Trim21-targeted compounds and uses thereof

Abstract

Described herein are compounds, pharmaceutical compositions, and methods for treating TRIM21-associated proliferative disorders, including cancers such as pancreatic cancer and head and neck cancers.

Description

[0001] TRIM21-TARGETED COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 657,500, filed on June 7, 2024, and U.S. Provisional Patent Application No.63 / 774,398, filed on March 19, 2025, the entire disclosures of which are incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with Government support under contract CA230220 awarded by the National Institutes of Health. The Government has certain rights in the invention. FIELD Disclosed herein are compounds, pharmaceutical compositions, and methods for treating TRIM21-associated proliferative disorders, including cancers such as pancreatic cancer and head and neck cancers. BACKGROUND PLRX-93936 is a compound that was evaluated in phase I / II clinical trials for the treatment of multiple myeloma and advanced solid tumors, but development of the drug was discontinued and a mechanism of action for the compound was never conclusively identified. SUMMARY In one aspect, disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Q is O or NH; R1is C1-C6alkyl, C3-C6cycloalkyl, or monocyclic heterocyclyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from hydroxy, amino, amido, and cyano; or R1is taken together with R2aand the atoms to which they are attached to form a ring; X1is CH or N; X2is CR2aor N; X3is CR2bor N; X4is CR2cor N; X5is CR2dor N; X6is CR3aor N; X7is CR3bor N; X8is CR3cor N; X9is CR3dor N; R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dare each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NRxRy, -C(O)(C1-C6 alkyl), cyano, aryl, C3-C6 cycloalkyl, heteroaryl, and heterocyclyl; wherein R2aand R2b, or R2band R2c, or R2cand R2dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; and wherein R3aand R3b, or R3band R3c, or R3cand R3dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; Rxand Ryare each independently selected from hydrogen, C1-C6alkyl, and C1-C6hydroxyalkyl; n is 0, 1, or 2; each R4is independently C1-C6 alkyl; or two R4, together with the atom(s) to which they are attached, are taken together to form a ring; R5is H or C1-C4 alkyl; R6aand R6bare each independently selected from hydrogen and C1-C6 alkyl, or R6aand R6bare taken together with the carbon atom to which they are attached to form an optionally substituted ring; and A is a 6- to 8-membered ring; with the proviso that at least one of R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dis not CH, or n is 1 or 2, or X1is CH. In some embodiments, Q is O. In some embodiments, Q is NH. In some embodiments, R1is C1-C3alkyl, C3-C4cycloalkyl, or a monocyclic 4- or 5- membered heterocyclyl having one heteroatom selected from N and O, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from -OH, -NH2, -N(CH3)2, and - C(O)NH2. In some embodiments, R1is selected from methyl, ethyl, cyclopropyl, azetidinyl, - CH2CH2NH2, -CH2CH2N(CH3)2, -CH2CH2OH, and -CH2C(O)NH2. In some embodiments, R1is C2-C4alkyl. In some embodiments, R1is ethyl. In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, R2ais hydrogen, and one of R2b, R2c, R2dis selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, or -C(O)(C1-C6alkyl), and the other two of R2b, R2c, and R2dare hydrogen. In some embodiments, one of R2b, R2c, R2dis halo, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, or -C(O)(C1-C2 alkyl). In some embodiments, one of R2b, R2c, R2dis selected from fluoro, chloro, bromo, methyl, trifluoromethyl, -COOCH3, and ethoxy. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, R2ais hydrogen, and one of R2b, R2c, R2dis selected from C1-C6 haloalkyl, amino, or -C(O)(C1-C6 alkyl), and the other two of R2b, R2c, and R2dare hydrogen. In some embodiments, one of R2b, R2c, R2dis C1-C2 haloalkyl or -C(O)(C1-C2 alkyl). In some embodiments, one of R2b, R2c, R2dis selected from trifluoromethyl and - COOCH3. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, and R2a, R2b, R2c, R2dare hydrogen. In some embodiments, X2is CR2a. In some embodiments, R2ais hydrogen or halo. In some embodiments, R2ais hydrogen. In some embodiments, X2is N. In some embodiments, X3is CR2b. In some embodiments, R2bis hydrogen, halo, C1- C3 alkyl, C1-C3 haloalkyl, -C(O)O(C1-C3 alkyl), and a monocyclic 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from O and N. In some embodiments, R2bis hydrogen or halo. In some embodiments, X4is CR2c. In some embodiments, R2cis hydrogen, halo, C1- C3haloalkyl, C1-C3alkoxy, -NRxRy, or cyano, wherein Rxis hydrogen and Ryis C1-C3hydroxyalkyl. In some embodiments, R2cis hydrogen. In some embodiments, X4is N. In some embodiments, X3is CR2b, X4is CR2c, and R2band R2care taken together with the carbon atoms to which they are attached to a 5- or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O. In some embodiments, X5is CR2d. In some embodiments, R2dis hydrogen or halo. In some embodiments, R2dis hydrogen. In some embodiments, X5is N. , In some em one of R3a, R3b, R3c, and R3dis selected from halo, C1-C6 alkyl, C1-C6 alkoxy, and amino, and the other three of R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis halo, C1-C2 alkyl, or C1-C2 alkoxy. In some embodiments, one of R3a, R3b, R3c, and R3dis fluoro, chloro, bromo, iodo, methyl, or methoxy. In some embodiments, X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from C1-C6 alkyl, C1-C6 alkoxy, and amino, and the other three of R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis C1-C2 alkyl or C1-C2 alkoxy. In some embodiments, one of R3a, R3b, R3c, and R3dis methyl or methoxy. In some embodiments, X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, and R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, X6is CR3aand R3ais hydrogen. In some embodiments, X6is N. In some embodiments, X7is CR3b. In some embodiments, R3bis selected from hydrogen, halo, C1-C3alkyl, cyano, phenyl, and monocyclic 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R3bis halo. In some embodiments, X8is CR3c. In some embodiments, R3cis selected from hydrogen, halo, C1-C3alkoxy, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3cis hydrogen. In some embodiments, X8is N. In some embodiments, X9is CR3d. In some embodiments, R3dis selected from hydrogen, halo, C1-C3alkyl, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3dis hydrogen. In some embodiments, X9is N. In some embodiments, A is a six-membered ring. In some embodiments, A is a piperazine ring. In some embodiments, n is 0. In some embodiments, n is 2, and wherein the two R4are taken together with the atom(s) to which they are attached to form a ring. In some embodiments, R5is hydrogen. In some embodiments, R6aand R6bare each hydrogen. In some embodiments, R6ais hydrogen and R6bis methyl. In some embodiments, R6aand R6bare taken together with the carbon atom to which they are attached to form a C3-C4cycloalkyl ring. In some embodiments, the compound of formula (I) is a compound of formula (I) illustrated herein, or a pharmaceutically acceptable salt thereof. Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also disclosed herein is a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the proliferative disease is associated with tripartite motif- containing 21 (TRIM21). In some embodiments, the proliferative disease is associated with a mutation in and / or increased activity of TRIM21. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is selected from pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, multiple myeloma, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, leukemia, lymphoma, prostate cancer, and sarcoma. In some embodiments, the method further comprises treating the subject with one or more additional therapies selected from chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy, or any combination thereof. In one aspect, disclosed herein is a method of treating a TRIM21-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Q is O or NH; R1is C1-C6 alkyl, C3-C6 cycloalkyl, or monocyclic heterocyclyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from hydroxy, amino, amido, and cyano; or R1is taken together with R2aand the atoms to which they are attached to form a ring; X1is CH or N; X2is CR2aor N; X3is CR2bor N; X4is CR2cor N; X5is CR2dor N; X6is CR3aor N; X7is CR3bor N; X8is CR3cor N; X9is CR3dor N; R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dare each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NRxRy, -C(O)(C1-C6 alkyl), cyano, aryl, C3-C6 cycloalkyl, heteroaryl, and heterocyclyl; wherein R2aand R2b, or R2band R2c, or R2cand R2dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; and wherein R3aand R3b, or R3band R3c, or R3cand R3dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; Rxand Ryare each independently selected from hydrogen, C1-C6alkyl, and C1-C6hydroxyalkyl; n is 0, 1, or 2; each R4is independently C1-C6 alkyl; or two R4, together with the atom(s) to which they are attached, are taken together to form a ring; R5is hydrogen or C1-C4 alkyl; R6aand R6bare each independently selected from hydrogen and C1-C6alkyl, or R6aand R6bare taken together with the carbon atom to which they are attached to form an optionally substituted ring; and A is a 6- to 8-membered ring. In some embodiments, Q is O. In some embodiments, Q is NH. In some embodiments, R1is C1-C3alkyl, C3-C4cycloalkyl, or a monocyclic 4- or 5- membered heterocyclyl having one heteroatom selected from N and O, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from -OH, -NH2, -N(CH3)2, and - C(O)NH2. In some embodiments, R1is selected from methyl, ethyl, cyclopropyl, azetidinyl, - CH2CH2NH2, -CH2CH2N(CH3)2, -CH2CH2OH, and -CH2C(O)NH2. In some embodiments, R1is C2-C4alkyl. In some embodiments, R1is ethyl. In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, one of R2a, R2b, R2c, and R2dis selected from hydrogen, halo, C1-C2alkyl, C1-C2haloalkyl, C1-C2alkoxy, or - C(O)(C1-C2 alkyl), and the other three of R2a, R2b, R2c, and R2dare hydrogen. In some embodiments, one of R2a, R2b, R2c, and R2dis selected from hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl, -COOCH3, and ethoxy. In some embodiments, X2is CR2a. In some embodiments, R2ais hydrogen or halo. In some embodiments, R2ais hydrogen. In some embodiments, X2is N. In some embodiments, X3is CR2b. In some embodiments, R2bis hydrogen, halo, C1- C3 alkyl, C1-C3 haloalkyl, -C(O)O(C1-C3 alkyl), and a monocyclic 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from O and N. In some embodiments, R2bis hydrogen or halo. In some embodiments, X4is CR2c. In some embodiments, R2cis hydrogen, halo, C1- C3 haloalkyl, C1-C3 alkoxy, -NRxRy, or cyano, wherein Rxis hydrogen and Ryis C1-C3 hydroxyalkyl. In some embodiments, R2cis hydrogen. In some embodiments, X4is N. In some embodiments, X3is CR2b, X4is CR2c, and R2band R2care taken together with the carbon atoms to which they are attached to a 5- or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O. In some embodiments, X5is CR2d. In some embodiments, R2dis hydrogen or halo. In some embodiments, R2dis hydrogen. In some embodiments, X5is N. In some embodiments, the group has a structure selected from:

[0002] In some embodiments, X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from hydrogen, halo, C1-C2alkyl, and C1-C2alkoxy, and the other three of R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, or methoxy. In some embodiments, X6is CR3aand R3ais hydrogen. In some embodiments, X6is N. In some embodiments, X7is CR3b. In some embodiments, R3bis selected from hydrogen, halo, C1-C3 alkyl, cyano, phenyl, and monocyclic 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R3bis halo. In some embodiments, X8is CR3c. In some embodiments, R3cis selected from hydrogen, halo, C1-C3 alkoxy, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3cis hydrogen. In some embodiments, X8is N. In some embodiments, X9is CR3d. In some embodiments, R3dis selected from hydrogen, halo, C1-C3 alkyl, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3dis hydrogen. In some embodiments, X9is N. In some embodiments, A is a six-membered ring. In some embodiments, A is a piperazine ring. In some embodiments, n is 0. In some embodiments, n is 2, and wherein the two R4are taken together with the atom(s) to which they are attached to form a ring. In some embodiments, the group has a formula selected from: . In some embodiments, R5is hydrogen. In some embodiments, R6aand R6bare each hydrogen. In some embodiments, R6ais hydrogen and R6bis methyl. In some embodiments, R6aand R6bare taken together with the carbon atom to which they are attached to form a C3-C4cycloalkyl ring. In some embodiments, the compound of formula (II) is a compound of formula (II) illustrated herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the administering step comprises administering to the subject a pharmaceutical composition comprising the compound of formula (II) and a pharmaceutically acceptable carrier. In some embodiments, the method further comprises a step of detecting and / or quantifying the amount of TRIM21 in a sample obtained from the subject, and subsequently administering the effective amount of the compound of formula (II), or the pharmaceutically acceptable salt thereof, to the subject based on the presence or amount of TRIM21 detected and / or quantified in the sample. In some embodiments, the method further comprises comparing the amount of TRIM21 to a reference level and identifying the subject as having a TRIM21-associated cancer when the amount of TRIM21 is greater than or equal to the reference level. In some embodiments, the sample comprises blood or a blood product, tumor tissue or suspected tumor tissue, lymph node tissue, urine, or saliva. In some embodiments, the TRIM21-associated cancer is a cancer associated with a mutation in and / or increased activity of TRIM21. In some embodiments, the cancer is selected from pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, multiple myeloma, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, leukemia, lymphoma, prostate cancer, and sarcoma. In some embodiments, the method further comprises treating the subject with one or more additional therapies selected from chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy, or any combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows the chemical structures of erastin and PRLX-93936, a drug with unknown mechanism of action that was previously tested in early-stage human clinical trials. FIG.2 shows the results from a genome-scale CRISPR / Cas9 drug modifier knockout screen to identify functional mediators required for PRLX-93936 anti-cancer activity. Screen was performed over 21 days using the Brunello sgRNA library. CRISPR guide abundance is summarized to the gene level using MAGeCK. The volcano plot depicts the adjusted q-value on the y-axis and the gene-level log2 fold change on the x-axis. TRIM21 was the top rescue hit. FIG.3 shows the results from a genome-scale CRISPR / Cas9 drug modifier activation screen to identify functional mediators sufficient for PRLX-93936 anti-cancer activity. Screen was performed over 13 days using the Calabrese-B sgRNA library. CRISPR guide abundance is summarized to the gene level using MAGeCK. The volcano plot depicts the adjusted q-value on the y-axis and the gene-level log2 fold change on the x-axis. TRIM21 was a top sensitization hit. FIGS 4A-4B show: (FIG.4A) the results from a 5-day cancer cell viability assay (PRISM) for 816 diverse cancer cell lines. Area under the dose-response curve (AUC) for each cancer cell line is indicated and grouped by cancer lineage. Boxplots illustrate the median AUC and the 25th / 75th percentiles. Whiskers illustrate the 10th / 90th percentiles; (FIG.4B) a statistical test for anti-cancer activity by lineage (Fisher exact test for more sensitive quartile with Benjamini-Hochberg adjustment). FIG.5A shows baseline cell line gene expression (RNA-seq) versus PRLX-93936 activity across more than 800 cancer cell lines. Linear modeling was employed to estimate effect size. Each point is a gene. TRIM21 expression is highlighted as the top feature predicting sensitivity. FIG 5B. shows a scatter plot comparing TRIM21 mRNA expression versus PRLX-93936 viability AUC. Each point is a cancer cell line. FIG.6. shows PRLX-93936 cancer cell viability assays (72H, CellTiterGlo) for two cell lines with high baseline TRIM21 expression and intrinsic sensitivity. Dose response curves are shown for intact TRIM21 (Control sgRNA) versus TRIM21 knockout (TRIM21 sgRNAs). FIG.7 shows PRLX-93936 cancer cell viability assays (72H, CellTiterGlo) for three cell lines with low baseline TRIM21 expression and intrinsic resistance. Dose response curves are shown for low TRIM21 (Wild type) versus TRIM21 overexpression (TRIM21 OE #1 and TRIM21 OE #2). FIG.8 shows PRLX-93936 cancer cell viability assays (72H, CellTiterGlo) for PANC1 cells with TRIM21 knockout + / - TRIM21 cDNA restoration of expression. A wild- type TRIM21 cDNA is compared with a point mutation expected to reduce TRIM21 activity (R55E). FIG 9A shows induction of luminescent caspase 3 / 7 reporter (CaspaseGlo) following 12 hours of PRLX-93936 treatment of PANC1 cells. Cells with intact TRIM21 expression (Control sgRNA) are compared with TRIM21 knockout (KO) cells. FIG 9B shows immunoblots of PANC1 cells treated with the indicated concentration of PRLX-93936 for 16 hours. Wild-type (WT) cells are compared with TRIM21 knockout (KO) cells. FIG.10 shows differentially expressed genes in PANC1 cells treated with 0.5 uM PRLX-93936 for 2 hours by RNA-seq. FIG.11 shows immunoblots of nuclear and cytoplasmic extracts from PANC1 cells treated with 0.5 uM PRLX-93936 for the indicated timepoints. FIG.12 shows the crystal structure of the TRIM21 PRYSPRY domain bound to JWZ- 8-103; close-up views show key contacts. FIGS.13A-13B show: (FIG.13A) Plasma concentrations of PRLX-93936 and JWZ- 8-103 following a single 3 mg / kg IP injection (n = 3; 8h experiment shown; Error bars: SD); (FIG.13B) Plasma concentrations of PRLX and JWZ-8-103 over 8h, following a single 1 mg / kg intravenous (IV) injection or 6 mg / kg oral (PO) administration (n=3; Error bars - SEM). FIG.14 shows data demonstrating tumor growth in NSG mice injected intraperitoneally (IP) with compound (50 mg / kg PRLX, 15 mg / kg JWZ-8-103, 50 mg / kg JWZ-8-103, or vehicle) daily for 3 weeks. Compound treatments started 21 days after tumor inoculation (n = 9 or 10). Tumor volumes were analyzed by two-way ANOVA, comparing to the vehicle (*** - p < 0.001; **** - p < 0.0001; Error bars - SEM). DETAILED DESCRIPTION As disclosed herein, using CRISPR drug modifier screens and systematic viability profiling, PRLX-93936 was unexpectedly found to act via the Tripartite motif containing-21 (TRIM21) E3 ubiquitin ligase, to simultaneously activate immune signaling and apoptotic pathways. TRIM21 is a RING-family E3 ligase enzyme. E3 ligase enzymes recognize substrate proteins and facilitate conjugation of ubiquitin and poly-ubiquitin chains (Buetow et al. Nat. Rev. Mol. Cell Biol.17, 626–642 (2016)). There is strong precedent for stimulating E3 ligase activities via small molecules for therapeutic benefit. For example, thalidomide derivatives act as molecular glues to stimulate CRBN-mediated ubiquitination and degradation of essential substrates such as IKZF1 (Fischer, E. S. et al. Nature 512, 49–53 (2014)) or CSNK1A1 (Petzold et al. Nature 532, 127–130 (2016)). Heterobifunctional ligase recruiting PROTACs are also being developed to expand available substrates (Jevtić et al. Cell Chem Biol 28, 1000–1013 (2021)). TRIM21 has dual actions: it can simultaneously i) bind and target antibody-conjugated proteins for proteasomal degradation via lysine 48 polyubiquitination (Clift, D. et al. Cell 171, 1692-1706.e18 (2017)), and ii) stimulate immune activation via lysine 63 polyubiquitination (Fletcher et al. Proc. Natl. Acad. Sci. U. S. A.112, 10014–10019 (2015)). By recognizing antibody-bound cargo, TRIM21 is believed to play an important role in pathogen clearance by the immune system (Kiss, L. et al. Nat. Commun.10, 4502 (2019)). Accordingly, disclosed herein are compounds, pharmaceutical compositions, and methods for treating TRIM21-associated cancers. Definitions Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. As used herein, the term “and / or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and / or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and / or C.” For the recitation of numeric ranges herein, each intervening number therebetween with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 1 to 2 carbon atoms (C1-C2 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. As used herein, the term “amido” refers to a group -C(O)NR2, wherein each R is independently selected from hydrogen and alkyl (e.g., C1-C4alkyl). A group -C(O)NH(alkyl) may be referred to herein as “alkylamido” and a group - C(O)N(alkyl)2 may be referred to herein as “dialkylamido.” As used herein, the term “amino” refers to a group -NR2, wherein each R is independently selected from hydrogen and alkyl (e.g., C1-C4 alkyl). A group -NH(alkyl) may be referred to herein as “alkylamino” and a group -N(alkyl)2may be referred to herein as “dialkylamino.” As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl,” e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl,” e.g., anthracenyl and phenanthrenyl). As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I. As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl. As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1- methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6- membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8- azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl). When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof. As used herein, in chemical structures the indication: represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound). For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. When substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from writing the structure from right to left. For example, if a bivalent group is shown as -CH2O-, such indication also encompasses -OCH2-; similarly, -OC(O)NH- also encompasses - NHC(O)O-. When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction. The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition. As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor. A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Compounds Disclosed herein are compounds of formula (I):

[0003] and pharmaceutically acceptable salts thereof, wherein: Q is O or NH; R1is C1-C6alkyl, C3-C6cycloalkyl, or monocyclic heterocyclyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from hydroxy, amino, amido, and cyano; or R1is taken together with R2aand the atoms to which they are attached to form a ring; X1is CH or N; X2is CR2aor N; X3is CR2bor N; X4is CR2cor N; X5is CR2dor N; X6is CR3aor N; X7is CR3bor N; X8is CR3cor N; X9is CR3dor N; R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dare each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NRxRy, -C(O)(C1-C6 alkyl), cyano, aryl, C3-C6 cycloalkyl, heteroaryl, and heterocyclyl; wherein R2aand R2b, or R2band R2c, or R2cand R2dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; and wherein R3aand R3b, or R3band R3c, or R3cand R3dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; Rxand Ryare each independently selected from hydrogen, C1-C6alkyl, and C1-C6hydroxyalkyl; n is 0, 1, or 2; each R4is independently C1-C6alkyl; or two R4, together with the atom(s) to which they are attached, are taken together to form a ring; R5is hydrogen or C1-C4alkyl; and R6aand R6bare each independently selected from hydrogen and C1-C6 alkyl, or R6aand R6bare taken together with the carbon atom to which they are attached to form an optionally substituted ring; and A is a 6- to 8-membered ring; with the proviso that at least one of R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dis not CH, or n is 1 or 2, or X1is CH. In some embodiments, Q is O. In some embodiments, Q is NH. In some embodiments, R1is C1-C3 alkyl, C3-C4 cycloalkyl, or a monocyclic 4- or 5- membered heterocyclyl having one heteroatom selected from N and O, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from -OH, -NH2, -N(CH3)2, and - C(O)NH2. In some embodiments, R1is selected from methyl, ethyl, cyclopropyl, azetidinyl, - CH2CH2NH2, -CH2CH2N(CH3)2, -CH2CH2OH, and -CH2C(O)NH2. In some embodiments, R1is C2-C4alkyl. In some embodiments, R1is ethyl. In some embodiments, R1is n-propyl. In some embodiments, R1is isopropyl. In some embodiments, R1is butyl (e.g., n-butyl, sec- butyl, isobutyl, or tert-butyl). In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, R2ais hydrogen, and one of R2b, R2c, R2dis selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, and -C(O)(C1-C6alkyl), and the other two of R2b, R2c, and R2dare hydrogen. In some embodiments, one of R2b, R2c, R2dis halo, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, or -C(O)(C1-C2alkyl). In some embodiments, one of R2b, R2c, R2dis selected from fluoro, chloro, bromo, methyl, trifluoromethyl, -COOCH3, and ethoxy. In some embodiments, one of R2b, R2c, R2dis fluoro. In some embodiments, one of R2b, R2c, R2dis chloro. In some embodiments, one of R2b, R2c, R2dis bromo. In some embodiments, one of R2b, R2c, R2dis methyl. In some embodiments, one of R2b, R2c, R2dis trifluoromethyl. In some embodiments, one of R2b, R2c, R2dis -COOCH3. In some embodiments, one of R2b, R2c, R2dis ethoxy. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, R2ais hydrogen, and one of R2b, R2c, R2dis selected from is C1-C6 haloalkyl, amino, or -C(O)(C1-C6 alkyl), and the other two of R2b, R2c, and R2dare hydrogen. In some embodiments, one of R2b, R2c, R2dis C1-C2haloalkyl or -C(O)(C1-C2alkyl). In some embodiments, one of R2b, R2c, R2dis selected from trifluoromethyl and -COOCH3. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, and R2a, R2b, R2c, R2dare hydrogen. In some embodiments, X2is CR2a. In some embodiments, R2ais hydrogen or halo. In some embodiments, R2ais hydrogen. In some embodiments, R2ais chloro. In some embodiments, X2is N. In some embodiments, X3is CR2b. In some embodiments, R2bis hydrogen, halo, C1- C3alkyl, C1-C3haloalkyl, -C(O)O(C1-C3alkyl), and a monocyclic 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from O and N. In some embodiments, R2bis hydrogen, chloro, bromo, methyl, trifluoromethyl, -C(O)OCH3, or morpholino. In some embodiments, R2bis hydrogen or halo. In some embodiments, R2bis hydrogen. In some embodiments, R2bis halo. In some embodiments, R2bis chloro. In some embodiments, X4is CR2c. In some embodiments, R2cis hydrogen, halo, C1- C3 haloalkyl, C1-C3 alkoxy, -NRxRy, or cyano, wherein Rxis hydrogen and Ryis C1-C3 hydroxyalkyl. In some embodiments, R2cis hydrogen, fluoro, chloro, bromo, trifluoromethyl, ethoxy, -NHCH2CH2OH, or cyano. In some embodiments, R2cis hydrogen. In some embodiments, X4is N. In some embodiments, X3is CR2b, X4is CR2c, and R2band R2care taken together with the carbon atoms to which they are attached to a 5- or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O. In some embodiments, X5is CR2d. In some embodiments, R2dis hydrogen or halo. In some embodiments, R2dis hydrogen. In some embodiments, R2dis halo. In some embodiments, R2dis bromo. In some embodiments, X5is N. In some embodiments, the group has a structure selected from:

[0004] In some embodiments, X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from halo, C1-C6 alkyl, C1-C6 alkoxy, and amino, and the other three of R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis halo, C1-C2 alkyl, or C1-C2 alkoxy. In some embodiments, one of R3a, R3b, R3c, and R3dis fluoro, chloro, bromo, iodo, methyl, or methoxy. In some embodiments, X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from C1-C6alkyl, C1-C6alkoxy, and amino, and the other three of R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis C1-C2 alkyl or C1-C2 alkoxy. In some embodiments, one of R3a, R3b, R3c, and R3dis methyl or methoxy. In some embodiments, each of R3a, R3b, R3c, and R3dis hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis fluoro. In some embodiments, one of R3a, R3b, R3c, and R3dis chloro. In some embodiments, one of R3a, R3b, R3c, and R3dis bromo. In some embodiments, one of R3a, R3b, R3c, and R3dis iodo. In some embodiments, one of R3a, R3b, R3c, and R3dis methyl. In some embodiments, one of R3a, R3b, R3c, and R3dis methoxy. In some embodiments, X6is CR3aand R3ais hydrogen. In some embodiments, X6is N. In some embodiments, X7is CR3b. In some embodiments, R3bis selected from hydrogen, halo, C1-C3alkyl, cyano, phenyl, and monocyclic 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R3bis selected from hydrogen, fluoro, chloro, iodo, methyl, cyano, phenyl, and pyridyl. In some embodiments, R3bis halo. In some embodiments, R3bis fluoro. In some embodiments, X8is CR3c. In some embodiments, R3cis selected from hydrogen, halo, C1-C3alkoxy, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3cis selected from hydrogen, chloro, bromo, methoxy, and -NH2. In some embodiments, R3cis hydrogen. In some embodiments, X8is N. In some embodiments, X9is CR3d. In some embodiments, R3dis selected from hydrogen, halo, C1-C3 alkyl, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3dis selected from hydrogen, chloro, methyl, and -NH2. In some embodiments, R3dis hydrogen. In some embodiments, X9is N. In some embodiments, A is a six-membered ring. In some embodiments, A is a piperazine ring. In some embodiments, n is 0. In some embodiments, n is 2, and wherein the two R4are taken together with the atom(s) to which they are attached to form a ring. In some embodiments, R5is hydrogen. In some embodiments, R6aand R6bare each hydrogen. In some embodiments, R6ais hydrogen and R6bis methyl. In some embodiments, R6aand R6bare taken together with the carbon atom to which they are attached to form a C3-C4cycloalkyl ring. In some embodiments, compound of formula (I) has a structure selected from:

[0005] Also disclosed herein are compounds of formula (II): and pharmaceutically acceptable salts thereof, wherein: Q is O or NH; R1is C1-C6alkyl, C3-C6cycloalkyl, or monocyclic heterocyclyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from hydroxy, amino, amido, and cyano; or R1is taken together with R2aand the atoms to which they are attached to form a ring; X1is CH or N; X2is CR2aor N; R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dare each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NRxRy, -C(O)(C1-C6 alkyl), cyano, aryl, C3-C6cycloalkyl, heteroaryl, and heterocyclyl; wherein R2aand R2b, or R2band R2c, or R2cand R2dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; and wherein R3aand R3b, or R3band R3c, or R3cand R3dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; Rxand Ryare each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl; n is 0, 1, or 2; each R4is independently C1-C6 alkyl; or two R4, together with the atom(s) to which they are attached, are taken together to form a ring; R5is hydrogen or C1-C4 alkyl; R6aand R6bare each independently selected from hydrogen and C1-C6alkyl, or R6aand R6bare taken together with the carbon atom to which they are attached to form an optionally substituted ring; and A is a 6- to 8-membered ring. In some embodiments, R1is C1-C3alkyl, C3-C4cycloalkyl, or a monocyclic 4- or 5- membered heterocyclyl having one heteroatom selected from N and O, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from -OH, -NH2, -N(CH3)2, and - C(O)NH2. In some embodiments, R1is selected from methyl, ethyl, cyclopropyl, azetidinyl, - CH2CH2NH2, -CH2CH2N(CH3)2, -CH2CH2OH, and -CH2C(O)NH2. In some embodiments, R1is C2-C4alkyl. In some embodiments, R1is ethyl. In some embodiments, R1is n-propyl. In some embodiments, R1is isopropyl. In some embodiments, R1is butyl (e.g., n-butyl, sec- butyl, isobutyl, or tert-butyl). In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments, X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, one of R2a, R2b, R2c, and R2dis selected from hydrogen, halo, C1-C2alkyl, C1-C2haloalkyl, C1-C2alkoxy, or - C(O)(C1-C2 alkyl), and the other three of R2a, R2b, R2c, and R2dare hydrogen.. In some embodiments, one of R2a, R2b, R2c, and R2dis selected from hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl, -COOCH3, and ethoxy. In some embodiments, R2a, R2b, R2c, and R2dare each hydrogen. In some embodiments, one of R2a, R2b, R2c, and R2dis fluoro. In some embodiments, one of R2a, R2b, R2c, and R2dis chloro. In some embodiments, one of R2a, R2b, R2c, and R2dis bromo. In some embodiments, one of R2a, R2b, R2c, and R2dis methyl. In some embodiments, one of R2a, R2b, R2c, and R2dis trifluoromethyl. In some embodiments, one of R2a, R2b, R2c, and R2dis -COOCH3. In some embodiments, one of R2a, R2b, R2c, and R2dis ethoxy. In some embodiments, the group has a structure selected from: In some em one o3a 3b f R , R , R3c, and R3dis selected from hydrogen, halo, C1-C2 alkyl, and C1-C2 alkoxy, and the other three of R3a, R3b, R3c, and R3dare hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, or methoxy. In some embodiments, R3a, R3b, R3c, and R3dare each hydrogen. In some embodiments, one of R3a, R3b, R3c, and R3dis fluoro. In some embodiments, one of R3a, R3b, R3c, and R3dis chloro. In some embodiments, one of R3a, R3b, R3c, and R3dis bromo. In some embodiments, one of R3a, R3b, R3c, and R3dis iodo. In some embodiments, one of R3a, R3b, R3c, and R3dis methyl. In some embodiments, one of R3a, R3b, R3c, and R3dis methoxy. In some embodiments, X7is CR3b. In some embodiments, R3bis selected from hydrogen, halo, C1-C3 alkyl, cyano, phenyl, and monocyclic 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, R3bis selected from hydrogen, fluoro, chloro, iodo, methyl, cyano, phenyl, and pyridyl. In some embodiments, R3bis halo. In some embodiments, R3bis fluoro. In some embodiments, X8is CR3c. In some embodiments, R3cis selected from hydrogen, halo, C1-C3 alkoxy, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3cis selected from hydrogen, chloro, bromo, methoxy, and -NH2. In some embodiments, R3cis hydrogen. In some embodiments, X8is N. In some embodiments, X9is CR3d. In some embodiments, R3dis selected from hydrogen, halo, C1-C3alkyl, and -NRxRy, wherein Rxand Ryare each hydrogen. In some embodiments, R3dis selected from hydrogen, chloro, methyl, and -NH2. In some embodiments, R3dis hydrogen. In some embodiments, X9is N. In some embodiments, A is a six-membered ring. In some embodiments, A is a piperazine ring. In some embodiments, n is 0. In some embodiments, n is 2, and wherein the two R4are taken together with the atom(s) to which they are attached to form a ring. I In some embodiments, the group . In some embodiments, R5is hydrogen. In some embodiments, A is a six-membered ring (e.g., a piperazine ring), n is 0, and R5is N. In some embodiments, R6aand R6bare each hydrogen. In some embodiments, R6ais hydrogen and R6bis methyl. In some embodiments, R6aand R6bare taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkyl ring. In some embodiments, the compound of formula (II) has a structure selected from:

[0006] pharmaceutically acceptable salts thereof. Certain compounds described herein may have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers, in mixtures and as pure or partially purified compounds, are included within the scope of this disclosure. The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. Compounds may also possess tautomeric forms, and all tautomers also constitute embodiments of the disclosure. Compounds described herein may also exhibit atropisomerism. Atropisomers are conformers that arise from restricted rotation about a single bond, and individual atropisomers can be isolated as separate chemical species. Examples of compounds exhibiting atropisomerism are ortho-substituted biphenyl and 1,1,2,2-tetra-tert-butylethane. Compounds disclosed herein may exhibit atropisomerism about the single bond marked with an asterisk in the depiction of formula (I) below. When a compound disclosed herein is shown without identifying the specific atropisomer, both atropisomers are included. Certain exemplary compounds described herein have been separated into their individual atropisomers, and in some embodiments, one atropisomer may have increased potency compared to the other. All atropisomers and mixtures thereof are within the scope of this disclosure.

[0007] The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I) or formula (II), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) or formula (II) are11C,13N,15O, and18F. Isotopically-labeled compounds of formula (I) or formula (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent. Compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. a. Methods of Synthesis Compounds disclosed herein can be prepared by a variety of methods, including those illustrated in the Examples. Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006). When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution). Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation. The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated. b. Pharmaceutically Acceptable Salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compound with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. Amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like. Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Pharmaceutical Compositions The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non- human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease or condition, the prophylactically effective amount will be less than the therapeutically effective amount. The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage. The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions. Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90% by weight of the composition. Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition. Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition. Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition. Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by weight of the composition. Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the composition. Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition. Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5% by weight of the composition. Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition. Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by weight of the composition. Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition. Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed.1975, pp.335-337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5% by weight of the composition. Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent. Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5% by weight, and more particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of carriers, and more particularly, from about 50% to about 75% by weight. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I) or a compound of formula (II)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type. The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure. Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac. Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners. Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants. The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I) or a compound of formula (II)), or a pharmaceutically acceptable salt thereof), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components. The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976). A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols. The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition. The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition. The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition. Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. Methods of Use The compounds disclosed herein have TRIM21-dependent anticancer activity. Accordingly, the compounds and pharmaceutical compositions disclosed herein can be used for treatment of proliferative diseases such as cancer, including TRIM21-dependent cancers. Accordingly, in some embodiments, the disclosure provides a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof). In some embodiments, the proliferative disease is associated with TRIM21. In some embodiments, the proliferative disease is associated with a mutation in and / or increased activity of TRIM21, e.g., due to increased expression of TRIM21. In some embodiments, the proliferative disease is cancer (e.g., a TRIM21-associated cancer). In some embodiments, the cancer is pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, multiple myeloma, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, leukemia, lymphoma, prostate cancer, and sarcoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the disclosed methods comprise detecting and / or quantifying the amount of TRIM21 in a sample obtained from the subject, and administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, based on the presence or amount of TRIM21 detected and / or quantified in the sample. In some embodiments, the methods comprise comparing the amount of TRIM21 to a reference level and identifying the subject as having a TRIM21-associated cancer when the amount of TRIM21 is greater than or equal to the reference level. “Reference level” as used herein refers to a value that is used to assess diagnostic, prognostic, or therapeutic efficacy and that has been linked or is associated herein with various clinical parameters (e.g., TRIM21-associated cancer). It is well-known that reference levels may vary depending on the nature of the assay used to determine the concentration, level, or amount of the analyte (e.g., antibodies employed, reaction conditions, sample purity, etc.) and that assays can be compared and standardized. It further is well within the ordinary skill of one in the art to adapt the disclosure herein for other assays to obtain assay-specific reference levels for those other assays based on the description provided by this disclosure. Whereas the precise value of the reference level may vary between assays, the findings as described herein should be generally applicable and capable of being extrapolated to other assays. The reference level may be based on positive controls from individuals identified as having a TRIM21-associated cancer. Alternatively, the reference level may be based on negative controls from a healthy subject (e.g., a subject not diagnosed with TRIM21- associated cancer). In some embodiments, the reference level is the reference level of TRIM21 in a sample or compiled samples from a subject(s) known to be afflicted with TRIM21-associated cancer. For example, a reference value may be based on the lowest value for the level of TRIM21 in known subjects with TRIM21-associated cancer, such that values for the level of TRIM21 equal to or higher than that value are indicative of TRIM21-associated cancer. Alternatively, in some embodiments, the reference level is the reference level of TRIM 21 in a sample or compiled samples from a subject(s) known to not have TRIM21-associated cancer. For example, a reference value may be based on the highest value for the level of TRIM21 in known subjects without a TRIM21-associated cancer (e.g., healthy subjects or subjects with cancer not associated with TRIM21), such that values for the leave of TRIM21 higher than that value are indicative of TRIM21-associated cancer. The “sample” broadly refers to any material, biological fluid, tissue, or cell obtained or otherwise derived from a subject. This includes blood and blood products (including whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, and serum), mucosal biopsy tissue and brushed cells, sputum, tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, lymph fluid, nipple aspirate, bronchial aspirate (e.g., bronchoalveolar lavage), bronchial brushing, synovial fluid, joint aspirate, organ secretions, cells, a cellular extract, and cerebrospinal fluid. This also includes experimentally separated fractions of all of the foregoing. For example, a blood sample can be fractionated into serum, plasma, or into fractions containing particular types of blood cells, such as red blood cells or white blood cells (leukocytes). In some embodiments, a sample can be a combination of samples from an individual, such as a combination of a tissue and fluid sample. The term “sample” also includes materials containing homogenized solid material, such as from a stool sample, a tissue sample, or a tissue biopsy, for example. In some embodiments, the biological sample may comprise tumor tissue, suspected tumor tissue, or lymph node tissue. Any suitable methods for obtaining a biological sample can be employed; exemplary methods include, e.g., phlebotomy, swab (e.g., buccal swab), and a fine needle aspirate biopsy procedure. Exemplary tissues susceptible to fine needle aspiration include lymph node, lung, lung washes, BAL (bronchoalveolar lavage), thyroid, breast, pancreas, and liver. Samples can also be collected, e.g., by micro dissection (e.g., laser capture micro dissection (LCM) or laser micro dissection (LMD)), bladder wash, smear (e.g., a PAP smear), or ductal lavage. In some embodiments, the methods further comprise obtaining the sample(s) from the subject. The sample(s) can be obtained using techniques known to those skilled in the art, and the sample(s) may be used directly as obtained from the source or following a pretreatment to modify the character of the sample. Such pretreatment may include, for example, preparing plasma from blood, diluting viscous fluids, filtration, precipitation, dilution, distillation, mixing, concentration, inactivation of interfering components, the addition of reagents, lysing, and the like. It will be appreciated that obtaining a sample from a subject may comprise extracting the sample directly from the subject or receiving the biological sample from a third party. The sample(s) may be obtained in a medical facility, e.g., at an Emergency Room, urgent care clinic, walk-in clinic, a long term care facility, or another appropriate site of medical practice. The sample(s) may be obtained in a home or residential setting (e.g., a senior living or hospice setting), at the site of the suspected myocardial infarction, or during transportation to a medical facility (e.g., ambulance). The present disclosure is not limited by the type of assay used to detect and / or quantify the level of TRIM21. The nature of methods and the test can be any assay known in the art such as, for example, immunoassays, point-of-care assays, clinical chemistry assay, protein immunoprecipitation, immunoelectrophoresis, chemical analysis, SDS-PAGE and Western blot analysis, or protein immunostaining, a protein assay, a competitive binding assay, a lateral flow assay, a functional protein assay, or chromatography or spectrometry methods, such as high-performance liquid chromatography (HPLC) or liquid chromatography–mass spectrometry (LC / MS). Also, the assay can be employed in a clinical chemistry format such as would be known by one of ordinary skill in the art. i. Dosages It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. ii. Combination Therapies A compound or composition described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. A compound or composition described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the compound described herein can be administered first, and the additional agent can be administered subsequently, or the order of administration can be reversed. In some embodiments, a compound or composition described herein is administered in combination with at least one of chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy, or any combination thereof. In some embodiments a compound or composition described herein is administered in combination with two or more of chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy. For example, in some embodiments, a compound or composition described herein is administered in combination with an immunotherapy, such as an immune checkpoint inhibitor. In some embodiments, a compound or composition described herein is administered in combination with a T cell transfer therapy, such as CAR T-cell therapy. In some embodiments, a compound or composition described herein is used in combination with chemotherapy. In some embodiments, a compound or composition described herein is used in combination with a chemotherapeutic agent identified on the “A to Z List of Cancer Drugs” published by the National Cancer Institute. Kits For use in the therapeutic applications described herein, kits and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical comosition comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof ). In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic. The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein. For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Examples Abbreviations used in the Examples include the following: DCM is dichloromethane; DMEM is Dulbecco's Modified Eagle Medium; DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; ESI is electrospray ionization; FBS is fetal bovine serum; HPLC is high performance liquid chromatography; LC-MS is liquid chromatography mass spectrometry; MeCN is acetonitrile; rt is room temperature; and TFA is trifluoroacetic acid. Example 1 Compound Syntheses Synthesis of tert-butyl 4-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-4,7- diazaspiro[2.5]octane-7-carboxylate (JWZ-8-27) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (200 mg, 1.0 eq) was dissolved in 5 mL of acetonitrile and 2-ethoxybenzeneamine (210 mg,1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (281 mg, 2.0 eq) was added dropwise. The resulting slurry was heated at 50 °C for 6 hours. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (254 mg, 79%). Step 2: 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(13mg, 2.0 eq), 4,7-Diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester (15mg, 1.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)-4,7-diazaspiro[2.5]octane-7-carboxylate (13 mg, 56%). Step 3: To tert-butyl 4-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)-4,7-diazaspiro[2.5]octane-7-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-27 (8 mg). LC-MS (ESI) m / z : [M+H]+: 391.25. Synthesis of 2-((4,7-diazaspiro[2.5]octan-7-yl)methyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)- one (JWZ-8-28) Step 1: 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(13mg, 2.0 eq), 4,7-Diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (13mg, 1.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 7-((3-(2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (15 mg, 56%). Step 2: To tert-butyl 7-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (15 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-28 (10 mg). LC-MS (ESI) m / z : [M+H]+: 391.20. Synthesis of 3-(2-ethoxyphenyl)-2-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one (JWZ-8-18) 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(13mg, 2.0 eq), 1- Methyl piperazine (7 mg, 1.5 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give 3-(2-ethoxyphenyl)-2-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one (11 mg, 61%). LC-MS (ESI) m / z : [M+H]+: 379.20. Synthesis of 2-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-(2- ethoxyphenyl)quinazolin-4(3H)-one (JWZ-8-29) Step 1: 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (13mg, 2.0 eq), 3,8-Diaza-bicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (15mg, 1.5 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl (1R,5S)-8-((3-(2- ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (13 mg, 56%). Step 2: To tert-butyl (1R,5S)-8-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-29 (9 mg). LC-MS (ESI) m / z : [M+H]+: 391.15. Synthesis of tert-butyl 5-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-2,5- d Step 1: 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (13mg, 2.0 eq), 2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid, 1,1-dimethylethyl ester (9.4 mg, 1.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 5-((3-(2- ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (9 mg, 40%). Step 2: To tert-butyl 5-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (9 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-30 (5 mg). LC-MS (ESI) m / z : [M+H]+: 377.15. Synthesis of 2-((3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)-3-(2-ethoxyphenyl)quinazolin- 4(3H)-one (JWZ-8-31) Step 1: 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(13mg, 2.0 eq), 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (9.4mg, 1.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 3-((3-(2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (12 mg, 53%). Step 2: To tert-butyl 3-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (12 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-31 (7 mg). LC-MS (ESI) m / z : [M+H]+: 377.20. Synthesis of 2-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-3-(2- e Step 1: 2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (13mg, 2.0 eq), 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (15mg, 1.5 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl (1R,5S)-3-((3-(2- ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (8 mg, 30%). Step 2: To tert-butyl (1R,5S)-3-((3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-32 (4 mg). LC-MS (ESI) m / z : [M+H]+: 391.20. S Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (50 mg, 1.0 eq) was dissolved in 5 mL of acetonitrile and (2-butoxyphenyl)amine (42 mg,1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (70 mg, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C for 6 hours. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (20% EtOAc / hexane) to give 3-(2-butoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (63 mg, 72%). Step 2: 3-(2-butoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (15mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(13mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (16mg, 2.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-butoxyphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (14 mg, 65%). Step 3: To tert-butyl 4-((3-(2-butoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (14 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-38 (10 mg). LC-MS (ESI) m / z : [M+H]+: 393.20. Synthesis of 3-(2-ethoxypyridin-3-yl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8- 39) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (50 mg, 1.0 eq) was dissolved in 5 mL of acetonitrile and 2-ethoxypyridin-3-amine (35 mg,1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (70 mg, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C for 6 hours. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxypyridin-3-yl)quinazolin-4(3H)-one (14 mg, 17 %). Step 2: 2-(chloromethyl)-3-(2-ethoxypyridin-3-yl)quinazolin-4(3H)-one (10 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (13mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (12 mg, 2.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-ethoxypyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (7 mg, 50 %). Step 3: To tert-butyl 4-((3-(2-ethoxypyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (7 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-39 (5 mg). LC-MS (ESI) m / z : [M+H]+: 366.20. Synthesis of 3-(4-bromo-2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-47) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (80 mg, 1.0 eq) was dissolved in 5 mL of acetonitrile and 4-Bromo-2-ethoxyaniline (88 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (0.11g, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 3-(4-bromo-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (140 mg, 87 %). Step 2: 3-(4-bromo-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (20 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (13mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (12 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(4-bromo-2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (16 mg, 58 %). Step 3: To tert-butyl 4-((3-(4-bromo-2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (10 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-47 (7 mg). LC-MS (ESI) m / z : [M+H]+: 443.05 and 445.10. Synthesis of methyl 3-isopropoxy-4-(4-oxo-2-(piperazin-1-ylmethyl)quinazolin-3(4H)- Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one ( 30 mg, 1.0 eq) was dissolved in 5 mL of acetonitrile and methyl 4-amino-3-isopropoxybenzoate (32 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(42 mg, 2.0 eq) was added dropwise. The resulting mixture was heated at 50° C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solid was purified by flash column chromatography (5%EtOAc / hexane) to give methyl 4-(2-(chloromethyl)-4-oxoquinazolin-3(4H)-yl)-3- isopropoxybenzoate ( 34 mg, 57 %). Step 2: Methyl 4-(2-(chloromethyl)-4-oxoquinazolin-3(4H)-yl)-3-isopropoxybenzoate (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (12mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (10 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80° C for 1h. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-isopropoxy-4-(methoxycarbonyl)phenyl)-4-oxo- 3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (14 mg, 67 %). Step 3: To tert-butyl 4-((3-(2-isopropoxy-4-(methoxycarbonyl)phenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate ( 14 mg) was added a solution of DCM / Trifluoroacetic acid ( 3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-48 ( 9 mg). LC-MS (ESI) m / z : [M+H]+: 437.25. Synthesis of 3-(2,5-diethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8- 49) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 5 mL of acetonitrile and 2,5-diethoxy aniline (28 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (42 mg, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2,5-diethoxyphenyl)quinazolin-4(3H)-one (29 mg, 53 %). Step 2: 2-(chloromethyl)-3-(2,5-diethoxyphenyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (12mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (10 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2,5-diethoxyphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (12 mg, 56 %). Step 3: To tert-butyl 4-((3-(2,5-diethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (12 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-49 (8 mg). LC-MS (ESI) m / z : [M+H]+: 409.25. Synthesis of 3-(5-bromo-2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-50) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (80 mg, 1.0 eq) was dissolved in 3 mL of acetonitrile and 5-bromo-2-ethoxyaniline (88 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (110 mg, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 3-(5-bromo-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (94 mg, 58 %). Step 2: 3-(5-bromo-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (20 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (14mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (12 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(5-bromo-2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (12 mg, 43 %). Step 3: tert-butyl 4-((3-(5-bromo-2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (12 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-50 (7 mg). LC-MS (ESI) m / z : [M+H]+: 443.10 and 445.10. Synthesis of 3-(2-ethoxyphenyl)-6-iodo-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ- 8-55) Step 1: To a solution of 2-Amino-5-iodobenzoicacid (200 mg, 1 eq) and Et3N(138 uL, 1.3 eq) in DCM (5 mL) at 0 °C was added chloracetyl chloride dropwise (67 uL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-6-iodo- 4H-benzo[d][1,3]oxazin-4-one (106 mg, 44%). Step 2: 2-(chloromethyl)-6-iodo-4H-benzo[d][1,3]oxazin-4-one (70mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (45mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(38 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 4 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (20% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)-6- iodoquinazolin-4(3H)-one (58 mg, 60%). Step 3: 2-(chloromethyl)-3-(2-ethoxyphenyl)-6-iodoquinazolin-4(3H)-one (30 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3 (19mg, 2.0 eq), Boc-piperazine (25 mg, 2.0 eq) and NaI (3 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-6-iodo-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (23 mg, 57%). Step 4: To intermediate 3-(2-ethoxyphenyl)-6-iodo-2-(piperazin-1- ylmethyl)quinazolin-4(3H)-one (10 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-55 (6 mg). LC-MS (ESI) m / z : [M+H]+: 491.10. Synthesis of 3-(2-ethoxyphenyl)-7-iodo-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ- 8-56) Step 1: To a solution of 2-amino-4-iodobenzoic acid (200 mg, 1 eq) and Et3N(138 uL, 1.3 eq) in DCM (5 mL) at 0 °C was added Chloracetyl chloride dropwise (67 uL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-7-iodo- 4H-benzo[d][1,3]oxazin-4-one (97 mg, 40%). Step 2: 2-(chloromethyl)-7-iodo-4H-benzo[d][1,3]oxazin-4-one (50mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (32mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (27 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 4 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)-7- iodoquinazolin-4(3H)-one (44 mg, 64%). Step 3: 2-(chloromethyl)-3-(2-ethoxyphenyl)-7-iodoquinazolin-4(3H)-one (30 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3(19mg, 2.0 eq), Boc-piperazine (25 mg, 2.0 eq) and NaI (3 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-7-iodo-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (35 mg, 87%). Step 4: To tert-butyl 4-((3-(2-ethoxyphenyl)-7-iodo-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (10 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-56 (6 mg). LC-MS (ESI) m / z : [M+H]+: 491.05. Synthesis of 3-(2-ethoxy-4-methylphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-73) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 2-ethoxy-4-methylphenylamine (23 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxy-4-methylphenyl)quinazolin-4(3H)-one (37 mg, 73 %). Step 2: 2-(chloromethyl)-3-(2-ethoxy-4-methylphenyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(14mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (17 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-ethoxy-4-methylphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (16 mg, 73 %). Step 3: tert-butyl 4-((3-(2-ethoxy-4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (16 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-73 (7 mg). LC-MS (ESI) m / z : [M+H]+: 379.20. Synthesis of 3-(2-ethoxy-5-fluorophenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-74) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 2-ethoxy-5-fluoroaniline (24 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxy-5-fluorophenyl)quinazolin-4(3H)-one (42 mg, 82 %). Step 2: 2-(chloromethyl)-3-(2-ethoxy-5-fluorophenyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(12 mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (17 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-ethoxy-5-fluorophenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (13 mg, 60 %). Step 3: tert-butyl 4-((3-(2-ethoxy-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-74 (7 mg). LC-MS (ESI) m / z : [M+H]+: 383.20. Synthesis of 3-(3-chloro-2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-75) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 3-chloro-2-ethoxyaniline (26 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (20% EtOAc / hexane) to give 3-(3-chloro-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (39 mg, 73 %). Step 2: 3-(3-chloro-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (12 mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (16 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(3-chloro-2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (14 mg, 65 %). Step 3: tert-butyl 4-((3-(2-ethoxy-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-75 (7 mg). LC-MS (ESI) m / z : [M+H]+: 399.25. Synthesis of 3-(4-chloro-2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-76) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 4-Chloro-2-ethoxyaniline (26 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 3-(4-chloro-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (35 mg, 65 %). Step 2: 3-(4-chloro-2-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (12 mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (16 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(4-chloro-2-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (9 mg, 40 %). Step 3: tert-butyl 4-((3-(4-chloro-2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (9 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-76 (6 mg). LC-MS (ESI) m / z : [M+H]+: 399.25. Synthesis of 3-(2-ethoxy-4-fluorophenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-77) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 2-ethoxy-4-fluoroaniline (24 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxy-4-fluorophenyl)quinazolin-4(3H)-one (38 mg, 74 %). Step 2: 2-(chloromethyl)-3-(2-ethoxy-4-fluorophenyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3(12 mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (16 mg, 1.3 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-ethoxy-4-fluorophenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (15 mg, 69 %). Step 3: tert-butyl 4-((3-(2-ethoxy-4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (15 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-77 (11 mg). LC-MS (ESI) m / z : [M+H]+: 383.20. Synthesis of 3-(2-ethoxy-4-fluorophenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-78) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 2-ethoxy-5-(trifluoromethyl)aniline (31 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxy-5-(trifluoromethyl)phenyl)quinazolin- 4(3H)-one (43 mg, 73 %). Step 2: 2-(chloromethyl)-3-(2-ethoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)- one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (12 mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (15 mg, 2.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x 5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-ethoxy-5- (trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (13 mg, 62 %). Step 3: tert-butyl 4-((3-(2-ethoxy-5-(trifluoromethyl)phenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-78 (8 mg). LC-MS (ESI) m / z : [M+H]+: 433.30.

[0008] Synthesis of 3-(2-bromo-6-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-79) Step 1: 2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (30 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 2-Bromo-6-ethoxyaniline (33 mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (27uL, 2.0 eq) was added dropwise. The resulting mixture was heated at 50 °C overnight. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine. The solution was concentrated, and the resulting solids was purified by flash column chromatography (20% EtOAc / hexane) to give 3-(2-bromo-6-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (46 mg, 76 %). Step 2: 3-(2-bromo-6-ethoxyphenyl)-2-(chloromethyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of acetonitrile, and to this solution was added K2CO3 (12 mg, 2.0 eq), tert-butyl piperazine-1-carboxylate (15 mg, 2.0 eq) and NaI (2mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed under reduced pressure and added H2O (5 mL) extracted with EtOAc (3x5 mL). The combined organic layers was removed under reduced pressure and the resulting solids was purified by HPLC to give tert-butyl 4-((3-(2-bromo-6-ethoxyphenyl)-4- oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (13 mg, 63 %). Step 3: tert-butyl 4-((3-(2-bromo-6-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-79 (8 mg). LC-MS (ESI) m / z : [M+H]+: 392.80 and 394.80. Synthesis of 3-(2-ethoxyphenyl)-7-methoxy-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-92) Step 1:To a solution of 2-Amino-4-methoxybenzoicacid (100 mg, 1 eq) and Et3N(108 uL, 1.3 eq) in DCM (3 mL) at 0 °C was added Chloracetyl chloride dropwise (53 uL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-7- methoxy-4H-benzo[d][1,3]oxazin-4-one (89 mg, 66%). Step 2: 2-(chloromethyl)-7-methoxy-4H-benzo[d][1,3]oxazin-4-one (50mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (46mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(40 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)-7- methoxyquinazolin-4(3H)-one (38 mg, 50%). Step 3: 2-(chloromethyl)-3-(2-ethoxyphenyl)-7-methoxyquinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3 (12mg, 2.0 eq), Boc-piperazine (16 mg, 2.0 eq) and NaI (4.9 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-7-methoxy-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (17 mg, 79%). Step 4: To tert-butyl 4-((3-(2-ethoxyphenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin- 2-yl)methyl)piperazine-1-carboxylate (10 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-92 (7 mg). LC-MS (ESI) m / z : [M+H]+: 395.25. Synthesis of 6-chloro-3-(2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-93)C Step 1: To a solution of 2-Amino-5-Chlorobenzoicacid (100 mg, 1 eq) and Et3N (106 uL, 1.3 eq) in DCM (3 mL) at 0 °C was added Chloracetyl chloride dropwise (51 uL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 6-chloro-2- (chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (101 mg, 75%). Step 2: 2-(chloromethyl)-7-methoxy-4H-benzo[d][1,3]oxazin-4-one (50mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (45mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(40 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 6-chloro-2-(chloromethyl)-3-(2- ethoxyphenyl)quinazolin-4(3H)-one (42 mg, 55%). Step 3: 6-chloro-2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (20 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3(12mg, 2.0 eq), Boc-piperazine (21 mg, 2.0 eq) and NaI (2.6 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((6-chloro-3-(2-ethoxyphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (18 mg, 63%). Step 4: To tert-butyl 4-((6-chloro-3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (12 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-93 (8 mg). LC-MS (ESI) m / z : [M+H]+: 399.20. Synthesis of 7-bromo-3-(2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-94) Step 1: To a solution of 2-Amino-4-bromo benzoic acid (100 mg, 1 eq) and Et3N(84 uL, 1.3 eq) in DCM (3 mL) at 0 °C was added Chloracetyl chloride dropwise (40 uL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 7-bromo-2- (chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (83 mg, 65%). Step 2: 7-bromo-2-(chloromethyl)-4H-benzo[d][1,3]oxazin-4-one (50mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (37mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (32 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 7-bromo-2-(chloromethyl)-3-(2- ethoxyphenyl)quinazolin-4(3H)-one (26 mg, 36%). Step 3: 7-bromo-2-(chloromethyl)-3-(2-ethoxyphenyl)quinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3(11mg, 2.0 eq), Boc-piperazine (14 mg, 2.0 eq) and NaI (1.7 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((7-bromo-3-(2-ethoxyphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (11 mg, 53%). Step 4: To tert-butyl 4-((7-bromo-3-(2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (11 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-94 (7 mg). LC-MS (ESI) m / z : [M+H]+: 443.15 and 445.15. Synthesis of 3-(2-ethoxyphenyl)-8-methyl-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-95) Step 1: To a solution of 3-Methyl-2-aminobenzoic acid (100 mg, 1 eq) and Et3N(120 uL, 1.3 eq) in DCM (2 mL) at 0 °C was added Chloracetyl chloride dropwise (58 uL, 1.1 eq). The reaction was then stirred at room temperature overnight. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-8- methyl-4H-benzo[d][1,3]oxazin-4-one (49 mg, 35%). Step 2: 2-(chloromethyl)-8-methyl-4H-benzo[d][1,3]oxazin-4-one (40mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (39mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (33 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)-8- methylquinazolin-4(3H)-one (47 mg, 75%). Step 3:2-(chloromethyl)-3-(2-ethoxyphenyl)-8-methylquinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3 (11mg, 2.0 eq), Boc-piperazine (17 mg, 2.0 eq) and NaI (2.1 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-8-methyl-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (9 mg, 40%). Step 4: To tert-butyl 4-((3-(2-ethoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin- 2-yl)methyl)piperazine-1-carboxylate (9 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-95 (5 mg). LC-MS (ESI) m / z : [M+H]+: 379.25. Synthesis of 3-(2-ethoxyphenyl)-6-fluoro-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-96) Step 1: To a solution of 2-Amino-5-fluorobenzoicacid (1.0g, 1 eq) and Et3N(1.17 mL, 1.3 eq) in DCM (10 mL) at 0 °C was added Chloracetyl chloride dropwise (0.54 mL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-6- fluoro-4H-benzo[d][1,3]oxazin-4-one (1.03g, 74%). Step 2: 2-(chloromethyl)-6-fluoro-4H-benzo[d][1,3]oxazin-4-one (60mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (58mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3(49 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)-6- fluoroquinazolin-4(3H)-one (45 mg, 48%). Step 3: 2-(chloromethyl)-3-(2-ethoxyphenyl)-6-fluoroquinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3 (11mg, 2.0 eq), Boc-piperazine (17 mg, 2.0 eq) and NaI (2.0 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-6-fluoro-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (14 mg, 64%). Step 4: To tert-butyl 4-((3-(2-ethoxyphenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (14 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-96 (9 mg). LC-MS (ESI) m / z : [M+H]+: 383.25.

[0009] Synthesis of 3-(2-ethoxyphenyl)-8-methoxy-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (JWZ-8-97) Step 1: To a solution of 2-amino-3-methoxybenzoic acid (112 mg, 1 eq) and Et3N(121 uL, 1.3 eq) in DCM (3 mL) at 0 °C was added Chloracetyl chloride dropwise (59 uL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-8- methoxy-4H-benzo[d][1,3]oxazin-4-one (57 mg, 38%). Step 2: 2-(chloromethyl)-8-methoxy-4H-benzo[d][1,3]oxazin-4-one (50mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and o-Phenetidine (46mg, 1.5 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (39 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (5% EtOAc / hexane) to give 2-(chloromethyl)-3-(2-ethoxyphenyl)-8- methoxyquinazolin-4(3H)-one (53 mg, 69%). Step 3: 2-(chloromethyl)-3-(2-ethoxyphenyl)-8-methoxyquinazolin-4(3H)-one (15 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3 (11mg, 2.0 eq), Boc-piperazine (16 mg, 2.0 eq) and NaI (2.0 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(2-ethoxyphenyl)-8-methoxy-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (13 mg, 60%). Step 4: To tert-butyl 4-((3-(2-ethoxyphenyl)-8-methoxy-4-oxo-3,4-dihydroquinazolin- 2-yl)methyl)piperazine-1-carboxylate (13 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-97 (8 mg). LC-MS (ESI) m / z : [M+H]+: 395.20. Synthesis of 3-(4-chloro-2-ethoxyphenyl)-6-fluoro-2-(piperazin-1-ylmethyl)quinazolin-4(3H)- one (JWZ-8-103) Step 1: To a solution of 2-Amino-5-fluorobenzoicacid (1.0g, 1 eq) and Et3N(1.17 mL, 1.3 eq) in DCM (10 mL) at 0 °C was added Chloracetyl chloride dropwise (0.54 mL, 1.1 eq). The reaction was then stirred at room temperature for 4 h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(chloromethyl)-6- fluoro-4H-benzo[d][1,3]oxazin-4-one (1.03g, 74%). Step 2: 2-(chloromethyl)-6-fluoro-4H-benzo[d][1,3]oxazin-4-one (60mg, 1.0 eq) was dissolved in 1 mL of acetonitrile and 4-chloro-2-ethoxyaniline (48mg, 1.0 eq) was added and stirred. To this well-stirred reaction mixture, PCl3 (77mg, 49 uL, 2.0 eq) was added dropwise. The resulting mixture was stirred at 50 °C for 6 hours. LC-MS indicated formation of desired product. The reaction mixture was poured into saturated Na2CO3 / ice mix, stirred for 30 min, and extracted with ethyl acetoacetate (20mL X 3). The combined organic layers were washed with water and brine. The solution was concentrated and further purified by flash column chromatography (20% EtOAc / hexane) to give 3-(4-chloro-2-ethoxyphenyl)-2- (chloromethyl)-6-fluoroquinazolin-4(3H)-one (77 mg, 75%). Step 3: 3-(4-chloro-2-ethoxyphenyl)-2-(chloromethyl)-6-fluoroquinazolin-4(3H)-one (40 mg, 1.0 eq) was dissolved in 1 mL of MeCN, and to this solution was added K2CO3 (30mg, 2.0 eq), Boc-piperazine (41mg, 2.0 eq) and NaI (4.9 mg, 0.3 eq). The mixture was heated at 80 °C for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give tert-butyl 4-((3-(4-chloro-2-ethoxyphenyl)-6-fluoro- 4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (24 mg, 43%). Step 4: To intermediate tert-butyl 4-((3-(4-chloro-2-ethoxyphenyl)-6-fluoro-4-oxo- 3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (24 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 2 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-103 (18 mg).1H NMR (500 MHz, DMSO) δ 8.52 (s, 2H), 7.86 – 7.75 (m, 3H), 7.53 (dd, J = 8.3, 1.4 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.4, 2.2 Hz, 1H), 4.17 – 4.01 (m, 2H), 3.45 – 3.30 (m, 2H), 2.95 (s, 3H), 2.60 – 2.52 (m, 2H), 2.45 (q, J = 5.5 Hz, 2H), 1.12 (t, J = 6.9 Hz, 3H). LC-MS (ESI) m / z : [M+H]+: 416.95. Synthesis of tert-butyl 4-((2-(2-ethoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-3- Step 1: To a mixture of o-Phenetidine (279mg, 1.0 eq), 2-Cyclopropyl-benzoic acid (330mg, 1.0 eq.) and DIPEA (1.06 mL, 3.0 eq) in DMF (5 mL) was added HATU (774mg, 1.0 eq). The resultant mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and purified by flash column chromatography (5% EtOAc / hexane) to give 2-cyclopropyl-N-(2-ethoxyphenyl)benzamide (410 mg, 71%). Step 2: To a mixture of 2-cyclopropyl-N-(2-ethoxyphenyl)benzamide (400 mg, 1.0 eq), Acetonitrile - dichloropalladium (74 mg, 0.2 eq) and Quinone (154 mg, 1.0 eq) under N2 protection was added dioxane (5 mL). The mixture was stirred at 80 °C overnight and then filter via celite. The solvent was removed under reduced pressure and purified by flash column chromatography (5% EtOAc / hexane) to give 2-(2-ethoxyphenyl)-3- methylisoquinolin-1(2H)-one (255 mg, 64%). Step 3: To a mixture of 2-(2-ethoxyphenyl)-3-methylisoquinolin-1(2H)-one (33mg, 1.0 eq), NBS (42 mg, 2.0 eq) in carbon tetrachloride (1 mL) was added benzoyl peroxide (3 mg, 0.1 eq). The mixture was heated to 80 °C for 2h. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give 2-(5-bromo-2- ethoxyphenyl)-3-(bromomethyl)isoquinolin-1(2H)-one (16 mg, 31%). Step 4: To a mixture of 2-(5-bromo-2-ethoxyphenyl)-3-(bromomethyl)isoquinolin- 1(2H)-one (15 mg, 1.0 eq), tert-butyl piperazine-1-carboxylate (9.6 mg, 1.5 eq), K2CO3 (14 mg, 3 eq), NaI (2 mg, 0.2 eq) was added MeCN (1 mL). The mixture was stirred at 80 °C for 2h. And the solvent was removed and purified by HPLC to give tert-butyl 4-((2-(5-bromo-2- ethoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)piperazine-1-carboxylate (15mg, 86%). Step 5: To a mixture of tert-butyl 4-((2-(5-bromo-2-ethoxyphenyl)-1-oxo-1,2- dihydroisoquinolin-3-yl)methyl)piperazine-1-carboxylate (15mg, 1.0 eq), palladium acetate (1mg, 0.1 eq), triphenylphosphine (3 mg, 0.4 eq) and potassium carbonate (8 mg, 2.0 eq) under nitrogen protection was added n-butanol (1 mL). The resulting mixture was then stirred overnight at 100 °C. After removal of the solvent, the residue was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined, washed with brine (10 mL), and concentrated under reduced pressure. The final product was purified by HPLC to give tert-butyl 4-((2-(2-ethoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-3- yl)methyl)piperazine-1-carboxylate (8 mg, 60%). Step 6: To intermediate tert-butyl 4-((2-(2-ethoxyphenyl)-1-oxo-1,2- dihydroisoquinolin-3-yl)methyl)piperazine-1-carboxylate (8 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ-8-115 (5 mg).1H NMR (500 MHz, DMSO) δ 8.47 (s, 2H), 8.17 (dd, J = 8.0, 1.3 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.68 (dd, J = 8.1, 1.2 Hz, 1H), 7.62 – 7.49 (m, 2H), 7.44 (ddd, J = 8.8, 7.5, 1.7 Hz, 1H), 7.31 (dd, J = 7.7, 1.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.2 Hz, 1H), 7.06 (td, J = 7.6, 1.2 Hz, 1H), 6.74 (s, 1H), 4.03 (qt, J = 7.0, 3.6 Hz, 2H), 3.92 (q, J = 6.6 Hz, 1H), 3.12 – 3.01 (m, 2H), 2.94 (s, 3H), 2.41 (dd, J = 12.0, 6.4 Hz, 2H), 2.25 (dt, J = 12.4, 4.8 Hz, 2H), 1.11 (t, J = 6.9 Hz, 3H). LC-MS (ESI) m / z : [M+H]+: 364.15. Synthesis of 2-(5-bromo-2-ethoxyphenyl)-3-(piperazin-1-ylmethyl)isoquinolin-1(2H)-one (JWZ-8-114) To tert-butyl 4-((2-(5-bromo-2-ethoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-3- yl)methyl)piperazine-1-carboxylate (5 mg) was added a solution of DCM / Trifluoroacetic acid (3:1) 1 mL. The mixture was stirred at room temperature for 1 hour. LC-MS indicated formation of desired product. The solvent was removed and purified by HPLC to give JWZ- 8-114 (3 mg). LC-MS (ESI) m / z : [M+H]+: 442.00 and 444.00. General Synthesis Procedure A. Compounds reported in Table 1 were synthesized by a general synthesis procedure A with different aryl and heteroaryl amines as exemplified by compound 003-0 below. Synthesis of 3-(4-chloro-2-cyclopropoxyphenyl)-6-fluoro-2-(piperazin-1-ylmethyl)quinazolin- 4 Step 1: 4-chloro-2-cyclopropoxy-1-nitrobenzene. To a solution of t-BuOK (1.17 g, 10.417 mmol, 1 equiv) in toluene (27 mL) was added a solution of cyclopropanol (0.67 g, 11.459 mmol, 1.1 equiv) in toluene (27 mL) at 0°C. A solution of 2,4-dichloronitrobenzene (2 g, 10.417 mmol, 1 equiv) in toluene (27 mL) was added steadily at while the temperature was kept below 10 °C. The resulting mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was poured into water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0 to 15% ethyl acetate in petroleum ether to afford 4-chloro-2- cyclopropoxy-1-nitrobenzene (600 mg, 26.96% yield, 90% purity). MS (ESIpos): m / z = 214 (M+H)+. Step 2: 4-chloro-2-cyclopropoxyaniline. A reaction mixture of 4-chloro-2- cyclopropoxy-1-nitrobenzene (550 mg, 2.575 mmol, 1 equiv), Fe (1.006 g, 18.025 mmol, 7 equiv), ammonium chloride (964 mg, 18.025 mmol, 7 equiv) in a mixed solvent of ethanol (12 mL) / water (6 mL) was stirred for 18 hours at 80 °C. The resulting mixture was filtered. The filtrate was concentrated to get a residue. The crude product was partitioned into water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get 4-chloro-2-cyclopropoxyaniline (450 mg, 95.18% yield, 80% purity). MS (ESIpos): m / z = 184 (M+H)+. Step 3: tert-butyl 4-((6-fluoro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)methyl)piperazine- 1-carboxylate. To a solution of 2-amino-5-fluorobenzoic acid (10 g, 64.463 mmol, 1 equiv) and [4-(tert-butoxycarbonyl)piperazin-1-yl]acetic acid (18.90 g, 77.356 mmol, 1.2 equiv) in pyridine (110 mL) was slowly added diphenyl phosphonate (60.39 g, 257.852 mmol, 4 equiv). The resulting reaction mixture was stirred for 6 h at 70 °C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with ethyl acetate and washed with sat. sodium bicarbonate and brine in sequence. The solution was concentrated under reduced pressure. The crude product was purified via silica gel column chromatography, eluted with 0 to 40% ethyl acetate in petroleum ether to afford tert-butyl 4-[(6-fluoro-4-oxo- 3,1-benzoxazin-2-yl)methyl]piperazine-1-carboxylate (7 g, 29.88% yield, 95%purity). MS (ESIpos): m / z = 364 (M+H)+. Step 4: tert-butyl 4-((3-(4-chloro-2-cyclopropoxyphenyl)-6-fluoro-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-[(6- fluoro-4-oxo-3,1-benzoxazin-2-yl)methyl]piperazine-1-carboxylate (400 mg, 1.101 mmol, 1 equiv) and 4-chloro-2-cyclopropoxyaniline (242 mg, 1.321 mmol, 1.2 equiv) in pyridine (12 mL) was slowly added diphenyl phosphonate (1031 mg, 4.404 mmol, 4 equiv). The reaction mixture was stirred for 20 h at room temperature. The resulting mixture was concentrated under vacuum. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with ethyl acetate and washed with sat. sodium bicarbonate and brine in sequence. The solution was concentrated under reduced pressure. The crude product was purified via prep-TLC (petroleum ether: ethyl acetate =2: 1) to afford tert-butyl 4- {[3-(4-chloro-2-cyclopropoxyphenyl)-6-fluoro-4-oxoquinazolin-2-yl]methyl}piperazine-1- carboxylate (500 mg, 85.87%yield, 85%purity). MS (ESIpos): m / z = 530 (M+H)+. Step 5: 3-(4-chloro-2-cyclopropoxyphenyl)-6-fluoro-2-(piperazin-1- ylmethyl)quinazolin-4(3H)-one (Compound 003-0). To a solution of tert-butyl 4-{[3-(4-chloro- 2-cyclopropoxyphenyl)-6-fluoro-4-oxoquinazolin-2-yl]methyl}piperazine-1-carboxylate (200 mg, 0.378 mmol, 1 equiv) in DCM (4 mL) was added trifluoroacetic acid (1 mL), and then then reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was re-dissolved in DMF and purified by Prep-HPLC with the following conditions: Column: Xselect CSH Prep Fluoro-Phenyl Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 2% B to 22% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.5 to get 3-(4-chloro-2-cyclopropoxyphenyl)-6-fluoro-2-(piperazin-1- ylmethyl)quinazolin-4-one (69.5 mg, 42.86% yield, 99.3% purity). MS (ESIpos): m / z = 429 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.48 (s, 2H), 7.83-7.76 (m, 3H), 7.56- 7.54 (m, 2H), 7.22 (d, 1H), 4.03-3.99 (m, 1H), 3.51 (d, 1H), 3.18 (d, 1H), 2.52-2.42 (m, 4H), 2.38-2.28 (m, 4H), 0.80-0.75 (m, 2H), 0.54-0.48 (m, 2H). The compounds in Table 1 were synthesized according to the general synthesis procedure A, using appropriate starting materials. Table 1. Additional Compounds and Characterization Data

[0010] General synthesis B. Compounds reported in Table 2 were synthesized by a general synthesis procedure B outlined in Scheme 1, with different hydroxyalkyl groups as exemplified by the synthesis of compound 020-0. Scheme 1. General Synthesis Procedure B Synthesis of 3-(2-(2-aminoethoxy)-4-chlorophenyl)-6-fluoro-2-(piperazin-1- Step 1: tert-butyl 4-((6-fluoro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)methyl)piperazine- 1-carboxylate. To a solution of 2-amino-5-fluorobenzoic acid (10 g, 64.463 mmol, 1 equiv) and [4-(tert-butoxycarbonyl)piperazin-1-yl]acetic acid (18.90 g, 77.356 mmol, 1.2 equiv) in pyridine (110 mL) was slowly added diphenyl phosphonate (60.39 g, 257.852 mmol, 4 equiv). The resulting reaction mixture was stirred for 6 h at 70 °C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to get a residue. The crude product was purified via silica gel column chromatography, eluted with 0 to 40% ethyl acetate in petroleum ether to afford tert-butyl 4-[(6-fluoro-4-oxo-3,1- benzoxazin-2-yl)methyl]piperazine-1-carboxylate (7 g, 29.88% yield, 95%purity).MS (ESIpos): m / z = 364 (M+H)+. Step 2: tert-butyl 4-((3-(4-chloro-2-hydroxyphenyl)-6-fluoro-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-[(6- fluoro-4-oxo-3,1-benzoxazin-2-yl)methyl]piperazine-1-carboxylate (7.00 g, 19.20 mmol, 1 equiv) and 2-amino-5-chlorophenol (3.30 g, 23.14 mmol, 1.2 equiv) in pyridine (100 mL) was slowly added diphenyl phosphonate (17.98 g, 76.80 mmol, 4 equiv). The reaction mixture was stirred for 2 h at 70 °C. The resulting mixture was cooled to room temperature and extracted with ethyl acetate and water. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to get a residue. The crude product was purified via revered phase liquid chromatography eluting with 10 to 45% acetonitrile in water (0.5% FA) to tert-butyl 4-((3-(4-chloro-2-hydroxyphenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperazine-1-carboxylate (2.80 g, 29.7%yield, 95.4%purity). MS (ESIpos): m / z = 489 (M+H)+. Step 3: tert-butyl 4-((3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)-4-chlorophenyl)-6- fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-{[3-(4-chloro-2-hydroxyphenyl)-6-fluoro-4-oxoquinazolin-2- yl]methyl}piperazine-1-carboxylate (110 mg, 0.225 mmol, 1 equiv), tert-butyl N-(2- hydroxyethyl)carbamate (47.15 mg, 0.293 mmol, 1.3 equiv) and PPh3 (236.04 mg, 0.900 mmol, 4 equiv) in THF (2 mL) was added DIAD (159.22 mg, 0.787 mmol, 3.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for overnight. The resulting mixture was extracted with ethyl acetate and water. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to get a residue. The crude product was purified by prep-TLC eluting with 50% ethyl acetate in petroleum ether to afford tert-butyl 4-{[3-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-4- chlorophenyl)-6-fluoro-4-oxoquinazolin-2-yl]methyl}piperazine-1-carboxylate (120 mg, 75.94%yield, 90%purity) as a yellow solid. MS (ESIpos): m / z = 632 (M+H)+. Step 4: 3-(2-(2-aminoethoxy)-4-chlorophenyl)-6-fluoro-2-(piperazin-1- ylmethyl)quinazolin-4(3H)-one (Compound 020-0). A solution of tert-butyl 4-{[3-(2-{2-[(tert- butoxycarbonyl)amino]ethoxy}-4-chlorophenyl)-6-fluoro-4-oxoquinazolin-2- yl]methyl}piperazine-1-carboxylate (1 g, 1.582 mmol, 1 equiv) and trifluoroacetic acid (2.5 mL) in DCM (10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to get 100 mg of crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: WelFlash C18, Regular C18 20-40μm, 330g; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 100 mL / min mL / min; Gradient (B%): 3% B to 33% B in 30 min; Wave Length: 254nm / 220nm nm; RT1(min): 23.6) to afford 3-[2-(2-aminoethoxy)-4-chlorophenyl]-6-fluoro- 2-(piperazin-1-ylmethyl)quinazolin-4-one (101.6 mg, 14.87%yield, 97.6%purity) as a white solid. MS (ESIpos): m / z = 432.15 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = δ 7.84- 7.70 (m, 3H), 7.48 (d, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 3.95 (t, 2H), 3.32 (d, 1H), 3.07 (d, 1H), 2.73-2.60 (m, 2H), 2.54-2.40 (m, 4H), 2.10-1.98 (m, 4H). The compounds in Table 2 were synthesized according to the general synthesis procedure B, using appropriate starting materials. Table 2. Additional Compounds and Characterization Data General Synthesis Procedure C. Compounds reported in Table 3 were synthesized by a general synthesis procedure C as shown in Scheme 2, with different C,N,O-linked substitution groups as exemplified by the syntheses of compounds 037-0 and 070-0. Scheme 2. General Synthesis Procedure C Synthesis of 8-amino-3-(4-chloro-2-ethoxyphenyl)-6-fluoro-2-(piperazin-1- ylmethyl)quinazolin-4(3H)-one; (Compound 037-0)

[0011] Step 1: tert-butyl 4-((8-((tert-butoxycarbonyl)amino)-3-(4-chloro-2-ethoxyphenyl)-6- fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate. A reaction mixture of tert-butyl 4-{[8-bromo-3-(4-chloro-2-ethoxyphenyl)-6-fluoro-4-oxoquinazolin-2- yl]methyl}piperazine-1-carboxylate (200 mg, 0.336 mmol, 1 equiv), tert-butyl carbamate (47.18 mg, 0.403 mmol, 1.2 equiv), Pd2(dba)3 (30.73 mg, 0.034 mmol, 0.1 equiv) , XantPhos (19.42 mg, 0.034 mmol, 0.1 equiv) and cesium carbonate (218.71 mg, 0.672 mmol, 2 equiv) in dioxane (4 mL) was stirred for 18 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with 50% ethyl acetate in petroleum ether to get tert-butyl 4-({8-[(tert-butoxycarbonyl)amino]-3- (4-chloro-2-ethoxyphenyl)-6-fluoro-4-oxoquinazolin-2-yl}methyl)piperazine-1-carboxylate (150 mg, 70.70%yield, 70%purity). MS (ESIpos): m / z = 632 (M+H)+. Step 2: 8-amino-3-(4-chloro-2-ethoxyphenyl)-6-fluoro-2-(piperazin-1- ylmethyl)quinazolin-4(3H)-one (Compound 037-0). To a solution of tert-butyl 4-({8-[(tert- butoxycarbonyl)amino]-3-(4-chloro-2-ethoxyphenyl)-6-fluoro-4-oxoquinazolin-2- yl}methyl)piperazine-1-carboxylate (150 mg, 0.237 mmol, 1 equiv) and TFA (1 mL) in dichloromethane (4 mL) was stirred for at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC with following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 18% B to48% B in9 min; Wave Length: 254 nm / 220 nm nm; RT1(min): 8.08 to get 8-amino-3-(4-chloro-2-methoxyphenyl)-6-fluoro-2-(piperazin-1-ylmethyl)quinazolin- 4-one (32.1 mg, 32.37%yield, 99.6%purity) as a white solid. MS (ESIpos): m / z = 432.05 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.42 (d, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 6.86-6.74 (m, 2H), 6.10 (s, 2H), 4.14-3.98 (m, 2H), 3.26 (d, 1H), 3.05 (d, 1H), 2.50-2.44 (m, 4H), 2.10-1.98 (m, 4H), 1.12 (t, 3H). Example: synthesis of 3-(4-chloro-2-ethoxyphenyl)-6-phenyl-2-(piperazin-1- Step 1: tert-butyl 4-((3-(4-chloro-2-ethoxyphenyl)-4-oxo-6-phenyl-3,4- dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate. A mixture of tert-butyl 4-((6- bromo-3-(4-chloro-2-ethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1- carboxylate (100 mg, 0.174 mmol, 1 equiv), phenylboronic acid (26 mg, 0.209 mmol, 1.2 equiv), Pd(dppf)Cl2 (12 mg, 0.017 mmol, 0.1 equiv), sodium carbonate (37 mg, 0.348 mmol, 2 equiv) in a mixed solvents of dioxane (2 mL) and water (0.5 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to get a residue. The crude product was purified via prep-TLC eluting with 40% ethyl acetate in petroleum ether to get tert-butyl 4-((3-(4-chloro- 2-ethoxyphenyl)-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1- carboxylate (80 mg, 79.89% yield, 95% purity). MS (ESIpos): m / z = 575 (M+H)+. Step 2: 3-(4-chloro-2-ethoxyphenyl)-6-phenyl-2-(piperazin-1-ylmethyl)quinazolin- 4(3H)-one; (Compound-070-0). To a solution of tert-butyl 4-{[3-(4-chloro-2-ethoxyphenyl)-4- oxo-6-phenylquinazolin-2-yl]methyl}piperazine-1-carboxylate (80 mg, 0.139 mmol, 1 equiv) in dichloromethane (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred for at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC with following conditions: Column: Waters Xbridge C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(10mM NH4HCO3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 28% B to 55% B in 7min; Wave Length: 254 / 220 nm; RT1(min): 6.98 to afford 3-(4-chloro-2-ethoxyphenyl)-6-phenyl-2-(piperazin-1- ylmethyl)quinazolin-4-one (47.0 mg, 71.13% yield, 99.9% purity) as a white solid. MS (ESIpos): m / z = 475.20 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.33 (s, 1H), 8.19 (d, 1H), 7.83-7.78 (m, 3H), 7.55-7.40 (m, 4H), 7.28 (d, 1H), 7.14 (dd, 1H), 4.15-4.01 (m, 2H), 3.32 (d, 1H), 3.08 (d, 1H), 2.49-2.42 (m, 4H), 2.13-2.00 (m, 4H), 1.13 (t, 3H).. The compounds in Table 3 were synthesized according to the general synthesis procedure C, using appropriate starting materials. Table 3. Additional Compounds and Characterization Data Example 2 Biological Assays Materials and Methods Transfection and Lentivirus production. HEK293T cells were seeded at a density of 35,000 per well in 1 mL of DMEM medium supplemented with 10% FBS and 1% penicillin streptomycin. The following day, a packaging mix was prepared by combining 800 ng psPAX2, 300 ng pMD2.G and 900 ng sgRNA backbone in 125 ul OptiMEM (Invitrogen). This mixture was then combined with 6 ul TransIT-LT1 (Mirus) in 125 ul OptiMEM, incubated for 25 min at room temperature and then added to cells. After two days of transfection, the medium containing lentivirus was collected and stored at −80 °C before use. To transduce target cells, the lentivirus was added to the cells in the presence of 1 ug / ml Polybrene. Crispr knockout of TRIM21. sgRNAs targeting TRIM21 were designed utilizing the CrisPick design tool (https: / / portals.broadinstitute.org / gppx / crispick / public). A total of 5 pairs of oligonucleotides targeting TRIM21, and a control pair of CHR2-2, were annealed and cloned into the pXPR_023 all-in-one Cas9 vector. In brief, vector was linearized using BsmBI (New England Biolabs). The annealed oligonucleotides were ligated into the linearized and purified vector backbone with T4 DNA ligase (New England Biolabs). Constructs were transformed, purified using the Miniprep Kit (Qiagen), and the guide sequence was confirmed by Sanger sequencing. PANC1 cells were stably transduced with lentivirus for TRIM21 pXPR_023 or the negative control CHR2-2 pXPR_023 in 12-well plates via centrifugation at 2,000 rpm and 30 °C for two hours. The next day, cells were split into flasks and selected with 2 ug / ml puromycin for 3 days. Gene knockout was confirmed by immunoblot. Gene overexpression. The TRIM21 gene cDNA was cloned into the pDONR_221 vector using BP Clonase (Thermo Fisher Scientific), and then the transferred into the pLX_311 mammalian expression vector using LR Clonase (Thermo Fisher Scientific). Lentivirus was generated as described above. Cell lines were transduced with the harvested virus, and infected cells were selected with 2 ug / mL blasticidin (Gibco) for 10 days. PANC1 CRISPR–Cas9 genome-wide knockout screen. PANC1 cells were stably transduced with pLX_311-Cas9. The Brunello genome-scale sgRNA library was obtained from the Broad Institute GPP. Virus was titrated to a goal infection efficiency of 30-50%. PANC1-Cas9 cells were infected with Brunello library virus in 12-well plates via centrifugation at 2,000 r.p.m. and 30 °C for 2 hours. The following day, cells were split into two replicate flasks and selected with 2 ug / ml puromycin for 5 d. After selection, replicates were seeded into 110 nM PRLX-93936 or DMSO control. Cells were maintained at 37 °C and 5% CO2 in CellSTACK 1,272 cm22-STACK flasks (Corning) in RPMI with 10% FBS. Cells were reseeded approximately every 3 days at a minimum of 40 million cells per passage to maintain approximately 500× library representation. Media and drugs were refreshed every 3–4 d for a total of 3 weeks. PRLX-93936 dose was gradually increased to 250 nM over the course of the screen. Genomic DNA was isolated from cell pellets using the NucleoSpin Blood XL columns (MACHEREY-NAGEL). Genomic DNA PCR and next-generation sequencing by standard Illumina methods were performed to determine guide abundance. PANC1 CRISPR–dCas9 genome-wide activation screen. PANC1 cells were stably transduced with pXPR_109 to express dCas9-VP64. The Calabrese B genome-scale virus library was obtained from the Broad Institute GPP. PANC1-dCas9-VP64 cells were infected with this library via centrifugation as described earlier. The following day, cells were split into two replicates and reseeded. One day later, 2 ug / ml of puromycin was added. After selection for 5 days, replicates were split into DMSO or 110 nM PRLX-93936 drug arms in duplicate and cultured for 2 weeks as described followed by genomic DNA isolation and sequencing as described earlier. CRISPR screen analysis. Guides targeting multiple genes or with <50 reads in the plasmid DNA pool were filtered. Counts were normalized against total library size. The guide-level log2 fold change was computed using the ratio between treatment versus vehicle control counts. The median log2 fold change from all guides targeting each gene was calculated. Statistical significance for each gene-level result was calculated using the MAGeCK-RRA method (MAGeCK version 0.5.9.5), using 10,000 permutations. Two-sided P values were corrected for multiple hypothesis testing using the Benjamini–Hochberg method. RNA-seq. PANC1 cells were seeded in 6-well plates. The following day, cells were treated in triplicate with 0.5 uM PRLX-93936 or DMSO vehicle control for 2 hours. RNA was isolated using the RNeasy Mini Kit (QIAGEN) with DNase treatment. RNA QC, library preparation, and Novaseq sequencing were performed by Genewiz. Gene-level expression values were obtained from RNA-seq using the nf-core / rnaseq pipeline (version 3.12.0). Salmon (version 1.10.1) was used to generate gene-level read counts. Differential gene expression was calculated using the DESeq2 package (version 1.28.0). These tools were run using the Stanford Sherlock computing cluster. Multiplexed cell line screening. The established PRISM cell proliferation assay was carried out as previously described. In brief, approximately 800 barcoded cell lines in pools of 20–25 were thawed and plated into 384-well plates (1,250 cells per well for adherent cells, 2,000 cells per well for suspension or mixed suspension–adherent pools). Cells were treated with an eight-point dose curve starting at 10 uM with threefold dilutions in triplicate and incubated for 120 hours. Following lysis, the barcode for each cell was detected by mRNA- based Luminex detection as previously described and input to a standardized R pipeline (https: / / github.com / broadinstitute / prism_data_processing) to generate viability estimates relative to vehicle treatment and fit dose–response curves. The area under the dose–response curve (AUC), which is correlated with drug potency, was used as a metric of drug potency for each cell line. Reference publicly available gene expression data were retrieved from the Cancer Cell Line Encyclopedia. Predictive biomarker relationships were determined by comparing each cell line baseline molecular feature (e.g., RNA-seq gene expression) versus the observed AUC models by univariate linear modeling. Results and Discussion To determine functional mediators of PRLX-93936, genome-scale CRISPR / Cas9 drug modifier knockout and activation screens were performed in the PANC1 pancreatic cancer cell line. In the knockout screen, conducted using the Brunello CRISPR guide RNA library, TRIM21 knockout was the top hit that rescued from PRLX-93936. Other rescue hits included genes necessary for NFkB (IKK-alpha and IKK-gamma) and interferon signaling (IRF2) (FIG. 2). IKK enzymes have been reported to be direct substrates of TRIM21 (Wada et al. J. Biochem. 146, 821–832 (2009)). The results of the CRISPR gene activation screen, conducted with the Calabrese-B CRISPR guide RNA library, were highly complementary (FIG. 3). TRIM21 overexpression sensitized to PRLX-93936 treatment, along with IRF2 and IRF overexpression. Next, predictive biomarkers for PRLX-93936 response were sought via large-scale proliferation assays across 816 cancer cell lines (FIG.4A). Sensitive cell lines were identified across multiple cancer types, including lineage-specific enrichment for activity against pancreatic cancer and head and neck cancer (upper aerodigestive cancers) (FIG.4B). Next, cell line molecular features were systematically compared with PRLX-93936 drug response by linear modeling. High expression of TRIM21 was the top predictive biomarker of cell line response (FIGS.5A-5B). Thus, in addition to functionally mediating the anti-cancer activity of PRLX-93936, TRIM21 expression is a promising predictive biomarker for the drug. To validate the functional role of TRIM21 in PRLX-93936 response, multiple isogenic cancer cell lines were generated. First, TRIM21 was knocked out via CRISPR Cas9 in TRIM21-expressing PANC1 and KP3 pancreatic cancer cells. Both cell lines are sensitive to PRLX-93936 at baseline. TRIM21 knockout completely rescues from PRLX-93936 activity in a dose response viability assay (FIG. 6). Next, experiments were conducted to determine whether ectopic expression of TRIM21 in resistant cell lines would alter sensitivity to the drug. Across three resistant cell lines of various lineages (ovarian cancer, lung cancer, and melanoma) all become highly sensitive (>500x sensitization) to PRLX-93936 upon TRIM21 overexpression by lentiviral transduction (FIG.7) To confirm on-target activity of our TRIM21 CRISPR guides, knockout-restoration studies were performed in PANC1 cells. Re-expression of wild-type TRIM21 in knockout cells via guide-resistant cDNA restores sensitivity (FIG. 8). RING E3 ligases rely on a critical “linchpin” residue, most commonly arginine, to catalyze transfer of a ubiquitin molecule from an E2 enzyme to a substrate (Lips et al. EMBO J. 39, e104863 (2020)). The TRIM21 R55E linchpin mutation does not fully restore sensitivity to cells. Thus, functional TRIM21 is necessary for PRLX-93936 activity. PRLX-93936 was previously reported to induce apoptosis (unlike the parent compound, erastin, which is a prototypic ferroptosis inducer). Here, PRLX-93936 was found to induce caspase 3 / 7 activation in a TRIM21-dependent manner (FIG. 9A). In addition, multiple hallmarks of apoptosis including cleavage of PARP, caspase 3, and caspase 7 are detectable by immunoblot at 16 hours (FIG. 9B). TRIM21 knockout prevents PARP and caspase cleavage. To identify downstream effectors of PRLX-93936, RNA-Seq was performed using drug-treated cells. Results demonstrated rapid induction of multiple NFkB and interferon gene targets including IRF1, RNFAIP3, NFKBIA, CD83, CXCL3, and other genes. (FIG. 10). PRLX-93936-induced increase in protein expression and nuclear localization of NFkB (RelA) and IRF1 were confirmed by immunoblot (FIG.11) To develop TRIM21 anti-cancer therapeutics, the series of compounds described in this application was synthesized. Compounds were tested against PANC1 (intact TRIM21) and PANC1-TRIM21 knockout cells to verify TRIM21 dependency. Cell line IC50 values (CellTiterGlo at 72 hours) for each compound against PANC1 cells are shown Table 4. Table 4. IC50 Values

[0012] Example 3 X-ray Crystallography Protein Purification. The coding sequence for human TRIM21 PRYSPRY (Uniprot P19474; residues 288-465) was amplified by PCR and cloned into an N-terminal His6- SUMO-TEV fusion vector by ligation-independent cloning. The coding sequence for human NUP98 APD (Uniprot P52948; residues 729-880) was ordered as a codon-optimized gBlock (IDT) and cloned into an N-terminal His6-GST-TEV fusion vector by ligation-independent cloning. The cloned genes were verified by Sanger and whole plasmid sequencing, transformed into Rosetta2(DE3)pLysS chemically competent E. coli cells (Novagene), and grown in Luria Broth supplemented with chloramphenicol and carbenicillin overnight. Saturated overnight cultures were distributed to 1 L flasks containing 2XYT medium supplemented with antibiotics. Protein expression was induced by addition of 400 µM IPTG (final concentration). The temperature was adjusted from 37 °C to 18 °C. After incubation overnight, cells were harvested by centrifugation. Cell pellets were resuspended in ~4 mL / L D800 buffer (20 mM HEPES, pH 7.5; 800 mM NaCl; 10 mM imidazole, pH 8.0; 10 % glycerol, 2 mM beta mercaptoethanol) supplemented with protease inhibitors (1 mM PMSF, 1 mM benzamidine, ~20 μg / mL pepstatin, aprotinin, and leupeptin) and frozen at -80 °C. For TRIM21 PRYSPRY purification, cell pellets were thawed briefly in warm water and lysed by sonication and addition of solid lysozyme before centrifugation at 16,233 g for 1 h at 12 °C. Clarified lysate was mixed with ~0.5 mL / L of growth cobalt resin (TaKaRa) for one hour before centrifugation at low speed to separate the beads, which were then washed by gravity flow with ~25 column volumes ice cold D800 buffer before a final wash with B50 (D800 with 50 mM NaCl) and elution with C50 (B50 with 400 mM imidazole, pH 8.0). Cobalt eluate was applied to a 5 mL anion exchange column (Q HP, Cytiva) and eluted with an 8-column volume gradient from B50 to D800. For TRIM21 PRYSPRY used for crystallography, the anion exchange column peak fractions were pooled and subjected to cleavage with TEV protease for ~4 h at room temperature before adjustment of the imidazole concentration to 50 mM and subsequent removal of uncleaved proteins, tags, and His6-TEV by Ni2+ affinity chromatography on a 5 ml Ni-FF cartridge (Cytiva). The Ni2+ flow through from this step was concentrated by ultrafiltration before application to a 24 mL gel filtration column (S200 increase, Cytiva) primed with GF150 buffer (20 mM Tris-HCl, pH 8.5, 150 mM NaCl, 1 mM TCEP). For uncleaved preparations, S200 peak fractions were again concentrated by ultrafiltration, supplemented with 5% glycerol (v:v, final), and aliquoted and frozen at -80 °C. For cleaved preparations used for crystallography, S200 peak fractions were concentrated and used without storage or addition of glycerol. Protein crystallography. TEV-cleaved TRIM21 PRYSPRY (Uniprot P19474; residues 288-465) was concentrated to ~15 mg / mL and mixed at a 1:1.5 molar ratio with JWZ-8-103 prepared as a 500 mM stock solution in deuterated DMSO. The mixture was allowed to sit for approximately one hour at room temperature before hanging drop crystallization experiments were set up on silanized glass cover slips. The protein-small molecule sample was mixed in a 1:1 ratio (v:v) with mother liquor and incubated ~48 h at 16 °C. Diffracting crystals grew in the following crystallization solution: 0.1 M Tris-HCl, pH 7.5; 4.2 M Ammonium formate. Crystals were cryopreserved in 1.2-fold concentrated mother liquor solution supplemented with ~1.2-fold molar excess JWZ-8-103 and ~10% glycerol by volume. Diffraction data were collected at Stanford SSRL experimental station BL-12-2 (wavelength = 0.97946 Å; temperature = ~80 K). The detector was a Dectris PILATUS 6M. Data reduction was done using the Xia-2-Aimless pipeline (Winter et al. Acta Crystallogr. D Biol. Crystallogr. 69, 1260–1273 (2013); Evans et al. Acta Crystallogr. D Biol. Crystallogr.69, 1204–1214 (2013)). Crystals formed in space group P41212 with unit cell dimension 99.3 Å, 99.3 Å, and 50.4 Å. Diffraction anisotropy was observed in the best datasets, with interpretable reflections in the best reciprocal space axes (along h k plane) to 1.84 Å and the worst to 2.59 Å (along l axis) as determined by CC1 / 2 > 0.3 (Karplus et al. Science 336, 1030–1033 (2012)). A resolution for refinement of 2.1 Å was chosen based on a completeness threshold of 70 % according to CTRUNCATE. To determine the structure of TRIM21 PRYSPRY, PHASER in CCP4 (McCoy et al. J. Appl. Crystallogr.40, 658–674 (2007); Winn et al. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011)). and a truncated version of the human TRIM21 AlphaFold2 model (Jumper et al. Nature 596, 583–589 (2021)) (AF-P19474-F1) were used. Initial maps showed clear difference in density unaccounted for by the input model. REFMAC5 (Kovalevskiy et al. Acta Crystallogr. D Struct. Biol.74, 215–227 (2018)) was used to further refine the model. Manual model adjustments were done in Coot (Emsley et al. Acta Crystallogr. D Biol. Crystallogr.60, 2126–2132 (2004)). At later stages of refinement, JWZ-8-103 was prepared using AceDRG (Long et al. Acta Crystallogr. D Struct. Biol.73, 112–122 (2017)) and placed it into the unaccounted-for density. After further refinement, ordered solvent was added, including a water contacting TRIM21-D355. Due to the diffraction anisotropy mentioned above, the final model was refined to high resolution shells extending in reciprocal space to 2.1 Å and, separately, to 2.5 Å to confirm that relatively high Rfree values observed at higher resolution could be ameliorated by a more conservated selection of experimental data, which was the case. There was no obvious streaking or otherwise anisotropy-related pathology observed in the real-space electron density map at any resolution analyzed.93 percent of the peptide bonds are in favorable regions of the Ramachandran plot, and the overall model has a clashscore of 4. The final model and reflections have been deposited in the PDB with identifier 9EK5. JWZ-8-103 binds a shallow pocket lined by hydrophobic amino acid side chains, including TRIM21-L370, -W381, and -W393 (FIG.12). Among the compound-protein interactions that drive SAR are hydrogen bonds between the terminal nitrogen of the JWZ-8- 103 piperazine ring and the D355 side chain acid. TRIM21-F450 and -W381 further coordinate the piperazine ring, and the terminal nitrogen of the piperazine moiety may form a cation-π interaction with these residues, further stabilizing this complex. Indeed, JWZ-8-60, in which the terminal nitrogen is substituted by oxygen, is completely inactive and does not bind TRIM21 by SPR. Observation of an ordered water coordinated by the D355 acid implies further space for chemical exploration. In addition to these interactions, the JWZ-8-103 chlorophenyl ring and its attached ortho-ethoxy group extend into a shallow hydrophobic patch defined by TRIM21-W383. TRIM21-L370, -Y393, -P394, and -Q395 position the quinazoline-4 (3H)-one core, enabling its complete desolvation. A buried hydrogen bond between the free pyramidic nitrogen and the backbone amide hydrogen of L371 reinforces the position of the compound core. Substitution of this nitrogen by carbon in compound 2 ablates activity, consistent with this interpretation. Cellular point mutations underscored the importance of these contacts; TRIM21-D355A rendered PRLX and its analogues inactive, while TRIM21-W381A, -W383A, and -F450A also demonstrated reduced compound activity. Thus, extensive hydrophobic and hydrogen bonding interactions mediate JWZ-8- 103-TRIM21 binding despite the lack of a deep compound binding cleft as commonly seen for substrate-competitive enzyme inhibitors. Further interactions with TRIM21 neo-client proteins, as described below, likely further stabilize compound binding. Example 4 Pharmacokinetics Study and In Vivo Data Pharmacokinetics Study. Pharmacokinetics were tested in male C57BL / 6 mice via intravenous dosing in the tail vein, intraperitoneal injection, and oral gavage. Triplicate mice were dosed at 1 mg / kg IV, 3 mg / kg IP, and 6 mg / kg PO formulated at 0.2 mg / mL (IV), 0.3 mg / mL (IP), and 0.6 mg / mL (PO) in 5 / 5 / 90 DMSO / Tween80 / water. Approximately 20 µL of blood was collected after 5, 15, 30, 60, 120, 240, 360, and 480 min. A micro-sampling technique was used where blood is collected in capillary hematocrit tubes to reduce the total blood taken from the mouse. This allowed a single mouse to be used for the entire time course and reduces inter-individual variability. Additionally, by using small sample volumes the health of the mouse is maintained. Plasma was generated by standard centrifugation techniques, yielding approximately 10 µL of plasma, which was immediately frozen. Plasma, 5 µL was treated with 75 µL of an 80 / 20 acetonitrile / water solution containing 20 ng / mL carbamazepine as an internal standard and allowed to sit on ice for approximately 30 min to precipitate plasma proteins. A standard curve ranging from 1 to 3300 ng / mL was prepared in mouse plasma and processed with the samples. Samples were filtered through a 0.2 micron filter and directly analyzed. Drug concentrations were determined by mass spectrometry using a Sciex 5500 mass spectrometer using multiple reaction monitoring using the mass transition of 365.2 to 99 for PRLX and 418.2 to 99 for JWZ-8-103 and comparing the peak area to the area of the carbamazepine internal standard. Pharmacokinetic parameters were calculated using a non-compartmental model (Phoenix WinNonlin, Pharsight Inc.). All procedures were approved by the Scripps Florida IACUC, and the Scripps vivarium is fully AAALAC accredited. In vivo Xenograft Procedures. All animal procedures were performed by the Transgenic, Knockout and Tumor Model Center (TKTC) in accordance with the Stanford Administrative Panel for Laboratory Animal Care (APLAC), under protocol number 34416. Six-week-old female NOD.Cg-PrkdcscidIl2rgtm1Wjl / SzJ (NSG) mice were obtained from Jackson Laboratories. Xenograft tumors were established using pathogen-free PANC1 cell lines (ATCC CRL-1469). A total of 5 × 106cells in a 100 µL suspension of PBS / Matrigel® (1:1) were injected subcutaneously into the shaved lateral flank of anesthetized mice. Tumor length and width were measured twice a week using external calipers. Starting seven days after inoculation, tumor volume (mm3) was calculated using the modified ellipsoidal formula: V = ½ (Length × Width2) (Miller et al. Tomography 2, 17–25 (2016)). When tumors reached an average size of 150 mm3, mice were treated daily for 21 days by intraperitoneal injection with vehicle, PRLX or JWZ-8-103, as indicated below. Mice were euthanized on day 60 or earlier if they met early euthanasia criteria (e.g., tumor > 2500 mm3). For PK / PD studies, compound administration was performed in tumor with an average of 500 mm3. After 24 h, terminal blood, liver, and tumors were obtained for downstream analysis. Compound preparation for in vivo administration. The injection solutions were prepared fresh on each day of compound administration. First, a stock solution was prepared for each compound by dissolving 15 mg of PRLX in 150 µL or 20 mg JWZ-8-103 in 200 µL of solvent (0.25% Tween-80, 0.1% benzyl alcohol, and 350 mM acetic acid). Later, stock solutions were 1:20 dilute using 100 mM potassium phosphate buffer and 32 mM sucrose, pH 6.8. The solutions were then filter-sterilized using 0.22 µm membrane. Mice received 200 µL containing Vehicle, PRLX (50 mg / kg) or JWZ-8-103 (50 mg / kg), an additional dilution was made using sterile 100 mM potassium phosphate buffer and 32 mM sucrose, pH 6.8 for JWZ- 8-103 (15 mg / kg). Tumor data collection. Investigators that provided treatment and monitored tumor growth were blinded to treatment designation. Tumor size was measured using electronic caliper, then volume values were plotted using GraphPad Prism version 10. Results and Discussion. JWZ-8-103 and PRLX-93936 were administered to mice as a single dose via intravenous (IV), intraperitoneal (IP), or oral (PO) routes (FIGS. 13A-13B). JWZ-8-103 displayed significantly improved pharmacokinetic profiles compared to PRLX- 93936. Following a single modest dose of 3 mg / kg (IP, FIG. 13A), JWZ-8-103 exhibited favorable plasma exposure (Cmax= 2.78 µM) and area under the curve AUC = 6.17 µM*h), a serum half-life of 2.3 hours, and low systemic clearance (CL= 18.3 mL / min / kg). Notably, JWZ-8-103 displayed oral bioavailability of 74%; with a maximum plasma concentration (Cmax) of 2.12 µM and an AUC of 8.89 µM*h following oral dosing underscoring its clinical potential via this route (Table 5). Table 5. Pharmacokinetic parameters of PRLX-93936 and JWZ-8-103 following IV, IP, and PO compound administration Anti-tumor efficacy was then evaluated in the PANC-1 xenograft model. A full randomized efficacy study was conducted in which 40 NSG mice were randomized into four groups (n = 10 / group) and treated daily for three weeks with vehicle, JWZ-8-103 (15 mg / kg or 50 mg / kg), or PRLX (50 mg / kg) via intraperitoneal injection. Mice treated with JWZ-8- 103 demonstrated potent tumor growth inhibition, with reductions of 85.8% and 87% in tumor volume at the end of the experiment at doses of 15 and 50 mg / kg, respectively. At 50 mg / kg, JWZ-8-103 induced robust tumor regression; at time of final dosing, the average vehicle tumor size was 545 mm³ versus 77 mm³ in the treated animals (FIG.14). Both agents were well-tolerated without signs of toxicity.

Claims

CLAIMS 1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: Q is O or NH; R1is C1-C6alkyl, C3-C6cycloalkyl, or monocyclic heterocyclyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from hydroxy, amino, amido, and cyano; or R1is taken together with R2aand the atoms to which they are attached to form a ring; X1is CH or N; X2is CR2aor N; X3is CR2bor N; X4is CR2cor N; X5is CR2dor N; X6is CR3aor N; X7is CR3bor N; X8is CR3cor N; X9is CR3dor N; R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dare each independently selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NRxRy, -C(O)(C1-C6 alkyl), cyano, aryl, C3-C6cycloalkyl, heteroaryl, and heterocyclyl; wherein R2aand R2b, or R2band R2c, or R2cand R2dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; and wherein R3aand R3b, or R3band R3c, orR3cand R3dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; Rxand Ryare each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl; n is 0, 1, or 2; each R4is independently C1-C6alkyl; or two R4, together with the atom(s) to which they are attached, are taken together to form a ring; R5is H or C1-C4alkyl; R6aand R6bare each independently selected from hydrogen and C1-C6 alkyl, or R6aand R6bare taken together with the carbon atom to which they are attached to form an optionally substituted ring; and A is a 6- to 8-membered ring; with the proviso that at least one of R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dis not CH, or n is 1 or 2, or X1is CH.

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

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is NH.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C3alkyl, C3-C4cycloalkyl, or a monocyclic 4- or 5-membered heterocyclyl having one heteroatom selected from N and O, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from -OH, -NH2, -N(CH3)2, and -C(O)NH2.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R1is selected from methyl, ethyl, cyclopropyl, azetidinyl, -CH2CH2NH2, -CH2CH2N(CH3)2, - CH2CH2OH, and -CH2C(O)NH2.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is C2-C4alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is ethyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X1is N.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X1is CH.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, R2ais hydrogen, and one of R2b, R2c, R2dis selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, and - C(O)(C1-C6 alkyl), and the other two of R2b, R2c, and R2dare hydrogen.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein one of R2b, R2c, R2dis halo, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, or -C(O)(C1-C2 alkyl).

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein one of R2b, R2c, R2dis selected from fluoro, chloro, bromo, methyl, trifluoromethyl, -COOCH3, and ethoxy.

13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, R2ais hydrogen, and one of R2b, R2c, R2dis selected from C1-C6 haloalkyl, amino, or -C(O)(C1-C6 alkyl), and the other two of R2b, R2c, and R2dare hydrogen.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein one of R2b, R2c, R2dis C1-C2haloalkyl or -C(O)(C1-C2alkyl).

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein one of R2b, R2c, R2dis selected from trifluoromethyl and -COOCH3.

16. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, and R2a, R2b, R2c, R2dare hydrogen.

17. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X2is CR2a.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2ais hydrogen or halo.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R2ais hydrogen.

20. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X2is N.

21. The compound of any one of claims 1-9 and 17-20, or a pharmaceutically acceptable salt thereof, wherein X3is CR2b.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R2bis hydrogen, halo, C1-C3alkyl, C1-C3haloalkyl, -C(O)O(C1-C3alkyl), and a monocyclic 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from O and N.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R2bis hydrogen or halo.

24. The compound of any one of claims 1-9 and 17-23, or a pharmaceutically acceptable salt thereof, wherein X4is CR2c.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R2cis hydrogen, halo, C1-C3 haloalkyl, C1-C3 alkoxy, -NRxRy, or cyano, wherein Rxis hydrogen and Ryis C1-C3hydroxyalkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R2cis hydrogen.

27. The compound of any one of claims 1-9 and 17-26, or a pharmaceutically acceptable salt thereof, wherein X4is N.

28. The compound of any one of claims 1-9 and 17-20, or a pharmaceutically acceptable salt thereof, wherein X3is CR2b, X4is CR2c, and R2band R2care taken together with the carbon atoms to which they are attached to a 5- or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O.

29. The compound of any one of claims 1-9 and 17-28, or a pharmaceutically acceptable salt thereof, wherein X5is CR2d.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R2dis hydrogen or halo.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R2dis hydrogen.

32. The compound of any one of claims 1-9 and 17-28, or a pharmaceutically acceptable salt thereof, wherein X5is N.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein the grouphas a structure selected from:

34. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein the grouphas a structure selected from:

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from halo, C1-C6 alkyl, C1-C6 alkoxy, and amino, and the other three of R3a, R3b, R3c, and R3dare hydrogen.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein one of R3a, R3b, R3c, and R3dis halo, C1-C2 alkyl, or C1-C2 alkoxy.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein one of R3a, R3b, R3c, and R3dis fluoro, chloro, bromo, iodo, methyl, or methoxy.

38. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from C1-C6 alkyl, C1-C6 alkoxy, and amino, and the other three of R3a, R3b, R3c, and R3dare hydrogen.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein one of R3a, R3b, R3c, and R3dis C1-C2alkyl or C1-C2alkoxy.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein one of R3a, R3b, R3c, and R3dis methyl or methoxy.

41. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, and R3a, R3b, R3c, and R3dare hydrogen.

42. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X6is CR3aand R3ais hydrogen.

43. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X6is N.

44. The compound of any one of claims 1-34 and 42-43, or a pharmaceutically acceptable salt thereof, wherein X7is CR3b.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R3bis selected from hydrogen, halo, C1-C3alkyl, cyano, phenyl, and monocyclic 5- or 6- membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S.

46. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R3bis halo.

47. The compound of any one of claims 1-34 and 42-46, or a pharmaceutically acceptable salt thereof, wherein X8is CR3c.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R3cis selected from hydrogen, halo, C1-C3 alkoxy, and -NRxRy, wherein Rxand Ryare each hydrogen.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R3cis hydrogen.

50. The compound of any one of claims 1-34 and 42-46, or a pharmaceutically acceptable salt thereof, wherein X8is N.

51. The compound of any one of claims 1-34 and 42-50, or a pharmaceutically acceptable salt thereof, wherein X9is CR3d.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein R3dis selected from hydrogen, halo, C1-C3 alkyl, and -NRxRy, wherein Rxand Ryare each hydrogen.

53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R3dis hydrogen.

54. The compound of any one of claims 1-34 and 42-50, or a pharmaceutically acceptable salt thereof, wherein X9is N.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein A is a six-membered ring.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein A is a piperazine ring.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein n is 0.

58. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein n is 2, and wherein the two R4are taken together with the atom(s) to which they are attached to form a ring.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein the grouphas a formula selected from:

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein R5is H.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare each hydrogen.

62. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein R6ais hydrogen and R6bis methyl.

63. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkyl ring.

64. The compound of claim 1, wherein the compound has a structure selected from:

65. A pharmaceutical composition comprising a compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

66. A method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof.

67. The method of claim 66, wherein the subject is a mammal.

68. The method of claim 66, wherein the subject is a human.

69. The method of any one of claims 66-68, wherein the proliferative disease is associated with tripartite motif-containing 21 (TRIM21).

70. The method of claim 69, wherein the proliferative disease is associated with a mutation in and / or increased activity of TRIM21.

71. The method of any one of claims 66-70, wherein the proliferative disease is cancer.

72. The method of claim 71, wherein the cancer is selected from pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, multiple myeloma, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, leukemia, lymphoma, prostate cancer, and sarcoma.

73. The method of any one of claims 66-72, further comprising treating the subject with one or more additional therapies selected from chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy, or any combination thereof.

74. A method of treating a TRIM21-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein: Q is O or NH; R1is C1-C6 alkyl, C3-C6 cycloalkyl, or monocyclic heterocyclyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from hydroxy, amino, amido, and cyano; or R1is taken together with R2aand the atoms to which they are attached to form a ring;X4is CR2cor N; X5is CR2dor N; X6is CR3aor N; X7is CR3bor N; X8is CR3cor N; X9is CR3dor N;selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -NRxRy, -C(O)(C1-C6alkyl), cyano, aryl, C3-C6 cycloalkyl, heteroaryl, and heterocyclyl; wherein R2aand R2b, or R2band R2c, or R2cand R2dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; and wherein R3aand R3b, or R3band R3c, or R3cand R3dare optionally taken together with the carbon atoms to which they are attached to form an optionally substituted ring; Rxand Ryare each independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl; n is 0, 1, or 2; each R4is independently C1-C6alkyl; or two R4, together with the atom(s) to which they are attached, are taken together to form a ring; R5is H or C1-C4alkyl; R6aand R6bare each independently selected from hydrogen and C1-C6 alkyl, or R6aand R6bare taken together with the carbon atom to which they are attached to form an optionally substituted ring; and A is a 6- to 8-membered ring.

75. The method of claim 74, or a pharmaceutically acceptable salt thereof, wherein Q is O.

76. The method of claim 74, or a pharmaceutically acceptable salt thereof, wherein Q is NH.

77. The method of any one of claims 74-76, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C3alkyl, C3-C4cycloalkyl, or a monocyclic 4- or 5-membered heterocyclyl having one heteroatom selected from N and O, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from -OH, -NH2, -N(CH3)2, and -C(O)NH2.

78. The method of claim 77, or a pharmaceutically acceptable salt thereof, wherein R1is selected from methyl, ethyl, cyclopropyl, azetidinyl, -CH2CH2NH2, -CH2CH2N(CH3)2, - CH2CH2OH, and -CH2C(O)NH2.

79. The method of any one of claims 74-78, or a pharmaceutically acceptable salt thereof, wherein R1is C2-C4 alkyl.

80. The method of claim 79, or a pharmaceutically acceptable salt thereof, wherein R1is ethyl.

81. The method of any one of claims 74-80, or a pharmaceutically acceptable salt thereof, wherein X1is N.

82. The method of any one of claims 74-80, or a pharmaceutically acceptable salt thereof, wherein X1is CH.

83. The method of any one of claims 74-42, or a pharmaceutically acceptable salt thereof, wherein X2is CR2a, X3is CR2b, X4is CR2c, X5is CR2d, one of R2a, R2b, R2c, and R2dis selected from hydrogen, halo, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, or -C(O)(C1-C2 alkyl), and the other three of R2a, R2b, R2c, and R2dare hydrogen.

84. The method of claim 83, or a pharmaceutically acceptable salt thereof, wherein one of R2a, R2b, R2c, and R2dis selected from hydrogen, fluoro, chloro, bromo, methyl, trifluoromethyl, -COOCH3, and ethoxy.

85. The method of any one of claims 74-82, or a pharmaceutically acceptable salt thereof, wherein X2is CR2a.

86. The method of claim 85, or a pharmaceutically acceptable salt thereof, wherein R2ais hydrogen or halo.

87. The method of claim 86, or a pharmaceutically acceptable salt thereof, wherein R2ais hydrogen.

88. The method of any one of claims 74-82, or a pharmaceutically acceptable salt thereof, wherein X2is N.

89. The method of any one of claims 74-82 and 85-88, or a pharmaceutically acceptable salt thereof, wherein X3is CR2b.

90. The method of claim 89, or a pharmaceutically acceptable salt thereof, wherein R2bis hydrogen, halo, C1-C3 alkyl, C1-C3 haloalkyl, -C(O)O(C1-C3 alkyl), and a monocyclic 5- or 6- membered heterocyclyl having 1 or 2 heteroatoms independently selected from O and N.

91. The method of claim 90, or a pharmaceutically acceptable salt thereof, wherein R2bis hydrogen or halo.

92. The method of any one of claims 74-82 and 85-91, or a pharmaceutically acceptable salt thereof, wherein X4is CR2c.

93. The method of claim 92, or a pharmaceutically acceptable salt thereof, wherein R2cis hydrogen, halo, C1-C3haloalkyl, C1-C3alkoxy, -NRxRy, or cyano, wherein Rxis hydrogen and Ryis C1-C3 hydroxyalkyl.

94. The method of claim 93, or a pharmaceutically acceptable salt thereof, wherein R2cis hydrogen.

95. The method of any one of claims 74-82 and 85-91, or a pharmaceutically acceptable salt thereof, wherein X4is N.

96. The method of any one of claims 74-82 and 85-88, or a pharmaceutically acceptable salt thereof, wherein X3is CR2b, X4is CR2c, and R2band R2care taken together with the carbon atoms to which they are attached to a 5- or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O.

97. The method of any one of claims 74-82 and 85-96, or a pharmaceutically acceptable salt thereof, wherein X5is CR2d.

98. The method of claim 97, or a pharmaceutically acceptable salt thereof, wherein R2dis hydrogen or halo.

99. The method of claim 98, or a pharmaceutically acceptable salt thereof, wherein R2dis hydrogen.

100. The method of any one of claims 74-82 and 85-96, or a pharmaceutically acceptable salt thereof, wherein X5is N.

101. The method of any one of claims 74-100, or a pharmaceutically acceptable salt thereof, wherein the grouphas a structure selected from:

102. The method of any one of claims 39-47, or a pharmaceutically acceptable salt thereof, wherein X6is CR3a, X7is CR3b, X8is CR3c, X9is CR3d, one of R3a, R3b, R3c, and R3dis selected from hydrogen, halo, C1-C2 alkyl, and C1-C2 alkoxy, and the other three of R3a, R3b, R3c, and R3dare hydrogen.

103. The method of claim 102, or a pharmaceutically acceptable salt thereof, wherein one of R3a, R3b, R3c, and R3dis selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, or methoxy.

104. The method of any one of claims 74-101, or a pharmaceutically acceptable salt thereof, wherein X6is CR3aand R3ais hydrogen.

105. The method of any one of claims 74-101, or a pharmaceutically acceptable salt thereof, wherein X6is N.

106. The method of any one of claims 74-101 and 104-105, or a pharmaceutically acceptable salt thereof, wherein X7is CR3b.

107. The method of claim 106, or a pharmaceutically acceptable salt thereof, wherein R3bis selected from hydrogen, halo, C1-C3 alkyl, cyano, phenyl, and monocyclic 5- or 6- membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S.

108. The method of claim 106, or a pharmaceutically acceptable salt thereof, wherein R3bis halo.

109. The method of any one of claims 74-101 and 104-108, or a pharmaceutically acceptable salt thereof, wherein X8is CR3c.

110. The method of claim 109, or a pharmaceutically acceptable salt thereof, wherein R3cis selected from hydrogen, halo, C1-C3alkoxy, and -NRxRy, wherein Rxand Ryare each hydrogen.

111. The method of claim 110, or a pharmaceutically acceptable salt thereof, wherein R3cis hydrogen.

112. The method of any one of claims 74-101 and 104-108, or a pharmaceutically acceptable salt thereof, wherein X8is N.

113. The method of any one of claims 74-101 and 104-112, or a pharmaceutically acceptable salt thereof, wherein X9is CR3d.

114. The method of claim 113, or a pharmaceutically acceptable salt thereof, wherein R3dis selected from hydrogen, halo, C1-C3alkyl, and -NRxRy, wherein Rxand Ryare each hydrogen.

115. The method of claim 114, or a pharmaceutically acceptable salt thereof, wherein R3dis hydrogen.

116. The method of any one of claims 74-101 and 104-112, or a pharmaceutically acceptable salt thereof, wherein X9is N.

117. The method of any one of claims 74-116, or a pharmaceutically acceptable salt thereof, wherein A is a six-membered ring.

118. The method of claim 117, or a pharmaceutically acceptable salt thereof, wherein A is a piperazine ring.

119. The method of any one of claims 74-118, or a pharmaceutically acceptable salt thereof, wherein n is 0.

120. The method of any one of claims 74-118, or a pharmaceutically acceptable salt thereof, wherein n is 2, and wherein the two R4are taken together with the atom(s) to which they are attached to form a ring.

121. The method of any one of claims 74-118, or a pharmaceutically acceptable salt thereof, wherein the grouphas a formula selected from:

122. The method of any one of claims 74-121, or a pharmaceutically acceptable salt thereof, wherein R5is H.

123. The method of any one of claims 74-122, or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare each hydrogen.

124. The method of any one of claims 74-122, or a pharmaceutically acceptable salt thereof, wherein R6ais hydrogen and R6bis methyl.

125. The method of any one of claims 74-122, or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkyl ring.

126. The method of claim 74, wherein the compound of formula (II) has a structure selected from:and pharmaceutically acceptable salts thereof.

127. The method of any one of claims 74-126, wherein the administering step comprises administering to the subject a pharmaceutical composition comprising the compound of formula (II) and a pharmaceutically acceptable carrier.

128. The method of any one of claims 74-126, further comprising a step of detecting and / or quantifying the amount of TRIM21 in a sample obtained from the subject, and subsequently administering the effective amount of the compound of formula (II), or the pharmaceutically acceptable salt thereof, to the subject based on the presence or amount of TRIM21 detected and / or quantified in the sample.

129. The method of claim 128, further comprising comparing the amount of TRIM21 to a reference level and identifying the subject as having a TRIM21-associated cancer when the amount of TRIM21 is greater than or equal to the reference level.

130. The method of claim 128 or claim 129, wherein the sample comprises blood or a blood product, tumor tissue or suspected tumor tissue, lymph node tissue, urine, or saliva.

131. The method of any one of claims 74-130, wherein the TRIM21-associated cancer is a cancer associated with a mutation in and / or increased activity of TRIM21.

132. The method of any one of claims 74-131, wherein the cancer is selected from pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, multiple myeloma, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, leukemia, lymphoma, prostate cancer, and sarcoma.

133. The method of any one of claims 74-132, further comprising treating the subject with one or more additional therapies selected from chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy, or any combination thereof.

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