymphomas (iNHL), refractory iNHL, and pituitary tumors); Eyes (e.g., retinoma, retinoblastoma, intraocular melanoma, posterior uveal melanoma, iris hamartoma); Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal cancer (including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, and combined laryngeal carcinoma), carcinoma in situ, verrucous, spindle cell, and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, and laryngeal sarcoma)), head and neck paraganglioma (e.g., carotid body paraganglioma, vagus nerve paraganglioma); · Thymus (e.g., thymoma); Heart (e.g. cardiac myxoma); Lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC) (including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, and pleuropulmonary blastoma); Lymphoid (e.g., lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL), Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (including B-cell lymphoma and T-cell lymphoma (e.g., Burkitt's lymphoma)); large B-cell lymphoma, diffuse large B-cell lymphoma lymphoma, DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T-cell lymphoma, nasal type; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma), lymphangioleiomyomatosis); ·Central nervous system system, CNS) (e.g., gliomas, including astrocytomas (e.g., pilocytic astrocytoma, pilocytic myxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrous astrocytoma, large round cell astrocytoma, protoplasmic astrocytoma, undifferentiated astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and gliomatosis cerebri), oligodendroglioma (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g. These include, but are not limited to, subependymomas, myxopapillary ependymomas, ependymomas (e.g., cellular, papillary, clear cell, elongated ependymal cell), poorly differentiated ependymomas, optic gliomas, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paraspinal nerve tumors, and astrocytic region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, neuroblastoma group tumors (neuroblastoma, ganglioneuroblastoma, ganglioneuromatosis), and trisomy 19 ependymomas; Neuroendocrine tissues (e.g., including the preganglionic system (adrenal medulla (pheochromocytoma) and extra-adrenal paraganglioma (extra-adrenal paraganglioma)); Skin (including, for example, clear cell hidradenoma, cutaneous benign fibrous histiocytoma, cylindroma, hidradenoma, melanoma (cutaneous melanoma, mucosal melanoma), pilomatricoma, and Spitz tumor); and Soft tissue (e.g., invasive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's sarcoma / primitive neurectodermal tumor) tumor, PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipoma-like tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, soft tissue melanoma, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, hemangiopericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, and well-differentiated liposarcoma.

[0153] In some embodiments, the chromosome 9p21 deletion or MTAP null associated disease or condition is a cancer selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell neoplasm, head and neck cancer, bile duct cancer, esophageal cancer, glioblastoma, gastric cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, renal cancer, colorectal cancer, prostate cancer, leukemia, and cervical cancer.

[0154] In some embodiments, the chromosome 9p21 deletion or MTAP null associated disease or condition is a cancer selected from ovarian cancer, lung cancer, lymphatic cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, and bladder cancer. Dosage

[0155] The effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated, and such dosage may be readily ascertained by one skilled in the art.

[0156] When treating or preventing a chromosome 9p21 deletion or MTAP null-associated disease or condition for which the compounds of the present disclosure are indicated, satisfactory results are generally obtained when the compounds of the present disclosure are administered at a daily dosage of about 0.1 milligrams to about 300 milligrams per kilogram of animal body weight. In some embodiments, the compounds of the present disclosure are administered as a single daily dose, in divided doses two to six times daily, or in sustained-release form. For most large mammals, the total daily dosage is about 1 milligram to about 1000 milligrams, or about 1 milligram to about 50 milligrams. For a 70 kg adult human, the total daily dosage is generally about 0.1 milligram to about 200 milligrams. This dosage regimen can be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dose is from about 1 milligram to about 900 milligrams, from about 1 milligram to about 800 milligrams, from about 1 milligram to about 700 milligrams, from about 1 milligram to about 600 milligrams, from about 1 milligram to about 400 milligrams, from about 1 milligram to about 300 milligrams, from about 1 milligram to about 200 milligrams, from about 1 milligram to about 100 milligrams, from about 1 milligram to about 50 milligrams, from about 1 milligram to about 20 milligrams, or from about 1 milligram to about 10 milligrams.

[0157] The compounds of the present application or compositions thereof can be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compounds can continue for several days; for example, treatment typically lasts for at least 7, 14, or 28 days per treatment cycle. Treatment cycles alternate periodically, with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments.

[0158] In some embodiments, the methods provided herein include administering to a subject an initial daily dose of about 1 to 800 mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week. combination

[0159] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents is one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is four additional therapeutic agents.

[0160] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) 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 is four additional therapeutic agents.

[0161] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist, or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen binding molecule (e.g., monospecific and multispecific antibodies in any format, such as DART™, Duobody™, BiTE™, BiKE, TriKE, XmAb™, TandAb™, scFv, Fab, Fab derivatives, and fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimetic (e.g., adnectin, affibody molecule, affilin, affimer, afftin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein, and the like). protein, DARPin™), finomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifiers or editing agents, cells comprising chimeric antigen receptors (CARs), engineered T cell receptors (TCR-T), including, for example, T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics, or any combination thereof. Illustrative Targets

[0162] In some embodiments, the one or more additional therapeutic agents include, for example, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator, or suppressor of a target (e.g., a polypeptide or polynucleotide), such as 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL proto-oncogene 1, ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); absent in melanoma 2 (ABL2; NCBI Gene ID: 26); 2, AIM2; NCBI Gene ID: 9447); acetyl-CoA acyltransferase 2 (acetyl-CoA acyltransferase 2, ACAA2; NCBI Gene ID: 10499); acid phosphatase 3 (acid phosphatase 3, ACP3; NCBI Gene ID: 55); adenosine deaminase (adenosinedeaminase, ADA, ADA1; NCBI Gene ID: 100); adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI Gene IDs: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 208) NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alphafetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene IDs: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI Gene IDs: 284, 285);angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis inducing factor mitochondria associated 1 (AIFM1; AIF; NCBI Gene ID: 9131); arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asterade homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472); ATP binding cassette subfamily B member 1 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 (BTLA, CD272; NCBI Gene ID: 151888); baculoviral IAP repeat containing protein protein, BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene ID: 329, 330, 331, 332; basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 682); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2 binding component 3 (BBC3, PUMA;NCBI Gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene IDs: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-carboxyglutamate protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptor (e.g., BDKRB1, BDKRB2; NCBI Gene IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and ectodomain external domain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CTS) 15, CHST15; NCBI Gene ID: 51363); carbonic anhydrase (CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677);Carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI Gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI Gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene IDs: 836, 840, 841, 864); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC motif chemokine ligand 21 (CC motif chemokine CC motif chemokine receptor 2 (CCL21; NCBI Gene ID: 6366); CC motif chemokine receptor 2 (CCR2; NCBI Gene ID: 729230); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NCBI Gene ID: 8317); cellular communication network factor 2 (CFC). 2, CCN2; NCBI Gene ID: 1490); cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR;NCBI Gene ID: 887); chorionic somatomammotropin hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208); markers of cluster of differentiation (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD3 beta (TRB), CD3 gamma (TRG), CD3 delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1)) , CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC 4, 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), C D128(IL8R1), CD132(IL2RG), CD135(FLT3), CD137(TNFRSF9, 4-1BB), CD142(TF, TFA), CD152(CTLA4), CD160, CD 182(IL8R2), CD193(CCR3), CD194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223(LAG3), CD 226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1044 232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI Gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI Gene IDs: 2155, 2159); collagen type IV alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI Gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily member 10 (collectinsubfamily member 10, COLEC10; NCBI Gene ID: 10584); colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene IDs: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene IDs: 718, 727); COP9 signalosome subunit 5 (COP9 signalosome subunit 5, COPS5; NCBI Gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371, NCBI Gene; NCBI Gene IDs: 160364, 170482, 283420); C-X-C motif chemokine ligand 12 (CX-Cmotif chemokine ligand 12, CXCL12; NCBI Gene ID: 6387); C-X-C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene IDs: 2833, 3577, 3579, 7852); cyclin D1 (cyclinD1, CCND1, BCL1; NCBI Gene ID: 595); cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, C DK12; NCBI Gene ID: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (cyclinG1, CCNG1; NCBI Gene ID: 900); cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene ID: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductase (cytochrome P450 oxidoreductase, POR; NCBI Gene ID: 5447); cytokine inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicases (e.g., DDX5, DDX6, DDX58; NCBI Gene IDs: 1655, 1656, 23586); delta-like canonical Notch ligands (e.g., DLL3, DLL4; NCBI Gene IDs: 10683, 54567); diablo IAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI Gene IDs: 1606, 8525);Dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene IDs: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167, NCBI Gene IDs: 780, 4921); DNA-dependent protein kinase (DNA-dependent protein kinase) kinase, PRKDC; NCBI Gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene IDs: 7150, 7153, 7155, 7156, 8940); dopachrometautomerase (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 5169); EMAP-like 4 (EMAP-like 4, EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene IDs: 51752, 64167); enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2;NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4); NCBI Gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecules (e.g., ERBB1, ERBB2, HER2, NEU, CD340); Eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene IDs: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI Gene IDs: 1973, 1984); exopolitin-1 (exportin-1, XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase synthase, FASN; FAS, NCBI Gene ID: 2194); Fc fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene IDs: 2205, 2214, 2217); Fc receptor like 5 (FCRL5, CD307; NCBI Gene ID: 83416); fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191);Fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene IDs: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene IDs: 2246, 2247, 2249, 2250); fibronectin 1 (fibronectin1, FN1, MSF; NCBI Gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI Gene IDs: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (fms-related receptor tyrosine kinase 3 ligand, FLT3LG; NCBI Gene ID: 2323; focal adhesion kinase 2, PTK2, FAK1; NCBI Gene ID: 5747; folate hydrolase 1, FOLH1, PSMA; NCBI Gene ID: 2346; folate receptor 1, FOLR1; NCBI Gene ID: 2348; forkhead box protein M1 M1, FOXM1; NCBI Gene ID: 2305); FURIN (FURIN, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534); galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene IDs: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (glucuronidase beta, GUSB; NCBI Gene ID: 2990); glutamate transfer receptor 1 (glutamate metabotropic receptor 1, GRM1; NCBI Gene ID: 2911); glutaminase (glutaminase, GLS; NCBI Gene ID: 2744);glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI Gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID: 2658); growth factor receptor-bound protein 2 (GFRP) 2, GRB2, ASH; NCBI Gene ID: 2885); guanylate cyclase 2C (guanylatecyclase 2C, GUCY2C, STAR, MECIL, MUCIL; NCBI Gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI Gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK; NCBI Gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96) ); NCBI Gene ID: 3309, 3315, 7184; heme oxygenase (e.g., HMOX1(HO1), HMOX2(HO1); NCBI Gene ID: 3162, 3163); heparanase (heparanase, HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatocyte growth factor (hepatocyte growth factor, HGF; NCBI Gene ID: 3082); HERV-H LTR-associated 2 (HHLA2, B7-H7;NCBI Gene ID: 11148); histamine receptor H2 (histaminereceptor H2, HRH2; NCBI Gene ID: 3274); histone deacetylases (e.g., HDAC1, HDAC7, HDAC9; NCBI Gene IDs: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI Gene IDs: 10320, 22806); immunoglobulin superfamily member 11 (immunoglobulin superfamily member 11, IGSF11; NCBI Gene ID: 152404); indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI Gene ID: 3620, 169355); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (inducible T cell costimulator ligand, ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptors (e.g., IGF1R, IGF2R; NCBI Gene IDs: 3480, 3482); insulin-like growth factors (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptor (insulin receptor, INSR, CD220; NCBI Gene ID: 3643); integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB); 1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene IDs: 3678, 3685, 3688, 3695, 3698; intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene ID: 3383); interleukin 1 receptor associated kinase 4 (IL-1R-associated kinase 4; NCBI Gene IDs: 3383); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene ID: 3383); interleukin 1 receptor associated kinase 4 (IL-1R-associated kinase 4; NCBI Gene IDs: 3383); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene IDs ...cellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene IDs: 3383); interleukin 1 receptor associated kinase 4 (IL-1R-associated kinase 4; NCBI Gene IDs: 3383); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene IDs: 3383); intercellular adhesion molecule 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), I L18, IL23A, IL24, IL-29 (IFNL1); NCBI Gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); isocitrate dehydrogenase (NADP(+)1) (e.g., IDH1, IDH2; NCBI Gene IDs: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI Gene IDs: 3716, 3717, 3718); kallikrein-related peptidase 3 (kallikrein-related peptidase 3, KLK3; NCBI Gene ID: 354; killer cell immunoglobulin-like receptor, Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J);NCBI Gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285; killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (kinesin family member 11, KIF11 (NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1; NCBI Gene ID: 3814); KIT proto-oncogene, receptor tyrosine kinase (KIT, c-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene, GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4035); leucine-rich repeat containing 15 15, LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene IDs: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T-cells (LAT; NCBI Gene ID: 27040);Luteinizing hormone / choriogonadotropin receptor (LHCGR; NCBI Gene ID: 3973); LY6 / PLAUR domain containing 3 (LYPD3; NCBI Gene ID: 27076); lymphocyte activating 3 (LAG3; CD223; NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene IDs: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); lysine demethylase 1A 1A, KDM1A; NCBI Gene ID: 23028; lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI Gene ID: 1902); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase like 2 (LOXL2; NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (macrophage stimulating 1 receptor) receptor, MST1R, CD136; NCBI Gene ID: 4486); MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740);Major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI gene IDs: 3105, 3133, 3134, 3135); major vault protein (MVP, VAULT1; NCBI gene ID: 9961); MALT1 paracaspase (MALT1; NCBI gene ID: 10892); MAPK-activated protein kinase 2 (MAPK-activated protein kinase 2; MALT1; NCBI gene ID: 10892 ... 2, MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene ID: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene ID: 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 oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTK) of rapamycin kinase, MTOR, FRAP1; NCBI Gene ID: 2475; melan-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene IDs: 4157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN; NCBI Gene ID: 10232);MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI gene ID: 4233); methionylaminopeptidase 2 2, METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequence (e.g., MICA, MICB; NCBI Gene ID: 4277, 100507436); mitogen-activated protein kinase (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene ID: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinase (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2), NCBI Gene ID: 4217, 1326); mitogen-activated protein kinase kinase kinase kinase 1 (mitogen-activated protein kinase kinase kinase kinase 1, MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene ID: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z, and REP), MUC5AC, MUC16 (CA125; NCBI Gene IDs: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082);Natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, a MAGE family member (necdin, NDN; NCBI Gene ID: 4692); nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI Gene IDs: 5819, 81607); neural cell adhesion molecule 1 (NEAM) 1, NCAM1, CD56; NCBI Gene ID: 4684; neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829); neurotrophin receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene ID: 4914, 4915, 4916); NFKB activating protein (NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain containing 3 (NLR family pyrin domain containing 3) 3, NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); Nuclear factor kappa B (NFKB1, NFKB2; NC; NCBI Gene IDs: 4790, 4791; nuclear factor, erythroid 2-like 2 (NFE2L2; NRF2; NCBI Gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); nucleolin (NCL; NCBI Gene ID: 4691); nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); nucleotide binding oligomerization domain containing 2 (NOD2; NCBI Gene ID: 64127); nudix hydrolase 1 1, NUDT1; NCBI Gene ID: 4521; O-6-methylguanine-DNA methyltransferase (MGMT; NCBI Gene ID: 4255); opioid receptor delta 1 (OPRD1; NCBI Gene ID: 4985); ornithine decarboxylase 1 (ODC1; NCBI Gene ID: 4953); oxoglutarate dehydrogenase dehydrogenase, OGDH; NCBI Gene ID: 4967; parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); periostin (POSTN; NCBI Gene ID: 10631); peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene IDs: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728);Phosphatidylinositol-4,5-bisphosphate 3-kinases (PIK3CA (PI3K alpha), PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma); NCBI Gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G8, PLA2G9, PLA2G10, PLA2G11, PLA2G12, PLA2G13, PLA2G14, PLA2G15, PLA2G16, PLA2G17, PLA2G18, PLA2G19, PLA2G20, PLA2G21, PLA2G22, PLA2G23, PLA2G24, PLA2G25, PLA2G26, PLA2G27, PLA2G28, PLA2G29, PLA2G30, PLA2G31, PLA2G32, PLA2G33, PLA2G34, PLA2G35, PLA2G36, PLA2G37, PLA2G38, PLA2G39, PLA2G40, PLA2G41, PLA2G42, PLA2G43, PLA2G44, PLA2G45, PLA2G46, PLA2G47, PLA2G48, PLA2G49, PLA2G40, PLA2G41, PLA2G42, PLA2G43, PLA2G44, PLA2G45, PLA2G46, PLA2G47, PLA2G48 A2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); placenta growth factor (PGF) factor, PGF; NCBI Gene ID: 5228; plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene IDs: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); polo-like kinase 1 1, PLK1; NCBI Gene ID: 5347); poly(ADP-ribose) polymerase (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL; NCBI Gene ID: 6490);Progesterone receptor (PGR; NCBI Gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI Gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI Gene ID: 80380); prominin 1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (PML; NCBI Gene ID: 5371); prosaposin (PSAP; NCBI Gene ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (prostaglandin E synthase, PTGES; NCBI Gene ID: 9536; prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene ID: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI Gene ID: 5698); protein arginine methyltransferase (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) 7, PTK7; NCBI Gene ID: 5754; protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene ID: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860);Purinergic receptor P2X7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf; NCBI Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); ras homolog family member C (RHOC; NCBI Gene ID: 389); Ras homolog, mTORC1-binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine / threonine protein kinase 1 (RBE; NCBI Gene ID: 6009). 1, RIPK1; NCBI Gene ID: 8737; retproto-oncogene (RET; NCBI Gene ID: 5979); retinoic acid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091); retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene IDs: 5914, 5916); retinoid X receptors (e.g., RXRA, RXRB, RXRG; NCBI Gene IDs: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinases (e.g., ROCK1, ROCK2; NCBI Gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (ribosomal protein S6 kinase B1) B1, RPS6KB1, S6K-beta1; NCBI gene ID: 6198; ring finger protein 128 (RNF128, GRAIL; NCBI gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROSproto-oncogene 1, ROS1;roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted frizzled related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6696); secretoglobin family 1A member 1 (secretoglobin family 1A member 1) 1, SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene IDs: 6401, 6402, 6403); semaphorin 4D (semaphorin4D, SEMA4D; CD100, NCBI Gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene IDs: 27036, 27180, 89790); signal regulatory protein alpha (signal regulatory protein alpha, SIRPA, CD172A; NCBI Gene ID: 140885); signal transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI Gene ID: 23410); signaling lymphocytic activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9);NCBI Gene IDs: 56833, 57823, 89886, 114836; SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); smooth, frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (epoxide hydrolase 2; NCBI Gene ID: 6608) 2, EPHX2; NCBI Gene ID: 2053); solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI Gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI Gene IDs: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecules ( molecule, SHH; NCBI Gene ID: 6469); Sp1 transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinase (e.g., SPHK1, SPHK2; NCBI Gene IDs: 8877, 56848); sphingosine-1-phosphate receptor 1 agonist (S1PR1, CD363; NCBI Gene ID: 1901); spleen-associated tyrosine kinase (SYK; NCBI Gene ID: 6850); splicing factor 3B factor 1 1, SF3B1; NCBI Gene ID: 23451); SRC proto-oncogene, non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin1 (stabilin1, STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family; leam member 1 (STEAP1; NCBI Gene ID: 26872); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interactor 1 (STING1; NCBI Gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene IDs: 8651, 9021); synapsin 3 (SYN3; NCBI Gene ID: 8224); syndecan 1 (syndecan 1, SDC1, CD138, syndecan; NCBI Gene ID: 6382; synuclein alpha (SNCA, PARK1; NCBI Gene ID: 6622); T cell immunoglobulin and mucin domain containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene IDs: 6869, 6870); TANK-binding kinase 1 (TBK1; NCBI Gene ID: 29110); tankyrase (TNKS; NCBI Gene ID: 8658); TATA-box binding protein associated factor, RNA polymerase I subunit B (TATA-box binding protein associated factor, RNA polymerase I subunit B) 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); and tenascin C. C, TNC; NCBI Gene ID: 3371); 3 prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombomodulin (THBD, CD141; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene IDs: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene IDs: 7606, 7608); thyroidstimulating hormone receptor (THR). receptor, TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL);NCBI Gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); transferrin (transferrin, TF; NCBI Gene ID: 7018); transferrin receptor transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene IDs: 7046, 7048, 7049); transforming protein E7 (E7; NCBI Gene ID: 1489079); transglutaminase 5 (transglutaminase5, TGM5; NCBI Gene ID: 9333); transient receptor potential cation channel subfamily V member 1 (transient receptor potential cation channel subfamily V member 1, TRPV1, VR1; NCBI Gene ID: 7442; transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed in myeloid cells (e.g., TREM1 (CD354) and TREM2; NCBI Gene IDs: 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 transducer 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF) factor, TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD137, 4-1BB), TNFRSF10A (CD261), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRS F12A, TNFRSF13B, TNFR13C (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI Gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 p53, TP53; NCBI Gene ID: 7157; tumor suppressor2, 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); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme 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 activating enzyme 1 (UBE2I, UBC9; NCBI Gene ID: 7329); 1, UBA1; NCBI Gene ID: 7317); UL16-binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing protein (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI Gene IDs: 7422, 7423); vimentin (VIM; NCBI Gene ID: 7431); vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunoregulatory receptor (V-set immunoregulatory receptor) receptor, 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 transcription regulator 1 (WWTR1; TAZ; NCBI Gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375); XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI Gene ID: 2829); Yes1 associated transcriptional regulator (YAP1; NCBI Gene ID: 10413); or zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535);

[0163] In some embodiments, the one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Adenosine A receptor (ADORA2A; NCBI gene ID: 135) 2Breceptor (adenosine A 2B receptor, ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); and integrin-associated protein (integrin-associated protein). associated protein, IAP, CD47; NCBI Gene ID: 961; interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin 2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (KRAS; NCBI Gene ID: 3845, including mutations such as KRAS G12C or G12D); mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1, HPK1; NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator regulator, MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293);programmed death-ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); signal-regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells triggering receptor expressed on myeloid cells 2, TREM1; NCBI Gene ID: 54210; triggering receptor expressed on myeloid cells 2, TREM2; NCBI Gene ID: 54209; tumor-associated calcium signal transducer 2, TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070; tumor necrosis factor receptor superfamily, member 4 (tumor necrosis factor receptor superfamily, member 9, TNFRSF4, CD134, OX40; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily, member 9 (tumor necrosis factor receptor superfamily, member 9, TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily, member 18 (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). Illustrated mechanism of action Immune checkpoint modulators

[0164] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor microenvironment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors modulate T cell responses (reviewed, e.g., in Xu, J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (reviewed, e.g., in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T cells (Tregs) or depletion of Tregs can relieve their suppression of anti-tumor immune responses and have anti-cancer effects (reviewed, e.g., in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0165] Examples of immune checkpoint proteins or receptors that can be combined with the compounds provided herein, or pharmaceutically acceptable salts thereof, include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 10225), CD160 (NCBI Gene ID: 11126), MS4A1 (CD20; NCBI Gene ID: 931), CD244 (SLAMF4; NCBI Gene ID: 51744); CD276 (B7H3; NCBI Gene ID: 80381); V-set domain-containing T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L;NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA), NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-L1; NCBI Gene ID: :5133); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID:1493); CD80 (B7-1; NCBI Gene ID:941), CD28 (NCBI Gene ID:940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI Gene ID:5819); CD226 (DNAM-1; NCBI Gene ID:10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID:5817); PVR-related immunoglobulin domain-containing (PVRI) G, CD112R; NCBI Gene ID: 79037); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4, NCBI Gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); Galectin 9 (LGALS9; NCBI Gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902);signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI gene ID: 6504); lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823); UL16-binding protein 1 (ULBP1; NCBI gene ID: 80329); UL16-binding protein 2 (ULBP2; NCBI Gene ID: 80328); UL16-binding protein 3 (ULBP3; NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4, NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5, NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6, NCBI Gene ID: 154064); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (killer cell immunoglobulin-like receptor, KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirilumab (IPH-2102, IPH-4102); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A; NCBI Gene ID: 3821); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI Gene ID: 22914); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI Gene ID: 3822); killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI Gene ID: 3823); killer cell lectin-like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 8302); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3;killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1; NCBI Gene ID: 3824); killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI Gene ID: 10219); sialic acid binding Ig-like lectin 7 (SIGLEC7; NCBI Gene ID: 27036); and sialic acid binding Ig-like lectin 9 (SIGLEC9; NCBI Gene ID: 27180).

[0166] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 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 inhibitor of T cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PV RIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1).In some embodiments, a compound or pharmaceutically acceptable salt provided herein is administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. Illustrative T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0167] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Illustrative NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and a long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-binding Ig-like lectin 7 (SIGLEC7); and sialic acid-binding Ig-like lectin 9 (SIGLEC9). In some embodiments, a compound or pharmaceutically acceptable salt provided herein is administered with one or more agonists or activators of one or more NK cell-stimulatory immune checkpoint proteins or receptors. Illustrative NK cell-stimulatory immune checkpoint proteins or receptors include: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7).See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0168] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0169] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, and KN-04. 4, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0170] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HL X-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimuzumab (CBT-501), LZM-009, prorugolimab (BCD-100), rodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), C X-072, CBT-502, dostallimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), embafolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimbelelimab (AB12 2), spartalizumab (PDR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4),KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), RG7769(PD-1 / TIM-3), TA K-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-15 5 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0171] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vibostolimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0172] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0173] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate the suppression of anti-tumor immune responses and have anti-cancer effects. See, e.g., Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof provided herein, is administered with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment.

[0174] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can modulate cell phenotype and induce the production of inflammatory cytokines. Illustrative Treg inhibitors include, but are not limited to, CCR4 (NCBI Gene ID: 1233) antagonists and degraders of Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI Gene ID: 10320), Helios (IKZF2; NCBI Gene ID: 22807), Aiolos (IKZF3; NCBI Gene ID: 22806), and Eos (IKZF4; NCBI Gene ID: 64375).

[0175] Examples of Helios degraders that may be co-administered include, but are not limited to, I-57 (Novartis) and compounds disclosed in WO 2019038717, WO 2020012334, WO 20200117759, and WO 2021101919.

[0176] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Illustrative targets of Treg depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18, NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0177] In some embodiments, Treg inhibitors or Treg depletors that may be co-administered include CC motif chemokine receptor 4 (CCR4), CC motif chemokine receptor 7 (CCR7), CC motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (protein tyrosine phosphatase receptor type C), and / or cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152). Phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit alpha E (ITGAE; CD103), interleukin 7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor alpha (FOLR1), folate receptor beta (FOLR2), leucine-rich repeat containing 32 32, LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulatory factor (ICOS; CD278), lymphocyte activation 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2;The present invention also includes an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of CD366, TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), and combinations thereof;

[0178] Examples of Treg-depleting anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in WO2021163064, WO2020138489, and WO2021152186.

[0179] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0180] Inhibition, depletion, or reprogramming of unstimulated myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550; WO 2016049641). Illustrative targets for depleting or reprogramming unstimulated myeloid cells include the triggering receptors TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209), which are expressed on myeloid cells. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more myeloid cell depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; an antibody disclosed in WO2019032624) or an anti-TREM-2 antibody (e.g., PY314; an antibody disclosed in WO2019118513). Cluster of differentiation agonists or activators

[0181] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an agent that targets a cluster of differentiation (CD) marker. Exemplary agents that target CD markers that may be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxon Fusp (SL-401), HLA-A2402 / HLA-A0201 restricted epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranelgene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverenvatinib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, Asnercept (APG-101), APO-010, and International Publication Nos. 2016196388, 2016033570, 2015157386, 199203459, 199221766, 2004080462, 2005020921, 2006009755,International Publication No. 2007078034, International Publication No. 2007092403, International Publication No. 2007127317, International Publication No. 2008005877, International Publication No. 2012154480, International Publication No. 2014100620, International Publication No. 2014039714, International Publication No. 2015134536, International Publication No. 2017167182, International Publication No. 2018112136, International Publication No. 2018112140, International Publication No. 2019155067, International Publication No. 2020076105, PCT Application No. US2019 / 063091, International Publication No. 19173692, International Publication No. 2016179517, International Publication No. 2017096179, International Publication No. 2017096182, International Publication No. 2017096281, International Publication No. 2018089628, International Publication No. 2017096179, International Publication No. 2018089628, International Publication No. 2018195321, International Publication No. 2020014643, International Publication No. 2019160882, International Publication No. 2018195321, International Publication No. 200140307, ​​International Publication No. 2002092784, International Publication No. 2007133811, International Publication No. 2009046541, International Publication No. 2010083253, International Publication No. 2011076781, International Publication No. 2013056352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205042, International Publication International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669, International Publication No. 2018107058, International Publication No. 2018190719, International Publication No. 2018210793, International Publication No. 2019023347, International Publication No. 2019042470, International Publication No. 2019175218, International Publication No. 2019183266, International Publication No. 2020013170, International Publication No. 2020068752, Cancer Discov. 2019 Jan 9(1):8, and compounds disclosed in Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0182] In some embodiments, CD marker targeting agents that may be co-administered include small molecule inhibitors, such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, robritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-26 3, CD117-ADC, AZD3229, telatinib, borolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), plerixafor, CTX-5861, and REGN-5678 (PSMA / CD28).

[0183] In some embodiments, agents targeting CD markers that may be co-administered include interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly ICLC (NSC-301463), reboxone, apoxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, levothyroxine ... and small molecule agonists such as siquimod, sergantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, ritenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0184] In some embodiments, agents targeting CD markers that may be co-administered include tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzalutamab (MOR-202), TAK-079, T AK573, daratumumab (DARZALEX®), TTX-030, selicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazarimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (caviraritumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulcapusp alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), F AP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, leratolimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enselimab (TSR-033), atipotuzumab, BrevaRex (MAB-AR-20).5), MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, Examples of antibodies include INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628.

[0185] In some embodiments, agents targeting CD markers that may be co-administered include CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, iso-cel, lysocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL-armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), Anti-CD19 CAR T-cell therapy (Acute lymphoblastic leukemia / Non-Hodgkin's lymphoma, University Hospital Heidelberg), Anti-CD19 CAR T-cell therapy (Silent IL-6 expression, Cancer, Shanghai Unicar Therapeutic Biopharmaceutical Therapeutic Technology), MB-CART2019.1(CD19 / CD20), GC-197(CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR(CD19 / APRIL), ICG-134, ICG-132(CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (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 cells, ICG-132 (CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01(NKG2D LIGAND Modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or cell therapies such as those disclosed in WO 2012079000 or WO 2017049166. Cluster of differentiation 47 (CD47) inhibitors

[0186] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blocking agents, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188), lemzoparimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSc i-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or International Publication No. 199727873, International Publication No. 199940940, International Publication No. 2002092784, International Publication No. 2005044857, International Publication No. 009046541, International Publication No. 2010070047, International Publication No. 2011143624, International Publication No. 2012170250, International Publication No. 2013109752, International Publication No. 2013119714, International Publication No. 2014087248, International Publication No. 2015191861, International Publication No. 2016022971, International Publication No. International Publication No. 2016023040, International Publication No. 2016024021, International Publication No. 2016081423, International Publication No. 2016109415, International Publication No. 2016141328, International Publication No. 2016188449, International Publication No. 2017027422, International Publication No. 2017049251, International Publication No. 2017053423,International Publication No. 2017121771, International Publication No. 2017194634, International Publication No. 2017196793, International Publication No. 2017215585, International Publication No. 2018075857, International Publication No. 2018075960, International Publication No. 2018089508, International Publication No. 2018095428, International Publication No. 2018137705, International Publication No. 2018233575, International Publication No. 2019027903, International Publication No. 2019034895, International Publication No. 2019042119, International Publication No. 2019042285, International Publication No. 2019042470, International Publication No. 2019 086573, International Publication No. 2019108733, International Publication No. 2019138367, International Publication No. 2019144895, International Publication No. 2019157843, International Publication No. 2019179366, International Publication No. 2019184912, International Publication No. 2019185717, International Publication No. 2019201236, International Publication No. 2019238012, International Publication No. 2019241732, International Publication No. 2020019135, International Publication No. 2020036977, International Publication No. 2020043188, and International Publication No. 2020009725. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is magrolimab.

[0187] In some embodiments, the CD47 inhibitor is IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217, (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / VEGF), or any combination thereof. GF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801. SIRPa targeting agent

[0188] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with a SIRPa targeting agent (NCBI Gene ID: 140885; UniProt P78324). Examples of SIRPa targeting agents that may be co-administered include SIRPa inhibitors, such as AL-008, RRx-001, and CTX-5861, and anti-SIRPPa antibodies, such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPPa / PD-L1). Additional SIRPα targeting agents of use may be those described in, for example, WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 2013056352, WO 2015138600, WO 2016179399, WO 2016205042, WO 201 7178653, WO 2018026600, WO 2018057669, WO 2018107058, WO 2018190719, WO 2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO 2019183266, WO 2020013170 and WO 2020068752. FLT3R agonists

[0189] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an FLT3R agonist. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with an FLT3 ligand. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with an FLT3L-Fc fusion protein, for example, as described in WO 2020 / 263830. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with GS-3583 or CDX-301. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with GS-3583. Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF)

[0190] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., TNFRSF1A (NCBI Gene ID: 7132), TN FRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS; NCBI Gene ID: 355), TNFRSF7 (CD27; NCBI Gene ID: 939), TNFRSF8 (CD30; NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137; NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797) , TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID; 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 2 3495), TNFRSF13C (CD268, NCBI gene ID; 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID; 608), TNFRSF18 (GITR, CD357, NCBI gene ID; 8784), TNFRSF19 (NCBI gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI gene ID; 27242), and TNFRSF25 (DR3, NCBI gene ID; 8718).

[0191] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tabolixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0192] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0193] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0194] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0195] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0196] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. WO 2017096179 and WO 2018089628.

[0197] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20). TGFβ antagonist

[0198] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with a TGFβ antagonist. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. TGFβ-specific antibodies can be prepared and characterized using methods known to those skilled in the art, for example, those described in PCT Publication WO 2018 / 129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist binds to a TGFβ latency-associated peptide (LAP), e.g., TGFβ1-LAP. TGFβ1-LAP-specific antibodies can be prepared and characterized using methods known to those skilled in the art, for example, those described in U.S. Pat. No. 8,198,412 or U.S. Pat. No. 10,017,567. In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-independent manner (e.g., independent of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) localized in the extracellular matrix, e.g., connective tissue of the liver. In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) localized in the thymus, lymph nodes, or tumor microenvironment (e.g., in patients with liver cancer). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) by latent TGFβ binding protein (LTBP).In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) by Glycoprotein-A Repeats Predominant protein (GARP), e.g., as described in U.S. Pat. No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is SK-181. In some embodiments, the TGFβ antagonist is an anti-latency-associated peptide (LAP) antibody that specifically binds to the LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in the extracellular matrix (ECM), e.g., of connective tissue in the liver. In some embodiments, the anti-LAP antibody specifically binds to LAP-TGFβ complexes on the surface of certain immunosuppressive cell types, such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived suppressor cells, for example, in the tumor microenvironment. In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to LAP-TGFβ complexes in any context. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that may be useful in connection with the compositions and methods provided herein are described, for example, in PCT Publication Nos. WO 2019 / 113123 (A1) and WO 2019 / 113464 (A1). Bispecific T cell engager

[0199] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered together with a bispecific T cell engager (e.g., Fc-less) or an anti-CD3 bispecific antibody (e.g., Fc-bearing). Illustrative anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), odronextamab (REGN-1979;CD20 / CD3), MCLA-117(CD3 / CLEC12A), JNJ-0819(hem / CD3), JNJ-7564(CD3 / hem), AMG-757(DLL3-CD3), AMG-330(CD33 / CD3) , AMG-420(BCMA / CD3), AMG-427(FLT3 / CD3), AMG-562(CD19 / CD3), AMG-596(EGFRvIII / CD3), AMG-673(CD33 / CD3), AMG-70 1 (BCMA / CD3), AMG-757 (DLL3 / CD3), AMG-211 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY974 (GPC3 / CD3) , GEMoab(CD3 / PSCA), RG6026(CD20 / CD3), RG6194(HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123), JNJ-9 383(MGD-015), AMG-424(CD38 / CD3), tidutamab(XmAb-18087(SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-0 07(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), tiduta Examples of suitable anti-CD3 binding bispecific molecules include tidutamab (XmAb-18087; SSTR2 / CD3), catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc domain. Illustrative bispecific T cell engagers that can be co-administered target CD3 and a tumor-associated antigen described herein, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565);These include receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230). Bispecific and trispecific natural killer (NK) cell engagers

[0200] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TKI). The antibody may be administered in combination with an NK cell activating receptor (NK cell activator, TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc) against an NK cell activating receptor, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Illustrative anti-CD16 bispecific antibodies, BiKE, or TriKE, that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc domain. Illustrative bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens 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 Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0201] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with an inhibitor of the MCL1 apoptosis regulator, a BCL2 family member (MCL1, TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1 / EAT, NCBI Gene ID: 4170). Examples of MCL1 inhibitors include 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. SHP2 inhibitors

[0202] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO2018172984 and WO2017211303. Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders

[0203] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184).

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

[0204] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an ASK inhibitor, for example, mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI Gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO2013112741 (Gilead Sciences). Bruton Tyrosine Kinase (BTK) inhibitors

[0205] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315. Cyclin-dependent kinase (CDK) inhibitors

[0206] In some embodiments, the compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (cyclin dependent kinase 6, CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (cyclin-dependent kinase 4, CDK5; CDK6; CDK7; CDK8; CDK9; CDK10; CDK11; CDK12 ... 3. Administered with an inhibitor of CDK3 (NCBI Gene ID: 1018); cyclin-dependent kinase 4 (cyclin-dependent kinase 6, CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); cyclin-dependent kinase 6 (cyclin-dependent kinase 6, CDK6, MCPH12; PLSTIRE; NCBI Gene ID: 1021); cyclin-dependent kinase 7 (cyclin-dependent kinase 7, CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID: 1022), or cyclin-dependent kinase 9 (cyclin-dependent kinase 9, CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02. Discoidin Domain Receptor (DDR) inhibitors

[0207] In some embodiments, the compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (discoidin domain receptor tyrosine kinase 2, DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations). Targeted E3 ligase ligand conjugates

[0208] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with a targeted E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survival) E3 ubiquitin ligase binding moiety, a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a cereblon E3 ubiquitin ligase binding moiety, a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety), and can be used to promote or increase degradation of the targeted protein, e.g., via the ubiquitin pathway. In some embodiments, a targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein described herein, and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., WO2018098280.In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding moiety that targets or binds Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4); rapidly accelerated 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, e.g., WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, WO 2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, for example, in WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649. Histone deacetylase (HDAC) inhibitors

[0209] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of a histone deacetylase, for example, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0210] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus Kinase (JAK) inhibitors

[0211] In some embodiments, the compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (Janus kinase 2, JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (Janus kinase 4, JAK5, JTK6; NCBI Gene ID: 3718). It is administered with an inhibitor of JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, or LJAK (NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. Lysyl Oxidase-Like Protein (LOXL) Inhibitors

[0212] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in conjunction with an inhibitor of a LOXL protein, e.g., 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). Matrix Metalloprotease (MMP) Inhibitors

[0213] In some embodiments, the compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, provided herein is selected from the group consisting of matrix metallopeptidases (MTMPs), ATPases, and ATP-dependent agonists. Inhibitors of metallopeptidase (MMP), such as MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO2012027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0214] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), (Ia), (Ia-1), (Ia-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, that inhibits the KRAS proto-oncogene, GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K - administered with an inhibitor of RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene, GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.Illustrative K-Ras inhibitors that may be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1(G12C), adagrasib (MRTX-849), ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849(G12C), and K-Ras(G12D) selective inhibitory peptides (including KRpep-2 and KRpep-2d). Illustrative KRAS mRNA inhibitors include anti-KRAS U1 adaptor, AZD-4785, siG12D-LODER™, and siG12D exosomes. Illustrative MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Illustrative Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Illustrative ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, rabocertinib, and ulixertinib. Illustrative Ras GTPase inhibitors that can be co-administered include lidigosertib. Illustrative PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Illustrative AKT inhibitors that can be co-administered include capivasertib and GSK2141795.Illustrative PI3K / mTOR inhibitors that may be co-administered include daptolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, cancer), racemetyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Additionally, K-RAS and mutant N-RAS can be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Mitogen-activated protein kinase (MEK) inhibitors

[0215] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uplosertib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0216] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha). alpha, p110-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, and copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG 7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication No. 2005113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Sciences, Inc.). Calistoga), WO 2013116562 (Gilead Calistoga), WO 2014100765 (Gilead Calistoga), WO 2014100767 (Gilead Calistoga), and WO 2014201409 (Gilead Sciences). Spleen Tyrosine Kinase (SYK) inhibitor

[0217] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celdulatinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut), and U.S. Patent Application Publication No. 20150175616. Toll-like receptor (TLR) agonists

[0218] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is an agonist of a Toll-like receptor (TLR), such as TLR1 (NCBI gene ID: 70 96), 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) agonists. Examples of TLR7 agonists that may be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and those disclosed in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 20090047249 (GileadSciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014056953 (Janssen), WO 2014076221 (Janssen), WO 2014128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (NoviraTherapeutics). An example of a TLR7 / TLR8 agonist that can be co-administered is NKTR-262. Examples of TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, and 3M-052, as well as U.S. Patent Application Publication No. 20140045849 (Janssen) and U.S. Patent Application Publication No. 201400736. 42 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics, and U.S. Patent Application Publication No. 20130251673 (NoviraExemplary TLR9 agonists that may be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Tyrosine kinase inhibitors (TKIs)

[0219] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a tyrosine kinase inhibitor (TKI). The TKI may target the epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, and imatinib. These include KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib, L-malic acid (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody).Exemplary EGFR-targeted agents include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®, and Booth, et al., Cancer Biol Ther. 2018 Feb. 1;19(2):132-137. Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab. chemotherapy drugs

[0220] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered in combination with a chemotherapeutic or anti-neoplastic agent.

[0221] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic drug" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptophytes, sarcodictyin; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi II), dynemycins, including dynemycin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin leucine, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenime antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, veracrine A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizablin (Veru-111); Platinum analogues, such as cisplatin and carboplatin, NC-6004 Nanoplatin; Aceglatone; Aldophosphamide glycosides; Aminolevulinic acid; Eniluracil; Amsacrine; Hestravcil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diaziquone; Elformutine; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Leucovorin; Lonidamine; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Losoxantrone; Fluoropyrimidines; Folinic acid; Podophyllic acid, 2-ethylhydrazide; Procarbazine; Polysaccharide K e-K, PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; trabectedin, triaziquone; 2,2',2''-trichlorotriemylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine ( GEMZAR®; 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan);Examples include FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated to antibodies or any of the targeting agents described herein to create antibody drug conjugates (ADCs) or targeted drug conjugates. Antihormonal drugs

[0222] Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0223] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0224] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0225] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (apatorsen).

[0226] Examples of progesterone receptor antagonists include onapristone. Additional progesterone-targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and levonorgestrel. Antiangiogenic agents

[0227] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered in combination with an anti-angiogenic agent.Antiangiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complexes (sulfated polysaccharide peptidoglycan complexes), and vasoconstrictors. Modulators of matrix metabolism, including proline analogs such as staurosporine, l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,l-3,4-dehydroproline, thiaproline, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinase-3 (chicken inhibitor of Other antiangiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, zilpacimab (ABT-165; DLL4 / VEGF), or nabicikizumab (OMP-305B83; DLL4 / VEGF). antifibrotic agents

[0228] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered in combination with an antifibrotic agent. Antifibrotic agents that may be co-administered include compounds such as beta-aminoproprionitrile (BAPN), as well as those disclosed in U.S. Pat. No. 4,965,288, which relates to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition, and U.S. Pat. No. 4,997,854, which relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, and are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Pat. Nos. 4,943,593, 5,021,456, 5,059,714, 5,120,764, and 5,182,297, which relate to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, 5,252,608, which relates to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication No. 20040248871, which are incorporated herein by reference.

[0229] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate resonance-stabilized products after binding to the carbonyl, such as the following primary amines: ethylenamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and selenohomocysteine ​​lactone.

[0230] Other antifibrotic agents are copper chelators, which may or may not permeate cells. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate. anti-inflammatory agents

[0231] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered in combination with an anti-inflammatory agent.Exemplary anti-inflammatory agents include, but are not limited to, arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765) , CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632), prostaglandin-endoperoxide synthase 1 (prostaglandin-endoperoxide and / or one or more inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0232] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that may be co-administered include mofezolac, GLY-230, and TRK-700.

[0233] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that may be co-administered include pormacoxib and imrecoxib.

[0234] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include LY3023703, GRC27864, and the compounds disclosed in International Publication Nos. WO 2015158204, WO 2013024898, WO 2006063466, WO 2007059610, WO 2007124589, WO 201 0100249, International Publication No. 2010034796, International Publication No. 2010034797, International Publication No. 2012022793, International Publication No. 2012076673, International Publication No. 2012076672, International Publication No. 2010034798, International Publication No. 2010034799, International Publication No. 2012022792, International Publication No. 2009103778, International Publication No. 2011048004, International Publication No. 2 012087771, International Publication No. 2012161965, International Publication No. 2013118071, International Publication No. 2013072825, International Publication No. 2014167444, International Publication No. 2009138376, International Publication No. 2011023812, International Publication No. 2012110860, International Publication No. 2013153535, International Publication No. 2009130242, International Publication No. 2009146696, International Publication Examples of compounds that may be used include those described in International Publication Nos. 2013186692, 2015059618, 2016069376, 2016069374, 2009117985, 2009064250, 2009064251, 2009082347, 2009117987, and 2008071173. Metformin has also been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0235] Carbonic anhydrases that may be co-administered (e.g., CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), C Examples of inhibitors of one or more of A9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632) include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0236] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include meclofenamate sodium and zileuton.

[0237] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that may be co-administered include the compounds described in WO 2015148954. Dual inhibitors of COX-2 / SEH that may be co-administered include the compounds described in WO 2012082647. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that may be co-administered include the compounds described in WO 2017160861.

[0238] Examples of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) genes that can be co-administered include GS-4875, GS-5290, BHM-078, and the compounds described in WO 2006124944, WO 2006124692, WO 2014064215, WO 2018005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70, Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35, Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8, Kaila, et al., Bioorg Med Chem. (2007) 15(19):6425-42, and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61. Tumor oxygenators

[0239] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered with an agent that promotes or increases tumor oxygenation or reoxygenation or prevents or reduces tumor hypoxia. Illustrative agents that may be co-administered include, for example, hypoxia inducible factor-1 alpha (HIF-1α) inhibitors such as PT-2977, PT-2385, VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165, and / or oxygen carrier proteins (e.g., hemenitric oxide and / or oxygen binding protein (HNOX)), such as OMX-302 and HNOX proteins described in WO2007137767, WO2007139791, WO2014107171, and WO2016149562. immunotherapy agents

[0240] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody.Examples of immunotherapeutic agents that may be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutumumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumumab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, diazepam, and azidotazumab. Nutuximab, dombanalimab, drozitumab, durigotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, framvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-73) 4016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minletumomab, mitumomab, mogamulitumab, moxetumomab, naptumomab, narutuzumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatuzumab, pasudotox, patritumab, pemtu These include momab, pertuzumab, pintumomab, pritumumab, racotumomab, radletuzumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubirituximab, veltuzumab, borsetuzumab, votumumab, zalutumumab, zimvelerimab, and 3F8.Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0241] The exemplified therapeutic antibodies may be further labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0242] In some embodiments, immunotherapeutic agents that may be co-administered are antibody drug conjugates (ADCs). Illustrative ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein.Examples of ADCs that may be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirin), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab sovatansine), depatuximab, vadasotuximab, labetuzumab, lazilatuzumab (e.g., lazilatuzumab vedotin), Roncatuximab (e.g., roncatuximab tesulin), sacituzumab (e.g., sacituzumab govitecan), datopotomab (e.g., datopotomab deruxtecan; DS-1062; Dato-DXd), patrituzumab (e.g., patrituzumab deruxtecan), rifastuzumab, indosatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitamab rilsodotin), indituximab, milatuzumab, robalbutuzumab (e.g., robalbutuzumab mabutesillin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamavutansine), dicitamab (e.g., dicitamab vedotin), terizotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMG Examples include N529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140.ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0243] Illustrative therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethylauristatin F (MMAE), monomethylauristatin H (MMAE), monomethylauristatin I ... F, MMAF), calicheamicins, ansamitocins, maytansine or analogs thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinking agent SC-DR002 (D6.5), duocarmycins, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or dimers thereof, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antineoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anti-cancer or anti-neoplastic agent) that can be conjugated to the drug-conjugated antibody, fragment thereof, or antibody mimetic comprises an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 comprises BPI-002.

[0244] In some embodiments, an ADC that may be co-administered comprises an antibody targeting tumor-associated calcium signal transducer 2 (TROP-2; TACSTD2, EGP-1, NCBI Gene ID: 4070). Illustrative anti-TROP-2 antibodies include, but are not limited to, TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius) BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University FirstHospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), as well as patents and patent applications published in International Publication No. 2020016662 (Abmart), International Publication No. 2020249063 (Bio-Thera Solutions), U.S. Patent Application Publication No. 20190048095 (Bio-Thera Solutions), International Publication No. 2013077458 (LivTech / Chiome), European Patent Application Publication No. 20110783675 (Chiome), International Publication No. 2015098099 (Daiichi Sankyo), and International Publication No. 2017002776 (Daiichi Sankyo), International Publication No. 2020130125 (Daiichi Sankyo), International Publication No. 2020240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021093730 (Daiichi Sankyo), U.S. Patent No. 9,850,312 (DaiichiSankyo), Chinese Patent No. 112321715 (Biosion), U.S. Patent Application Publication No. 2006193865 (Immunomedics / Gilead), International Publication No. 2011068845 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2016296633 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017021017 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017209594 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018271992 (Immunomedics / Gilead), International Publication No. 2018217227 (Immunomedi cs / Gilead), U.S. Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent No. 843 No. 5529 (Immunomedics / Gilead), U.S. Patent No. 9492566 (Immunomedics / Gilead), WO 2003074566 (Gilead), WO 2020257648 (Gilead), U.S. Patent Application Publication No. 2013039861 (Gilead), WO 2014163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (Abruzzo Theranostic / Oncoxx), WO 2018036428 (Sichuan KelunIn some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Pat. Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anti-cancer agent linked by a linker. In some embodiments, the linker includes a linker disclosed in U.S. Pat. No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lutotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxanes, geldanmycin, ansamycins, and epothilones. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with sacituzumab govitecan.

[0245] In some embodiments, an ADC that may be co-administered comprises an antibody targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66a, NCBI gene ID: 634). In some embodiments, the CEACAM5 antibody is hMN-14 (e.g., as described in WO 1996011013). In some embodiments, the CEACAM5-ADC is as described in WO 2010093395 (anti-CEACAM-5-CL2A-SN38). In some embodiments, antibodies and / or fusion proteins provided herein are administered with CEACAM5-ADC IMMU-130.

[0246] In some embodiments, an ADC that may be co-administered comprises an antibody that targets 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, antibodies and / or fusion proteins provided herein are administered with HLA-DR-ADC IMMU-140. Cancer gene therapy and cell therapy

[0247] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered in conjunction with cancer gene therapy and cell therapy. Cancer gene and cell therapies include the insertion of normal genes into cancer cells to replace mutated or altered genes; genetic modifications to silence mutated genes; genetic approaches to directly kill cancer cells; for example, the infusion of immune cells designed to enhance the immune response against cancer cells or to replace large portions of the patient's own immune system (T cells or natural killer cells) to kill or find and kill cancer cells; and genetic approaches to modify cellular activity to further alter the endogenous immune responsiveness to cancer. cell therapy

[0248] In some embodiments, a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13), or a pharmaceutically acceptable salt thereof, provided herein is administered in combination with one or more cell therapies. Illustrative cell therapies include, but are not limited to, the co-administration of one or more of a population of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor infiltrating lymphocytes (TIL), and / or dendritic cells (DC). In some embodiments, the cell therapy involves the co-administration of a T cell therapy, e.g., a population of α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves the co-administration of NK cell therapy, e.g., NK-92 cells. Optionally, the cell therapy may involve the co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0249] In some embodiments, cell therapy involves the co-administration of cells containing a chimeric antigen receptor (CAR). In such therapy, a population of immune effector cells is engineered to express a CAR, which contains a tumor antigen-binding domain. In T cell therapy, T cell receptors (TCRs) are engineered to target tumor-derived peptides displayed on the surface of tumor cells.

[0250] Regarding the structure of the CAR, in some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a signaling functional domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0251] In some embodiments, the costimulatory domain is selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD 4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 912), and CD1E (NCBI gene ID: 913). 12), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL 1. It comprises a functional domain of one or more proteins selected from the group consisting of CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0252] In some embodiments, the transmembrane domain is selected from the group consisting of the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E , ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0253] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapeutic agent (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof, or antibody mimetic) described herein binds to a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also referred to as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNF receptor superfamily member 17, TNFRSF17, BCMA; Tn antigen (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 alpha-2 (IL-13Ra2 or CD213A2); mesothelin;Interleukin 11 receptor alpha (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 beta (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); mucin 1, cell surface binding (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrinB2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX (CAIX); proteasome (macropain) subunit, beta, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of the breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type-A receptor 2 (EphA2); fucosyl-GM1;sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight-melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); and chromosome X open reading frame 61 (X open reading frame 61). frame 61, CXORF61); CD97; CD179a; anaplastic lymphomakinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K);Olfactory receptor 51E2 (ORS IE2); TCR gamma alternate reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (melanomacancer testis antigen-2, MADCT-1; melanoma cancer testis antigen-2 (MAD-CT-2); fos-related antigen 1; tumor protein p53 (p53); p53 mutants; prostein; survivin; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or galectin-8); melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutants; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2) 2, TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1;v-myc avian myeloma viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites); squamous cell carcinoma antigen recognized by T-cells 3 (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 2, SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E7); human papilloma virus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2);The target is selected from the group consisting of CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of an MHC-presented tumor-associated antigen.

[0254] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-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, TRAI L-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptors, alphafetoprotein (AFP), angiogenic factors, exogenous cognate The antigen is selected from the group consisting of: binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin D1, ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0255] In some embodiments, the antigen binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) presented on a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer-testis antigen. In some embodiments, the cancer testis antigen is acrosin binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI Gene ID: 84519), alpha-fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI Gene ID: 174); A-kinaseanchoring protein 4 (AKAP4; AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI Gene ID: 8852), ATPase family AAA domain containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI Gene ID: 29028), or kinetochore scaffold 1 (kinetochore scaffold 1). 1, KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI gene ID: 57082), centrosomal protein 55 (centrosomal protein 55, CEP55; C10orf3, CT111, MARCH, URCC6; NCBI gene ID: 55165), cancer / testis antigen 1A (cancer / testisantigen 1A, CTAG1A; ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1; NCBI gene ID: 246100), cancer / testis antigen 1B (cancer / testisantigen 1B.NCBI Gene ID: 30848), CCCTC-binding factor like (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2; NCBI Gene ID: 140690), catenin alpha 2 (catenin alpha 2, CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI Gene ID: 1496), cancer / testis antigen 83 (cancer / testisantigen 83, CT83; CXorf61, KK-LC-1, KKLC1; NCBI Gene ID: 203413), cyclin A1 (cyclin A1, CCNA1; CT146; NCBI Gene ID: 8900), and DEAD-box helicase 43 (DEAD-box helicase 43). 43, DDX43; CT13, HAGE; NCBI Gene ID: 55510), developmental pluripotency associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testis expressed 1 (FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 neighbor (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI Gene ID: 158521), HORMA domain containing 1 (HORMAD1; CT46, NOHMA; NCBI Gene ID: 84072), insulin-like growth factor 2 mRNA binding protein 3 (insulin-like growth factor 2 mRNA binding protein 3) 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), maelstromspermatogenic transposon silencer (MAEL; CT128, SPATA35; NCBI Gene ID: 84944), MAGE family member A1 (SPANX family member A2, MAGEA1; CT1.1, MAGE1; NCBI Gene ID: 4100); MAGE family member A3 (MAGE family member D2, MAGEA3; CT1.3, HIP8, HYPD, MAGE3, MAGEA6; NCBI Gene ID: 4102); MAGE family member A4 (MAGE family member D2, MAGEA4; CT1.4, MAGE-41, MAGE-X2, MAGE4, ​​MAGE4A, MAGE4B; NCBI Gene ID: 4103); MAGE family member A11 (MAGE family member D2, MAGEA11; CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI Gene ID: 4110); MAGE family member C1 (MAGE family member C1MAGEC1; CT7, CT7.1; NCBI Gene ID: 9947); MAGE family member C2 (MAGE family member D2, MAGEC2; CT10, HCA587, MAGEE1; NCBI Gene ID: 51438); MAGE family member D1 (MAGE family member D2, MAGED1; DLXIN-1, NRAGE; NCBI Gene ID: 9500); MAGE family member D2 (MAGE family member D2, MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI gene ID: 10916), kinesin family member 20B (kinesinfamily member 20B, KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI gene ID: 9585), NDC80 kinetochore complex NUF2 component (NUF2; CDCA1, CT106, NUF2R;NCBI Gene ID: 83540), nuclear RNA export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI Gene ID: 56001), PAS domain-containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI Gene ID: 139135), PDZ-binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI Gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI Gene ID: 55124), and preferentially expressed antigen in melanoma. melanoma, PRAME; CT130, MAPE, OIP-4, OIP4; NCBI gene ID: 23532), spermassociated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI gene ID: 9043), sperm protein associated with the nucleus, X-linked, family member A1 (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCBI gene ID: 30014), SPANX family member A2 (SPANX family member A2, SPANXA2; CT11.1, CT11.3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI gene ID: 728712), SPANX family member C (SPANXfamily member C, SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE;NCBI gene ID: 64663), SPANX family member D (SPANXfamily 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 (SSXfamily member 2, SSX1; CT5.1, SSRC; NCBI gene ID: 6756), SSX family member 2 (SSX family member 2, SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757), synaptonemal complex protein 3 (synaptonemal complex protein 3, SSX; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757), and dJ171K16.1 (dJ171K16.1; NCBI gene ID: 64648). 3, SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI Gene ID: 50511), testisexpressed 14, intercellular bridge forming factor, TEX14 (CT113, SPGF23; NCBI Gene ID: 56155), transcription factor Dp family member 3, TFDP3 (CT30, DP4, HCA661; NCBI Gene ID: 51270), serine protease 50, PRSS50 (CT20, TSP50; NCBI Gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI Gene ID: 7272), and zinc finger protein 165 (ZF165; NCBI Gene ID: 50611). 165, ZNF165; CT53, LD65, ZSCAN7; NCBI Gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer-testis antigens presented on major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasms are described, for example, in Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and summarized in the CT database website at cta.lncc.br / index.php. Illustrative TCR and TCR-like antibodies that bind to MHC-presented epitopes of NY-ESO-1 are described, for example, in Stewart-Jones, et al., Proc Natl Acad Sci USA. 2009Apr7;106(14):5784-8, International Publication No. 2005113595, International Publication No. 2006031221, International Publication No. 2010106431, International Publication No. 2016177339, International Publication No. 2016210365, International Publication No. 2017044661, International Publication No. 2017076308, International Publication No. 2017109496, International Publication No. 2018132739, International Publication No. 2019084538, International Publication No. 2019162043, International Publication No. 2020086158, and International Publication No. 2020086647. Illustrative TCR and TCR-like antibodies that bind to epitopes of MHC-presented PRAME are described, for example, in WO2011062634, WO2016142783, WO2016191246, WO2018172533, WO2018234319, and WO2019109821. Illustrative TCR and TCR-like antibodies that bind to epitopes of MHC-presented MAGE variants are described in, for example, WO2007032255, WO2012054825, WO2013039889, WO2013041865, WO2014118236, WO2016055785, WO2017174822, WO2017174823, WO2017174824, WO2017175006, WO2018097951, WO2018170338, WO2018225732, and WO2019204683. An illustrative TC that binds to an epitope on MHC-presented alpha-fetoprotein (AFP); Illustrative TCRs and TCR-like antibodies that bind to an MHC-presented epitope of SSX2 are described, for example, in WO 2015011450. Illustrative TCRs and TCR-like antibodies that bind to an MHC-presented epitope of KK-LC-1 (CT83) are described, for example, in WO 2017189254.

[0256] Examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogenreclucel (U.S. Pat. No. 9,089,520, WO 2016100236), AU-105, ACTR-087, activated allogeneic natural killer cells (CNDO-109-AANK), MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Immunoglobulins. Leclucel-T, valtalucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL These include CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0257] In some embodiments, the one or more additional co-administered therapeutic agents can be categorized by their mechanism of action, e.g., into the following groups: Drugs that target adenosine deaminase, such as pentostatin or cladribine; · Drugs that target ATM, such as AZD1390; MET-targeting agents such as savortinib, capmatinib, tetponitinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; Antroquinol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mirdametinib (PD-0325901), pimasertib, refametinib, or any of the following: WO 2011008709, WO 2013112741, WO 2006124944, WO 2006124692, WO 2014064215, WO 2018005435; Zhou, et al., Cancer Lett. 2017 Nov 1, 408:130-137; Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9): 1015-35, Wu, et al., Bioorg Med Chem Lett. (2009) 19(13): 3485-8, Kaila, et al., Bioorg Med Chem. (2007) 15(19): 6425-42, or Hu, et al., Bioorg Med Chem Lett. (2011) 21(16): 4758-61; agents that target mitogen-activated protein kinases, such as the compounds disclosed in Drugs that target thymidine kinase, such as agratimazine besadenovec (ProstAtak, PancAtak, GliAtak, GMCI, or AdV-tk); · Targeted agents that target the interleukin pathway, such as pegilodecakin (AM-0010) (PEGylated IL10) and CA-4948 (IRAK4 inhibitor); Drugs that target members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, medistrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); Drugs that target CD73, such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 antibodies (e.g., oleculab); ·Drugs that target DKK3, such as MTG-201; · Drugs that target EEF1A2, such as platydysine; Drugs that target EIF4A1, such as rohinitib; · Drugs that target endoglin, such as TRC105 (inflotuximab); Drugs that target exopolitin-1, such as eltanexor; Agents that target fatty acid amide hydrolases, such as the compounds disclosed in WO2017160861; Drugs that target heat shock protein 90 beta family member 1, such as anlotinib; · Drugs that target lactoferrin, such as ruxotemitide (LTX-315); agents that target lysyl oxidase, such as the compounds disclosed in U.S. Pat. No. 4,965,288, U.S. Pat. No. 4,997,854, U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, or U.S. Patent Application Publication No. 20040248871; · Drugs targeting MAGE family members, such as KITE-718, MAGE-A10C796T, or MAGE-A10 TCR; Agents targeting MDM2, such as ALRN-6924, CMG-097, milademethane monotosylate monohydrate (DS-3032b), or AMG-232; · Drugs targeting MDM4, such as ALRN-6924; · Agents targeting Melan-A, such as MART-1 F5 TCR-engineered PBMCs; Drugs that target mesothelin, such as CSG-MESO or TC-210; Drugs that target METAP2, such as M8891 or APL-1202; · Drugs targeting NLRP3, such as BMS-986299; Drugs that target oxoglutarate dehydrogenase, such as devimistat (CPI-613); · Drugs that target placental growth factors, such as aflibercept; agents targeting SLC10A3, such as the compounds disclosed in WO 2015148954, WO 2012082647, or WO 2017160861; · Agents targeting transforming growth factor alpha (TGFa), such as the compounds disclosed in WO 2019103203; Drugs that target the tumor protein p53, such as kevetrin (a stimulatory factor); · Drugs that target vascular endothelial growth factor A, such as aflibercept; Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250; · Drugs targeting VISTA, such as CA-170 or HMBD-002; Drugs that target WEE1, such as adavosertib (AZD-1775); · Small molecule inhibitors targeting ABL1, such as imatinib, rebastinib, asciminib, and ponatinib (ICLUSIG®); · Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, preladenant, etrumadenant (AB928), or PBF-509; · Small molecule inhibitors targeting arachidonate 5-lipoxygenase, such as meclofenamate sodium or zileuton; · Small molecule inhibitors targeting the ATR serine / threonine kinase, such as BAY-937, selalasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib); · Small molecule inhibitors targeting the AXL receptor tyrosine kinase, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posertinib (HM71224), ibrutinib (Imbruvica), M small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as -2951 (evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebrutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; · Small molecule inhibitors targeting neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195); · Small molecule inhibitors targeting the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; · Small molecule inhibitors targeting the SRC proto-oncogene non-receptor tyrosine kinase, such as VAL-201, tirbanibulin (KX2-391), or irginatinib maleate (NS-018); · Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), and AT-101 (gossypol); small molecule inhibitors targeting bromodomain and ectodomain (BET) bromodomain-containing proteins, such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mibebresisb, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; · Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01; Small molecule inhibitors that target carbonic anhydrase, such as polmacoxib, acetazolamide, or methazolamide; · Small molecule inhibitors targeting catenin beta 1, such as CWP-291 or PRI-724; · Small molecule antagonists targeting CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Vicriviroc); blixafortide, a small molecule antagonist targeting C-X-C motif chemokine receptors (e.g., CXCR4); Small molecule inhibitors that target cereblon, such as avadomide (CC-122), CC-92480, CC-90009, or iveldomide; · Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737; ·Small molecule inhibitors that target complement components, such as Imprime PGG (Biothera Pharmaceuticals); Small molecule inhibitors targeting C-X-C motif chemokine ligands (e.g., CXCL12), such as olaptesed pegol (NOX-A12); · Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; Small molecule inhibitors targeting DEAD-box helicase 5, such as spinoxin (RX-5902); small molecule inhibitors targeting DGKa, such as those described in WO2021130638; · Small molecule inhibitors targeting Diablo IAP-binding mitochondrial proteins, such as BI-891065; · Small molecule inhibitors targeting dihydrofolate reductase, such as pralatrexed or pemetrexed disodium; Small molecule inhibitors targeting DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin; · Small molecule inhibitors targeting MARCKS, such as BIO-11006; · Small molecule inhibitors targeting RIPK1, such as GSK-3145094; · Small molecule inhibitors targeting Rho-associated coiled-coil-containing protein kinases, such as AT13148 or KD025; Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecampegol, or amrubicin; ·Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201; · Small molecule inhibitors targeting DOT1-like histone lysine methyltransferases, such as pinometostat (EPZ-5676); Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497; · Small molecule inhibitors targeting fatty acid synthase, such as TVB-2640 (Sagimet Biosciences); Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144); Small molecule inhibitors targeting focal adhesion kinase (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; · Small molecule inhibitors targeting folate receptor 1, such as pralatrexate; · Small molecule inhibitors targeting FOXM1, such as thiostrepton; · Small molecule inhibitors targeting galectin-3, such as berapectin (GR-MD-02); Small molecule antagonists that target the glucocorticoid receptor, such as relacorilant (CORT-125134); Small molecule inhibitors that target glutaminase, including but not limited to CB-839 (telaglenastat) or bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Small molecule inhibitors that target the GNRHR, such as elagolix, relugolix, or degarelix; · Small molecule inhibitors targeting EPAS1, such as velzutifan (PT-2977 (Merck & Co.)); · Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as restrictive ivosidenib (AG-120), vorasidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221); · Small molecule inhibitors targeting lysine demethylase 1A, such as CC-90011; Small molecule inhibitors targeting MAPK-interacting serine / threonine kinases, such as tomivosertib (eFT-508); · Small molecule inhibitors targeting Notch receptors, such as AL-101 (BMS-906024); Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as volasertib or onvansertib; small molecule inhibitors of poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazolepali (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121 (e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102; · Small molecule inhibitors targeting the polycomb protein EED, such as MAK683; ·Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974; Small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as HP-5000, rofecoxib, ketorolac tromethamine, bromfenac sodium, otenaproxyl (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reformulated celecoxib (DRGT-46), AAT-076, MacuOshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumizole, firocoxib, rofecoxib, rutaecarpine, tilmacoxib, zaltoprofen, or imrecoxib; Small molecule inhibitors targeting protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715, or GSK3326595; small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in WO 2018172984 or WO 2017211303; · Small molecule antagonists that target retinoic acid receptors, such as tamibarotene (SY-1425); · Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A; · Small molecule inhibitors targeting S100 calcium-binding protein A9, such as tasquinimod; Small molecule inhibitors targeting selectin E, such as uproleselan sodium (GMI-1271); · Small molecule inhibitors targeting SF3B1, such as H3B-8800; ·Small molecule inhibitors targeting sirtuin-3, such as YC8-02; small molecule inhibitors targeting SMO, such as sonidegib (Odomzo®, formerly LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, or patidegib and taladegib; ·Small molecule antagonists targeting somatostatin receptors, such as OPS-201; · Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva®, ABC294640); · Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608); · Small molecule inhibitors targeting tankyrase, such as G007-LK or stenoparib (2X-121(e-7499)); · Small molecule inhibitors targeting TFGBR1, such as galunisertib and PF-06952229; Small molecule inhibitors that target thymidylate synthase, such as idetrexed (ONX-0801); · Small molecule inhibitors targeting the tumor protein p53, such as CMG-097; · Small molecule inhibitors targeting valosin-containing proteins, such as CB-5083; Small molecule inhibitors targeting WT1, such as ombipepimut-S (DSP-7888); · Small molecule agonists that target adenosine receptors, such as namodenoson (CF102); small molecule agonists targeting asparaginase, such as crisantaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegaspargase; · Small molecule agonists targeting CCAAT enhancer binding protein alpha, such as MTL-501; · Small molecule agonists targeting the cytochrome P450 family, such as mitotane; ·Small molecule agonists targeting DExD / H-box helicase 58, such as RGT-100; · Small molecule agonists targeting the GNRHR, such as leuprorelin acetate, leuprorelin acetate extended-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate; Small molecule agonists targeting GRB2, such as prexigebersen (BP1001); Small molecule agonists targeting NFE2L2, such as omaveloxolone (RTA-408); · Small molecule agonists targeting NOD2, such as mifamurtide (liposomal); Small molecule agonists targeting RAR-related orphan receptor gamma, such as cintirorgon (LYC-55716); Small molecule agonists that target the retinoic acid receptor (RAR), such as tretinoin; Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic GAMP (cGAMP), or cyclic di-AMP; · Small molecule agonists that target thyroid hormone receptor beta, such as levothyroxine sodium; · Small molecule agonists targeting tumor necrosis factor, such as tasonermin; ·Antisense agents targeting baculovirus IAP repeats containing 5, such as EZN-3042; ·Antisense agents targeting GRB2, such as plexigeneversen; ·Antisense agents targeting heat shock protein 27, such as apatrusen; Antisense agents targeting STAT3, such as danvatirsen (IONIS-STAT3-2.5Rx); · Gene therapy targeting CC motif chemokine receptors, such as SB-728-T; Interleukin-targeted gene therapies, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55; · Antibodies targeting claudin-18, such as claudiximab; ·Antibodies targeting clusterin, such as AB-16B5; ·Antibodies that target complement components, such as ravulizumab (ALXN-1210); ·Antibodies targeting C-X-C motif chemokine ligands, such as BMS-986253 (HuMax-Inflam); Antibodies targeting delta-like canonical Notch ligand 4 (DLL4) (DLL4 / VEGF), such as demcizumab and nabicixizumab; ·Antibodies targeting the EPH receptor A3, such as fivatuzumab (KB-004); ·Antibodies targeting epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); · Antibodies targeting fibroblast growth factors, such as GAL-F2 and B-701 (vofatamab); ·Antibodies targeting hepatocyte growth fac...

Claims

1. Compounds of formula (I) 【Chemical 867】 or a pharmaceutically acceptable salt thereof, wherein: 【Chemical 868】 is a single bond or a double bond, Ring A is C ５～７ cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, and the cycloalkyl, phenyl, heterocyclyl, or heteroaryl of ring A are each independently selected from 1 to 4 R ６ and optionally substituted with X is N or CR ７ and R １ But H, C １～６ Alkyl, C １～６ Haloalkyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R １ wherein said alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z １ and optionally substituted with R ２ H, -CN, C １～５ Alkyl, C １～５ Haloalkyl, C ２～６ alkynyl, cyclopropyl, cyclobutyl, or oxetanyl; R ２ wherein said alkyl, haloalkyl, alkoxyalkyl, alkynyl, cyclopropyl, or cyclobutyl is each independently selected from 1 to 4 Z ２ and each Z ２ But independently, C ２～６ Alkynyl, halo, -CN, -OR ２ａ , cyclopropyl, cyclobutyl, or oxetanyl; R ２ａ But H, C １～３ Haloalkyl, C ３～６ cycloalkyl, or C １～３ is alkyl, R ５ But H, C １～３ Alkyl, or C １～３ Is it a haloalkyl? Or R １ and R ２ together with the carbon to which they are attached, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, R １ and R ２ wherein the cycloalkyl or heterocyclyl formed from ５ or optionally replaced by Or R ２ and R ５ together with the carbon to which they are attached form cyclopropyl, cyclobutyl, or oxetanyl, R ２ and R ５ wherein said cyclopropyl or cyclobutyl formed from is optionally substituted with 1 to 4 halo; R ３ But H, C １～６ Alkyl, C １～６ Haloalkyl, —COR ３ａ , -COOR ３ａ , -CONR ３ａ R ３ｂ , -SO ２ R ３ａ , -SO ２ NR ３ａ R ３ｂ , C ６～１０ Aryl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R ３ wherein said alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z ３ and optionally substituted with R ４ But H, C １～６ Alkyl, C １～６ Haloalkyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; R ４ wherein said alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z ４ or optionally replaced by Or R ３ and R ４ together with the nitrogen to which they are attached form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, R ３ and R ４ wherein the heterocyclyl or heteroaryl formed from ９ and R ３ and R ４ and the heterocyclyl formed from is a heterocyclyl having 0 to 2 additional heteroatoms, each independently being N, O, or S; and R ３ and R ４ wherein the heteroaryl formed from is a heteroaryl having 0 to 2 additional heteroatoms, each independently being N, O, or S; Or R ２ and R ４ together with the atoms to which they are attached form a 5- to 10-membered heterocyclyl, and R ２ and R ４ wherein the heterocyclyl formed from ８ and optionally substituted with Each R ６ are independently halo, —OH, —OCH ３ , oxo, -CN, C １～３ Alkyl, C １～３ haloalkyl, or cyclopropyl; R ７ H, halo, CN, halomethyl, -CH ３ , or -OCH ３ and Each Z １ , Z ３ , Z ４ , Z ５ , Z ８ , or Z ９ But independently, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkoxyalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, halogen, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, oxo, —NO ２ , -CN, -O-R １２ａ , —C(O)—R １２ａ , -C(O)O-R 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 ), -NR １２ａ S (O) ２ N (R １２ｂ ) (R １２ｃ ), -NR １２ａ S (O) ２ O (R １２ｂ ), -OC(O)R １２ａ , -OC(O)OR １２ａ , -OC(O)-N(R １２ａ ) (R １２ｂ ), -S-R １２ａ , -S(O)R １２ａ , -S(O)(NH)R １２ａ , -S(O) ２ R １２ａ , -S(O) ２ N (R １２ａ ) (R １２ｂ ), -S(O)(NR １２ａ ) R １２ｂ , or -Si(R １２ａ ) ３ and each Z １ , Z ３ , Z ４ , Z ５ , Z ８ , or Z ９ wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of 1 to 4 Z １ａ and optionally substituted with Each Z １ａ But independently, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkoxyalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, halogen, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, oxo, —NO ２ , -CN, -O-R １２ａ , -C(O)R １２ａ , -C(O)O-R 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) ２ O (R １２ｂ ), -OC(O)R １２ａ , -OC(O)OR １２ａ , -OC(O)-N(R １２ａ ) (R １２ｂ ), -S-R １２ａ , -S(O)R １２ａ , -S(O)(NH)R １２ａ , -S(O) ２ R １２ａ , -S(O) ２ N (R １２ａ ) (R １２ｂ ), -S(O)(NR １２ａ ) R １２ｂ , or -Si(R １２ａ ) ３ and Z １ａ wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of 1 to 4 Z １ｂ and optionally substituted with Each Z １ｂ But independently, C １～９ Alkyl, C １～８ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, halogen, C ３～１５ Cycloalkyl, heterocyclyl, C ６～１０ Aryl, heteroaryl, oxo, —OH, —CN, —NO ２ , -NH ２ , -N ３ , -SH, -O(C １～９ alkyl), —O(C １～８ haloalkyl), —O(C ２～６ alkenyl), —O(C ２～６ alkynyl), —O(C ３～１５ cycloalkyl), -O(heterocyclyl), -O(C ６～１０ aryl), -O (heteroaryl), -NH(C １～９ alkyl), -NH(C １～８ haloalkyl), -NH(C ２～６ alkenyl), -NH(C ２～６ alkynyl), -NH(C ３～１５ cycloalkyl), -NH(heterocyclyl), -NH(C ６～１０ aryl), -NH (heteroaryl), -N(C １～９ alkyl) ２ , -N(C １～８ haloalkyl) ２ , -N(C ２～６ alkenyl) ２ , -N(C ２～６ alkynyl) ２ , -N(C ３～１５ cycloalkyl) ２ , -N(heterocyclyl) ２ , -N(C ６～１０ aryl) ２ , —N(heteroaryl) ２ , -N(C １～９ alkyl) (C １～８ haloalkyl), -N(C １～９ alkyl) (C ２～６ alkenyl), -N(C １～９ alkyl) (C ２～６ alkynyl), -N(C １～９ alkyl) (C ３～１５ cycloalkyl), -N(C １～９ alkyl)(heterocyclyl), -N(C １～９ alkyl) (C ６～１０ aryl), -N(C １～９ alkyl)(heteroaryl), —C(O)(C １～９ alkyl), —C(O)(C １～８ haloalkyl), —C(O)(C ２～６ alkenyl), —C(O)(C ２～６ alkynyl), —C(O)(C ３～１５ cycloalkyl), -C(O)(heterocyclyl), -C(O)(C ６～１０ aryl), —C(O)(heteroaryl), —C(O)O(C １～９ alkyl), —C(O)O(C １～８ haloalkyl), —C(O)O(C ２～６ alkenyl), —C(O)O(C ２～６ alkynyl), —C(O)O(C ３～１５ cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C ６～１０ -C(O)O (aryl), -C(O)NH ２ , -C(O)NH(C １～９ alkyl), —C(O)NH(C １～８ haloalkyl), —C(O)NH(C ２～６ alkenyl), —C(O)NH(C ２～６ alkynyl), —C(O)NH(C ３～１５ cycloalkyl), —C(O)NH(heterocyclyl), —C(O)NH(C ６～１０ aryl), —C(O)NH (heteroaryl), —C(O)N(C １～９ alkyl) ２ , -C(O)N(C １～８ haloalkyl) ２ , -C(O)N(C ２～６ alkenyl) ２ , -C(O)N(C ２～６ alkynyl) ２ , -C(O)N(C ３～１５ cycloalkyl) ２ , —C(O)N(heterocyclyl) ２ , -C(O)N(C ６～１０ aryl) ２ , —C(O)N(heteroaryl) ２ , -NHC(O)(C １～９ alkyl), -NHC(O)(C １～８ haloalkyl), —NHC(O)(C ２～６ alkenyl), -NHC(O)(C ２～６ alkynyl), -NHC(O)(C ３～１５ cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C ６～１０ aryl), -NHC(O)(heteroaryl), -NHC(O)O(C １～９ alkyl), -NHC(O)O(C １～８ haloalkyl), -NHC(O)O(C ２～６ alkenyl), -NHC(O)O(C ２～６ alkynyl), -NHC(O)O(C ３～１５ cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C ６～１０ aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C １～９ alkyl), -NHC(O)NH(C １～８ haloalkyl), -NHC(O)NH(C ２～６ alkenyl), -NHC(O)NH(C ２～６ alkynyl), -NHC(O)NH(C ３～１５ cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C ６～１０ aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C １～９ alkyl), -N(C １～９ alkyl)(S(O)(C １～９ alkyl), -S(C １～９ alkyl), -S(C １～８ haloalkyl), -S(C ２～６ alkenyl), -S(C ２～６ alkynyl), -S(C ３～１５ -Cycloalkyl), -S(heterocyclyl), -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 haloalkyl), -S(O)(C ２～６ alkenyl), -S(O)(C ２～６ alkynyl), -S(O)(C ３～１５ cycloalkyl), -S(O)(heterocyclyl), -S(O)(C ６～１０ -aryl), -S(O) (heteroaryl), -S(O) ２ (C １～９ alkyl), -S(O) ２ (C １～８ haloalkyl), -S(O) ２ (C ２～６ alkenyl), -S(O) ２ (C ２～６ alkynyl), -S(O) ２ (C ３～１５ cycloalkyl), —S(O) ２ (heterocyclyl), -S(O) ２ (C ６～１０ aryl), -S(O) ２ (heteroaryl), —S(O)(NH)(C １～９ alkyl), -S(O) ２ NH (C １～９ alkyl), or —S(O) ２ N (C １～９ alkyl) ２ and Z １ｂ wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of 1 to 3 C １～９ Alkyl, C １～８ Haloalkyl, halogen, —OH, —NH ２ , -O(C １～９ alkyl), —O(C １～８ haloalkyl), —O(C ３～１５ cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C １～９ alkyl), -NH(C １～８ haloalkyl), -NH(C ３～１５ -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C １～９ alkyl) ２ , -N(C ３～１５ cycloalkyl) ２ , -NHC(O)(C １～８ haloalkyl), —NHC(O)(C ３～１５ cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C １～９ alkyl), -NHC(O)O(C １～８ haloalkyl), -NHC(O)O(C ２～６ alkynyl), -NHC(O)O(C ３～１５ cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C １～９ alkyl), S(O) ２ (C １～９ alkyl), -S(O) ２ (C １～８ haloalkyl), -S(O) ２ (C ３～１５ cycloalkyl), —S(O) ２ (heterocyclyl), -S(O) ２ (aryl), —S(O) ２ (heteroaryl), —S(O)(NH)(C １～９ alkyl), -S(O) ２ NH (C １～９ alkyl), or —S(O) ２ N (C １～９ alkyl) ２ and Z is optionally substituted with １ｂ wherein the heteroaryl is a 5- to 10-membered heteroaryl; and Z １ｂ wherein the heterocyclyl is a 3- to 10-membered heterocyclyl; Each R ３ａ , R ３ｂ , R １２ａ , R １２ｂ , or R １２ｃ However, independently, H, C １～６ Alkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl, or 5 to 10 heteroaryl, and each R ３ａ , R ３ｂ , R １２ａ , R １２ｂ , or R １２ｃ wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each selected from 1 to 4 Z １ｂ and optionally substituted with A compound or a pharmaceutically acceptable salt thereof, wherein each heteroaryl or heterocyclyl in the compound of formula (I) has 1 to 3 heteroatoms, each independently being N, O, or S, unless otherwise specified.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. X is CR ７ 2. The compound of claim 1, wherein:

4. R ７ H, halo, CN, -CH ３ 4. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein:

5. R ７ 5. The compound of claim 1, 3, or a pharmaceutically acceptable salt thereof, wherein:

6. R ７ 5. The compound of claim 1, 3, or a pharmaceutically acceptable salt thereof, wherein:

7. Ring A is phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, and said phenyl, heterocyclyl, or heteroaryl of Ring A is selected from the group consisting of 1 to 3 R ６ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with:

8. Structure of Formula (Ia) 【Chemical 869】 and During the ceremony, each K and Q is independently N, CH, or CR ６ and Each J and L is independently CH or CR ６ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9. Structure of Formula (Ia-1) 【Chemical 870】 and In the formula, each R ９ are independently H or R ６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

10. Structure of Formula (Ia-2) 【Chemistry 871】 and In the formula, each R ９ are independently H or R ６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

11. Structure of Formula (Ia-3) 【Chemical 872】 and In the formula, each R ９ are independently H or R ６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

12. Structure of Formula (Ib) 【Chemical 873】 and During the ceremony, Each L １ , L ２ , and L ３ But independently, CR ９ , C.R. ９ R ９ ,O,S,N,NR ９ or CO, Each dashed line represents each L １ , L ２ , L ３ , and L １ and L ３ represents an optional bond to satisfy the valence requirements of the two Cs bonded to Each R ９ are independently H or R ６ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

13. Structure of Formula (Ib-1) 【Chemistry 874】 and In the formula, each R ９ are independently H or R ６ 13. The compound according to any one of claims 1 to 7 and 12, or a pharmaceutically acceptable salt thereof, wherein:

14. Structure of formula (Ib-2) 【Chemical 875】 and In the formula, each R ９ are independently H or R ６ 13. The compound according to any one of claims 1 to 7 and 12, or a pharmaceutically acceptable salt thereof, wherein:

15. Structure of formula (Ib-3) 【Chemical 876】 and In the formula, each R ９ are independently H or R ６ 13. The compound according to any one of claims 1 to 7 and 12, or a pharmaceutically acceptable salt thereof, wherein:

16. Structure of formula (Ib-4) 【Chemical 877】 and In the formula, each R ９ are independently H or R ６ 13. The compound according to any one of claims 1 to 7 and 12, or a pharmaceutically acceptable salt thereof, wherein:

17. Each R ６ are independently halo, —OH, —CN, C １～３ Alkyl, or C １～３ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

18. Each R ６ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein are independently F or Cl.

19. R ６ But -CH ３ 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. R ９ The compound according to any one of claims 9 to 16, or a pharmaceutically acceptable salt thereof, wherein is H.

21. Structure of formula (Ib-5) 【Chemical 878】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

22. Structure of formula (Ib-6) 【Chemical 879】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

23. Structure of formula (Ib-7) 【Chemical 880】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

24. Structure of formula (Ib-8) 【Chemical 881】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

25. Structure of Formula (Ib-9) 【Chemical 882】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

26. Structure of Formula (Ib-9) 【Chemical 883】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

27. Structure of formula (Ib-11) 【Chemical 884】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula:

28. R ５ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein is H.

29. R ２ But H, C １～３ Alkyl, or C １～３ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

30. R ２ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein is H.

31. R １ is a 5-10 membered heteroaryl containing 1-3 heteroatoms, each independently being N, O, or S; R １ wherein said heteroaryl is selected from the group consisting of 1 to 3 Z １ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, optionally substituted with:

32. R １ is 1 to 3 Z, which may be the same or different １ 32. The compound of any one of claims 1 to 31, which is a monocyclic heteroaryl or bicyclic heteroaryl optionally substituted with: or a pharmaceutically acceptable salt thereof.

33. R １ is a 5-6 membered heteroaryl containing one or two N, and R １ wherein said heteroaryl is selected from the group consisting of 1 to 3 Z １ 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, optionally substituted with:

34. R １ but, 【Chemical 885】 and 34. The compound according to any one of claims 1 to 33, wherein m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

35. R １ is 1 to 3 Z, which may be the same or different １ 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, which is a fused bicyclic heteroaryl optionally substituted with:

36. R １ is a [5,6] or [6,5] fused bicyclic heteroaryl containing 1 to 3 heteroatoms, each independently N, O, or S; R １ wherein said heteroaryl is selected from the group consisting of 1 to 3 Z １ 36. The compound of any one of claims 1 to 32 and 35, or a pharmaceutically acceptable salt thereof, optionally substituted with:

37. R １ is imidazopyridinyl, benzimidazolyl, pyrazolopyridinyl, benzothiazolyl, benzoxazolyl, benzothiophene, or benzothiadiazole; R １ wherein the imidazopyridinyl, benzimidazolyl, pyrazolopyridinyl, benzothiazolyl, benzoxazolyl, benzothiophene, or benzothiadiazole is selected from the group consisting of 1 to 3 Z １ 37. The compound of any one of claims 1 to 32, 35, and 36, or a pharmaceutically acceptable salt thereof, optionally substituted with:

38. R １ but, 【Chemical 886】 35. The compound according to any one of claims 1 to 34, wherein:

39. R １ but, 【Chemical 887】 and n is 0, 1, or 2; Z １ｃ But H or Z １ 38. The compound according to any one of claims 1 to 32 and 35 to 37, or a pharmaceutically acceptable salt thereof, wherein:

40. Each Z １ independently halo, -CN, C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 40. The compound of any one of claims 1 to 37 and 39, or a pharmaceutically acceptable salt thereof, which is haloalkoxy.

41. Each Z １ independently halo, -CN, C １～６ Alkyl, or C １～６ 41. The compound of any one of claims 1 to 37, 39, and 40, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

42. R １ but, 【Chemical 888】 42. The compound according to any one of claims 1 to 32 and 39 to 41, or a pharmaceutically acceptable salt thereof, wherein:

43. R ３ But H, C １～６ Alkyl, C １～６ Haloalkyl, —COR ３ａ , -COOR ３ａ , -CONR ３ｂ R ３ｂ , -SO ２ R ３ａ , -SO ２ NR ３ｂ R ３ｂ , C ６～１０ Aryl, C ３～１０ cycloalkyl, heterocyclyl, or heteroaryl; R ３ wherein said alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z ３ and optionally substituted with R ４ But H, C １～６ Alkyl, C １～６ Haloalkyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, heterocyclyl, or heteroaryl; R ４ wherein said alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z ４ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, optionally substituted with:

44. R ３ But H, C １～６ Alkyl, C １～６ Haloalkyl, —COR ３ａ , -COOR ３ａ , -CONR ３ｂ R ３ｂ , C ６～１０ Aryl, C ３～６ cycloalkyl, heterocyclyl, or heteroaryl; R ３ wherein said aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z ３ and optionally substituted with Each R ３ａ and R ３ｂ But independently, C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ aryl, or heteroaryl; R ３ａ wherein each of said alkyl, cycloalkyl, aryl, or heteroaryl is selected from 1 to 4 Z １ｂ and each Z １ｂ independently halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, which is haloalkoxy.

45. R ３ But H, C １～６ Alkyl, C １～６ Haloalkyl, —COR ３ａ , -COOR ３ａ , C ６～１０ aryl, or heteroaryl; R ３ wherein each of said aryl or heteroaryl groups is selected from 1 to 4 Z ３ and optionally substituted with R ３ａ But C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ aryl, or heteroaryl; R ３ａ wherein each of said alkyl, cycloalkyl, aryl, or heteroaryl is selected from 1 to 4 Z １ｂ and each Z １ｂ independently halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which is haloalkoxy.

46. R ３ But, -COR ３ａ or -COOR ３ａ and R ３ａ But C １～６ Alkyl, C ３～８ cycloalkyl, phenyl, 5- or 6-membered heteroaryl, R ３ａ wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is each selected from 1 to 3 Z １ｂ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, optionally substituted with:

47. R ３ａ But C １～６ Alkyl or C ３～８ is cycloalkyl, and R ３ａ wherein said alkyl or cycloalkyl is each selected from 1 to 3 Z １ｂ 47. The compound of any one of claims 1 to 46, optionally substituted with:

48. R ３ But, -COR ３ａ and R ３ａ But C １～３ Alkyl or C ３～６ cycloalkyl, and each R ３ａ wherein said alkyl or cycloalkyl is each selected from 1 to 3 Z １ｂ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, optionally substituted with:

49. R ３ But, -COR ３ａ and R ３ａ But C ３～６ is cycloalkyl, and R ３ａ wherein said cycloalkyl is selected from 1 to 3 Z １ｂ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, which is a fused bicyclic, bridged bicyclic, or spiro bicyclic optionally substituted with:

50. R ３ａ wherein said cycloalkyl is selected from 1 to 4 Z １ｂ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, which is monocyclic optionally substituted with

51. Each Z １ｂ independently halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ haloalkoxy, or C １～６ 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, which is alkoxy.

52. Each Z ３ independently halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ haloalkoxy, or C １～６ 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, which is alkoxy.

53. Structure of Formula (Ib-12) 【Chemical 889】 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, having the formula:

54. Each R ３ が、-COCH ３ -COC ２ H ５ -COOC ２ H ５ , 【Chemical 890】 43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein:

55. R ４ But H, C １～３ Alkyl, C １～３ Haloalkyl, C ６～１０ Aryl, C ３～８ cycloalkyl, 5- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; R ４ wherein said aryl, cycloalkyl, heterocyclyl, or heteroaryl is each selected from 1 to 4 Z ４ 55. The compound of any one of claims 1 to 52 and 54, or a pharmaceutically acceptable salt thereof, optionally substituted with:

56. R ４ But H, C １～３ Alkyl, C １～３ Haloalkyl, phenyl, C ３～８ cycloalkyl, or 5- or 6-membered heteroaryl; R ４ wherein said phenyl, cycloalkyl, or heteroaryl is each selected from 1 to 4 Z ４ 56. The compound of any one of claims 1 to 52, 54, and 55, or a pharmaceutically acceptable salt thereof, optionally substituted with:

57. R ４ is H or C １～３ 57. The compound according to any one of claims 1 to 52 and 54 to 56, or a pharmaceutically acceptable salt thereof, which is alkyl.

58. R ４ But CD ３ 58. The compound according to any one of claims 1 to 52 and 54 to 57, or a pharmaceutically acceptable salt thereof.

59. Z ４ Halo, -OH, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ haloalkoxy, or C １～６ 57. The compound according to any one of claims 1 to 52 and 54 to 56, or a pharmaceutically acceptable salt thereof, which is alkoxy. 【Request Item 60】 【Chemistry 891】 but, 【Chemical 892】 43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein:

61. R ３ and R ４ together with the nitrogen to which they are attached form a 5-7 membered heterocyclyl having 0-3 additional heteroatoms, each independently N, O, or S; R ３ and R ４ wherein the heterocyclyl formed from ９ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, optionally substituted with:

62. R ３ and R ４ wherein the heterocyclyl formed from ９ 62. The compound of any one of claims 1 to 42 and 61, wherein R is a monocyclic optionally substituted with R or a pharmaceutically acceptable salt thereof. 【Request Item 63】 【Chemistry 893】 but, 【Chemical 894】 and ring D is a ring having 1 to 3 Z ９ 63. The compound of any one of claims 1 to 42, 61, and 62, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclyl optionally additionally substituted with R.

64. Ring D is a ring having 1 to 3 Z ９ 64. The compound of claim 63, which is monocyclic and optionally additionally substituted with:

65. R ３ and R ４ together with the nitrogen to which they are attached form a 5- to 7-membered heterocyclyl, R ３ and R ４ wherein said heterocyclyl formed from optionally has an additional heteroatom N, and R ３ and R ４ wherein the heterocyclyl formed from ９ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, optionally substituted with:

66. Each Z ９ are independently oxo, halo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ haloalkoxy, or C １～６ 66. The compound according to any one of claims 1 to 42 and 61 to 65, or a pharmaceutically acceptable salt thereof, which is alkoxy.

67. At least one Z ９ 67. The compound of any one of claims 1 to 42, 61, 62, 64, and 66, or a pharmaceutically acceptable salt thereof, wherein is oxo.

68. Structure of formula (Ib-13) 【Chemical 895】 and 43. The compound according to any one of claims 1 to 42, wherein q is 1 or 2, or a pharmaceutically acceptable salt thereof. 【Request Item 69】 【Chemistry 896】 but, 【Chemical 897】 43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein:

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

71. 71. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

72. 72. The pharmaceutical composition of claim 71, further comprising an additional therapeutic agent.

73. A method for treating a disease or condition associated with chromosome 9p21 deletion, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 70 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71 or 72.

74. 73. A method for treating a disease or condition associated with methylthioadenosine phosphorylase (MTAP) deficiency or any other MTAP loss-of-function event, including, but not limited to, loss of mRNA expression, mRNA splicing defects, stop codons or frameshift mutations in the open reading frame, any mutations that result in enhanced MTAP proteolysis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 70 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71 or 72.

75. A method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 70 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71 or 72.

76. 76. The method of claim 75, wherein the cancer is selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell neoplasm, 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, renal cancer, colorectal cancer, prostate cancer, leukemia, cervical cancer, endometrial cancer, and soft tissue cancer.

77. 76. The method of claim 75, wherein the cancer is selected from ovarian cancer, lung cancer, lymphatic cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, and bladder cancer.

78. 78. The method of any one of claims 75 to 77, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent or modality.

79. 79. The method of claim 78, wherein the additional therapeutic agents or additional therapeutic modalities comprise one, two, three, or four additional therapeutic agents and / or therapeutic modalities.

80. 79. The pharmaceutical composition of claim 72; or the method of claim 78, wherein the additional therapeutic agent or treatment modality is selected from an immune checkpoint modulator, an antibody drug conjugate (ADC), an anti-apoptotic agent, a targeted anti-cancer therapy, a chemotherapeutic agent, surgery, or radiation therapy.

81. 81. The pharmaceutical composition or method of claim 80, wherein the immune checkpoint modulator is selected from an anti-PD-(L)1 antibody, an anti-TIGIT antibody, an anti-CTLA4 antibody, an anti-CCR8 antibody, an anti-TREM1 antibody, an anti-TREM2 antibody, a CD47 inhibitor, a DGKα inhibitor, a Helios (IKZF2) degrader, an HPK1 degrader, an HPK1 inhibitor, a FLT3 agonist, a CD39 inhibitor, a CD73 inhibitor, an adenosine A2a and / or A2b receptor antagonist, a natural killer cell engager, and a CAR-T cell therapy.

82. 71. Use of a compound according to any one of claims 1 to 70, 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.

83. 83. The use of a compound according to claim 82, wherein the disease or condition is cancer.

84. 71. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, for use in therapy.

85. 73. A compound according to any one of claims 1 to 70 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71 or 72, for use in a method for treating a disease or condition, such as a disease or condition associated with chromosome 9p21 deletion or any other MTAP deficiency.

86. 86. The compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 85, wherein the disease or condition is cancer.

87. 87. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition for use according to claim 85 or 86, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent or treatment modality.

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