WO2025024249A1

WO2025024249A1 - Ligands and compositions and methods of use thereof

Info

Publication number: WO2025024249A1
Application number: PCT/US2024/038669
Authority: WO
Inventors: Lindsey Ingerman JAMES; Jarod Michael WAYBRIGHT; Thomas Franklin WESTBROOK
Original assignee: Baylor College Of Medicine; The University Of North Carolina At Chapel Hill
Priority date: 2023-07-21
Filing date: 2024-07-19
Publication date: 2025-01-30

Abstract

The present invention relates to ligands for M-phase phosphoprotein (MPP8) and pharmaceutical compositions thereof and their utility as anti-cancer agents.

Description

LIGANDS AND COMPOSITIONS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The present invention is directed to ligands for M-phase phosphoprotein (MPP8) and pharmaceutical compositions thereof and their utility as anti-cancer agents. BACKGROUND Cancer is the second leading cause of death in the US. In 2017, about 1.7 million people were diagnosed with cancer and 0.6 million people died from the disease. Drug resistance and the resulting ineffectiveness of the drug treatment are responsible for up to 90% of the cancer-related deaths. Drug resistance in cancer is a well-known phenomenon that results when cancer becomes tolerant to pharmaceutical treatment. Resistance to anti-cancer drugs arises from a wide variety of factors, such as genetic mutations and/or epigenetic changes, conserved but upregulated drug efflux, and various other cellular and molecular mechanisms. Current major treatments for cancer management include surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy and immunotherapy. Despite the achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs continue to be a major problem in cancer therapies and responsible for most relapses, one of the major causes of death in cancer. Many classical chemotherapeutic anti-cancer agents kill cancer cells by directly damaging their DNA, which has the problem of non-specificity and relatively high toxicity. In recent decades, more and more targeted drugs have been developed to precisely target/block changes that drive cancer growth and proliferation. Although these drugs show remarkable effects during initial treatment, a large majority of patients develop resistance as treatment proceeds. For example, 30%-55% of patients with non-small cell lung cancer (NSCLC) relapse and die from the disease afterwards. The 50%-70% of ovarian adenocarcinomas reoccur within one year after surgery and associated chemotherapy. About 20% of pediatric acute lymphoblastic leukemia patients develop recurrence. Thus, due to growing occurrence of drug resistance to current traditional anti-cancer drugs employed in treating cancer, there has been an ongoing need for improving anti-cancer therapies and/or developing new treatment options, which can act via different cellular mechanisms to combat cancers. SUMMARY Provided herein are ligands, which can bind to M-phase phosphoprotein 8 (MPP8) protein. MPP8 was initially identified as a methyl-H3K9-binding protein, exhibiting increased expression levels in various human tumor cells. Further analysis revealed that MPP8 plays an important role in tumor cell invasion and migration. Mechanically, MPP8 targets the E-cadherin gene promoter and mediates the expression of this critical regulator of EMT via its methyl-H3K9 binding ability (Yuan, Bo et al., Int. J. Clin. Exp. Pathol., 2017, 10 (12), 12003-12009). MPP8 is a component of the Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin. The complex recruits the histone methyl-transferase SETDB1 to spread H3K9me3 repressive marks across genes and transgenes in an integration site-dependent manner. The deposition of these repressive marks leads to heterochromatin formation and inhibits gene expression. Proteins that interpret these marks, often referred to as “readers,” are important in chromatin regulation as they are often members of or are essential in the establishment of protein complexes that alter chromatin structure, making them an important node for cell signaling. MPP8 has been identified as a histone 3 lysine 9 trimethyl (H3K9me3) reader being vital for heterochromatin formation and more importantly is implicated in cancer metastasis. Thus, one aspect of the current disclosure is directed to a MPP8 ligand. In some embodiments, the ligands disclosed herein acts as an antagonist. One aspect of the current disclosure is directed to a compound of Formula (III):

Formula (III) wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, - NHR6, -NR6R7, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1- C6)alkoxy, and substituted or unsubstituted (C1-C6)aromatic oxy, wherein R₆ and R₇ are independently selected from –H and (C1-C6)alkyl; R3, R4, and R5 are independently selected from –H and (C1-C6)alkyl; W is C or N; X is halo or sulfonate; Y is selected from substituted or unsubstituted (C3-C8)cycloalkyl and substituted or unsubstituted (C4-C8)heterocycloalkyl m and p are independently selected from integers 1, 2, and 3; and n is selected from integers 2, 3, 4, 5, and 6, and any pharmaceutically acceptable salt or stereoisomer thereof. Another aspect of the disclosure is directed to a pharmaceutical composition comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s). Another aspect of the disclosure is directed to a method for treating a disease or condition that is treatable by inhibition of the MMP8 protein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition as disclosed herein. In some embodiments, the disease is cancer. DESCRIPTION OF THE DRAWINGS FIG.1 shows in vitro results of Compound 12 in selective cell death. Compound 12 induces cell death in a subset of TNBC cell lines but has no effect on “normal” cells; FIG.2 shows the results of in vitro metabolic study using mice liver microsomes (MLM) to investigate the time-dependent loss of positive control imipramine; FIG. 3 shows the results of in vitro metabolic study using MLM to investigate the time- dependent loss of test Compound 12; FIG. 4 shows the mean plasma concentration vs time profile of a formulation containing Compound 12 administered at 3 mg/kg i.v. in CD1 mice; FIG.5 shows a schematic diagram of in vivo CRISPR screen. The effect on cellular viability is measured after infection of a custom pool of sgRNA containing HUSH components and controls in the MDA-MB-231-LM2 xenograft model; FIG. 6 shows the results of the in vivo CRISPR screen as a bar graph. The normalized log2 fold changes for each sgRNA targeting multiple components of the HUSH complex in the dox treated condition are plotted on the y-axis; FIG. 7 shows a graph illustrating that MPP8 knockout impairs growth of TNBC tumor xenografts. WT or MPP8 KO LM2 cells were injected subcutaneously into mice and tumor growth was measured twice weekly; FIG. 8 shows a bar graph illustrating that the pharmacologic inhibition of MPP8 impairs TNBC tumor growth. Mice were injected subcutaneously with LM2 cells and then treated twice weekly with 10 mg/kg of liposomes loaded with vehicle, Compound 12, or Compound 3 for 2 weeks; FIG. 9 shows a bar graph illustrating that Compound 12 treatment impairs TNBC primary tumor growth in vivo. Cells were pre-treated with vehicle or 2 µM Compound 12 and then injected with luciferase-labeled LM2 cells subcutaneously. Primary tumor size was measured twice weekly; FIG.10 shows that Compound 12 treatment impairs TNBC metastasis in vivo. Cells were pre- treated with vehicle or 2 µM Compound 12 and then injected with luciferase-labeled LM2 cells by tail vein. After 21 days, lung metastatic burden was measured using IVIS: FIG.11 shows a graph the of the pharmacokinetic (PK) properties of liposomal encapsulated Compound 12 following IV injection at 3 mg/kg; FIG.12 shows a table the of the pharmacokinetic (PK) properties of liposomal encapsulated Compound 12 following IV injection at 3 mg/kg; FIG. 13 shows various MALDI-TOF MS spectra demonstrating increased covalent labeling of MPP8 CD by Compound 3 as compared to Compound 12 under identical incubation conditions ([MPP8] = 10μM, [ligand] = 20μM, incubation time: 30 min); Fig.14 shows a graph illustrating that Compound 3 (Compd.3) causes increased cell death in MYC-hyperactivated HMECs compared to Compound 12 (Compd.12); and FIG.15 shows a graph illustrating that Compound 12 (Compd.12) and Compound 3 (Compd. 3) induce cell death in MYC-hyperactivated TNBC cells. MDA-MB-231-LM2 cells were treated with the indicated doses of UNC7713 or UNC8364 and cell viability was measured 72 hours after treatment by PI staining. DETAILED DESCRIPTION The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including, but not limited to, defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Since drug resistance is the main limitation for cancer therapy, other treatment strategies are needed. One such strategy targets the M-phase phosphoprotein 8 (MPP8). There are currently no known small molecule ligands (e.g., antagonists) that bind to MPP8 and/or can be used in oncology or immune-oncology. Not to be bound by theory, but it is believed that a small molecule ligand that binds to MPP8 and prevents H3K9me3 recognition could serve as an important tool in the validation of MPP8 as a drug target in oncology. Using a time-resolved fluorescence energy transfer assay, a library of compounds that are biased to interact with methyl-lysine (Kme) reader proteins and methyltransferases were screened for MPP8 binding activity. This screen revealed a series of quinazoline-based compounds, which are disclosed herein. It was found that a nucleophilic cysteine was present adjacent to the binding site of the MPP8 ligands, so these ligands were further modified to include a reactive electrophilic moiety. The resultant compounds were able to achieve covalent binding to the chromodomain, as determined by mass spectrometry. Furthermore, additional studies set out to identify MYC selective dependencies in triple negative breast cancer (TNBC) as an entry point for therapeutic hypotheses and small molecule development. A series of studies demonstrated the effects MPP8 ligands have on various TNBC cell lines in vitro and in vivo. Not to be bound by theory, but it is believed that the MPP8 ligands disclosed herein exhibiting cell death in a subset of TNBC cells while not impacting cell viability in normal cell types, strongly support the notion that MPP8 antagonism is MYC synthetic lethal. Notably, when the chromodomain cysteine is mutated to an alanine, blocking the ability of MPP8 ligands to engage MPP8 in a covalent fashion, cell death is not observed upon treatment with such ligands. This further confirms the ligands’s mechanism of action and on-target activity. These MPP8 ligands, pharmaceutical compositions containing these ligands, and methods of use thereof are described further in more detail below. A poster was presented at the 2023 AACR Annual Meeting at the Orange County Convention Center in Orlando, Florida on April 19, 2023 (see Stephany Gonzalez Tineo et al.“Evaluating potency of a first in-class covalent antagonist of the H3K9me3 reader protein MPP8 in bladder cancer” abstract #6283). This poster originated from the inventors own work. I. Definitions As used herein, the term “reader protein” refers to proteins that bind to histone tails and their post-translational modifications (PTMs) such as acetylation, methylation and phosphorylation, to recruit components of the transcriptional machinery and chromatin remodeling complexes. The term “antagonist” refers to a compound that binds to the cellular target protein, but does not cause any physiological changes unless another ligand is present. As used herein, the term “alkyl group” refers to a saturated hydrocarbon radical containing 1 to 8, 1 to 6, 1 to 4, or 5 to 8 carbons. In some embodiments, the saturated radical contains more than 8 carbons. An alkyl group is structurally similar to a noncyclic alkane compound modified by the removal of one hydrogen from the noncyclic alkane and the substitution therefor of a non-hydrogen group or radical. Alkyl group radicals can be branched or unbranched. Lower alkyl group radicals have 1 to 4 carbon atoms. Higher alkyl group radicals have 5 to 8 carbon atoms. Examples of alkyl, lower alkyl, and higher alkyl group radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, t butyl, amyl, t amyl, n-pentyl, n-hexyl, i-octyl and like radicals. The term “halo” refers to halogens such as Chlorine (C), Bromine (Br), Fluorine (F) and Iodine (I). The term “cycloalkyl” refers to a hydrocarbon with 3-8 members or 3-7 members or 3-6 members or 3-5 members or 3-4 members and can be monocyclic or bicyclic. The ring may be saturated or may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term “heterocycloalkyl” refers to a molecule with 3-8 members or 3-7 members or 3-6 members or 3-5 members or 3-4 members and can be monocyclic or bicyclic, wherein at least one member is a heteroatom selected from nitrogen, oxygen and/or sulfur. The ring may be saturated or may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Examples include piperazine and/or morpholine moieties. The term “aryl” refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0,1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The term “benzyl” refers to a substituent or molecular fragment possessing the structure C6H5CH2–. Benzyl features a benzene ring attached to a CH2 group. The term “aromatic oxy” refers to a substituent or molecular fragment possessing the structure C6H5O–. Benzyl features a benzene ring attached to an oxygen atom (BnO). As used herein, the term “alkoxy” refers to a moiety of the formula—ORa where Ra is an alkyl group as defined herein containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted. As used herein, the term “substituted” refers to a moiety (such as benzyl, aromatic oxy, aryl, cycloalkyl, alkyl, and/or heterocycloalkyl) wherein the moiety is bonded to one or more additional organic or inorganic substituent radicals. In some embodiments, the substituted moiety comprises 1, 2, 3, 4, or 5 additional substituent groups or radicals. Suitable organic and inorganic substituent radicals include, but are not limited to, halogen, hydroxyl, cycloalkyl, aryl, substituted aryl, heteroaryl, heterocyclic ring, substituted heterocyclic ring, amino, mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkyl carboxamide, substituted alkyl carboxamide, dialkyl carboxamide, substituted dialkyl carboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, alkoxy, substituted alkoxy or haloalkoxy radicals, wherein the terms are defined herein. Unless otherwise indicated herein, the organic substituents can comprise from 1 to 4 or from 5 to 8 carbon atoms. When a substituted moiety is bonded thereon with more than one substituent radical, then the substituent radicals may be the same or different. As used herein, the term “unsubstituted” refers to a moiety (such as heteroaryl, aryl, alkenyl, and/or alkyl) that is not bonded to one or more additional organic or inorganic substituent radical as described above, meaning that such a moiety is only substituted with hydrogens. It will be understood that the structures provided herein and any recitation of “substitution” or “substituted with” includes the implicit proviso that such structures and substitution are in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “stereoisomer” refers to isomers that differ in spatial arrangement of atoms, rather than the order of their atomic connectivity. Examples include enantiomers and diastereomers. As used herein, the term “Tm” refers to the stability of a protein (e.g., MPP8). In general, Tm defines the midpoint temperature of a transistion where the folded and unfolded states of a protein are at equilibrium. The higher the Tm of a protein, the higher its thermal stability. The thermal stability of a protein can be modulated with the addition of a ligand, which can bind to the protein and either stabilize the protein (e.g. increase the Tm) or destabilitse the protein (e.g., decrease Tm) relative to its stability in its native state. These changes are expressed as ΔTm as a function of ligand concentration. As used herein, the term “subject” broadly refers to any animal, including, but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As used herein, the term “patient” typically refers to a subject that is being treated for a disease or condition. As used herein, the term “effective amount” refers to the amount of a composition sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like. As used herein, the terms “co-administration” and “co-administering” refer to the administration of at least two agent(s) (e.g., MPP8 antagonist and one or more additional therapeutics) or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy. Those of skill in the art understand that the formulations and/or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and/or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent. As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. The terms “pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject. As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference in its entirety. As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention, which upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. As used herein, the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term “a therapeutically effective amount” of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. As used herein, the term “anticancer agent” or anti-neoplastic agent, refers to a therapeutic agent that is useful for treating or controlling the growth of cancerous cells. The term “about” means that the values described may include ± 20% of the specific value, such as ± 10%, such as ± 5%, ± 1%, ± 0.5%, or ± 0.1% according to the invention, to implement the technical proposal of this invention. II. Compounds Provided herein are MPP8 ligands and methods of use thereof for the treatment of disease, such as cancers and other diseases dependent on the activity of MPP8. In some embodiments, the compounds disclosed herein comprise a compound of Formula (I):

Formula (I) wherein Q is absent or selected from

; R1, R2 and R7 are independently selected from –H, halo, -NO2, -OH, -OCF3, -CF3 -NH2, - NHR_6a, -NR_6aR_6b, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁- C6)alkoxy, and substituted or unsubstituted (C1-C6)aromatic oxy, wherein R6a and R6b are independently selected from –H and (C1-C6)alkyl; G is selected from

Z is –C- or –S(=O)-; R3, R4, and R5 are independently selected from –H and (C1-C6)alkyl; R_3a, R_3b, R_3c, and R_3d are independently selected from –H, halo, and (C₁-C₆)alkyl; R₉ is absent, –H, (C₁-C₆)alkyl, halo or –O- and connected via a bond to X which is –CH₂ forming an epoxide; R_8a and R_8b in each instance are independently selected from –H and halo; W is C or N; X is –H, -CCH3, -CH2, -CH3, -CHCH2N(CH3)2, -C=CH2, halo, sulfonate or absent; Y is selected from substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C₃-C₈)cycloalkyl, substituted or unsubstituted (C₄-C₈)heterocycloalkyl, substituted or unsubstituted benzyl, and -NH((C1-C8)alkyl); m and p are independently selected from integers 1, 2, and 3; n, o, and q are independently selected from integers 2, 3, 4, 5, and 6; and ---- represents a single, double bond, or triple bond; and any pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments,

In some embodiments, R8a and R8b are hydrogen. In some embodiments, R₇ is a substituted (C₁-C₆)alkoxy. In some embodiments, R₇ is –OCF₃. In some embodiments, R₁ and R₂ are –H and R₇ is –OCF₃. In some embodiments, R7 is H. In some embodiments, the pharmaceutically acceptable salt or stereoisomer of a compound of Formula (I) is a solvate. In some embodiments, the pharmaceutically acceptable salt or stereoisomer of a compound of Formula (I) is crystalline. In some embodiments, the compound disclosed herein comprises a compound of Formula (II): compound is a compound of formula (II)

wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, - NHR6a, -NR6aR6b, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1- C₆)alkoxy, and substituted or unsubstituted (C₁-C₆)aromatic oxy, wherein R_6a and R_6b are independently selected from –H and (C1-C6)alkyl; A is selected from

. R₃, R₄, and R₅ are independently selected from –H and (C₁-C₆)alkyl; R6 is absent, –H, (C1-C6)alkyl or halo; W is C or N; X is -CH₂, halo, -H or sulfonate; or absent; Y is selected from substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C₄-C₈)heterocycloalkyl and -NH((C₁-C₈)alkyl); m and p are independently selected from integers 1, 2, and 3; n is selected from integers 2, 3, 4, 5, and 6; ---- represents a single or double bond; and any pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, ---- represents a double bond and X is –CH2. In some embodiments, ---- represents a single bond. In some embodiments, R9 is halo. In some embodiments, R9 is –F. In some embodiments, R₉ is (C₁-C₈)alkyl. In some embodiments, R₉ is –CH₃. In some embodiments, the compound disclosed herein comprises a compound of Formula (III):

Formula (III) wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, - NHR_6a, -NR_6aR_6b, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁- C₆)alkoxy, and substituted or unsubstituted (C₁-C₆)aromatic oxy, wherein R_6a and R_6b are independently selected from –H and (C1-C6)alkyl; R3, R4, and R5 are independently selected from –H and (C1-C6)alkyl; W is C or N; X is halo or sulfonate; Y is selected from substituted or unsubstituted (C3-C8)cycloalkyl and substituted or unsubstituted (C₄-C₈)heterocycloalkyl; m and p are independently selected from integers 1, 2, and 3; and n is selected from integers 2, 3, 4, 5, and 6, and any pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, W is N. In some embodiments, Y is substituted or unsubstituted (C3-C8)cycloalkyl. In some embodiments, W is N and Y is substituted or unsubstituted (C₃-C₈)cycloalkyl. In some embodiments, m is 2. In some embodiments, W is N; Y is substituted or unsubstituted (C3-C8)cycloalkyl; and m is 2. In some embodiments, p is 2. In some embodiments, W is N; Y is substituted or unsubstituted (C₃-C₈)cycloalkyl; and p is 2. In some embodiments, m and p are 2. In some embodiments, W is N; Y is substituted or unsubstituted (C₃-C₈)cycloalkyl; m is 2; and p is 2. In some embodiments, n is 3. In some embodiments, the compound disclosed herein comprises a compound of

wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, - NHR6, -NR6R7, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)alkoxy, and substituted or unsubstituted (C₁-C₆)aromatic oxy, wherein R₆ and R₇ are independently selected from –H and (C1-C6)alkyl; R3, R4, and R5 are independently selected from –H and (C1-C6)alkyl; R_7a, R_7b, R_7c, R_7d, R_7e, R_7f, R_7g, and R_7h are independently selected from –H, halo, and substituted or unsubstituted (C₁-C₆) alkyl; X is selected from halo and sulfonates; and Y is selected from substituted or unsubstituted (C₃-C₈)cycloalkyl and substituted or unsubstituted (C4-C8)heterocycloalkyl; and stereoisomers thereof. In some embodiments, R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h are independently selected from –H, -F, and methyl. In some embodiments, X is halo. In some embodiments X is Cl. In some embodiments, R_7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h are independently selected from –H, -F, and methyl; and X is halo. In some embodiments, R3, R4 and R5 are independently selected from –H, methyl, and ethyl. In some embodiments, R_7a, R_7b, R_7c, R_7d, R_7e, R_7f, R_7g, and R_7h are independently selected from –H, -F, and methyl; X is halo; and R₃, R₄ and R₅ are independently selected from –H, methyl, and ethyl. In some embodiments, R5 is –H. In some embodiments, R3, R4 and R5 are independently selected from –H, methyl, and ethyl. In some embodiments, R_7a, R_7b, R_7c, R_7d, R_7e, R_7f, R_7g, and R_7h are independently selected from –H, -F, and methyl; X is halo; and R₅ is –H, methyl. In some embodiments, R3 and R5 are –H, and R4 is selected from –H, methyl, and ethyl. In some embodiments, R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h are independently selected from –H, -F, and methyl; X is halo; and R₃ and R₅ are –H, and R₄ is selected from –H, methyl, and ethyl. In some embodiments, R4 and R5 are-H, and R3 is selected from –H, methyl, and ethyl. In some embodiments, R5 is H, and R3 and R4 are independently selected from methyl and ethyl. In some embodiments, R_7a, R_7b, R_7c, R_7d, R_7e, R_7f, R_7g, and R_7h are independently selected from –H, -F, and methyl; X is halo; and R₅ is H, and R₃ and R₄ are independently selected from methyl and ethyl. In some embodiments, R₃, R₄, and R₅ are hydrogen. In some embodiments, R₅ is H, and R₃ and R₄ are independently selected from methyl and ethyl. In some embodiments, R_7a, R_7b, R_7c, R_7d, R7e, R7f, R7g, and R7h are independently selected from –H, -F, and methyl; X is halo; and R5 is H, and R₃, R₄, and R₅ are hydrogen. In some embodiments, the compound disclosed herein comprises a compound of Formula (IIIB):

Formula (IIIB) wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, - NHR₆, -NR₆R₇, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁-C₆)alkoxy, and substituted or unsubstituted (C1-C6)aromatic oxy, wherein R6 and R7 are independently selected from –H and (C₁-C₆)alkyl; R₄ is selected from –H and (C₁-C₆)alkyl; and Y is selected from substituted or unsubstituted (C4-C8)cycloalkyl. In some embodiments, R₁ and R₂ are independently selected from –H, halo, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁-C₆)alkoxy, and substituted or unsubstituted (C1-C6)aromatic oxy. In some embodiments, R1 and R2 are independently selected from –H, -F,-OCH3, -OBn, and -OCF₃. In some embodiments, R₁ and R₂ are -OCH₃. In some embodiments, Y is unsubstituted (C3-C8)cycloalkyl. In some embodiments, R1 and R2 are independently selected from –H, -F,-OCH3, -OBn, and -OCF3; and Y is unsubstituted (C₃-8)cycloalkyl. In some embodiments, Y is unsubstituted C₆-cycloalkyl. In some embodiments, R₁ and R₂ are independently selected from –H, -F,-OCH3, -OBn, and -OCF3; and Y unsubstituted C6-cycloalkyl. In some embodiments, R₄ is –H. In some embodiments, Y is unsubstituted C₆-cycloalkyl. In some embodiments, R₁ and R₂ are independently selected from –H, -F,-OCH₃, -OBn, and -OCF₃; Y unsubstituted C6-cycloalkyl; and R4 is –H. In some embodiments, the compound is

pharmaceutically acceptable salt or stereoisomer. In some embodiments, R4 is (C1-C6)alkyl. In some embodiments, R4 is –ethyl. In some embodiments, Y is unsubstituted C₆-cycloalkyl. In some embodiments, R₁ and R₂ are independently selected from –H, -F,-OCH₃, -OBn, and -OCF₃; Y unsubstituted C₆-cycloalkyl; and R₄ is ethyl. In some embodiments, the compound is

pharmaceutically acceptable salt or stereoisomer. A compound of any one of Formulae (I), (II), (III), (IIIA) and (IIIB) may be selected from the compound listed in Table 1. Compounds of Formulae (I), (II), (III), (IIIA) and (IIIB) that are not listed in Table 1 are also within the scope herein. Table 1

The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and/or recrystallization or by the forming diastereomers and separation thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art. In some embodiments, the compounds disclosed herein are enantiomers having an enantiomeric excess (% ee) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are diastereomers having a diastereomeric excess (% de) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are present as enantiomeric or diastereomeric mixtures. The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In some embodiments, the compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutically acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In some embodiments, the compounds and salts described herein include isotopically labeled compounds. In general, isotopically labeled compounds are identical to those recited in the various formulae and structures presented herein, 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 most common in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certain isotopically labeled compounds described herein, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the compounds disclosed herein bind to or inhibit the MMP8 protein and exhibit a ΔTm ranging from about 1 µM to about 50 µM, from about 10 µM to about 40 µM, from about 15 µM to about 35 µM, from about 20 µM to about 35 µM, or from about 25 µM to about 35 µM. In some embodiments, the disclosed compounds exhibit a ΔTm of less than about 40 µM, about 35 µM, about 30 µM, about 25 µM, or less than about 20 µM. In some embodiments, the compounds disclosed herein bind to or inhibit the MMP8 protein and exhibit a % labeling from about 1% to about 99%, from about 10% to about 95%, from about 15% to about 90%, from about 20% to about 85%, from about 25% to about 80%, from about 30% to about 70%, or from about 35% to about 60%. In some embodiments, the compounds disclosed herein bind or inhibit the MMP8 protein and exhibit a % Cell Death from about 30% to about 99%, from about 40% to about 95%, from about 50% to about 95%, from about 55% to about 90%, from about 60% to about 85%, or from about 60% to about 80%. The table below shows exemplary compounds disclosed herein, wherein the ΔTm, % labeling, and % cell death were determined with the methods disclosed herein.

III. Pharmaceutical Compositions In certain embodiments, compounds or salts of Formulae (I), (II), and/or (III) disclosed herein, are combined with one or more additional agents to form pharmaceutical compositions. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure. A pharmaceutical composition, as used herein, refers to a mixture of a compound or salt of Formulae (I), (II) and/or (III) with any suitable substituents and functional groups disclosed herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds or salts of Formulae (I), (II), and/or (III) with any suitable substituents and functional groups disclosed herein can be used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy). The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. Moreover, the pharmaceutical compositions described herein, which include a compound of Formulae (I), (II) and/or (III) or a salt thereof with any suitable substituents and functional groups disclosed herein, can be formulated into any suitable dosage form, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules. One may administer the compounds and/or compositions in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often in a depot preparation or sustained release formulation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. In addition, the drug may be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. The pharmaceutical compositions will include at least one compound of Formulae (I), (II), and/or (III) or a salt thereof as disclosed herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In some embodiments, compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. In some embodiments, the pharmaceutical solid dosage forms described herein can include a compound of Formulae (I), (II) and/or (III) or salt thereof and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound described herein. In one embodiment, some or all of the particles of the compound described herein are coated. In another embodiment, some or all of the particles of the compound described herein are microencapsulated. In still another embodiment, the particles of the compound described herein are not microencapsulated and are uncoated. Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like. Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. Suitable binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like. Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like. Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol. There is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein. Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757 (2002). The pharmaceutical compositions described herein may include sweetening agents such as, but not limited to, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Potential excipients for intranasal formulations include formulation solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents. See, e.g., Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions. For administration by inhalation, the compounds described herein may be in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch. Buccal formulations that include compounds described herein may be administered using a variety of formulations which include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound is provided essentially throughout. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. With regard to the bioerodible (hydrolysable) polymeric carrier, virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compounds described herein, and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water- swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as “carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is one such polymer). Other components may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. Transdermal formulations described herein may incorporate certain pharmaceutically acceptable excipients which are conventional in the art. In some embodiments, formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. For intravenous injections, compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the field. For other parenteral injections, appropriate formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field. Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulary agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. In certain embodiments, the delivery system for pharmaceutical compounds is lipid-based formulation. Exemplary lipids that can be employed in such delivery systems include, but are not limited to, triglyceride oils, partial glycerides, surfactants, co-surfactants, and any combination thereof. In some embodiments, the lipid-based formulation comprises triglyceride oils derived from vegetable oils. In some embodiments, the lipid-based formulation comprises surfactants that can be water-insoluble surfactants or water-soluble surfactants or a combination of both. In some embodiments, the lipid-based formulation contains a surfactant that is a phospholipid. In some embodiments, the phospholipid is selected from a group consisting of dipalmitoylphosphatidylcholine (DPPC) (a phospholipid consisting of two C16 palmatic acid groups attached to a phosphatidylcholine head group), distearoylphosphatidylcholine (DSPC) (a phospholipid consisting of two C18 stearic acid groups attached to a phosphatidylcholine head group) and a combination thereof. In some embodiments, the compounds of Formulae (I), (II), and/or (III) are formulated in a lipid-based formulation comprising DPPC and/or DSPC. The loading of the compound of Formulae (I), (II), and/or (III) in such a lipid-based formulation can vary. For example, the loading ranges from about 5% to about 20%, about 7% to about 18%, about 8% to about 15%, about 9% to about 14%, or about 10% to about 12% by weight based on the total weight of the lipid-based formulation. In some embodiments, the compounds described herein may be administered topically and are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted. In some embodiments, the compounds of Formulae (I), (II), and/or (III) or salt thereof as disclosed herein are combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof. In another embodiment, the compounds of Formulae (I), (II) and/or (III) or salts thereof as disclosed herein are combined with another therapeutic agent capable of inhibiting BRAF, MEK, CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof. Generally, an agent, such as a compound of Formulae (I), (II), and/or (III) or salts thereof as disclosed herein, is administered in an amount effective for treating the disease or disorder (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that is capable of at least partially treating, preventing or reversing a disease or disorder. The dose required to obtain an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered. Determination of effective amounts may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies. An agent can be administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease or disorder. In some embodiments, an agent is administered to a subject with a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder. In some embodiments, the compositions described herein are provided as pharmaceutical and/or therapeutic compositions. The pharmaceutical and/or therapeutic compositions of the present disclosure can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intra- arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers; aqueous, powder, or oily bases; thickeners; and the like can be necessary or desirable. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. Compositions and formulations for parenteral, intrathecal or intraventricular administration can include sterile aqueous solutions that can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Pharmaceutical and/or therapeutic compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. The pharmaceutical and/or therapeutic formulations, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical/nutraceutical industries. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present disclosure can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present disclosure can also be formulated as suspensions in aqueous, non-aqueous, oil-based, or mixed media. Suspensions can further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension can also contain stabilizers. In one embodiment of the present disclosure, the pharmaceutical compositions can be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature, these formulations vary in the components and the consistency of the final product. The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. Dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well-known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect, and the practical level of therapeutic effect obtainable. Generally, it is advisable to follow well-known pharmacological principles for administrating chemotherapeutic agents (e.g., it is generally advisable to not change dosages by more than 50% at a time and no more than every 3-4 agent half-lives). For compositions that have relatively little or no dose-related toxicity considerations, and where maximum efficacy is desired, doses in excess of the average required dose are not uncommon. This approach to dosing is commonly referred to as the “maximal dose” strategy. In certain embodiments, the compounds are administered to a subject at a dose of about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. Dosing may be once per day or multiple times per day for one or more consecutive days. IV. Methods of Treatment The present disclosure provides compounds and methods for inhibiting and/or antagonizing the activity of the M-phase phosphoprotein 8 (MPP8). In some embodiments, the present disclosure provides compounds and methods that bind inhibit and/or antagonizes MPP8 activity. In some embodiments, the present disclosure provides compounds that are MPP8 antagonists. Binding to MPP8 and/or inhibition of MPP8 activity may be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include measure (a) a direct decrease in MPP8 activity; (b) a decrease in cell proliferation and/or cell viability; (c) a decrease in gene expression; (d) a decrease in the levels of downstream targets of MPP8 activity; (e) a decrease in heterochromatin formation; and (f) a decrease in tumor volume and/or tumor volume growth rate. Kits and commercially available assays can be utilized for determining one or more of the above. Binding of compounds disclosed herein to the MPP8 protein can be determined using known methods in the arts, such as, but not limited to, time-resolved fluorescence energy transfer (TR-FRET). The disclosure provides compounds and methods for treating a subject suffering from a disease, comprising administering a compound or salt described herein, for example, a compound or salt of Formulae (I), (II) and/or (III) or salts thereof as disclosed herein, to the subject. In some embodiments, the disease is selected from a disease associated with MPP8 expression (e.g., aberrant expression, overexpression, etc.) and/or activity (e.g., cancer). In certain embodiments, the disease is mediated by MPP8 activity and/or expression (e.g., aberrant expression, overexpression, etc.). In some embodiments, the disease or condition is treatable by inhibition of and/or antagonizing of the MPP8 protein. In some embodiments, the method comprises treating a disease or condition that is treatable by inhibition of MPP8 by administering to a subject in need thereof a therapeutically effective amount of a compound or a salt thereof of Formulae (I), (II), and/or (III) or a pharmaceutical composition as disclosed herein. In some embodiments, such a disease or condition to be treated is selected from diseases or conditions in the fields of oncology, inflammation, immuno-oncology, immunology, and autoimmunology. In some embodiments, the disclosure provides a method for treating cancer in a subject, comprising administering a compound or salt described herein, for example, a compound or salt of Formulae (I), (II), and/or (III) or salts thereof as disclosed herein, to the subject. In some embodiments, the cancer is mediated by a MPP8 expression (e.g., aberrant expression, overexpression, etc.) and/or activity. In some embodiments, the cancer is a MYC-driven cancer. In certain embodiments, the disclosure provides method of treating a disease in a subject, wherein the method comprises determining if the subject has an MPP8-mediated condition (e.g., cancer) and administering to the subject a therapeutically effective dose of a compound or salt described herein, for example, a compound or salt of Formulae (I), (II), and/or (III) or a salt thereof as disclosed herein. Determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) MPP8 can be undertaken by assessing the nucleotide sequence encoding MPP8 or by assessing the amino acid sequence of MPP8. Methods for detecting an MPP8 nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. Methods for detecting an MPP8 protein are known by those of skill in the art. These methods include, but are not limited to, detection using a binding agent, e.g., an antibody, specific for MPP8, protein electrophoresis and Western blotting, and direct peptide sequencing. Methods for determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) MPP8 or is mediated by MPP8 activity can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In certain embodiments, the disclosure provides a method of inhibiting and/or antagonizing MPP8 activity in a sample, comprising administering the compound or salt described herein to said sample comprising MPP8. The disclosure provides methods for treating a disease by administering a compound or salt of Formulae (I), (II), and/or (III) or salt thereof as disclosed herein to a subject suffering from the disease, wherein the compound binds to MPP8 and/or inhibits MPP8 activity and/or antagonizes MPP8 activity. In some embodiments, the compound covalently binds to MPP8. In some embodiments, the compound covalently binds to the –SH group of the side chain of a cysteine amino acid present in the MPP8 protein. The disclosure also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to the mammal a therapeutically effective amount of a compound or salt of Formulae (I), (II), and/or (III) with any suitable substituents and functional groups disclosed herein. In some embodiments, such hyperproliferative disorders are non-cancerous, such as, but not limited to benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH). In some embodiments, such hyperproliferative disorders are cancerous. In some embodiments, such hyperproliferative disorders are MYC-driven cancers. In some embodiments, the method relates to the treatment of cancer such as acute myeloid leukemia (AML), cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., lymphoma and Kaposi’s Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt’s lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. In some embodiments, the method relates to the treatment of MYC-driven cancers. Cancers are optionally classified prior to treatment to determine suitability of an individual for the treatment. Methods of analysis for classification may include, without limitation, cytometry profiling by FACS, mass cytometry, etc.; phospho-cytometry; quantitative PCR, optionally combined with CIBERSORT, sequencing, microarray analysis; and the like, to determine the status of MYC and MYC-related pathways in the cancer cells; and/or to determine the immunobiology status of the patient. MYC status may be monitored by determining expression levels and/or phosphorylation status of MYC, STAT1, STAT2, etc. In some embodiments, the classification step may include analyzing a gene expression profile of the patient sample. In some embodiments, the method relates to the treatment of cancers selected from the group consisting of breast, liver, colorectal, neuroblastoma, AML, and lymphoma cancers. In some embodiments, the method relates to the treatment of breast cancer, wherein the type of breast cancer is selected from invasive ductal carcinoma, invasive lobular carcinoma, inflammatory breast cancer, Paget’s disease of the breast, angiosarcoma of the breast, phyllodes tumors, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), HER2 breast cancer, triple-negative breast cancer (TNBC), and metastatic breast cancer. In some embodiments, the method relates to a decrease in tumor volume and/or growth rate when an effective amount of a compound as disclosed herein is being administered to a subject in need thereof. In such embodiments, the decrease in tumor volume ranges from about 1% to about 99%, from about 1% to about 90%, from about 10% to about 80%, from about 20% to about 75%, from about 25% to about 70%, from about 30% to about 65%, from about 35% to about 60%, from about 35% to about 55%, from about 35% to about 50%, or from about 40% to about 50%. In some embodiments, the decrease in tumor volume is at least about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or at least about 95%. In such embodiments, the decrease in tumor growth rate ranges from about 1% to about 99%, from about 5% to about 90%, from about 10% to about 85%, from about 15% to about 80%, from about 20% to about 75%, from about 25% to about 70%, from about 30% to about 65%, from about 35% to about 60%, from about 40% to about 55%, or from about 40% to about 50%. In some embodiments, the decrease in tumor growth rate is at least about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or at least about 95%. Subjects that can be treated with compounds of Formulae (I), (II), and/or (III) or salts thereof as disclosed herein, or pharmaceutically acceptable salt of the compounds, according to the methods of this disclosure include, for example, subjects that have been diagnosed as having acute myeloid leukemia (AML), acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., lymphoma and Kaposi’s Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt’s lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T- Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, viral-induced cancer, leukemia, hematologic malignancy, solid tumor cancer, castration-resistant prostate cancer, Ewing’s sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or diabetes. In some embodiments, subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a MYC-driven cancer. The MYC oncogene drives the pathogenesis of many hematopoietic malignancies, including, but not limited to, Burkitt’s lymphoma (BL), Diffuse large B cell lymphoma (DLBCL) and Acute Lymphoblastic Leukemia (ALL). These malignancies are often “oncogene-addicted” to MYC. Cancer cells suspected of being associated with MYC can be assessed for over-expression of MYC. In some embodiments, subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed cancers selected from the group consisting of breast, liver, colorectal, neuroblastoma, AML, and lymphoma cancers. In some embodiments, the subjects have been diagnosed with breast cancer, wherein the type of breast cancer is selected from invasive ductal carcinoma, invasive lobular carcinoma, inflammatory breast cancer, Paget’s disease of the breast, angiosarcoma of the breast, phyllodes tumors, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), HER2 breast cancer, triple-negative breast cancer (TNBC), and metastatic breast cancer. In some embodiments, subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH). In some embodiments, subjects that are treated with the compound of the disclosure exhibit a decrease in tumor volume and/or tumor growth rate after an effective amount of the compound is administered to the subject. The disclosure further provides methods of inhibiting and/or antagonizing MPP8 activity, by contacting the MPP8 protein with an effective amount of a compound or salt of Formulae (I), (II) and/or (III) disclosed herein (e.g., by contacting a cell, tissue, or organ that expresses MPP8). In some embodiments, the disclosure provides methods of inhibiting and/or antagonizing MMP8 activity in vitro by contacting the compound disclosed herein with cells. In some embodiments, these cells are derived from a cancerous cell line. In some embodiments, such cancerous cell lines are MYC-driven cancerous cell lines. In some embodiments, the cancer cell lines is a breast cancer cell line, such as, but not limited to a triple negative breast cancer cell (TNBC) line. Exemplary TNBC cell lines include, but are not limited to, HCC1937, SUM149, MDA-MB-231, HCC70, and LM2. In some embodiments, the percentage of inhibition of the MPP8 protein is expressed as a function of cell death observed in such cell lines. In some embodiments, the percentage of cell death observed in such cells is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the percentage of cell death observed in such cells ranges from about 1% to about 95%, from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, from about 5% to about 60%, from about 10% to about 55%, from about 15% to about 50%, from about 20% to about 40%, or from about 25% to about 35%. In some embodiments, cell death is selectively observed in cancerous cells compared to normal cells. In some embodiments, the selectivity of cell death observed in cancerous cells versus healthy cells when cells are contacted with an effective amount of MPP8 compound as disclosed herein is from about 1:100, from about 1:75, from about 1:70, from about 1:60, from about 1:50, from about 1:40, from about 1:30, from about 1:20, or from about 1:10 healthy cells:cancerous cells. In some embodiments, the selectivity of cell death observed in cancerous cells versus healthy cells when cells are contacted with an effective amount of MPP8 compound as disclosed herein ranges from about 1:60 to about 1:5 healthy cells:cancerous cells. In some embodiments, the disclosure provides methods of inhibiting and/or antagonizing MPP8 activity in a subject including, but not limited to, rodents and mammals, e.g., humans, by administering to the subject an effective amount of a compound or salt of Formulae (I), (II) and/or (III) disclosed herein. Thus, the present disclosure is directed to methods of inhibiting MMP8 activity in a in vitro and in vivo testing environment, which a skilled artisan would be familiar with. In some embodiments, the percentage of inhibition of the MPP8 protein in vitro and/or in vivo is at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, such a compound is a MPP8 antagonist. For example, in some embodiments, the disclosure provides methods of inhibiting MPP8 activity in a cell by contacting the cell with an amount of a compound as disclosed herein sufficient to inhibit the activity. In some embodiments, the disclosure provides methods of inhibiting MPP8 activity in a tissue by contacting the tissue with an amount of a compound or salt of Formulae (I), (II) and/or (III) as disclosed herein, sufficient to inhibit the MPP8 activity in the tissue. In some embodiments, the disclosure provides methods of inhibiting MPP8 activity in an organism (e.g., mammal, human, etc.) by contacting the organism with an amount of a compound or salt of Formulae (I), (II) and/or (III) as disclosed herein, sufficient to inhibit the MPP8 activity in the organism. In some embodiments, the methods disclosed herein are directed to compounds that are able to decrease gene expression. For example, methods of decreasing gene expression comprises contacting the MPP8 protein with an effective amount of a compound or salt of Formulae (I), (II) and/or (III) disclosed herein (e.g., by contacting a cell, tissue, or organ that expresses MPP8). In some embodiments, the disclosure provides methods of decreasing gene expression in a subject including, but not limited to, rodents and mammals, e.g., humans, by administering to the subject an effective amount of a compound of Formulae (I), (II) and/or (III) disclosed herein. In some embodiments, the percentage of decrease in gene expression due to MPP8 binding of the compound disclosed herein is at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%. In some embodiments, gene expression due to MPP8 binding of the compound disclosed herein is 100%, i.e., completely silenced. The compositions containing the compounds or salts thereof described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating clinician. In prophylactic applications, compositions containing the compounds or salts thereof described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating clinician. The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 to about 5000 mg per day, in some embodiments, about 1 to about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. EXAMPLES Example 1: GENERAL PROCEDURE A

Preparation of Intermediate 1 2,4-dichloro-6,7-dimethoxyquinazoline (500 mg, 1.9 mmol, 1 eq.) was dissolved in DMF (10 mL) followed by the addition of tert-butyl 4-aminopiperidine-1-carboxylate (773 mg, 3.8 mmol, 2 eq.) and DIPEA (499 mg, 672 uL, 3.8 mmol, 2 eq. ). The mixture was stirred overnight and was then diluted with ethyl acetate and washed with water. The organic layer was then washed with brine and water and dried over sodium sulfate. The solution was concentrated under vacuum and the obtained residue treated with 20% TFA in DCM for two hours and was concentrated under vacuum. The crude material was purified via reverse phase flash chromatography (water +0.1% TFA and Methanol) to afford intermediate 1 as a TFA salt (726 mg, 86 % over two steps). ¹H NMR (400 MHz, Methanol- d₄) δ 7.64 – 7.54 (s, 1H), 7.07 – 6.94 (s, 1H), 4.58 – 4.42 (m, 1H), 4.04 – 3.89 (d, J = 1.8 Hz, 6H), 3.56 – 3.48 (m, 2H), 3.27 – 3.18 (m, 2H), 2.45 – 2.24 (m, 2H), 2.05 – 1.83 (m, 2H). ESI-MS: Calculated: 322.12 Found: 323.1 [M+H]⁺.

= 2.62 min.

Intermediate 2 Preparation of 2-chloro-N-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxyquinazolin-4-amine (Intermediate 2) Intermediate 1 (300 mg, 0.93 mmol, 1 eq.) was dissolved in methanol (6 mL) followed by the addition of cyclohexanone (547 mg, 5.6 mmol, 6 eq) and the mixture was stirred for 10 minutes at room temperature. Sodium cyanoborohydride (175 mg, 2.8 mmol, 3 eq.) was then added and the mixture was heated to 50°C overnight. Following confirmation of conversion by LC-MS, the crude material was concentrated under vacuum and purified via reverse phase flash chromatography (water +0.1% TFA and Methanol) to afford intermediate 2 as a TFA salt (200 mg, 53 %). ¹H NMR (400 MHz, Methanol-d4) δ 7.63 – 7.55 (s, 1H), 7.02 – 6.89 (s, 1H), 4.60 – 4.47 (m, 1H), 3.96 – 3.94 (s, 6H), 3.73 – 3.56 (m, 2H), 3.27 – 3.16 (m, 2H), 2.45 – 2.33 (d, J = 13.9 Hz, 2H), 2.18 – 1.90 (m, 6H), 1.76 – 1.67 (m, 1H), 1.59 – 1.05 (m, 6H). ESI-MS: Calculated: 404.20 Found: 405.2 [M+H]⁺. tR = 3.64 min.

EXAMPLE 2: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)-6,7 dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 12). Intermediate 2 (100 mg, 0.025 mmol, 1 eq.) was dissolved in iPr-OH (2 mL) followed by the addition of N-boc-1,3-propandiamine (86 mg, 0.050 mmol, 2 eq.) and DIPEA (96 mg, 129 uL, 0.075 mmol, 3 eq.) and the reaction was stirred at 160°C for two hours in a u-wave reactor. The crude mixture was concentrated and purified by reverse phase flash chromatography (water +0.1% HCl and Methanol) to obtain the protected intermediate which was subsequently concentrated under vacuum and treated with 5M HCl in Dioxane (4 mL) for two hours, concentrated under vacuum and purified by reverse phase flash chromatography (water +0.1% HCl and Methanol) to yield free amine as a TFA salt (56 mg, 51% yield over two steps). The isolated amine (20 mg, 0.42 mmol, 1 eq)) was dissolved in DCM (5 mL) and DMF to solubilize followed by the addition of DIPEA (6.5 mg, 9 uL, 1.2 eq) and chloroacetyl chloride (5.2 mg, 3.7 uL, 1.1 eq) in DCM (2 mL) was added dropwise at 0*C and stirred for 30 minutes. The crude mixture was concentrated under vacuum and purified via reverse phase flash chromatography (water +0.1% HCl and Methanol) to afford the title compound as an HCl salt. (13 mg, 60%). ¹H NMR (400 MHz, Methanol-d4) δ 7.67 – 7.57 (d, J = 1.2 Hz, 1H), 6.94 – 6.83 (s, 1H), 4.61 – 4.48 (m, 1H), 4.10 – 4.02 (s, 2H), 3.96 – 3.92 (s, 3H), 3.91 – 3.87 (s, 3H), 3.71 – 3.58 (m, 2H), 3.57 – 3.48 (m, 2H), 3.39 – 3.32 (m, 3H), 3.28 – 3.19 (m, 1H), 2.48 – 2.36 (m, 2H), 2.22 – 2.01 (m, 4H), 1.99 – 1.87 (m, 4H), 1.76 – 1.68 (m, 1H), 1.61 – 1.11 (m, 5H). ESI-MS: Calculated: 518.28 Found: 260.2 [M+2H]⁺/2, 520.30 [M+2H]⁺. tR = 2.24 min.

EXAMPLE 3: Preparation of 2-chloro-N-(3-((4-((1-(3,3-dimethylcyclohexyl)piperidin- 4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 1). Title compound was synthesized from intermediate 1 (200 mg, 0.62 mmol 1 eq.) and 3,3-dimethylcyclohexan-1-one (469 mg, 520 mL 3.7 mmol, 6 eq) following general procedure A (22 mg, 15% across four synthetic steps).¹H NMR (400 MHz, Methanol-d₄) δ 7.81 – 7.69 (s, 1H), 7.00 – 6.89 (s, 1H), 4.69 – 4.58 (s, 1H), 4.15 – 4.04 (s, 2H), 4.02 – 3.91 (d, J = 6.7 Hz, 6H), 3.70 – 3.61 (m, 2H), 3.60 – 3.52 (t, J = 7.1 Hz, 2H), 3.48 – 3.33 (m, 5H), 2.44 – 2.34 (m, 2H), 2.27 – 2.17 (m, 3H), 1.98 – 1.87 (m, 3H), 1.85 – 1.75 (m, 1H), 1.69 – 1.55 (m, 1H), 1.51 – 1.38 (m, 3H), 1.26 – 1.15 (m, 1H), 1.07 – 1.04 (s, 3H), 1.02 – 0.99 (s, 3H). ESI-MS: Calculated: 546.3 Found: 274.2 [M+2H]⁺/2, 548.3 [M+2H]⁺. t

2.70 min.

EXAMPLE 4: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 2). Title compound was synthesized from intermediate 1 (200 mg, 0.62 mmol 1 eq.) and cycloheptanone (420 mg, 440 mL 3.7 mmol, 6 eq) following general procedure A (18 mg, 15% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.77 – 7.70 (s, 1H), 7.00 – 6.90 (br, 1H), 4.70 – 4.58 (br, 1H), 4.11 – 4.03 (s, 2H), 3.97 – 3.95 (s, 3H), 3.95 – 3.92 (s, 3H), 3.62 – 3.33 (m, 9H), 2.42 – 2.34 (t, J = 13.6 Hz, 2H), 2.31 – 2.14 (td, J = 15.7, 14.1, 9.0 Hz, 4H), 1.98 – 1.77 (m, 6H), 1.70 – 1.52 (m, 6H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+2H]⁺. tR = 2.95 min.

EXAMPLE 5: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 3). Title compound was synthesized from intermediate 2 (65 mg, 0.02 mmol, 1 eq) and tert-butyl (3-(methylamino)propyl)carbamate (60 mg, 0.04 mmol, 2 eq) according to general procedure A (20 mg, 33% across three steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.81 – 7.69 (s, 1H), 7.41 – 7.28 (s, 1H), 4.70 – 4.55 (m, 1H), 4.14 – 4.04 (s, 2H), 4.01 – 3.88 (d, J = 5.9 Hz, 6H), 3.86 – 3.77 (m, 2H), 3.71 – 3.58 (m, 2H), 3.50 – 3.39 (m, 2H), 3.35 – 3.32 (m, 2H), 3.32 – 3.31 (s, 3H), 3.28 – 3.23 (m, 1H), 2.45 – 2.30 (m, 2H), 2.25 – 2.14 (d, J = 12.7 Hz, 4H), 2.04 – 1.84 (m, 4H), 1.77 – 1.66 (d, J = 13.1 Hz, 1H), 1.65 – 1.51 (m, 2H), 1.47 – 1.34 (q, J = 12.9 Hz, 2H), 1.31 – 1.16 (m, 1H).ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+2H]⁺. t_R = 2.64 min.

EXAMAPLE 6: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)-N-methylacetamide(Compound 4). Title compound was synthesized from intermediate 2 (100 mg, 0.025 mmol, 1 eq) and tert-butyl (3-aminopropyl)(methyl)carbamate (140 mg, 0.075 mmol, 3 eq.) according to general procedure A to give final compound as an HCl salt (16 mg, 20% across three steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.81-7.66 (d, J = 4.1 Hz, 1H)*, 7.29-7.24 (s 0.5 H)*, 6.80 (S, 0.5H)*, 4.70 – 4.49 (m, 1H), 4.36 – 4.24 (s, 1H)*, 4.05 – 4.03 (s, 1H)*, 3.97 – 3.94 (d, J = 3.4 Hz, 3H)*, 3.94 – 3.91 (d, J = 2.9 Hz, 3H)*, 3.83 – 3.74 (t, J = 7.5 Hz, 1H), 3.69 – 3.58 (m, 2H), 3.57 – 3.36 (m, 4H), 3.14 – 3.09 (s, 3H), 2.48 – 2.30 (m, 2H), 2.30 – 2.08 (m, 4H), 2.08 – 1.86 (m, 4H), 1.78 – 1.65 (m, 1H), 1.64 – 1.46 (m, 2H), 1.46 – 1.31 (m, 2H), 1.31 – 1.14 (m, 1H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+2H]⁺. tR = 2.67 min. *Split peaks due to rotamers around N-methylated amide bond.

EXAMAPLE 7: Preparation of 2-chloro-N-(3-((4-((1-cyclobutylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 5). Title compound was synthesized from intermediate 1 (410 mg, 0.94 mmol 1 eq.) and cyclobutanone (197 mg, 2.82 mmol 3 eq.) following general procedure A. (9 mg, 20% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (s, 1H), 6.93 (s, 1H), 4.59 (t, J = 11.9 Hz, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.73 (p, J = 8.2 Hz, 1H), 3.67 – 3.58 (m, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H), 3.13 – 3.08 (m, 2H), 2.44 – 2.30 (m, 5H), 2.33 – 2.22 (m, 1H), 2.08 – 1.80 (m, 6H). ESI-MS: Calculated: 490.3 Found: 246.2 [M+2H]⁺/2, 491.3 [M+H]⁺. t_R = 2.18 min.

EXAMAPLE 8: Preparation of 2-chloro-N-(3-((4-((1-cyclopentylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 6). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and cyclopentanone (246 mg, 2.92 mmol 3 eq.) following general procedure A. (3 mg, 5% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 6.92 (s, 1H), 4.59 (t, J = 11.8 Hz, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.76 (d, J = 12.7 Hz, 2H), 3.56 (dt, J = 21.4, 7.4 Hz, 3H), 3.35 (t, J = 7.2 Hz, 3H), 3.30 – 3.25 (m, 1H), 2.41 (d, J = 13.9 Hz, 2H), 2.27 – 2.13 (m, 4H), 2.10 – 1.96 (m, 2H), 1.96 – 1.82 (m, 3H), 1.84 – 1.64 (m, 3H). ESI-MS: Calculated: 504.3 Found: 253.2 [M+2H]⁺/2, 505.3 [M+H]⁺. tR = 2.17 min.

EXAMAPLE 9: Preparation of N-(3-((4-((1-(bicyclo[2.2.1]heptan-2-yl)piperidin-4- yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)-2-chloroacetamide (Compound 7). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and bicyclo[2.2.1]heptan-2-one (536 mg, 4.86 mmol 5 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with propane-1,3-diamine (10 mg, 26% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 1H), 6.93 (s, 1H), 4.57 (t, J = 11.7 Hz, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.80 – 3.67 (m, 2H), 3.66 – 3.36 (m, 4H), 3.41 – 3.18 (m, 3H), 2.71 (s, 1H), 2.45 – 2.31 (m, 3H), 2.24 – 1.99 (m, 3H), 1.98 – 1.85 (m, 2H), 1.71 (d, J = 8.8 Hz, 2H), 1.68 – 1.56 (m, 1H), 1.55 (s, 1H), 1.56 – 1.48 (m, 1H), 1.48 (d, J = 9.3 Hz, 1H), 1.34 – 1.18 (m, 1H). ESI-MS: Calculated: 530.3 Found: 266.2 [M+2H]⁺/2, 531.3 [M+H]⁺. t_R = 2.42 min.

EXAMAPLE 10: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin- 4-yl)(methyl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 8). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (450 mg 1.75 mmol, 1 eq.) and tert-butyl 4-(methylamino)piperidine-1-carboxylate (484 mg, 2.3 mmol, 1.3 eq.) according to general procedure A with heating at 50*C in the first synthetic step (8 mg, 10% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.53 – 7.37 (s, 1H), 7.10 – 6.85 (s, 1H), 5.02 – 4.93 (m, 1H), 4.30 – 4.02 (s, 2H), 4.00 – 3.96 (s, 3H), 3.93 – 3.91 (s, 3H), 3.80 – 3.67 (m, 2H), 3.57 – 3.50 (t, J = 7.1 Hz, 2H), 3.49 – 3.45 (s, 3H), 3.44 – 3.33 (m, 3H), 2.47 – 2.35 (s, 2H), 2.31 – 2.17 (m, 4H), 2.04 – 1.83 (m, 4H), 1.80 – 1.69 (d, J = 12.9 Hz, 1H), 1.64 – 1.19 (m, 5H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+H]⁺. t_R = 2.75in.

EXAMAPLE 11: Preparation of 2-chloro-N-(3-((4-((1-cyclooctylpiperidin-4- yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 9). Title compound was synthesized from intermediate 1 (250 mg, 0.57 mmol 1 eq.) and cyclooctanone (578 mg, 4.6 mmol 8 eq.) following general procedure A (16 mg, 13% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (s, 1H), 6.92 (s, 1H), 4.60 (t, J = 13.3 Hz, 1H), 4.05 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.61 – 3.42 (m, 5H), 3.45 – 3.40 (m, 2H), 3.35 (t, J = 7.2 Hz, 2H), 2.42 (dd, J = 13.4, 3.9 Hz, 2H), 2.15 – 1.99 (m, 4H), 1.98 – 1.77 (m, 6H), 1.77 – 1.42 (m, 8H). ESI-MS: Calculated: 546.3 Found: 274.2 [M+2H]⁺/2, 547.3 [M+H]⁺. t_R = 3.15 min.

EXAMAPLE 12: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4- yl)amino)-7-fluoro-6-methoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 10). Title compound was synthesized from 2,4-dichloro-7-fluoro-6-methoxyquinazoline (250 mg, 1.01 mmol, 1 eq.) according to general procedure A with the following changes. The first synthetic step utilized 1-cyclohexylpiperidin-4-amine (623 mg, 1.52 mmol, 1.5 eq.) which was concentrated under a stream of nitrogen before purification by reverse phase chromatography followed by reaction in a u-wave reaction was using propane-1,3-diamine (0.9 eq) and HCl (1 eq.) at 160* for one hour. (15 mg, 20% across three steps. ¹H NMR (400 MHz, Methanol-d4) δ 8.10 – 7.94 (d, J = 8.3 Hz, 1H), 7.41 – 6.96 (br, 1H), 4.68 – 4.58 (br, 1H), 4.08 – 4.04 (s, 2H), 4.05 – 3.95 (s, 3H), 3.71 – 3.62 (m, 2H), 3.60 – 3.51 (m, 2H), 3.49 – 3.33 (m, 4H), 3.27 – 3.21 (m, 1H), 2.47 – 2.33 (m, 2H), 2.30 – 2.16 (m, 4H), 2.01 – 1.84 (m, 4H), 1.81 – 1.65 (m, 1H), 1.64 – 1.49 (m, 2H), 1.49 – 1.33 (m, 2H), 1.33 – 1.17 (m, 1H). ESI-MS: Calculated: 506.3 Found: 254.9 [M+2H]⁺/2, 508.3 [M+2H]⁺. tR = 2.42 min.

EXAMPLE 13: Preparation of 2-chloro-N-(3-((4-((1-cyclohexyl-3,3-difluoropiperidin- 4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 11). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (150 mg, 0.58 mmol, 1 eq.) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (274 mg, 1.2 mmol, 2 eq.) according to general procedure A to yield final compound as an HCl salt (14 mg, 22% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.89 – 7.81 (s, 1H), 7.05 – 6.91 (br, 1H), 5.54 – 5.45 (m, 1H), 4.11 – 4.05 (s, 2H), 4.06 – 4.01 (m, 1H), 4.01 – 3.90 (d, J = 5.5 Hz, 6H), 3.79 – 3.70 (br, 2H), 3.68 – 3.51 (m, 2H), 3.50 – 3.41 (m, 1H), 3.39 – 3.32 (m, 2H), 2.65 – 2.51 (br, 2H), 2.46 – 2.36 (m, 1H), 2.36 – 2.20 (m, 2H), 2.05 – 1.86 (m, 4H), 1.77 – 1.70 (m, 1H), 1.67 – 1.54 (m, 2H), 1.52 – 1.37 (m, 2H), 1.34 – 1.17 (m, 1H). ESI-MS: Calculated: 554.3 Found: 278.9 [M+2H]⁺/2, 556.3

2.75 min.

EXAMAPLE 14: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 7-fluoro-6-methoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 13). Title compound was synthesized according to the synthesis of the title compound in Example 12 and general procedure A from 2-chloro-N-(1-cyclohexylpiperidin-4-yl)-7-fluoro- 6-methoxyquinazolin-4-amine (35 mg, 0.089 mmol, 1 eq.) with tert-butyl (3-(methylamino)propyl)carbamate (50 mg, 0.27 mmol, 3 eq.) in the u-wave reaction (9 mg, 25% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 8.09 – 7.97 (d, J = 8.4 Hz, 1H), 7.59 – 7.39 (d, J = 11.4 Hz, 1H), 4.73 – 4.57 (tt, J = 11.9, 4.2 Hz, 1H), 4.06 – 4.03 (s, 2H), 4.03 – 3.99 (s, 3H), 3.85 – 3.78 (t, J = 7.6 Hz, 2H), 3.72 – 3.61 (d, J = 12.4 Hz, 2H), 3.53 – 3.37 (d, J = 12.8 Hz, 2H), 3.35 – 3.32 (d, J = 1.1 Hz, 2H), 3.31 – 3.30 (s, 3H), 3.28 – 3.21 (m, 1H), 2.48 – 2.33 (m, 2H), 2.28 – 2.14 (t, J = 14.4 Hz, 4H), 2.12 – 1.93 (m, 4H), 1.78 – 1.65 (d, J = 13.0 Hz, 1H), 1.65 – 1.49 (qd, J = 12.1, 3.1 Hz, 2H), 1.49 – 1.36 (q, J = 13.0 Hz, 2H), 1.31 – 1.18 (tdd, J = 12.9, 9.4, 3.5 Hz, 1H). ESI-MS: Calculated: 520.3 Found: 261.2 [M+2H]⁺/2, 522.3 [M+2H]⁺. tR = 2.55 min.

EXAMPLE 15: Preparation of N-(3-((7-(benzyloxy)-4-((1-cyclohexylpiperidin-4-yl)amino)- 6-methoxyquinazolin-2-yl)amino)propyl)-2-chloroacetamide (Compound 14). Title compound was synthesized from 7-(benzyloxy)-2,4-dichloro-6-methoxyquinazoline (100 mg, 0.30 mmol, 1 eq.) and 1-cyclohexylpiperidin-4-amine (300 mg, 0.70 mmol, 3 eq.) according to general procedure A (14 mg, 32% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.81 – 7.70 (s, 1H), 7.52 – 7.42 (m, 2H), 7.42 – 7.28 (m, 3H), 7.05 – 6.92 (br, 1H), 5.28 – 5.18 (s, 2H), 4.70 – 4.52 (br, 1H), 4.11 – 4.02 (s, 2H), 4.01 – 3.89 (s, 3H), 3.67 – 3.59 (m, 2H), 3.58 – 3.51 (t, J = 6.9 Hz, 2H), 3.39 – 3.32 (m, 3H), 3.28 – 3.14 (m, 2H), 2.45 – 2.34 (m, 2H), 2.30 – 2.14 (m, 4H), 2.05 – 1.83 (m, 4H), 1.77 – 1.68 (m, 1H), 1.64 – 1.48 (m, 2H), 1.48 – 1.32 (m, 2H), 1.31 – 1.12 (m, 1H). ESI-MS: Calculated: 594.3 Found: 298.2 [M+2H]⁺/2, 596.3 [M+2H]⁺. tR = 2.77 min.

EXAMPLE 16: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 15). Title compound was synthesized according from common intermediate of the compound in Example 4 (65 mg, 0.16 mmol, 1 eq.) using tert-butyl (3-(methylamino)propyl)carbamate (58 mg, 0.31 mmol, 2 eq.) in the u-wave reaction (21 mg, 25% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.78 – 7.70 (s, 1H), 7.41 – 7.28 (s, 1H), 4.70 – 4.58 (m, 1H), 4.10 – 4.04 (s, 2H), 3.99 – 3.89 (d, J = 5.0 Hz, 6H), 3.86 – 3.78 (m, 2H), 3.59 – 3.38 (m, 5H), 3.36 – 3.32 (m, 2H), 3.32 – 3.31 (s, 3H), 2.49 – 2.31 (m, 2H), 2.31 – 2.12 (m, 4H), 2.05 – 1.92 (m, 2H), 1.91 – 1.75 (m, 4H), 1.74 – 1.46 (m, 6H). ESI-MS: Calculated: 546.3 Found: 274.2 [M+2H]⁺/2, 548.3 [M+2H]⁺. t_R = 2.39 min.

EXAMPLE 17: Preparation of 2-chloro-N-(3-((4-((1-cyclohexyl-3- methylpiperidin-4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 16). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (150 mg, 0.58 mmol, 1 eq.) and tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (310 mg, 1.45 mmol, 2.5 eq.) according to general procedure A to give final mixture of diastereomers (14 mg, 10% yield across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.23 – 8.17 (s, 1H), 7.85 – 7.76 (d, J = 3.6 Hz, 1H), 7.08 – 6.88 (br, 2H), 4.80 – 4.62 (br, 1H), 4.62 – 4.32 (br, 1H), 4.10 – 4.06 (s, 2H), 4.06 – 4.02 (s, 1H), 3.98 – 3.92 (m, 6H), 3.69 – 3.47 (m, 5H), 3.44 – 3.34 (m, 8H), 3.20 – 3.04 (m, 1H), 2.70 – 2.51 (m, 2H), 2.38 – 2.04 (m, 5H), 2.04 – 1.83 (m, 5H), 1.75 – 1.67 (d, J = 12.9 Hz, 1H), 1.65 – 1.49 (m, 2H), 1.49 – 1.34 (m, 2H), 1.30 – 1.18 (m, 3H), 1.12 – 1.01 (dd, J = 13.9, 6.7 Hz, 3H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+2H]⁺. tR = 2.33 min.

EXAMPLE 18: Preparation of 2-chloro-N-(3-((4-((1-cycloheptyl-3,3- difluoropiperidin-4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 17). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (150 mg, 0.58 mmol, 1 eq.) according to Compound 11 and general procedure A with cycloheptanone (12 mg, 15% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.91 – 7.79 (s, 1H), 7.04 – 6.92 (s, 1H), 5.58 – 5.41 (m, 1H), 4.12 – 4.05 (s, 2H), 4.03 – 3.87 (d, J = 7.3 Hz, 6H), 3.86 – 3.69 (m, 2H), 3.68 – 3.46 (m, 4H), 3.40 – 3.32 (m, 2H), 2.61 – 2.46 (m, 2H), 2.45 – 2.35 (m, 1H), 2.34 – 2.12 (m, 2H), 1.99 – 1.77 (m, 6H), 1.73 – 1.49 (m, 6H). ESI-MS: Calculated: 568.3 Found : 285.2 [M+2H]⁺/2, 570.3

2.80 min.

EXAMPLE 19: Preparation of 2-chloro-N-(3-((4-((1-cyclohexyl-2- methylpiperidin-4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 18). Title compound was synthesized similarly to the title compound of Example 17 from 2,4-dichloro-6,7-dimethoxyquinazoline (150 mg, 0.58 mmol, 1 eq.) and tert-butyl 4- amino-2-methylpiperidine-1-carboxylate (310 mg, 1.45 mmol, 2.5 eq.) according to general procedure A as a mix of diastereomers (15 mg, 6% across six synthetic steps). ¹H NMR (400 MHz, Methanol- d4) δ 8.06 – 7.94 (s, 1H), 7.79 – 7.69 (s, 1H), 7.01 – 6.76 (br, 2H), 4.86 – 4.62 (br, J = 43.8 Hz, 2H), 4.21 – 4.12 (m, 1H), 4.12 – 4.02 (s, 2H), 4.04 – 3.96 (s, 2H), 3.99 – 3.86 (d, J = 6.0 Hz, 6H), 3.63 – 3.46 (m, 4H), 3.45 – 3.32 (m, 3H), 3.23 – 3.11 (m, 1H), 2.51 – 2.09 (m, 8H), 2.01 – 1.87 (m, 4H), 1.78 – 1.68 (m, 2H), 1.59 – 1.46 (dd, J = 15.6, 6.6 Hz, 6H), 1.46 – 1.34 (m, 2H), 1.28 – 1.17 (m, 1H). ESI- MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+2H]⁺. t_R = 2.27 min.

EXAMPLE 20: Preparation of 2-chloro-N-(3-((4-((1-cycloheptyl-3,3-difluoropiperidin- 4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 19). Title compound was synthesized according to the synthesis of the title compound of Example 18 (Compound 17) and general procedure A from 2-chloro-N-(1-cycloheptyl-3,3- difluoropiperidin-4-yl)-6,7-dimethoxyquinazolin-4-amine (55 mg, 0.12 mmol, 1 eq.) with tert-butyl (3-(methylamino)propyl)carbamate (68 mg, 0.36 mmol, 3 eq.) in the u-wave reaction (10 mg, 20% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.91 – 7.82 (s, 1H), 7.38 – 7.30 (s, 1H), 5.49 – 5.39 (m, 1H), 4.12 – 4.05 (s, 2H), 4.04 – 3.89 (d, J = 6.2 Hz, 6H), 3.91 – 3.73 (m, 3H), 3.68 – 3.55 (m, 2H), 3.37 – 3.33 (m, 1H), 3.33 – 3.31 (s, 3H), 2.70 – 2.51 (m, 2H), 2.46 – 2.34 (m, 1H), 2.34 – 2.12 (m, 2H), 2.08 – 1.75 (m, 6H), 1.73 – 1.52 (br, 6H). ESI-MS: Calculated: 582.3 Found: 292.2 [M+2H]⁺/2, 584.3 [M+2H]⁺ t_R = 2.84 min.

EXAMPLE 21: Preparation of 2-chloro-N-(3-((4-((1-(3,3-dimethylcyclohexyl)- 3,3-difluoropiperidin-4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 20). Title compound was synthesized similarly to the title compound in Example 13 from 2-chloro-N-(3,3-difluoropiperidin-4-yl)-6,7-dimethoxyquinazolin-4-amine (270 mg, 0.75 mmol, 1 eq.) and 3,3-dimethylcyclohexan-1-one (950 mg, 1.04 mL, 7.5 mmol, 10 eq.) according to general procedure A (24 mg, 23% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.89 – 7.79 (s, 1H), 7.05 – 6.88 (s, 1H), 5.55 – 5.36 (m, 1H), 4.12 – 4.04 (s, 2H), 4.02 – 3.89 (d, J = 6.5 Hz, 6H), 3.85 – 3.54 (m, 6H), 3.39 – 3.33 (m, 2H), 2.64 – 2.20 (m, 4H), 2.05 – 1.78 (m, 4H), 1.68 – 1.36 (m, 4H), 1.31 – 1.17 (m, 1H), 1.18 – 1.05 (s, 3H), 1.05 – 0.93 (s, 3H). ESI-MS: Calculated: 582.3 Found: 292.2 [M+2H]⁺/2, 584.3 [M+2H]⁺.

= 2.98 min.

EXAMPLE 22: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4- yl)(ethyl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 21). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (300 mg, 1.2 mmol, 1 eq.) and tert-butyl 4-(ethylamino)piperidine-1-carboxylate (530 mg, 2.4 mmol, 2 eq.) according to general procedure A with heating at 50ºC in the first synthetic step (25 mg, 16% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.09 – 6.97 (s, 1H), 6.89 – 6.70 (br, 1H), 3.87 – 3.79 (s, 2H), 3.75 – 3.70 (s, 3H), 3.70 – 3.62 (s, 3H), 3.66 – 3.57 (br, 2H), 3.47 – 3.37 (m, 2H), 3.37 – 3.26 (t, J = 6.9 Hz, 2H), 3.19 – 3.08 (m, 3H), 3.02 – 2.96 (m, 1H), 2.12 – 1.84 (m, 4H), 1.78 – 1.60 (m, 4H), 1.51 – 1.39 (m, 1H), 1.39 – 1.23 (m, 5H), 1.25 – 1.09 (m, 2H), 1.07 – 0.89 (m, 1H). ESI-MS: Calculated: 546.3 Found: 274.2 [M+2H]⁺/2, 548.3 [M+2H]⁺. t_R = 2.44 min.

EXAMPLE 23: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4- yl)(ethyl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 22). Title compound was synthesized similarly to the title compound in Example 22 from 2-chloro-N-(1-cyclohexylpiperidin-4-yl)-N-ethyl-6,7-dimethoxyquinazolin-4-amine (50 mg, 0,12 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (87 mg, 0.46 mmol, 4 eq.) according to general procedure A (10 mg, 20% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.37 – 7.34 (s, 1H), 7.33 – 7.29 (s, 1H), 4.98 – 4.92 (m, 1H), 4.08 – 4.03 (s, 2H), 4.02 – 3.98 (s, 3H), 3.96 – 3.91 (s, 3H), 3.92 – 3.86 (m, 2H), 3.83 – 3.76 (m, 2H), 3.74 – 3.63 (m, 3H), 3.35 – 3.33 (s, 3H), 3.28 – 3.23 (m, 1H), 2.57 – 2.39 (m, 3H), 2.32 – 2.25 (m, 2H), 2.25 – 2.16 (m, 3H), 1.97 – 1.90 (m, 4H), 1.75 – 1.68 (m, 1H), 1.61 – 1.51 (m, 2H), 1.51 – 1.37 (m, 5H), 1.30 – 1.20 (m, 1H). ESI-MS: Calculated: 560.3 Found: 281.2 [M+2H]⁺/2, 562.3 [M+2H]⁺.

= 2.47 min.

EXAMPLE 24: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin- 4-yl)(methyl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 23). Title compound was synthesized similarly to the title compound in Example 10 from 2-chloro-6,7-dimethoxy-N-methyl-N-(piperidin-4-yl)quinazolin-4-amine (250 mg, 0.74mmol 1 eq.) and cycloheptanone (420 mg, 3.7 mmol, 5 eq.) according to general procedure A (30 mg, 22% yield across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.48 – 7.38 (s, 1H), 7.17 – 6.86 (s, 1H), 4.07 – 4.05 (s, 2H), 4.00 – 3.95 (s, 3H), 3.94 – 3.91 (s, 3H), 3.62 – 3.51 (m, 4H), 3.50 – 3.39 (m, 6H), 3.39 – 3.33 (t, J = 6.6 Hz, 2H), 2.59 – 2.41 (br, 2H), 2.32 – 2.13 (m, 4H), 2.07 – 1.70 (m, 6H), 1.70 – 1.43 (m, 6H). ESI-MS: Calculated: 546.3 Found: 274.9 [M+2H]⁺/2, 547.3 [M+H]⁺. tR = 2.40 min.

EXAMPLE 25: Preparation of 2-chloro-N-(3-((4-((1-(3,3-dimethylcyclohexyl)piperidin- 4-yl)(methyl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 24). Title compound was synthesized similarly to the title compound of Example 10 from 2-chloro-6,7-dimethoxy-N-methyl-N-(piperidin-4-yl)quinazolin-4-amine (250 mg, 0.74mmol 1 eq.) and 3,3-dimethylcyclohexan-1-one (47 mg, 3.7 mmol, 5 eq.) according to general procedure A (25 mg, 20% yield across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.47 – 7.36 (s, 1H), 7.07 – 6.99 (s, 1H), 4.14 – 4.05 (s, 2H), 4.02 – 3.93 (s, 3H), 3.93 – 3.85 (s, 3H), 3.77 – 3.65 (m, 2H), 3.58 – 3.51 (t, J = 7.0 Hz, 2H), 3.50 – 3.46 (s, 3H), 3.46 – 3.34 (m, 5H), 2.58 – 2.41 (br, 2H), 2.30 – 2.18 (d, J = 13.0 Hz, 3H), 1.99 – 1.89 (m, 3H), 1.89 – 1.74 (m, 1H), 1.65 – 1.54 (m, 1H), 1.52 – 1.34 (m, 3H), 1.30 – 1.14 (m, 1H), 1.08 – 1.03 (s, 3H), 1.03 – 0.96 (s, 3H). ESI-MS: Calculated: 560.3 Found: 281.9 [M+2H]⁺/2, 561.3 [M+H]⁺. tR = 2.44 min.

EXAMPLE 26: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 7-(trifluoromethyl)quinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 25). Title compound was synthesized similarly to the title compound of Example 27 from 2-chloro-N-(1-cyclohexylpiperidin-4-yl)-7-(trifluoromethyl)quinazolin-4-amine (85 mg, 0.21 mmol) and tert-butyl (3-(methylamino)propyl)carbamate (78mg, 42, 2 eq.) according to general procedure A (12 mg, 25% across three synthetic steps). 1H NMR (400 MHz, Methanol-d4) δ 8.57 – 8.42 (d, 1H), 8.15 – 8.01 (s, 1H), 7.80 – 7.67 (d, J = 8.6, 1.7 Hz, 1H), 4.79 – 4.61 (m, 1H), 4.12 – 3.99 (s, 2H), 3.96 – 3.82 (br, 2H), 3.70 – 3.60 (m, 2H), 3.56 – 3.42 (m, 1H), 3.38 – 3.35 (s, 3H), 3.35 – 3.32 (m, 2H), 3.28 – 3.22 (m, 1H), 2.48 – 2.36 (m, 2H), 2.33 – 2.12 (m, 4H), 2.08 – 1.89 (m, 4H), 1.80 – 1.64 (d, J = 13.2 Hz, 1H), 1.64 – 1.51 (m, 2H), 1.51 – 1.34 (m, 2H), 1.28 – 1.17 (m, 1H). ESI-MS: Calculated: 540.3 Found: 271.9 [M+2H]⁺/2, 542.3 [M+2H]2⁺. = 2.60 min.

EXAMPLE 27: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 7-(trifluoromethyl)quinazolin-2-yl)amino)propyl)acetamide (Compound 26). Title compound was synthesized similarly to the title compound of Example 2 from 2,4-dichloro-7-(trifluoromethyl)quinazoline (100 mg, 0.37 mmol, 1 eq.) and 1-cyclohexylpiperidin- 4-amine (205 mg, 1.12 mmol, 3 eq.) according to general procedure A (12 mg, 30% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.56 – 8.46 (d, J = 8.6 Hz, 1H), 7.80 – 7.74 (s, 1H), 7.74 – 7.61 (d, J = 8.6 Hz, 1H), 4.78 – 4.63 (m, 1H), 4.16 – 4.03 (s, 2H), 3.71 – 3.31 (m, 8H), 3.29 – 3.23 (m, 1H), 2.45 – 2.35 (m, 2H), 2.33 – 2.14 (m, 4H), 2.04 – 1.84 (m, 4H), 1.78 – 1.68 (m, 1H), 1.62 – 1.50 (m, 2H), 1.50 – 1.36 (q, J = 13.1 Hz, 2H), 1.33 – 1.17 (m, 1H). ESI-MS: Calculated: 526.2 Found: 264.3 [M+2H]⁺/2, 527.2 [M+H]⁺.

= 2.32 min.

EXAMPLE 28: Preparation of 2-chloro-N-(3-((4-((1-(3,3-dimethylcyclohexyl)- 3,3-difluoropiperidin-4-yl)amino)-6,7-dimethoxyquinazolin-2- yl)(methyl)amino)propyl)acetamide (Compound 27) Title compound was synthesized similarly to the title compound of Example 21 from 2-chloro- N-(1-(3,3-dimethylcyclohexyl)-3,3-difluoropiperidin-4-yl)-6,7-dimethoxyquinazolin-4-amine (50 mg, 0.11 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (80 mg, 0.44 mmol, 4 eq.) according to general procedure A (6 mg, 10% yield across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.91 – 7.82 (s, 1H), 7.38 – 7.29 (s, 1H), 5.49 – 5.32 (m, 1H), 4.08 – 4.06 (s, 2H), 4.03 – 3.98 (s, 3H), 3.98 – 3.94 (s, 3H), 3.90 – 3.55 (m, 5H), 3.36 – 3.34 (m, 1H), 3.33 – 3.31 (s, 3H), 2.65 – 2.19 (m, 4H), 2.01 – 1.75 (m, 4H), 1.68 – 1.40 (m, 4H), 1.31 – 1.14 (m, 2H), 1.11 – 1.05 (s, 3H), 1.05 – 0.98 (s, 3H). ESI-MS: Calculated: 596.3 Found: 299.2 [M+2H]⁺/2, 597.3 [M+H]⁺. t_R = 2.99 min.

EXAMPLE 29: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4- yl)(ethyl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 28). Title compound was synthesized similarly to the title compound of Example 22 from 2-chloro-N-ethyl-6,7-dimethoxy-N-(piperidin-4-yl)quinazolin-4-amine (150 mg, 0.43 mmol, 1 eq.) and cycloheptanone (240 mg, 2.1 mmol, 5 eq.) according to general procedure A (25 mg, 16% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.35 – 7.19 (s, 1H), 4.08 – 4.06 (s, 2H), 4.00 – 3.97 (s, 3H), 3.94 – 3.92 (s, 3H), 3.90 – 3.83 (m, 2H), 3.60 – 3.48 (m, 4H), 3.47 – 3.32 (m, 6H), 2.33 – 2.09 (m, 4H), 2.02 – 1.74 (m, 6H), 1.74 – 1.46 (m, 10H). ESI-MS: Calculated: 560.3 Found: 281.2 [M+2H]⁺/2, 562.3

2.48 min.

EXAMPLE 30: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4- yl)(ethyl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 29). Title compound was synthesized similarly to the title compound of Example 29 from 2-chloro- N-(1-cycloheptylpiperidin-4-yl)-N-ethyl-6,7-dimethoxyquinazolin-4-amine (55 mg, 0.12 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (87 mg, 0.46 mmol, 4 eq.) according to general procedure A (18 mg, 25% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.42 – 7.35 (s, 1H), 7.32 – 7.20 (s, 1H), 4.09 – 4.02 (s, 2H), 4.02 – 3.97 (s, 3H), 3.96 – 3.93 (s, 3H), 3.92 – 3.86 (m, 2H), 3.83 – 3.76 (t, J = 7.5 Hz, 2H), 3.66 – 3.53 (d, J = 12.4 Hz, 2H), 3.48 – 3.32 (m, 4H), 2.62 – 2.47 (m, 2H), 2.35 – 2.11 (m, 4H), 2.05 – 1.91 (m, 2H), 1.91 – 1.73 (m, 4H), 1.68 – 1.48 (m, 6H), 1.51 – 1.40 (t, J = 6.9 Hz, 3H). ESI-MS: Calculated: 574.3 Found: 288.2 [M+2H]⁺/2, 575.3 [M+H]⁺. t_R = 2.72 min.

EXAMPLE 31: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)(methyl)amino)- 6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 30). Title compound was synthesized similarly to the title compound of Example 10 from 2-chloro-N-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxy-N-methylquinazolin-4-amine (100 mg, 0.24 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (135 mg, 0.72 mmol, 3 eq.) according to general procedure A (17% across three synthetic steps). ¹H NMR (400 MHz, Methanol- d4) δ 7.47 – 7.33 (s, 2H), 5.04 – 4.94 (m, 1H), 4.08 – 4.01 (s, 2H), 3.99 – 3.97 (s, 3H), 3.96 – 3.90 (s, 3H), 3.82 – 3.75 (t, J = 7.5 Hz, 2H), 3.74 – 3.65 (m, 2H), 3.50 – 3.38 (m, 5H), 3.34 – 3.32 (m, 2H), 3.29 – 3.23 (m, 1H), 2.62 – 2.34 (m, 2H), 2.34 – 2.12 (m, 4H), 2.09 – 1.86 (m, 4H), 1.78 – 1.65 (m, 1H), 1.64 – 1.49 (qd, J = 12.2, 3.3 Hz, 2H), 1.48 – 1.33 (m, 2H), 1.31 – 1.17 (m, 1H). ESI-MS: Calculated: 546.3 Found: 274.2 [M+2H]⁺/2, 547.3 [M+H]⁺. tR = 2.26in.

EXAMPLE 32: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin- 4-yl)(methyl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 31). Title compound was synthesized similarly to the title compound of Example 24 from 2-chloro-N-(1-cycloheptylpiperidin-4-yl)-6,7-dimethoxy-N-methylquinazolin-4-amine (100 mg, 0.23 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (130 mg, 0.69 mmol, 3 eq). according to general procedure A (20 mg, 15% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.43 – 7.41 (s, 1H), 7.40 – 7.36 (s, 1H), 4.08 – 4.01 (s, 2H), 4.01 – 3.96 (s, 3H), 3.96 – 3.89 (s, 3H), 3.83 – 3.70 (t, J = 7.4 Hz, 2H), 3.64 – 3.56 (m, 2H), 3.55 – 3.41 (m, 6H), 3.36 – 3.32 (m, 2H), 2.57 – 2.43 (m, 2H), 2.30 – 2.17 (m, 4H), 2.04 – 1.91 (m, 2H), 1.91 – 1.78 (m, 4H), 1.70 – 1.51 (m, 6H). MS: Calculated: 560.3 Found: 281.3 [M+2H]⁺/2, 561.3 [M+H]⁺. tR = 2.39 min.

EXAMPLE 33: Preparation of 2-chloro-N-(3-((4-((1-(3,3-dimethylcyclohexyl)piperidin- 4-yl)(methyl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 32). Title compound was made similarly to the title compound of Example 25 from 2-chloro-N-(1-(3,3-dimethylcyclohexyl)piperidin-4-yl)-6,7-dimethoxy-N-methylquinazolin-4-amine (80 mg, 0.18 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (100 mg, 0.54 mmol, 3 eq.) according to general procedure A (18 mg, 30% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.47 – 7.40 (s, 1H), 7.40 – 7.30 (s, 1H), 5.04 – 4.93 (d, J = 12.0 Hz, 1H), 4.07 – 4.02 (s, 2H), 4.02 – 3.97 (s, 3H), 3.95 – 3.90 (s, 3H), 3.84 – 3.67 (m, 4H), 3.55 – 3.38 (m, 6H), 3.35 – 3.33 (m, 1H), 2.49 – 2.34 (m, 2H), 2.34 – 2.18 (m, 3H), 2.00 – 1.87 (m, 3H), 1.84 – 1.75 (m, 1H), 1.68 – 1.53 (m, 1H), 1.52 – 1.36 (m, 3H), 1.28 – 1.13 (m, 1H), 1.11 – 1.04 (s, 3H), 1.04 – 0.94 (s, 3H).ESI-MS: Calculated: 574.3 Found: 288.2 [M+2H]⁺/2, 575.3 [M+H]⁺.

= 2.56 min.

EXAMPLE 34: Preparation of 2-chloro-N-(3-((4-((1-cyclohexyl-3,3-difluoropiperidin- 4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 33). Title compound was made similarly to the title compound of Example 13 from 2-chloro-N-(1-cyclohexyl-3,3-difluoropiperidin-4-yl)-6,7-dimethoxyquinazolin-4-amine (40 mg, 0.09 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (51 mg, 0.27 mmol, 3 eq.) according to general procedure A (9 mg, 20% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.88 – 7.83 (s, 1H), 7.37 – 7.26 (s, 1H), 5.62 – 5.28 (m, 1H), 4.07 – 4.06 (s, 2H), 4.04 – 4.00 (m, 1H), 4.00 – 3.98 (s, 3H), 3.98 – 3.96 (s, 3H), 3.91 – 3.60 (m, 4H), 3.52 – 3.33 (m, 2H), 2.71 – 2.12 (m, 4H), 2.12 – 1.84 (m, 4H), 1.81 – 1.65 (m, 1H), 1.65 – 1.51 (m, 2H), 1.51 – 1.31 (m, 2H), 1.31 – 1.17 (m, 1H). ESI-MS: Calculated: 568.3 Found: 285.9 [M+2H]⁺/2, 569.3 [M+H]⁺. t_R = 2.72

EXAMPLE 35: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4-yl)amino)- 7-(trifluoromethyl)quinazolin-2-yl)amino)propyl)acetamide (Compound 34). Title compound was synthesized similarly to the title compound of Example 27 from 2,4-dichloro-7-(trifluoromethyl)quinazoline (100 mg, 0.37 mmol 1 eq.) and 1-cycloheptylpiperidin- 4-amine (184 mg, 0.94 mmol, 2.5 eq.) according to general procedure A (20 mg, 23% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.60 – 8.44 (d, J = 8.6 Hz, 1H), 7.82 – 7.72 (s, 1H), 7.72 – 7.57 (d, J = 8.7 Hz, 1H), 4.78 – 4.54 (m, 1H), 4.11 – 4.04 (d, J = 1.9 Hz, 2H), 3.67 – 3.59 (t, J = 7.1 Hz, 2H), 3.59 – 3.49 (m, 3H), 3.47 – 3.32 (m, 4H), 2.49 – 2.34 (m, 2H), 2.34 – 2.17 (m, 4H), 1.99 – 1.77 (m, 6H), 1.68 – 1.46 (m, 6H). ESI-MS: Calculated: 540.3 Found: 271.9 [M+2H]⁺/2, 542.3 [M+2H]2⁺. t_R = 2.55 min.

EXAMPLE 36: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4-yl)amino)- 7-fluoro-6-methoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 35). Title compound was synthesized similarly to the title compound of Example 12 from 2,4-dichloro-7-fluoro-6-methoxyquinazoline (75 mg, 0.30 mmol, 1 eq.) and 1-cycloheptylpiperidin- 4-amine (180 mg, 0.90 mmol, 3 eq.) according to general procedure A (9 mg, 18% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.10 – 7.94 (d, J = 8.3 Hz, 1H), 7.32 – 7.07 (br, 1H), 4.73 – 4.58 (br, 1H), 4.08 – 4.06 (s, 2H), 4.02 – 3.98 (s, 3H), 3.61 – 3.50 (m, 4H), 3.49 – 3.39 (m, 2H), 3.39 – 3.33 (m, 2H), 2.44 – 2.35 (m, 2H), 2.34 – 2.16 (m, 4H), 1.99 – 1.89 (m, 2H), 1.89 – 1.79 (m, 4H), 1.68 – 1.56 (m, 6H). ESI-MS: Calculated: 520.3 Found: 261.2 [M+2H]⁺/2, 522.3 [M+2H]⁺. t_R = 2.65 min.

EXAMPLE 37: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4-yl)amino)- 7-(trifluoromethyl)quinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 36). Title compound was synthesized similarly to the title compound of Example 35 from 2-chloro-N-(1-cycloheptylpiperidin-4-yl)-7-(trifluoromethyl)quinazolin-4-amine (100 mg, 0.23 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (132 mg, 073 mmol, 3 eq.) according to general procedure A (22 mg, 22% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.60 – 8.44 (d, J = 8.6 Hz, 1H), 8.20 – 8.04 (s, 1H), 7.78 – 7.63 (m, 1H), 4.80 – 4.55 (m, 1H), 4.11 – 4.00 (s, 2H), 3.93 – 3.76 (br, 2H), 3.58 – 3.50 (m, 3H), 3.44 – 3.38 (m, 1H), 3.38 – 3.36 (s, 3H), 3.35 – 3.32 (m, 1H), 2.51 – 2.27 (m, 3H), 2.27 – 2.15 (m, 4H), 2.05 – 1.95 (m, 2H), 1.92 – 1.77 (m, 4H), 1.68 – 1.55 (m, 6H). ESI-MS: Calculated: 554.3 Found: 278.9 [M+2H]⁺/2, 556.3 [M+2H]2⁺. t_R = 2.60 min.

EXAMPLE 38: Preparation of 2-chloro-N-(3-((6,7-dimethoxy-4-(((1r,4r)-4-(piperidin- 1-yl)cyclohexyl)amino)quinazolin-2-yl)amino)propyl)acetamide (Compound 37). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol 1 eq.) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (248 mg, 1.16 mmol 1.2 eq.) following general procedure A replacing cyclohexanone with glutaraldehyde (15 mg, 25% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.64 (s, 1H), 6.92 (s, 1H), 4.32 (tt, J = 11.8, 3.9 Hz, 1H), 4.05 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.54 (d, J = 9.9 Hz, 4H), 3.37 (t, J = 7.1 Hz, 2H), 3.32 – 3.22 (m, 1H), 3.13 – 3.02 (m, 2H), 2.28 (dd, J = 25.6, 12.3 Hz, 4H), 2.00 (d, J = 14.3 Hz, 2H), 1.95 – 1.78 (m, 7H), 1.73 – 1.59 (m, 2H), 1.61 – 1.45 (m, 1H). ESI-MS: Calculated: 518.3 Found: 260.2 [M+2H]⁺/2, 519.3 [M+H]⁺. t_R = 2.22 min.

EXAMPLE 39: Preparation of 2-chloro-N-(3-((4-((1-(3,3-dimethylcyclohexyl)piperidin- 4-yl)amino)-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 38). Title compound was synthesized similarly to the title compound of Example 3 from 2-chloro-N-(1-(3,3-dimethylcyclohexyl)piperidin-4-yl)-6,7-dimethoxyquinazolin-4-amine (95 mg, 0.22 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (120 mg, 0.66 mmol, 3 eq.) according to general procedure A (22 mg, 36% across three synthetic steps). 1H NMR (400 MHz, Methanol-d4) δ 7.76 – 7.72 (s, 1H), 7.40 – 7.32 (s, 1H), 4.69 – 4.58 (m, 1H), 4.13 – 4.06 (s, 2H), 3.96 – 3.95 (s, 3H), 3.94 – 3.93 (s, 3H), 3.86 – 3.77 (t, J = 7.4 Hz, 2H), 3.70 – 3.61 (m, 2H), 3.53 – 3.38 (m, 3H), 3.32 – 3.31 (s, 3H), 2.49 – 2.34 (m, 2H), 2.32 – 2.17 (m, 3H), 2.06 – 1.85 (m, 3H), 1.85 – 1.71 (m, 1H), 1.71 – 1.53 (m, 2H), 1.52 – 1.33 (m, 4H), 1.26 – 1.15 (m, 1H), 1.09 – 1.03 (s, 3H), 1.01 – 0.97 (s, 3H). ESI-MS: Calculated: 560.3 Found: 281.4 [M+2H]²⁺/2, 562.3 [M+2H]²⁺. tR = 2.55 min.

EXAMPLE 40: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)(ethyl)amino)propyl)acetamide (Compound 39). Title compound was synthesized from intermediate 2 (50 mg, 0.12 mmol, 1 eq.) and tert-butyl (3-(ethylamino)propyl)carbamate (100 mg, 0.49 mmol, 4 eq.) according to general procedure A (8 mg, 12% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.78 – 7.66 (s, 1H), 7.36 – 7.22 (s, 1H), 4.68 – 4.54 (br, 1H), 4.11 – 4.04 (s, 2H), 3.99 – 3.97 (s, 3H), 3.97 – 3.94 (s, 3H), 3.80 – 3.60 (m, 6H), 3.51 – 3.41 (m, 1H), 3.36 – 3.32 (m, 2H), 2.49 – 2.34 (m, 2H), 2.31 – 2.09 (m, 4H), 2.08 – 1.91 (m, 4H), 1.80 – 1.67 (d, J = 13.0 Hz, 1H), 1.64 – 1.51 (q, J = 12.1 Hz, 2H), 1.51 – 1.36 (q, J = 12.8 Hz, 3H), 1.36 – 1.21 (q, J = 6.8 Hz, 5H). ESI-MS: Calculated: 546.3 Found: 274.2 [M+2H]⁺/2, 548.3 [M+2H]2⁺. tR = 3.19 min.

EXAMPLE 41: Preparation of 2-chloro-N-(3-((6,7-dimethoxy-4-(((1r,4r)-4-(piperidin- 1-yl)cyclohexyl)amino)quinazolin-2-yl)(methyl)amino)propyl)acetamide (Compound 40). Title compound was synthesized similarly to Compound 37 from 2-chloro-6,7-dimethoxy-N- ((1s,4s)-4-(piperidin-1-yl)cyclohexyl)quinazolin-4-amine (50 mg, 0.08 mmol 1 eq.) and tert-butyl (3- (methylamino)propyl)carbamate (30 mg, 0.16 mmol 2 eq.) following general procedure A (16 mg, 33% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.29 (s, 1H), 4.31 (t, J = 11.4 Hz, 1H), 4.07 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.84 – 3.75 (m, 2H), 3.56 (d, J = 11.4 Hz, 2H), 3.45 – 3.29 (m, 3H), 3.30 (s, 3H), 3.09 (t, J = 12.1 Hz, 2H), 2.29 (d, J = 11.0 Hz, 4H), 2.03 – 1.93 (m, 4H), 1.96 – 1.81 (m, 5H), 1.73 (q, J = 12.0 Hz, 2H), 1.63 – 1.47 (m, 1H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 533.3 [M+H]⁺. tR = 2.32 min.

EXAMPLE 42: Preparation of 2-chloro-N-(1-(4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)piperidin-3-yl)acetamide (Compound 41). Title compound was synthesized from intermediate 2 (60 mg, 0.15 mmol 1 eq.) and tert-butyl piperidin-3-ylcarbamate (180 mg, 0.89 mmol, 6 eq) following general procedure A (8 mg, 10% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (s, 1H), 7.12 (s, 1H), 4.75 – 4.64 (m, 2H), 4.16 – 4.09 (m, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.62 (t, J = 10.9 Hz, 2H), 3.52 – 3.35 (m, 2H), 3.28 – 3.19 (m, 2H), 2.47 (d, J = 14.1 Hz, 1H), 2.36 (d, J = 13.6 Hz, 1H), 2.18 (d, J = 11.3 Hz, 2H), 2.10 – 1.83 (m, 6H), 1.80 – 1.71 (m, 4H), 1.64 – 1.21 (m, 6H). ESI-MS: Calculated: 544.29 Found: 273.2 [M+2H]⁺/2, 546.3[M+2H]⁺. tR = 2.36 min.

EXAMPLE 43: Preparation of 2-chloro-1-(4-(4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl)ethan-1-one (Compound 42). Title compound was synthesized from intermediate 2 (60 mg, 0.15 mmol 1 eq.) and butane-1,4-diamine (170 mg, 0.89 mmol, 6 eq) following general procedure A (4 mg, 6% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.15 (s, 1H), 4.63 – 4.53 (m, 1H), 4.34 (s, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.84 – 3.76 (m, 4H), 3.64 (d, J = 12.3 Hz, 2H), 3.40 – 3.31 (m, 2H), 3.26 – 3.18 (m, 2H), 2.40 (d, J = 13.8 Hz, 2H), 2.25 – 1.92 (m, 8H), 1.74 (d, J = 13.1 Hz, 1H), 1.68 – 1.16 (m, 6H). ESI-MS: Calculated: 530.23 Found: 266.3 [M+2H]⁺/2, 532.3[M+2H]⁺. t_R = 2.33 min.

EXAMPLE 44: Preparation of 2-chloro-N-(1-(4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl)acetamide (Compound 43). Title compound was synthesized from intermediate 2 (60 mg, 0.15 mmol 1 eq.) and tert-butyl piperazine-1-carboxylate (180 mg, 0.89 mmol, 6 eq) following general procedure A (4 mg, 4% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.13 (s, 1H), 4.60 – 4.48 (m, 2H), 4.03 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.75 – 3.59 (m, 2H), 3.43 – 3.33 (m, 2H), 3.29 – 3.17 (m, 2H), 2.40 (d, J = 13.9 Hz, 2H), 2.27 – 1.88 (m, 10H), 1.81 – 1.11 (m, 8H). ESI-MS: Calculated: 544.29 Found: 273.2 [M+2H]⁺/2, 546.3[M+2H]⁺. t_R = 2.95 min.

EXAMPLE 45: Preparation of 2-chloro-N-(1-(4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)pyrrolidin-3-yl)acetamide (Compound 44). Title compound was synthesized from intermediate 2 (60 mg, 0.15 mmol 1 eq.) and tert-butyl piperidin-3-ylcarbamate (170 mg, 0.89 mmol, 6 eq) following general procedure A (8 mg, 11% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.13 (s, 1H), 4.65 – 4.48 (m, 2H), 4.05 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.64 (br, J = 12.4 Hz, 6H), 3.26 – 3.19 (m, 2H), 2.43 (d, J = 14.4 Hz, 2H), 2.35 – 1.87 (m, 8H), 1.74 (d, J = 13.1 Hz, 1H), 1.67 – 1.08 (m, 6H). ESI-MS: Calculated: 530.28 Found: 266.3 [M+2H]⁺/2, 532.3[M+2H]⁺. tR = 2.27 min.

EXAMPLE 46: Preparation of 2-chloro-N-(2-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)acetamide (Compound 45). Title compound was synthesized from intermediate 2 (60 mg, 0.15 mmol 1 eq.) and tert-butyl piperidin-3-ylcarbamate (140 mg, 0.89 mmol, 6 eq) following general procedure A (8 mg, 5% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (s, 1H), 6.93 (s, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.69 – 3.57 (m, 4H), 3.57 – 3.43 (m, 4H), 2.38 (d, J = 13.7 Hz, 2H), 2.23 – 1.91 (m, 6H), 1.74 (d, J = 13.2 Hz, 1H), 1.61 – 1.17 (m, 6H). ESI-MS: Calculated: 504.26 Found: 253.2 [M+2H]⁺/2, 506.2 [M+2H]⁺. t_R = 2.24 min.

EXAMPLE 47: Preparation of 2-chloro-N-(4-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)butyl)acetamide (Compound 46). Title compound was synthesized from intermediate 2 (60 mg, 0.15 mmol 1 eq.) and butane- 1,4-diamine (78 mg, 0.89 mmol, 6 eq) following general procedure A (4 mg, 5% across two synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 6.93 (s, 1H), 4.59 (br, 1H), 4.03 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.73 – 3.49 (m, 4H), 3.27 – 3.15 (m, 1H), 2.42 (d, J = 13.9 Hz, 2H), 2.22 – 1.90 (m, 8H), 1.80 – 1.62 (m, 6H), 1.62 – 1.15 (m, 6H). ESI-MS: Calculated: 532.29 Found: 267.2 [M+2H]⁺/2, 534.3[M+2H]⁺. t_R = 2.23 min.

EXAMPLE 48: Preparation of N-(4-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)butyl)acrylamide (Compound 47). Title compound was synthesized similarly to the title compound of Example 47 from N²-(4-aminobutyl)-N⁴-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxyquinazoline-2,4-diamine (25 mg, 0.03 mmol 1 eq.) and acryloyl chloride (2.3 mg, 0.03 mmol, 1 eq.) according to general procedure A (8 mg, 50%). NMR (400 MHz, Methanol-d4) δ 7.74 – 7.63 (d, J = 24.1 Hz, 1H), 6.28 – 6.19 (m, 2H), 5.76 – 5.61 (dd, J = 8.3, 3.8 Hz, 1H), 3.98 – 3.96 (s, 3H), 3.94 – 3.91 (s, 2H), 3.73 – 3.60 (m, 2H), 3.08 – 3.00 (m, 1H), 2.51 – 2.34 (d, J = 13.9 Hz, 2H), 2.25 – 1.94 (m, 5H), 1.88 – 1.58 (m, 5H), 1.58 – 1.16 (m, 11H). ESI-MS: Calculated: 510.3 Found 256.3 [M+2H]⁺/2, 512.3 [M+2H]²⁺. t_R = 2.48 min.

EXAMPLE 49: Preparation of N-(2-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)acrylamide (Compound 48). Title compound was synthesized similarly to the title compound of Example 46 from N²-(2-aminoethyl)-N⁴-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxyquinazoline-2,4-diamine (25 mg, 0.04 mmol, 1 eq) and acryloyl chloride ( 3 mg, 0.04 mmol, 1 eq.) according to general procedure A (10 mg, 38%). 1H NMR (400 MHz, Methanol-d4) δ 7.72 – 7.61 (s, 1H), 7.04 – 6.89 (s, 1H), 6.30 – 6.15 (d, J = 8.5 Hz, 2H), 5.78 – 5.61 (dd, J = 8.7, 3.4 Hz, 1H), 4.77 – 4.63 (br, 1H), 4.04 – 3.95 (s, 3H), 3.95 – 3.86 (s, 4H), 3.79 – 3.51 (m, 8H), 3.46 – 3.36 (m, 2H), 3.28 – 3.21 (m, 1H), 2.53 – 2.32 (m, 2H), 2.23 – 1.97 (m, 4H), 1.80 – 1.66 (d, J = 12.9 Hz, 1H), 1.64 – 1.51 (m, 2H), 1.51 – 1.34 (m, 2H), 1.34 – 1.18 (m, 1H). ESI-MS: Calculated: 482.3 Found: 242.3 [M+2H]⁺/2, 484.3 [M+2H]²⁺. tR = 2.48 min.

EXAMPLE 50: Preparation of N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acrylamide (Compound 49). Title compound was synthesized similarly to the title compound of Example 2 from N2-(3- aminopropyl)-N4-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxyquinazoline-2,4-diamine (30 mg, 0.07 mmol 1 eq.) and acryloyl chloride (7.4 mg, 0.08 mmol, 1 eq.) according to general procedure A (6 mg, 19% yield). ¹H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.25 – 6.20 (m, 2H), 5.66 (dd, J = 8.8, 3.2 Hz, 1H), 4.62 – 4.50 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.65 (d, J = 12.3 Hz, 2H), 3.55 (br, 2H), 3.41 – 3.34 (m, 2H), 2.42 (d, J = 13.9 Hz, 2H), 2.19 – 2.04 (m, 4H), 2.00 – 1.85 (m, 4H), 1.73 (d, J = 13.0 Hz, 2H), 1.65 – 1.13 (m, 7H). ESI-MS: Calculated: 496.32 Found: 249.3 [M+2H]⁺/2, 498.30 [M+2H]2⁺. t_R = 2.24 min.

EXAMPLE 51: Preparation of N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)-2-fluoroacetamide (Compound 50). Title compound was synthesized similarly to the title compound of Example 2 from N2-(3- aminopropyl)-N4-(1-cyclohexylpiperidin-4-yl)-6,7-d imethoxyquinazoline-2,4-diamine (20 mg, 0.045 mmol 1 eq.) and 2-fluoroacetyl chloride (4.4 mg, 0.045 mmol, 1 eq.) according to general procedure A (10 mg, 44%). ¹H NMR (400 MHz, Methanol-d4) δ 7.71 – 7.64 (s, 1H), 6.99 – 6.86 (br, 1H), 4.89 – 4.87 (s, 1H), 4.79 – 4.74 (s, 1H), 4.62 – 4.53 (m, 1H), 3.98 – 3.96 (s, 3H), 3.94 – 3.91 (s, 3H), 3.72 – 3.61 (m, 2H), 3.59 – 3.50 (m, 2H), 3.42 – 3.36 (t, J = 7.1 Hz, 2H), 3.36 – 3.32 (m, 1H), 3.28 – 3.19 (m, 1H), 2.52 – 2.32 (m, 2H), 2.21 – 2.12 (m, 2H), 2.11 – 1.87 (m, 6H), 1.78 – 1.70 (m, 1H), 1.61 – 1.49 (m, 2H), 1.49 – 1.35 (m, 2H), 1.31 – 1.19 (m, 1H). ESI-MS: Calculated: 502.31 Found: 252.3 [M+2H]⁺/2, 504.3 [M+2H]²⁺. tR = 2.38 min.

EXAMPLE 52: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)-2-fluoroacetamide (Compound 51). Title compound was synthesized similarly to the title compound of Example 2 from N2-(3-aminopropyl)-N4-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxyquinazoline-2,4-diamine (30 mg, 0.07 mmol 1 eq.) and 2-chloro-2-fluoroacetyl chloride (8.9 mg, 0.07 mmol, 1 eq.) according to general procedure A (6 mg, 20% yield). ¹H NMR (400 MHz, Methanol-d₄) δ 7.70 – 7.63 (s, 1H), 6.99 – 6.86 (s, 1H), 6.69 – 6.57 (s, 1H), 6.52 – 6.42 (s, 1H), 4.62 – 4.55 (m, 1H), 4.00 – 3.94 (s, 3H), 3.94 – 3.88 (s, 3H), 3.69 – 3.59 (m, 2H), 3.59 – 3.49 (t, J = 7.4 Hz, 2H), 3.46 – 3.33 (m, 4H), 3.27 – 3.20 (m, 1H), 2.50 – 2.35 (m, 2H), 2.21 – 2.10 (m, 2H), 2.10 – 1.90 (m, 5H), 1.78 – 1.67 (m, 1H), 1.61 – 1.33 (m, 4H), 1.31 – 1.16 (m, 1H). ESI-MS: Calculated: 536.26 Found: 269.2 [M+2H]⁺/2, 538.2 [M+2H]²⁺. tR = 2.65 min.

EXAMPLE 53: Preparation of 2-chloro-N-(2-((4-((1-cyclobutylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)acetamide (Compound 52). Title compound was synthesized from intermediate 1 (410 mg, 0.94 mmol 1 eq.) and cyclobutanone (197 mg, 2.82 mmol 3 eq.) following general procedure A, (9 mg, 14% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (s, 1H), 6.93 (s, 1H), 4.08 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.78 – 3.67 (m, 1H), 3.71 – 3.53 (m, 5H), 3.49 (dd, J = 7.7, 6.0 Hz, 2H), 3.23 – 3.11 (m, 2H), 2.40 – 2.23 (m, 6H), 2.09 – 1.99 (m, 1H), 2.02 – 1.87 (m, 2H), 1.90 – 1.79 (m, 1H). ESI-MS: Calculated: 476.2 Found: 239.1 [M+2H]⁺/2, 477.2 [M+H]⁺. t_R = 2.15 min.

EXAMPLE 54: Preparation of 2-chloro-N-(4-((4-((1-cyclobutylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)butyl)acetamide (Compound 53). Title compound was synthesized from intermediate 1 (410 mg, 0.94 mmol 1 eq.) and cyclobutanone (197 mg, 2.82 mmol 3 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with butane-1,4-diamine (8 mg, 20% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 6.93 (s, 1H), 4.59 (t, J = 11.8 Hz, 1H), 4.04 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.82 – 3.71 (m, 1H), 3.62 (d, J = 12.7 Hz, 2H), 3.58 – 3.53 (m, 2H), 3.34 – 3.22 (m, 2H), 3.13 – 3.02 (m, 2H), 2.44 – 2.18 (m, 6H), 2.07 – 1.79 (m, 4H), 1.77 – 1.60 (m, 4H). ESI-MS: Calculated: 504.3 Found: 253.2 [M+2H]⁺/2, 505.3 [M+H]⁺. tR = 2.15 min.

EXAMPLE 55: Preparation of 2-chloro-N-(5-((4-((1-cyclobutylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)pentyl)acetamide (Compound 54). Title compound was synthesized from intermediate 1 (410 mg, 0.94 mmol 1 eq.) and cyclobutanone (197 mg, 2.82 mmol 3 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with pentane-1,5-diamine (7 mg, 20% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 6.93 (s, 1H), 4.54 (t, J = 11.4 Hz, 1H), 4.00 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.74 (p, J = 8.5 Hz, 1H), 3.64 (d, J = 12.7 Hz, 2H), 3.55 – 3.47 (m, 2H), 3.30 – 3.20 (m, 2H), 3.03 – 2.98 (m, 2H), 2.47 – 2.21 (m, 5H), 2.10 – 1.90 (m, 3H), 1.92 – 1.80 (m, 2H), 1.71 (p, J = 7.3 Hz, 2H), 1.60 (p, J = 7.1 Hz, 2H), 1.46 (h, J = 7.2, 6.2 Hz, 2H). ESI-MS: Calculated: 518.3 Found: 260.2 [M+2H]⁺/2, 519.3 [M+H]⁺. t_R = 2.11 min.

EXAMPLE 56: Preparation of 2-chloro-N-(2-((4-((1-cyclopentylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)acetamide (Compound 55). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and cyclopentanone (246 mg, 2.92 mmol 3 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with ethane-1,2-diamine (15 mg, 12% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (s, 1H), 6.93 (s, 1H), 4.07 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.72 (d, J = 12.5 Hz, 2H), 3.69 – 3.53 (m, 3H), 3.50 (dd, J = 7.8, 6.0 Hz, 2H), 3.36 (t, J = 13.5 Hz, 2H), 2.36 (dd, J = 14.3, 3.6 Hz, 2H), 2.19 (d, J = 8.2 Hz, 2H), 2.12 – 1.96 (m, 2H), 1.90 – 1.65 (m, 7H). ESI-MS: Calculated: 490.3 Found: 246.2 [M+2H]⁺/2, 491.3 [M+H]⁺.

= 2.22 min.

EXAMPLE 57: Preparation of 2-chloro-N-(4-((4-((1-cyclopentylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)butyl)acetamide (Compound 56). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and cyclopentanone (246 mg, 2.92 mmol 3 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with butane-1,4-diamine (16 mg, 15% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.65 (s, 1H), 6.92 (s, 1H), 4.62 – 4.57 (m, 1H), 4.04 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.81 – 3.72 (m, 2H), 3.57 (s, 3H), 3.37 – 3.15 (m, 4H), 2.44 – 2.35 (m, 2H), 2.20 (d, J = 6.7 Hz, 3H), 2.12 – 1.96 (m, 2H), 1.85 (dd, J = 8.3, 4.1 Hz, 2H), 1.81 – 1.61 (m, 7H). ESI-MS: Calculated: 518.3 Found: 260.2 [M+2H]⁺/2, 519.3 [M+H]⁺. tR = 2.29 min.

EXAMPLE 58: Preparation of 2-chloro-N-(5-((4-((1-cyclopentylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)pentyl)acetamide (Compound 57). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and cyclopentanone (246 mg, 2.92 mmol 3 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with pentane-1,5-diamine (9 mg, 22% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 6.93 (s, 1H), 4.55 (s, 1H), 4.00 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.78 (d, J = 12.6 Hz, 2H), 3.55 – 3.50 (m, 3H), 3.26 – 3.17 (m, 4H), 2.41 (d, J = 14.0 Hz, 2H), 2.26 – 2.18 (m, 3H), 2.11 – 1.99 (m, 2H), 1.93 – 1.63 (m, 7H), 1.59 (q, J = 7.2 Hz, 2H), 1.47 (td, J = 8.3, 4.1 Hz, 2H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 533.3 [M+H]⁺. tR = 2.29 min.

EXAMPLE 59: Preparation of N-(2-((4-((1-(bicyclo[2.2.1]heptan-2-yl)piperidin-4- yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)ethyl)-2-chloroacetamide (Compound 58). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and bicyclo[2.2.1]heptan-2-one (536 mg, 4.86 mmol 5 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with ethane-1,2-diamine (10 mg, 9% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (s, 1H), 6.93 (s, 1H), 4.08 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.80 – 3.57 (m, 4H), 3.57 – 3.30 (m, 5H), 2.70 (s, 1H), 2.42 – 2.28 (m, 3H), 2.30 – 1.96 (m, 3H), 1.78 – 1.41 (m, 7H), 1.30 (ddd, J = 13.0, 5.2, 2.4 Hz, 1H). ESI-MS: Calculated: 516.3 Found: 259.2 [M+2H]⁺/2, 517.3 [M+H]⁺. t_R = 2.31 min.

EXAMPLE 60: Preparation of N-(4-((4-((1-(bicyclo[2.2.1]heptan-2-yl)piperidin-4- yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)butyl)-2-chloroacetamide (Compound 59). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and bicyclo[2.2.1]heptan-2-one (536 mg, 4.86 mmol 5 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with propane-1,4-diamine (4 mg, 15 % across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 1H), 6.92 (s, 1H), 4.58 (t, J = 12.2 Hz, 1H), 4.04 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.80 – 3.67 (m, 2H), 3.58 – 3.53 (m, 4H), 3.37 – 3.20 (m, 3H), 2.72 (s, 1H), 2.45 – 2.32 (m, 3H), 2.22 – 2.11 (m, 2H), 2.11 – 2.00 (m, 1H), 1.75 – 1.64 (m, 6H), 1.65 – 1.39 (m, 4H), 1.31 – 1.23 (m, 1H). ESI-MS: Calculated: 544.3 Found: 273.2 [M+2H]⁺/2, 545.3 [M+H]⁺. tR = 2.44 min.

EXAMPLE 61: Preparation of N-(5-((4-((1-(bicyclo[2.2.1]heptan-2-yl)piperidin-4- yl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)pentyl)-2-chloroacetamide (Compound 60). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and bicyclo[2.2.1]heptan-2-one (536 mg, 4.86 mmol 5 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with pentane-1,5-diamine (5 mg, 15% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (s, 1H), 6.93 (s, 1H), 4.59 – 4.48 (m, 1H), 4.00 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.75 (t, J = 13.7 Hz, 2H), 3.60 – 3.42 (m, 3H), 3.30 – 3.14 (m, 4H), 2.71 (s, 1H), 2.47 – 2.25 (m, 3H), 2.22 – 2.09 (m, 2H), 2.10 – 1.98 (m, 1H), 1.78 – 1.66 (m, 4H), 1.58 (dt, J = 16.7, 7.8 Hz, 5H), 1.46 (p, J = 7.6, 6.8 Hz, 3H), 1.32 – 1.20 (m, 1H). ESI-MS: Calculated: 558.3 Found: 280.2 [M+2H]⁺/2, 559.3 [M+H]⁺. 2.51 min.

EXAMPLE 62: Preparation of N-(2-((4-((1-(tert-butyl)piperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)-2-chloroacetamide (Compound 61). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.77 mmol 1 eq.) and 1-(tert-butyl)piperidin-4-amine (241 mg, 1.54 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with ethane-1,2-diamine (6 mg, 8% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (s, 1H), 6.93 (s, 1H), 4.04 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.74 (d, J = 12.5 Hz, 2H), 3.64 (dd, J = 8.2, 5.9 Hz, 2H), 3.50 (dd, J = 8.2, 6.0 Hz, 2H), 3.49 – 3.34 (m, 3H), 2.45 – 2.37 (m, 2H), 2.14 – 1.98 (m, 2H), 1.49 (s, 9H). ESI-MS: Calculated: 478.3 Found: 240.2 [M+2H]⁺/2, 479.3 [M+H]⁺. t_R = 2.10 min.

EXAMPLE 63: Preparation of N-(3-((4-((1-(tert-butyl)piperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)-2-chloroacetamide (Compound 62). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.77 mmol 1 eq.) and 1-(tert-butyl)piperidin-4-amine (241 mg, 1.54 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with propane-1,3-diamine (8 mg, 22% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 1H), 6.93 (s, 1H), 4.58 (t, J = 12.2 Hz, 1H), 4.05 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.78 (d, J = 12.5 Hz, 2H), 3.59 – 3.50 (m, 2H), 3.38 – 3.31 (m, 4H), 2.46 (d, J = 13.9 Hz, 2H), 2.13 – 1.99 (m, 2H), 1.97 – 1.85 (m, 2H), 1.48 (s, 9H). ESI-MS: Calculated: 492.3 Found: 247.2 [M+2H]⁺/2, 493.3 [M+H]⁺. tR = 2.17 min.

EXAMPLE 64: Preparation of N-(4-((4-((1-(tert-butyl)piperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)butyl)-2-chloroacetamide (Compound 63). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.77 mmol 1 eq.) and 1-(tert-butyl)piperidin-4-amine (241 mg, 1.54 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with butane-1,5-diamine (9 mg, 21% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.67 (s, 1H), 6.93 (s, 1H), 4.59 (s, 1H), 4.03 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.79 (d, J = 12.5 Hz, 2H), 3.67 – 3.51 (m, 2H), 3.37 – 3.18 (m, 4H), 2.45 (d, J = 14.1 Hz, 2H), 2.04 (q, J = 13.6, 12.3 Hz, 2H), 1.68 (td, J = 13.0, 12.6, 6.3 Hz, 4H), 1.48 (s, 9H). ESI-MS: Calculated: 506.3 Found: 254.2 [M+2H]⁺/2, 507.3 [M+H]⁺. tR = 2.27 min.

EXAMPLE 65: Preparation of N-(5-((4-((1-(tert-butyl)piperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)pentyl)-2-chloroacetamide (Compound 64). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.77 mmol 1 eq.) and 1-(tert-butyl)piperidin-4-amine (241 mg, 1.54 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with pentane-1,5-diamine (8 mg, 28% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 1H), 6.94 (s, 1H), 4.59 – 4.48 (m, 1H), 4.00 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.79 (d, J = 12.5 Hz, 2H), 3.58 – 3.49 (m, 3H), 3.29 – 3.13 (m, 3H), 2.45 (d, J = 13.2 Hz, 2H), 2.14 – 1.98 (m, 2H), 1.72 (p, J = 7.1 Hz, 2H), 1.60 (q, J = 7.1 Hz, 2H), 1.48 (s, 9H), 1.53 – 1.40 (m, 2H). ESI-MS: Calculated: 520.3 Found: 261.2 [M+2H]⁺/2, 521.3 [M+H]⁺. t_R = 2.31 min.

EXAMPLE 66: Preparation of 2-chloro-N-(3-((6,7-dimethoxy-4-((1-methylpiperidin- 4-yl)amino)quinazolin-2-yl)amino)propyl)acetamide (Compound 65). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and formaldehyde (195 mg, 1.95 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with propane-1,3-diamine (4 mg, 21% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (s, 1H), 6.93 (s, 1H), 4.58 (t, J = 11.0 Hz, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.65 (d, J = 12.9 Hz, 2H), 3.58 – 3.49 (m, 2H), 3.42 – 3.30 (m, 4H), 2.93 (s, 3H), 2.39 (d, J = 14.0 Hz, 2H), 2.11 – 1.95 (m, 2H), 1.92 (p, J = 7.1 Hz, 2H). ESI-MS: Calculated: 450.2 Found: 226.1 [M+2H]⁺/2, 451.2 [M+H]⁺. t_R = 2.05 min.

EXAMPLE 67: Preparation of 2-chloro-N-(2-((6,7-dimethoxy-4-((1-methylpiperidin- 4-yl)amino)quinazolin-2-yl)amino)ethyl)acetamide (Compound 66). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and formaldehyde (195 mg, 1.95 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with ethane-1,2-diamine (6 mg, 18% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.64 (s, 1H), 6.93 (s, 1H), 4.08 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.69 – 3.59 (m, 4H), 3.50 (dd, J = 7.7, 6.0 Hz, 2H), 3.44 – 3.35 (m, 3H), 2.93 (s, 3H), 2.34 (d, J = 14.5 Hz, 2H), 2.12 – 1.96 (m, 2H). ESI-MS: Calculated: 436.2 Found: 219.1 [M+2H]⁺/2, 437.2 [M+H]⁺. tR = 1.90 min.

EXAMPLE 68: Preparation of 2-chloro-N-(4-((6,7-dimethoxy-4-((1-methylpiperidin- 4-yl)amino)quinazolin-2-yl)amino)butyl)acetamide (Compound 67). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and formaldehyde (195 mg, 1.95 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with butane-1,4-diamine (4 mg, 30% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (s, 1H), 6.93 (s, 1H), 4.62 – 4.57 (m, 1H), 4.04 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.65 (d, J = 12.7 Hz, 2H), 3.59 – 3.52 (m, 3H), 3.37 – 3.27 (m, 3H), 2.94 (s, 3H), 2.39 (d, J = 13.9 Hz, 2H), 2.10 – 1.95 (m, 2H), 1.73 – 1.61 (m, 4H). ESI-MS: Calculated: 464.2 Found: 233.1 [M+2H]⁺/2, 465.2 [M+H]⁺.

= 2.34 min.

EXAMPLE 69: Preparation of 2-chloro-N-(5-((6,7-dimethoxy-4-((1-methylpiperidin- 4-yl)amino)quinazolin-2-yl)amino)pentyl)acetamide (Compound 68). Title compound was synthesized from intermediate 1 (425 mg, 0.97 mmol 1 eq.) and formaldehyde (195 mg, 1.95 mmol 2 eq.) following general procedure A, replacing tert-butyl(3-aminopropyl)carbamate with pentane-1,5-diamine (9 mg, 12% across three synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.65 (s, 1H), 6.93 (s, 1H), 4.61 – 4.49 (m, 1H), 4.00 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.71 – 3.62 (m, 2H), 3.59 – 3.39 (m, 3H), 3.25 (t, J = 6.9 Hz, 3H), 2.94 (s, 3H), 2.39 (d, J = 13.9 Hz, 2H), 2.11 – 1.95 (m, 2H), 1.71 (h, J = 7.0 Hz, 2H), 1.60 (p, J = 7.2 Hz, 2H), 1.52 – 1.39 (m, 2H). ESI-MS: Calculated: 478.3 Found: 240.2 [M+2H]⁺/2, 479.3 [M+H]⁺. tR = 2.13 min.

EXAMPLE 70: Preparation of 2-chloro-N-(3-((6,7-dimethoxy-4-((1-(tetrahydro-2H-pyran- 4-yl)piperidin-4-yl)amino)quinazolin-2-yl)amino)propyl)acetamide (Compound 69). Title compound was synthesized from intermediate 1 (220 mg, 0.68 mmol, 1 eq.) and tetrahydro-4H-pyran-4-one (341 mg, 3.4 mmol, 5 eq.) according to general procedure A (14 mg, 15% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.75 – 7.69 (s, 1H), 7.03 – 6.90 (s, 1H), 4.66 – 4.55 (s, 1H), 4.11 – 4.04 (m, 4H), 3.96 – 3.94 (s, 3H), 3.94 – 3.92 (s, 3H), 3.78 – 3.70 (d, J = 12.6 Hz, 2H), 3.59 – 3.31 (m, 9H), 2.45 – 2.33 (m, 2H), 2.28 – 2.09 (m, 4H), 1.96 – 1.78 (m, 4H). ESI-MS: Calculated: 520.3 Found: 261.2[M+2H]²⁺/2, 522.3 [M+2H]²⁺.^. tR = 2.16 min.

EXAMPLE 71: Preparation of 2-chloro-N-(3-((4-(3-(cyclohexylamino)pyrrolidin-1-yl)-6,7- dimethoxyquinazolin-2-yl)amino)propyl)acetamideplease (Compound 70) Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol, 1 eq) and tert-butyl pyrrolidin-3-ylcarbamate (359 mg, 1.93 mmol, 2 eq.) according to general procedure A as a mixture of diastereomers (12 mg, 15% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.55 – 7.48 (s, 1H), 7.07 – 6.89 (s, 1H), 4.56 – 4.38 (s, 2H), 4.34 – 4.22 (s, 3H), 4.19 – 4.02 (d, J = 2.5 Hz, 2H), 3.96 – 3.92 (dd, J = 6.7, 2.2 Hz, 6H), 3.60 – 3.38 (t, J = 6.7 Hz, 2H), 2.73 – 2.55 (d, J = 10.3 Hz, 1H), 2.49 – 2.34 (s, 1H), 2.28 – 2.16 (m, 2H), 2.08 – 1.80 (m, 4H), 1.80 – 1.64 (d, J = 13.1 Hz, 1H), 1.57 – 1.40 (m, 4H), 1.40 – 1.16 (m, 1H).ESI-MS: Calculated: 504.3 Found: 253.2[M+2H]²⁺/2, 506.3 [M+2H]²⁺.^. tR = 2.53 min.

EXAMPLE 72: Preparation of 2-chloro-N-(2-((4-((6-(dimethylamino)hexyl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)acetamide (Compound 71). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (2.00 g, 7.72 mmol 1 eq.) and hexane-1,6-diamine (1.79 g, 15.4 mmol 2 eq.) following general procedure A (14 mg, 4% across four synthetic steps).

NMR (400 MHz, Methanol-d₄) δ 7.51 (s, 1H), 6.89 (s, 1H), 4.03 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.72 – 3.60 (m, 4H), 3.55 – 3.47 (m, 2H), 3.14 – 3.06 (m, 2H), 2.85 (s, 6H), 1.82 – 1.66 (m, 4H), 1.55 – 1.39 (m, 4H). ESI-MS: Calculated: 466.3 Found: 234.2 [M+2H]⁺/2, 467.3 [M+H]⁺. tR = 2.28 min.

EXAMPLE 73: Preparation of 2-chloro-N-(3-((4-((6-(dimethylamino)hexyl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 72). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (2.00 g, 7.72 mmol 1 eq.) and hexane-1,6-diamine (1.79 g, 15.4 mmol 2 eq.) following general procedure A (13 mg, 3% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.53 (s, 1H), 6.90 (s, 1H), 4.04 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.67 (t, J = 7.2 Hz, 2H), 3.57 – 3.49 (m, 2H), 3.34 (t, J = 6.8 Hz, 2H), 3.15 – 3.06 (m, 2H), 2.86 (s, 6H), 1.88 (p, J = 6.8 Hz, 2H), 1.75 (dp, J = 21.3, 7.4 Hz, 4H), 1.54 – 1.39 (m, 4H). ESI-MS: Calculated: 480.3 Found: 241.2 [M+2H]⁺/2, 481.3 [M+H]⁺. t_R = 2.51 min.

EXAMPLE 74: Preparation of 2-chloro-N-(4-((4-((6-(dimethylamino)hexyl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)butyl)acetamide (Compound 73). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (2.00 g, 7.72 mmol 1 eq.) and hexane-1,6-diamine (1.79 g, 15.4 mmol 2 eq.) following general procedure A (18 mg, 4% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.51 (s, 1H), 6.89 (s, 1H), 4.02 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.66 (t, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.34 – 3.23 (m, 2H), 3.13 – 3.07 (m, 2H), 2.86 (s, 6H), 1.83 – 1.56 (m, 8H), 1.51 – 1.40 (m, 4H). ESI-MS: Calculated: 494.3 Found: 248.2 [M+2H]⁺/2, 495.3 [M+H]⁺.

= 2.57 min.

EXAMPLE 75: Preparation of 2-chloro-N-(2-((6,7-dimethoxy-4-((6-(piperidin- 1-yl)hexyl)amino)quinazolin-2-yl)amino)ethyl)acetamide (Compound 74). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (2.00 g, 7.72 mmol 1 eq.) and hexane-1,6-diamine (1.79 g, 15.4 mmol 2 eq.) following general procedure A (12 mg, 3% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.59 (s, 1H), 6.91 (s, 1H), 4.06 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.76 – 3.61 (m, 4H), 3.59 – 3.44 (m, 4H), 3.11 – 2.95 (m, 2H), 2.95 – 2.83 (m, 2H), 1.96 – 1.87 (m, 2H), 1.82 – 1.73 (m, 6H), 1.54 – 1.42 (m, 6H). ESI-MS: Calculated: 506.3 Found: 254.2 [M+2H]⁺/2, 507.3 [M+H]⁺. tR = 2.79 min.

EXAMPLE 76: Preparation of 2-chloro-N-(3-((6,7-dimethoxy-4-((6-(piperidin- 1-yl)hexyl)amino)quinazolin-2-yl)amino)propyl)acetamide (Compound 75). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (2.00 g, 7.72 mmol 1 eq.) and hexane-1,6-diamine (1.79 g, 15.4 mmol 2 eq.) following general procedure A (19 mg, 6% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.59 (s, 1H), 6.90 (s, 1H), 4.06 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.67 (t, J = 7.1 Hz, 2H), 3.60 – 3.47 (m, 4H), 3.35 (t, J = 6.8 Hz, 2H), 3.11 – 3.02 (m, 2H), 2.90 (td, J = 12.5, 3.2 Hz, 2H), 1.98 – 1.81 (m, 4H), 1.85 – 1.71 (m, 8H), 1.57 – 1.40 (m, 4H). ESI-MS: Calculated: 520.3 Found: 261.2 [M+2H]⁺/2, 521.3 [M+H]⁺. tR = 2.68 min.

EXAMPLE 77: Preparation of 2-chloro-N-(4-((6,7-dimethoxy-4-((6-(piperidin- 1-yl)hexyl)amino)quinazolin-2-yl)amino)butyl)acetamide (Compound 76). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (2.00 g, 7.72 mmol 1 eq.) and hexane-1,6-diamine (1.79 g, 15.4 mmol 2 eq.) following general procedure A (10 mg, 3% across four synthetic steps).

(400 MHz, Methanol-d4) δ 7.59 (s, 1H), 6.91 (s, 1H), 4.03 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.66 (t, J = 7.1 Hz, 2H), 3.56 – 3.47 (m, 4H), 3.35 – 3.24 (m, 2H), 3.11 – 3.02 (m, 2H), 2.90 (td, J = 12.5, 3.1 Hz, 2H), 1.96 – 1.86 (m, 2H), 1.87 – 1.58 (m, 12H), 1.59 (s, 0H), 1.51 – 1.40 (m, 4H). ESI-MS: Calculated: 534.3 Found: 268.2 [M+2H]⁺/2, 535.3 [M+H]⁺. tR = 3.23 min.

EXAMPLE 78: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpyrrolidin-3-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 77). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0. 97 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (360 mg, 1.93 mmol, 2 eq.) according to general procedure A as a mixture of diastereomers (12 mg, 13% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.89 – 7.80 (d, J = 9.4 Hz, 1H), 6.98 – 6.86 (s, 1H), 5.23 – 4.90 (m, 2H), 4.11 – 4.05 (d, J = 4.3 Hz, 2H), 4.00 – 3.94 (d, J = 1.1 Hz, 6H), 3.96 – 3.64 (m, 3H), 3.60 – 3.45 (d, J = 17.3 Hz, 2H), 2.75 – 2.43 (m, 1H), 2.42 – 2.12 (m, 4H), 1.99 – 1.89 (dd, J = 12.4, 7.7 Hz, 4H), 1.75 – 1.67 (d, J = 12.6 Hz, 1H), 1.64 – 1.14 (m, 6H). ESI-MS: Calculated: 504.3 Found: 253.2[M+2H]²⁺/2, 506.2 [M+2H]⁺.^. tR = 2.64 min.

EXAMPLE 79: Preparation of -chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)-2,2-difluoropropyl)acetamide (Compound 78) Title compound was synthesized from intermediate 2 (80 mg, 0.20 mmol, eq.) and 2,2-difluoropropane-1,3-diamine (44 mg, 0.40 mmol, 2 eq.) according to general procedure A (19 mg, 34% across two synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.80 – 7.73 (s, 1H), 7.09 – 6.94 (s, 1H), 4.74 – 4.56 (m, 1H), 4.16 – 4.14 (s, 2H), 4.14 – 4.05 (t, J = 14.3 Hz, 2H), 3.98 – 3.96 (s, 3H), 3.96 – 3.94 (s, 3H), 3.89 – 3.77 (t, J = 14.3 Hz, 2H), 3.69 – 3.57 (d, J = 12.1 Hz, 2H), 3.46 – 3.35 (t, J = 12.6 Hz, 2H), 3.29 – 3.22 (m, 1H), 2.45 – 2.32 (m, 2H), 2.32 – 2.19 (m, 4H), 2.01 – 1.92 (d, J = 13.0 Hz, 2H), 1.77 – 1.68 (d, J = 13.0 Hz, 1H), 1.68 – 1.49 (m, 2H), 1.49 – 1.36 (m, 2H), 1.30 – 1.18 (m, 1H). ESI-MS: Calculated: 554.26 Found: 278.2[M+2H]²⁺/2, 555.3

= 2.42 min.

EXAMPLE 80: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylazetidin-3-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 79). Title compound was synthesized similarly to the title compound of Example 2 from 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.34 mmol, 1 eq.) and tert-butyl 3-aminoazetidine-1-carboxylate (100 mg, 0.58 mmol, 1.5 eq.) according to general procedure A (6 mg, 3% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.85 – 7.74 (s, 1H), 7.55 – 7.40 (s, 1H), 5.21 – 5.09 (m, 1H), 4.89 – 4.80 (m, 1H), 4.63 – 4.52 (m, 1H), 4.14 – 4.10 (s, 2H), 4.08 – 4.02 (s, 3H), 4.01 – 3.93 (s, 3H), 3.84 – 3.72 (m, 2H), 3.72 – 3.60 (m, 2H), 3.51 – 3.41 (m, 2H), 3.28 – 3.24 (m, 1H), 2.34 – 2.19 (br, 2H), 2.10 – 2.00 (m, 2H), 1.96 – 1.87 (m, 2H), 1.79 – 1.66 (m, 1H), 1.61 – 1.48 (m, 2H), 1.48 – 1.33 (m, 2H), 1.33 – 1.21 (m, 1H). ESI-MS: Calculated: 490.25 Found: 246.2[M+2H]²⁺/2, 491.2 [M+H]⁺.^. tR = 2.42 min.

EXAMPLE 81: Preparation of N-(3-((4-((1-benzylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)-2-chloroacetamide (Compound 80). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (150 mg, 0.58 mmol 1 eq.) and 1-benzylpiperidin-4-amine (132 mg, 0.70 mmol 1.2 eq.) following general procedure A (18 mg, 18% across three synthetic steps).

NMR (400 MHz, Methanol-d4) δ 7.63 (s, 1H), 7.59 – 7.46 (m, 5H), 6.91 (s, 1H), 4.57 (s, 1H), 4.39 (s, 2H), 4.07 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.63 (d, J = 12.6 Hz, 2H), 3.53 (t, J = 7.1 Hz, 2H), 3.47 – 3.29 (m, 4H), 2.38 (d, J = 13.6 Hz, 2H), 2.12 – 1.96 (m, 2H), 1.92 (p, J = 7.1 Hz, 2H). ESI-MS: Calculated: 526.3 Found: 264.2 [M+2H]⁺/2, 527.3 [M+H]⁺. tR = 2.43 min.

EXAMPLE 82: Preparation of N-(2-((4-((1-cyclopentylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)ethyl)acrylamide (Compound 81). Title compound was synthesized as described for Compound 55 using acryloyl chloride instead of 2-chloroacetyl chloride (15 mg, 27% across 3 synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (s, 1H), 6.93 (s, 1H), 6.30 – 6.15 (m, 2H), 5.67 (dd, J = 8.7, 3.4 Hz, 1H), 4.72 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.73 (d, J = 12.6 Hz, 2H), 3.68 (d, J = 6.0 Hz, 2H), 3.64 – 3.49 (m, 3H), 3.40 – 3.22 (m, 2H), 2.37 (d, J = 13.9 Hz, 2H), 2.27 – 2.14 (m, 3H), 2.03 (qd, J = 13.9, 3.8 Hz, 2H), 1.92 – 1.65 (m, 5H). ESI-MS: Calculated: 468.3 Found: 235.2 [M+2H]⁺/2, 469.3 [M+H]⁺. tR = 2.22 min.

EXAMPLE 83: Preparation of N-(3-((4-((1-cyclopentylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acrylamide (Compound 82). Title compound was synthesized as described for Compound 6 using acryloyl chloride instead of 2-chloroacetyl chloride (15 mg, 19% across three synthetic steps). ¹H NMR (400 MHz, Methanol- d₄) δ 7.65 (s, 1H), 6.93 (s, 1H), 6.31 – 6.14 (m, 2H), 5.66 (dd, J = 9.0, 3.0 Hz, 1H), 4.57 (t, J = 12.5 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.76 (d, J = 12.5 Hz, 2H), 3.64 – 3.51 (m, 4H), 3.38 (t, J = 7.1 Hz, 2H), 3.32 – 3.20 (m, 2H), 2.48 – 2.30 (m, 2H), 2.32 – 2.06 (m, 2H), 2.07 – 1.94 (m, 2H), 1.94 – 1.62 (m, 7H). ESI-MS: Calculated: 482.3 Found: 242.2 [M+2H]⁺/2, 483.3 [M+H]⁺. t_R = 2.41 min.

EXAMPLE 84: Preparation of 2-chloro-N-(3-((4-(4-(cyclohexylamino)piperidin-1-yl)-6,7- dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 83), Title compound was synthesized similarly to the title compound of Example 2 from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol, 1 eq.) and tert-butyl piperidin-4- ylcarbamate (580 mg, 2.9 mmol, 3 eq.) according to general procedure A (14 mg, 23% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.26 – 7.19 (s, 1H), 7.11 – 6.74 (br, 1H), 4.81 – 4.65 (m, 2H), 4.11 – 4.02 (s, 2H), 4.01 – 3.96 (s, 3H), 3.96 – 3.92 (s, 3H), 3.82 – 3.68 (m, 1H), 3.59 – 3.44 (m, 4H), 3.40 – 3.33 (t, J = 6.8 Hz, 2H), 2.40 – 2.24 (m, 2H), 2.24 – 2.05 (s, 2H), 2.05 – 1.80 (m, 6H), 1.80 – 1.65 (m, 1H), 1.55 – 1.28 (m, 4H), 1.33 – 1.06 (q, J = 9.0, 8.2 Hz, 1H). ESI-MS: Calculated: 518.29 Found: 260.9 [M+2H]²⁺/2, 520.2 [M+H]⁺.^. tR = 2.68 min.

EXAMPLE 85: Preparation of 2-chloro-N-(3-((4-(((1-cyclohexylpiperidin-4-yl)methyl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 84). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (150 mg, 0.58 mmol 1 eq.) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (149 mg, 0.70 mmol 1.2 eq.) following general procedure A (11 mg, 18% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.54 (s, 1H), 6.92 (s, 1H), 4.06 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.65 (d, J = 6.5 Hz, 2H), 3.54 (d, J = 11.2 Hz, 4H), 3.39 – 3.31 (m, 2H), 3.23 – 3.11 (m, 1H), 3.15 – 3.00 (m, 2H), 2.22 – 2.05 (m, 5H), 1.97 – 1.84 (m, 4H), 1.66 (dt, J = 25.2, 12.5 Hz, 3H), 1.55 – 1.33 (m, 4H), 1.32 – 1.12 (m, 1H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 533.3 [M+H]⁺. t_R = 2.58 min.

EXAMPLE 86: Preparation of 2-chloro-N-(3-((4-(4-cyclohexyl-1,4-diazepan-1-yl)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 85). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (125 mg, 0.48 mmol 1 eq.) and tert-butyl 1,4-diazepane-1-carboxylate (116 mg, 0.58 mmol 1.2 eq.) following general procedure A (22 mg, 59% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.36 (s, 1H), 7.00 (s, 1H), 4.55 (d, J = 11.8 Hz, 1H), 4.50 – 4.41 (m, 1H), 4.23 – 4.04 (m, 2H), 4.05 (s, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 3.88 – 3.70 (m, 1H), 3.67 – 3.59 (m, 2H), 3.53 (t, J = 6.9 Hz, 2H), 3.41 – 3.30 (m, 4H), 2.45 (d, J = 26.9 Hz, 2H), 2.07 (d, J = 11.1 Hz, 2H), 1.98 – 1.83 (m, 4H), 1.71 (d, J = 13.1 Hz, 1H), 1.54 (qd, J = 11.8, 2.9 Hz, 2H), 1.47 – 1.32 (m, 2H), 1.22 (qt, J = 12.2, 3.2 Hz, 1H). ESI-MS: Calculated: 518.3 Found: 260.2 [M+2H]⁺/2, 519.3 [M+H]⁺.

= 2.39 min.

EXAMPLE 87: Preparation of 2-chloro-N-(3-((4-((1-cycloheptylpiperidin-4-yl)amino)- 8-(trifluoromethoxy)quinazolin-2-yl)amino)propyl)acetamide (Compound 86). Title compound was synthesized similarly to the title compound of Example 2 from 2,4-dichloro-8-(trifluoromethoxy)quinazoline (100 mg, 0.35 mmol, 1 eq.) and 1-cycloheptylpiperidin-4-amine (200 mg, 1.1 mmol, 3 eq.) according to general procedure A (22 mg, 23% across four synthetic steps). 1H NMR (400 MHz, Methanol-d4) δ 8.44 – 8.32 (d, J = 8.3 Hz, 1H), 7.89 – 7.73 (m, 1H), 7.63 – 7.44 (t, J = 8.3 Hz, 1H), 4.79 – 4.62 (tt, J = 11.9, 4.6 Hz, 1H), 4.11 – 3.99 (s, 2H), 3.70 – 3.58 (t, J = 7.0 Hz, 2H), 3.55 – 3.35 (m, 6H), 2.49 – 2.36 (m, 2H), 2.36 – 2.15 (m, 4H), 2.04 – 1.74 (m, 6H), 1.70 – 1.51 (m, 6H). ESI-MS: Calculated: 556.3 Found: 557.2 [M+H] ⁺. tR = 2.55 min.

EXAMPLE 88: Preparation of 2-chloro-N-(3-((4-(((1r,4r)- 4-(cyclohexylamino)cyclohexyl)amino)-6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 87). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol 1 eq.) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (248 mg, 1.16 mmol 1.2 eq.) following general procedure A (16 mg, 21% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.64 (s, 1H), 6.92 (s, 1H), 4.33 – 4.28 (m, 1H), 4.06 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.52 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 7.1 Hz, 2H), 3.37 – 3.29 (m, 1H), 3.31 – 3.16 (m, 1H), 2.25 (d, J = 8.3 Hz, 4H), 2.12 (d, J = 10.0 Hz, 2H), 1.99 – 1.85 (m, 4H), 1.78 – 1.61 (m, 5H), 1.45 – 1.29 (m, 4H), 1.30 – 1.19 (m, 1H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 533.3 [M+H]⁺. t_R = 2.41 min.

EXAMPLE 89: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 8-(trifluoromethoxy)quinazolin-2-yl)amino)propyl)acetamide (Compound 88). Title compound was synthesized similarly to the title compound of Example 2 from 2,4-dichloro-8-(trifluoromethoxy)quinazoline (100 mg, 0.35 mmol, 1 eq.) and 1-cyclohexylpiperidin- 4-amine (193 mg, 1.06 mmol, 3 eq.) according to general procedure A (22 mg, 23% across four synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.39 – 8.29 (d, J = 8.3,1H), 7.94 – 7.78 (d, J = 8.0Hz, 1H), 7.54 – 7.45 (t, J = 8.3 Hz, 1H), 4.75 – 4.65 (m, 1H), 4.11 – 4.02 (s, 2H), 3.74 – 3.54 (m, 4H), 3.47 – 3.34 (m, 4H), 3.28 – 3.21 (m, 1H), 2.46 – 2.33 (m, 2H), 2.33 – 2.14 (m, 4H), 2.12 – 1.89 (m, 4H), 1.78 – 1.65 (m, 1H), 1.65 – 1.52 (m, 2H), 1.51 – 1.36 (m, 2H), 1.30 – 1.11 (m, 1H). ESI- MS: Calculated: 542.24 Found: 272.9 [M+2H]²⁺/2, 544.2 [M+2H]2⁺.^. tR = 2.36 min.

EXAMPLE 90: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)propanamide (Compound 89). Title compound was synthesized similarly to the title compound of Example 2 from N2-(3- aminopropyl)-N4-(1-cyclohexylpiperidin-4-yl)-6,7-dimethoxyquinazoline-2,4-diamine (20 mg, 0.05 mmol, 1 eq.) and 2-chloropropanoyl chloride (5.7 mg, 0.05 mmol, I eq.) according to general procedure A (6.4 mg, 26%). ¹H NMR (400 MHz, Methanol-d4) δ 7.74 – 7.61 (s, 1H), 7.00 – 6.85 (br, 1H), 4.66 – 4.50 (m, 1H), 4.48 – 4.40 (q, J = 6.8 Hz, 1H), 3.99 – 3.95 (s, 3H), 3.95 – 3.90 (s, 3H), 3.70 – 3.63 (d, J = 12.5 Hz, 2H), 3.59 – 3.50 (m, 2H), 3.44 – 3.33 (m, 3H), 3.28 – 3.18 (m, 1H), 2.60 – 2.37 (m, 2H), 2.31 – 2.13 (m, 2H), 2.13 – 1.85 (m, 6H), 1.81 – 1.69 (m, 1H), 1.67 – 1.20 (m, 9H). ESI-MS: Calculated: 532.29 Found: 267.3 [M+2H]²⁺/2, 544.2

= 2.38 min.

EXAMPLE 91: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin- 4-yl)amino)pyrimidin-2-yl)amino)propyl)acetamide (Compound 90). Title compound was synthesized from 2,4-dichloropyrimidine (200 mg, 1.3 mmol, 1 eq.) according to general procedure A (15 mg, 12% across six synthetic steps). 1H NMR (400 MHz, Methanol-d4) δ 7.58 – 7.55 (d, J = 7.3 Hz, 1H), 6.13 – 6.04 (d, J = 7.3 Hz, 1H), 4.10 – 4.01 (s, 2H), 3.67 – 3.54 (d, J = 12.9 Hz, 2H), 3.54 – 3.38 (m, 3H), 3.26 – 3.17 (m, 1H), 3.10 – 2.97 (t, J = 7.8 Hz, 2H), 2.44 – 2.27 (d, J = 13.9 Hz, 2H), 2.25 – 2.12 (d, J = 12.2 Hz, 3H), 2.08 – 1.79 (m, 7H), 1.77 – 1.64 (d, J = 13.2 Hz, 1H), 1.58 – 1.27 (m, 5H), 1.30 – 1.16 (t, J = 3.6 Hz, 1H). ESI-MS: Calculated: 408.2 Found: 205.2 [M+2H]⁺/2, 410.2 [M+2H]2⁺. t_R = 2.12 min.

EXAMPLE 92: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylazepan-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 91). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol, 1 eq.) and tert-butyl 4-aminoazepane-1-carboxylate (310 mg, 1.45 mmol, 1.5 eq.) according to general procedure A as a mixture of diastereomers (18 mg, 10% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.85 – 7.72 (d, J = 9.8 Hz, 1H), 7.04 – 6.65 (s, 1H), 4.79 – 4.60 (d, J = 29.5 Hz, 1H), 4.12 – 4.06 (d, J = 5.2 Hz, 2H), 4.03 – 3.92 (t, J = 1.7 Hz, 6H), 3.73 – 3.43 (m, 5H), 3.41 – 3.34 (ddd, J = 9.2, 6.4, 3.0 Hz, 2H), 2.53 – 2.13 (m, 6H), 2.14 – 2.02 (m, 2H), 2.00 – 1.88 (tt, J = 7.0, 3.7 Hz, 4H), 1.77 – 1.67 (d, J = 13.2 Hz, 1H), 1.64 – 1.50 (m, 2H), 1.49 – 1.36 (m, 2H), 1.32 – 1.16 (t, J = 12.6 Hz, 1H). ESI-MS: Calculated: 532.3 Found: 267.2 [M+2H]⁺/2, 534.3 [M+2H]2⁺. tR = 2.55 min

EXAMPLE 93: Preparation of N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)amino)propyl)acetamide (Compound 92). Title compound was synthesized according to procedure of the title compound of Example 2 with the following with the free amine following microwave reaction and deprotection (140 mg, 0.25 mmol) of free amine was dissolved in DMC (10 mL), DIPEA (42 mg, 55 uL, 0.31 mmol, 1.2 eq.), and acetyl chloride (20 mg, 18 uL, 0.25 mmol, 1 eq) in DCM (5 mL) was added dropwise at 0*C and stirred for 30 minutes. The crude mixture was concentrated under vacuum and purified via reverse phase flash chromatography (water +0.1% HCl and Methanol) to afford the title compound as an HCl salt (48 mg, 40%). ¹H NMR (400 MHz, Methanol-d4) δ 7.73 – 7.63 (s, 1H), 7.04 – 6.83 (s, 1H), 4.61 – 4.48 (m, 1H), 3.97 – 3.94 (s, 3H), 3.93 – 3.89 (s, 3H), 3.73 – 3.61 (m, 2H), 3.60 – 3.48 (m, 2H), 3.28 – 3.20 (m, 3H), 2.46 – 2.36 (m, 2H), 2.20 – 2.01 (m, 4H), 2.00 – 1.93 (m, 6H), 1.90 – 1.82 (d, J = 7.1 Hz, 2H), 1.79 – 1.70 (m, 1H), 1.63 – 1.15 (m, 5H). ESI-MS: Calculated: 484.32 Found: 243.2 [M+2H]⁺/2, 486.3 [M+2H]⁺. tR = 2.11 min

EXAMPLE 94: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4- yl)amino)furo[3,2-d]pyrimidin-2-yl)amino)propyl)acetamide (Compound 93). Title compound was synthesized from 2,4-dichlorofuro[3,2-d]pyrimidine (350 mg, 1.85 mmol 1 eq.) according to general procedure A (34 mg, 22% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 8.04 – 7.92 (d, J = 2.1 Hz, 1H), 6.84 – 6.77 (d, J = 2.1 Hz, 1H), 4.53 – 4.44 (d, J = 12.7 Hz, 1H), 4.09 – 4.00 (s, 2H), 3.68 – 3.59 (d, J = 12.5 Hz, 3H), 3.59 – 3.45 (d, J = 7.1 Hz, 3H), 3.29 – 3.18 (m, 1H), 2.42 – 2.31 (d, J = 13.7 Hz, 2H), 2.20 – 2.05 (d, J = 11.5 Hz, 3H), 2.05 – 1.83 (m, 8H), 1.81 – 1.69 (d, J = 13.1 Hz, 2H), 1.64 – 1.15 (m, 6H). ESI-MS: Calculated: 448.2 Found: 225.2 [M+2H]⁺/2, 450.2 [M+2H2]⁺. t_R = 1.97 min.

EXAMPLE 95: Preparation of 2-chloro-N-(3-((6-((1-cyclohexylpiperidin-4-yl)amino)- 7H-purin-2-yl)amino)propyl)acetamide (Compound 94). Title compound was synthesized from 2,6-dichloro-7H-purine (75 mg, 0.44 mmol 1 eq.) according to general procedure A (22 mg, 18 mg across six synthetic steps). 1H NMR (400 MHz, Methanol-d4) δ 8.13 – 8.06 (s, 1H), 4.58 – 4.39 (m, 1H), 4.10 – 4.01 (s, 2H), 3.67 – 3.57 (m, 3H), 3.55 – 3.44 (m, 4H), 3.37 – 3.32 (m, 4H), 3.27 – 3.20 (m, 2H), 2.51 – 2.10 (m, 7H), 2.10 – 1.83 (m, 9H), 1.77 – 1.65 (d, J = 13.2 Hz, 1H), 1.60 – 1.46 (qd, J = 11.9, 3.2 Hz, 2H), 1.48 – 1.35 (m, 2H), 1.31 – 1.19 (m, 1H). ESI-MS: Calculated: 448.2 Found: 225.2 [M+2H]⁺/2, 450.2 [M+2H2]⁺. t_R = 1.97 min.

EXAMPLE 96: Preparation of 2-chloro-N-((1-(4-((1-cyclohexylpiperidin-4-yl)amino)- 6,7-dimethoxyquinazolin-2-yl)pyrrolidin-3-yl)methyl)acetamide (Compound 95). Title compound was synthesized from Intermediate 2 (40 mg, 0.1 mmol, 1 eq.) and tert-butyl (pyrrolidin-3-ylmethyl)carbamate (59 mg, 0.3 mmol, 3 eq.) according to general procedure A (12 mg, 22% across 3 synthetic steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.79 – 7.64 (s, 1H), 7.36 – 7.17 (s, 1H), 4.70 – 4.54 (d, J = 11.9 Hz, 1H), 4.15 – 4.10 (s, 2H), 3.99 – 3.96 (s, 3H), 3.96 – 3.92 (s, 4H), 3.89 – 3.54 (d, J = 12.1 Hz, 5H), 3.54 – 3.36 (d, J = 6.7 Hz, 3H), 3.24 – 3.15 (m, 1H), 2.75 – 2.48 (d, J = 26.9 Hz, 1H), 2.48 – 2.34 (d, J = 12.1 Hz, 2H), 2.27 – 2.12 (d, J = 11.7 Hz, 5H), 2.04 – 1.80 (d, J = 13.4 Hz, 3H), 1.78 – 1.68 (d, J = 13.2 Hz, 1H), 1.67 – 1.17 (m, 6H). ESI-MS: Calculated: 544.3 Found: 273.2 [M+2H]⁺/2, 546.2 [M+2H2]⁺. t_R = 2.70 min.

EXAMPLE 97: Preparation of 2-chloro-N-(3-((6,7-dimethoxy-4-(((1s,4s)-4-(piperidin- 1-yl)cyclohexyl)amino)quinazolin-2-yl)amino)propyl)acetamide (Compound 96). Title compound was synthesized from 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol 1 eq.) and tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (248 mg, 1.16 mmol 1.2 eq.) following general procedure A replacing cyclohexanone with glutaraldehyde (12 mg, 3% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 7.80 (s, 1H), 6.93 (s, 1H), 4.51 (p, J = 3.8, 3.4 Hz, 1H), 4.05 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.61 – 3.51 (m, 4H), 3.39 – 3.28 (m, 3H), 3.11 – 2.96 (m, 2H), 2.42 – 2.33 (m, 2H), 2.09 – 1.95 (m, 6H), 1.96 – 1.70 (m, 7H), 1.59 – 1.48 (m, 1H). ESI-MS: Calculated: 518.3 Found: 260.2 [M+2H]⁺/2, 519.3 [M+H]⁺.

= 2.57 min.

EXAMPLE 98: Preparation of 2-chloro-N-(3-((4-((1-cyclohexylpiperidin-4-yl)amino)- 5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)acetamide (Compound 97). Title compound was synthesized from 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (200 mg, 0.99 mmol 1 eq.) and tert-butyl 4-aminopiperidine-1-carboxylate (395 mg, 1.97 mmol 2 eq.) following general procedure A (22 mg, 9% across six synthetic steps). ¹H NMR (400 MHz, Methanol-d₄) δ 4.43 (tt, J = 11.8, 4.1 Hz, 1H), 4.04 (s, 2H), 3.64 – 3.55 (m, 2H), 3.45 (t, J = 7.0 Hz, 2H), 3.42 – 3.30 (m, 3H), 3.30 – 3.25 (m, 1H), 3.21 (tt, J = 12.0, 3.4 Hz, 1H), 2.59 – 2.54 (m, 2H), 2.36 – 2.25 (m, 4H), 2.14 (d, J = 11.1 Hz, 2H), 2.03 – 1.90 (m, 4H), 1.87 – 1.80 (m, 6H), 1.76 – 1.67 (m, 1H), 1.52 (qd, J = 12.1, 3.1 Hz, 2H), 1.46 – 1.30 (m, 2H), 1.23 (ddt, J = 16.7, 12.9, 6.4 Hz, 1H). ESI-MS: Calculated: 462.3 Found: 232.2 [M+2H]⁺/2, 463.3 [M+H]⁺. 2.24 min. EXAMPLE 99: Thermal Shift Assay DSF experiments were performed using an Applied Biosystems ViiA 7 Real-Time PCR System. Clear, DNase/RNase free, polypropylene 384-well PCR plates (Genesee Scientific, Cat #: 24- 305) were used for screening. Compounds were diluted from 10 mM DMSO stocks into thermal shift buffer containing 50 mM NaCl and 25 mM TRIS pH 6.5 to 5X the desired concentration and 2 µL plated in a 384-well qPCR plate. A stock of MPP8 purified chromodomain is diluted with thermal shift buffer containing 12.5X SPYRO orange die to 62.5 µM, and 8 µL was plated for a final concentration of SPYRO orange of 10X and 50 µM MPP8 chromodomain. The plates were spun down quickly and incubated in the dark for 30 minutes prior to analysis. Data analysis was completed using Applied Biosystems Protein Thermal Shift™ software and GraphPad Prism 8. EXAMPLE 100: Metabolic stability of test compounds in mice liver microsomes Metabolic stability assays using species-specific liver microsomes are widely implemented in drug discovery to guide structural modification, predict in vivo performance, develop structure-metabolic stability relationships and triage (sorting) compounds for in vivo animal studies. The objective of the study was to evaluate the metabolic stability of test compounds in liver MLM. This was accomplished by incubating test compounds with microsomes and monitoring disappearance with time using LC-MS/MS. Imipramine in MLM was run as positive control. MATERIALS Test Compounds: Compound 12 and Compound 92 Consumables and reagents: Pooled male mice liver microsomes (MSMCPL, Gibco), NADPH (2646-71-1, SRL India), Imipramine hydrochloride (10899, Sigma, Germany), Potassium phosphate monobasic (P5655, Sigma, Germany), Potassium phosphate dibasic (P2222, Sigma, Germany), DMSO (D5879, Sigma, Germany), 96 well-plates (PCR-96MR-HS-C, Axygen, Union City, California). Equipment: Single and multi-channel pipettes (Eppendorf, Germany), Thermo-shaker (Grant-bio, England), Refrigerated centrifuge (Kubota, Tokyo, Japan), LC-MS/MS (Waters ACQUITYTM, ultra-performance LC, Canada), API-4000 MDS SCIEX (Applied Biosystems, Canada). METHOD 1. Preparation of reagents 1.1 Preparation of potassium phosphate buffer, 50 mM (pH 7.4) Potassium phosphate buffer (Kphos) was prepared by adding 0.647 g potassium phosphate monobasic (KH₂PO₄) and 3.527 g potassium phosphate dibasic (K₂HPO₄) to 400 mL of Milli-Q water. pH of the buffer was adjusted to 7.4 and volume was made up to 500 mL. 1.2 Preparation of microsomes Microsomes (20 mg/mL) were diluted in Kphos buffer to prepare a concentration of 0.714 mg/mL and 0.357 mg/mL for positive control. 1.3 Preparation of test compounds Stock solutions of Compound 12 and Compound 92 were prepared in NMP at 78.92 mg/mL and 57.941 mg/mL respectively. These were diluted in DMSO to prepare stocks of 1 mM. 1.4 Preparation of NADPH solution A stock solution of 3.33 mM NADPH (3.33X) was prepared by dissolving appropriate amount of NADPH in Kphos buffer. 2. Assay Conditions

3. Assay A 1120 µL aliquot of Kphos buffer (50 mM, pH 7.4) containing liver microsomes of 0.714 mg/mL for test compounds and 0.357 mg/mL for positive control were added to individual 2 mL tubes (final concentration 0.5 mg/mL for test compound and 0.25 mg/mL for positive control). Test compounds (1 mM) and positive control were directly spiked into respective tubes to prepare a concentration of 1.428 µM (final concentration 1 µM). From the above mix, 70 µL was added to individual wells of 96 well reaction plates and pre-incubated in a 37 °C water bath for 5 min. All the reactions were initiated by adding 30 µL of 3.33 mM NADPH (final concentration 1 mM). Reactions without NADPH and buffer controls (minus NADPH) at 0 min and 60 min were also incubated to rule out non-NADPH metabolism or chemical instability in the incubation buffer. All reactions were terminated using 100 µL of ice-cold acetonitrile containing internal standard at 0, 5, 15, 30 and 60 min. The plates were centrifuged at 4000 RPM for 15 min and 100 µL aliquots were submitted for analysis by LC-MS/MS. 4. Bio-Analysis Samples were monitored for parent compounds disappearance in MRM mode using LC-MS/MS. The LC-MS/MS conditions and MRM chromatogram will be provided as per client request. DATA ANALYSIS The percent remaining of test compounds and positive control in each sample was determined by considering peak area ratio in the 0 minute sample as 100%. The Half-life of compounds in microsomes is calculated by formula: Half-life (t_1/2) (min) = 0.693/k, where k is gradient of line determined from plot of peak area ratio (compound peak area / internal standard peak area) against time. In vitro intrinsic clearance (CL’int) (units in mL/min/kg) was calculated using the formula. = ^0.693 . ^{mL incubation} . ^{45 mg microsomes} . ^{liver weig htin gm *} in vitro T1/2 mg microsomes gm liver Kg b.w For liver microsomes, scaling factor used was 45 mg microsomal protein per gm liver. *Indicates liver weight (gm) which varies species wise. For mice the liver weights are 90 gm. RESULTS: • Metabolic stability of positive control compound Imipramine (MLM) used in the experiment was consistent with literature values and validation results generated in-house. • Compound 12 and Compound 92 showed < 50% compound remaining in mice liver microsomes. Compounds were also stable in minus NADPH and buffer stability samples. The table below shows the data obtained from this study in addition to FIGs.2-3. Percentage turnover of positive control and test compounds in MLM

EXAMPLE 101: Metabolic stability study of additional test compounds in male mouse liver microsomes. The following study design was carried out: 1. The master solution was prepared according to the Table below: Stock Final Reagent Volume Concentration Concentration Phosphate buffer 200 mM 200 μL 100 mM Ultra-pure H2O - 108 μL - MgCl2 solution 50 mM 40 μL 5 mM Microsomes 20 mg/mL 10 μL 0.5 mg/mL 2. 40 μL of 10 mM NADPH solution was added to each well. The final concentrations of NADPH was 1 mM. The mixture was pre-warmed at 37°C for 5 minutes. The negative control samples were prepared by replacing NADPH solutions with 40 μL of ultra-pure H₂O. The negative control was used to exclude the misleading factor that resulted from instability of chemical itself. Samples with NADPH were prepared in duplicate. Negative controls were prepared in singlet. 3.The reaction was started with the addition of 2 μL of 400 μM control compound or test compound solutions. Verapamil was used as positive control in this study. The final concentration of test compound or control compound was 2 μM. 4. Aliquots of 50 µL were taken from the reaction solution at 0, 5, 15, 30 and 60 minutes. The reaction was stopped by the addition of 4 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 μM ketoprofen). Samples were centrifuged at 3, 220 g for 40 minutes. Aliquot of 90 µL of the supernatant was mixed with 90 µL of ultra-pure H2O and then used for LC-MS/MS analysis. 5. Data Analysis All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1/2) was determined from the slope value:

Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro CLint, in µL/min/mg protein) was done using the following equation (mean of duplicate determinations):

Conversion of the in vitro t1/2 (min) into the scale-up unbound intrinsic clearance (Scale-up CLint, in mL/min/kg) was done using the following equation (mean of duplicate determinations): Conversion of the Scale-up CLint (mL/min/kg) into the Predicted hepatic intrinsic clearance (Predicted hepatic CL, in mL/min/kg) was done using the following equation (mean of duplicate determinations): Predicted tic

Unbound Fraction in plasma (Fu) and Blood-to-plasma Concentration Ratio (RB) are assumed at 1. Scaling Factors for Intrinsic Clearance Prediction in Liver Microsomes Liver Weight Microsomal Liver blood Scaling Species (g liver/kg body Concentration flow (Q, Fac ight)^a tor we (mg/g liver)^b mL/min/kg)^a Human 25.7 48.8 20.7 1254.2 Rat 40.0 44.8 55.2 1792.0 Mouse 87.5 50.0 90.0 4375.0 Dog 32.0 77.9 30.9 2492.8 Monkey 30.0 50.0 43.6 1500.0 a. Davies and Morris, 1993, Pharmaceutical Research, 10 (7), pp 1093-1095 b. Barter et al, 2007, Current Drug Metabolism, 8 (1), pp 33-45; Iwatsubo et al, 1997, Journal of Pharmacology and Experimental Therapeutics, 283 (2), pp 462-469 Test compounds were screened for metabolic stability. The table below summarizes the data for these compounds:

EXAMPLE 102: In vivo studies of Compound 12 in Female Athymic Nude Mice. To determine the pharmacokinetics of Compound 12 in female Athymic Nude mice following a single intraperitoneal administration at a dose of 30 and 60 mg/kg respectively METHODS:

Clinical Observation: Following a single intraperitoneal dose administration of Compound 12 in female Athymic Nude mice essentially no adverse clinical signs were observed at a 30 mg/kg dose (n- 4), whereas significant adverse clinical signs were observed at a 60 mg/kg dose (n=4) Results: • Individual plasma concentration-time of Compound 12 in female Athymic Nude mice following a single intraperitoneal administration (Dose: 30 mg/kg) ranged from 814.42 ng/mL post 0.05 hr administration to 191.08 ng/mL post about 1 hr administration to 46.7 ng/mL post 4 hr administration. • Individual plasma concentration-time data of Compound 12 in female Athymic Nude mice following a single intraperitoneal administration (Dose: 60 mg/kg) ranged from 77.8 ng/mL post 0.05 hr administration to about 9.47 ng/mL post 1 hr administration to being below the limit of quantitation post 4 hr administration. Bioanalytical Summary LC Conditions: Mobile Phase A: 0.1% Formic acid in Acetonitrile; B: 10 mM Ammonium Formate; Column: Cortecs Hilic, 2.7 µm, 50 X 4.6 mm; Injection Volume (µL) 5; Column Oven Temperature (ºC) 45; Retention Time (in min) for Analyte: Compound 12 1.46; IS: Sai Compound: 1.38 : LC Gradient Used:

Mass Conditions

MRM Transitions:

Extraction Procedure: The extraction procedure for plasma samples and the spiked plasma calibration standards were identical: A 10 µL of study sample plasma or spiked plasma calibration standard was added to individual pre-labeled micro-centrifuge tubes followed by 100 µL of internal standard prepared in Acetonitrile (Sai Compound, 100 ng/mL) was added except for blank, where 100 µL of Acetonitrile was added. Samples were vortexed for 5 minutes. Samples were centrifuged for 10 minutes at a speed of 4000 rpm at 4 °C. Following centrifugation, 100 µL of clear supernatant was transferred in 96 well plates and analyzed using LC-MS/MS. EXAMPLE 103: Compound 12 i.v. pharmacokinetic profile in CD1 Mouse 1. Preparation of Formulation A 1 mg/ml stock solution in DMSO was prepared by dissolving 0.85 mg of Compound 12 in 0.746 mL DMSO with vortexing. A Formulation validation was carried out where Compound 12 was i.v. administered.

2. Pharmacokinetic study Parameters:

3. Data and Results: Table showing plasma concentration time data: IV Dose 3 mg/kg

Table showing a Summary of Compound 12 i.v. pharmacokinetic parameters: IV Dose: 3 mg/kg

For additional pharmacokinetic data see Fig.4. Analytical Methods: HPLC Instrument: Prominence (Degasser DGU-20A5R(C), Serial NO. L20705619752 IX; Liquid Chromatograph LC-30AD Serial NO. L20555611120 AE and L20555611116 AE;Communications Bus Module CBM-20A, Serial NO. L20235635001 CD, Auto SIL-20AC HT, Serial No. L20355305356 AE; Rack changer II, Serial No. L20585300757 SS). Column: AB Sciex Triple Quan 5500 LC/MS/MS instrument (Serial NO. EF20711807) MS: HALO, 90A, C18, 2.7µm,2.1x50 mm HPLC Conditions: Mobile Phase: 5% Acetonitrile in Water (0.1%Formic acid) Solution B: 95% Acetonitrile in Water (0.1%Formic acid) Flow rate: 0.5 mL/min Time (min) A (%) B (%) 0.20 95.0 5.00 1.20 5.00 95.0 1.90 5.00 95.0 1.91 95.0 5.00 2.30 95.0 5.00 Injection volume: 10μL Preparation of Plasma sample The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution.10 µL of working solutions ( 0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) were added to 10 μL of blank CD1 mice plasma to achieve calibration standards of 0.5~1000 ng/mL (0.5,1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) in a total volume of 20 μL. 5 quality control samples at 1 ng/mL, 2 ng/mL, 5 ng/mL, 100 ng/mL and 800 ng/mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards. 20 μL standards, 20 μL QC samples and 20 μL unknown samples (10 µL plasma with 10 µL blank solution) were added to 200 μL of acetonitrile containing IS mixture for precipitating protein respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 degree Celsius, 4000 rpm for 15 min, the supernatant was diluted at a ratio of 1:2 with H2O (V/V, 1:2), then 10 µL of diluted supernatant was injected into the LC/MS/MS system for quantitative analysis. Clinical Observation: No abnormal clinical symptoms were observed. EXAMPLE 104: MPP8 perturbation impairs TNBC tumor growth and metastasis in vivo A targeted sgRNA mini-pool approach in the LM2 xenograft model was used to test whether HUSH is essential for tumor growth (Figure 5) (Minn, A.J., Kang, Y., Serganova, I., Gupta, G.P., Giri, D.D., Doubrovin, M., Ponomarev, V., Gerald, W.L., Blasberg, R., and Massagué, J. (2005). Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115, 44–55) . Multiple validated sgRNAs targeting each HUSH complex component were transduced independently into separate populations of LM2 cells, and then these separate populations were pooled together prior to subcutaneous injection. Genomic DNA from initial and endpoint cell populations was extracted and sequenced to measure changes in sgRNA abundance over time. It was observed that sgRNAs targeting the HUSH complex were significantly depleted in endpoint tumors (Figure 6), suggesting that HUSH perturbation leads to growth deficiency in MYC-driven tumors in vivo. To further explore the dependency of MYC-driven TNBC on MPP8, two complementary approaches were used. First, LM2 cells with sgRNA-mediated knockout of MPP8 were engineered and compared to the growth of these xenografts to parental cells. Excitingly, MPP8 knockout significantly impaired the growth of LM2 xenografts (Figure 7). Encouraged by these results, it was sought to test whether pharmacologic antagonism of the MPP8 chromodomain could mimic the effects of genetic depletion in vivo. To do so, liposomal-encapsulated compounds were prepared to achieve satisfactory pharmacokinetic (PK) properties and treated mice carrying LM2 xenografts with liposomes loaded with Compound 12 or Compound 3, a very close structural analog (Figs. 11-12). Specifically, Compound 3 contains a methylated amine at the 2’ position of the quinzoline core and demonstrates improved in vitro labeling of MPP8 as determined by MALDI-MS and increased cell death in MYC-hyperactivated cells relative to Compound 12 (Figs.13-15). Strikingly, treatment with 10 mg/kg of liposomal-encapsulated small molecule significantly slowed the growth of LM2 tumors compared to empty liposomes (Figure 8). Finally, to address the potential role of MPP8 in regulating metastasis, it was tested whether treatment with Compound 12 could impair the metastatic potential of the well-characterized LM2 model. Luciferase-labeled LM2 cells were pre-treated with vehicle or Compound 12 (2 µM), injected either subcutaneously or into the tail veins of mice, and then primary tumor size and lung metastatic burden were compared between the two groups 21 days after injection. Importantly, it was found that treatment with Compound 12 significantly reduced primary tumor size and lung metastatic burden relative to vehicle, suggesting that MPP8 activity is critical for both the growth and metastatic potential of MYC-driven TNBC (Figures 9 and 10). EXAMPLE 105: Liposomal formulation of Compound 12 and Compound 3 Lipids, i.e., 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] ammonium salt (DSPE-PEG2kDa), and plant-based cholesterol (Chol) were purchased from Avanti Polar Lipids. Liposomes were formulated using the film hydration method (Mei, K.-C., Liao, Y.-P., Jiang, J., Chiang, M., Khazaieli, M., Liu, X., Wang, X., Liu, Q., Chang, C.H., Zhang, X., et al. (2020). Liposomal Delivery of Mitoxantrone and a Cholesteryl Indoximod Prodrug Provides Effective Chemo-immunotherapy in Multiple Solid Tumors. ACS Nano 14, 13343–13366). In brief, lipids are made as stock solutions in chloroform before formulating into a mixture of DSPC: Chol: DSPE-PEG = 55: 30: 5 (molar ratio). The solvent was evaporated off using a rotary evaporator (Heidolph) in a sterile round bottom flask to afford a lipid film, which was then warmed up to 65oC under nitrogen and hydrated with vortex by 240 mM sterile-filtered ammonium sulfate solution (made from injection water at pH 5.5 (Cheung, C.C.L., Ma, G., Ruiz, A., and Al-Jamal, W.T. (2020). Microfluidic Production of Lysolipid- Containing Temperature-Sensitive Liposomes. JoVE (Journal of Visualized Experiments). The resulting milky multi-lamellar lipid vesicles were then extruded sequentially through polycarbonate membranes (Cytiva/Whatman) with pore sizes of 1000, 800, 400, 200, and finally 100 nm to produce the final colloidal liposomes with hydrodynamic sizes at 120 ± 20 nm and polydispersity index ≤ 0.2, measured by dynamic light scattering (NanoBrook 90Plus PALS). To enable drug loading, the exterior ammonium sulfate solution was exchanged by phosphate-buffered saline at pH 7.4 using size exclusion chromatography (Sephadex G-25 resin, PD-10 column, Cytiva). A transmembrane pH gradient was created for the recovered liposomes (exterior = pH 7.4 PBS, interior = pH 5.5 ammonium sulfate), which is ready for drug loading (Mayer, L.D., Tai, L.C., Bally, M.B., Mitilenes, G.N., Ginsberg, R.S., and Cullis, P.R. (1990). Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. Biochim Biophys Acta 1025, 143–151). The drug loading was performed by co-incubating Compound 12 and Compound 3 solution with the “loadable” liposomes at the drug: lipid ratio = 20% (w/w), at 65oC for 1h under nitrogen, then air-cooled to room temperature. Compound 12 and Compound 3 have excitation and emission at 330/389 and 335/380 nm. Because the fluorescence of the encapsulated drugs was quenched. The drug encapsulation efficiency was determined by measuring the fluorescence intensity of the unencapsulated drug versus the total drug fluorescence intensity by lysing liposomes with 10% Triton X-100 in PBS. The encapsulation efficiency is defined as (total drug – encapsulated drug)/total drug x 100% and was used to calculate liposomal drug loading (Al-Ahmady, Z., Lozano, N., Mei, K.-C., Al-Jamal, W.T., and Kostarelos, K. (2016). Engineering thermosensitive liposome-nanoparticle hybrids loaded with doxorubicin for heat-triggered drug release. International Journal of Pharmaceutics 514, 133–141). The unencapsulated drugs were removed using size exclusion chromatography with Sephadex G-25 resin preconditioned with PBS at pH 7.4. The resulting liposomes were concentrated using a centrifugal concentrator (30 kDa, Vivaspin, Sartorius) to adjust the liposomal drug concentration for injection and stored at 4oC before use. EXAMPLE 106: In vivo studies in mice 4-5-week-old female athymic nude mice were obtained from Envigo for LM2 xenograft and tail vein injection studies. For xenograft experiments, mice were randomized onto treatment at 20mm³ and treated twice weekly with vehicle or 10mg/kg liposome-encapsulated Compound 12/Compound 3 by tail vein injection. Tumor volume was measured using calipers three times per week. Tumors were harvested between 1000 and 1500mm³ and tumor chunks were collected and snap frozen at endpoint for downstream analysis.

Claims

THAT WHICH IS CLAIMED: 1. A compound of formula (III):

Formula (III) wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, -NHR6, -NR6R7, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)alkoxy, and substituted or unsubstituted (C₁-C₆)aromatic oxy, wherein R₆ and R₇ are independently selected from –H and (C₁- C6)alkyl; R3, R4, and R5 are independently selected from –H and (C1-C6)alkyl; W is C or N; X is halo or sulfonate; Y is selected from substituted or unsubstituted (C3-C8)cycloalkyl and substituted or unsubstituted (C₄-C₈)heterocycloalkyl; m and p are independently selected from integers 1, 2, and 3; and n is selected from integers 2, 3, 4, 5, and 6, and any pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of claim 1, wherein W is N.

3. The compound of claim 2, wherein Y is substituted or unsubstituted (C₃-C₈)cycloalkyl.

4. The compound of claim 3, wherein m is 2.

5. The compound of claim 4, wherein p is 2.

6. The compound of claim 2, wherein m and p are 2.

7. The compound of claim 2, wherein n is 3.

8. The compound of claim 6, wherein the compound is a compound of formula (IIIA):

Formula (IIIA) wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, -NHR6, -NR6R7, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁-C₆)alkoxy, and substituted or unsubstituted (C₁-C₆)aromatic oxy, wherein R₆ and R₇ are independently selected from –H and (C1-C6)alkyl; R3, R4, and R5 are independently selected from –H and (C1-C6)alkyl; R_6a, R_6b, R_6c, R_6d, R_6e, R_6f, R_6g, and R_6h are independently selected from –H, halo, and substituted or unsubstituted (C1-C6) alkyl; X is selected from halo and sulfonates; and Y is selected from substituted or unsubstituted (C₃-C₈)cycloalkyl and substituted or unsubstituted (C4-C8)heterocycloalkyl; and stereoisomers thereof.

9. The compound of claim 8, wherein R_6a, R_6b, R_6c, R_6d, R_6e, R_6f, R_6g, and R_6h are independently selected from –H, -F, and methyl.

10. The compound of claim 9, wherein X is halo.

11. The compound of claim 10, wherein X is Cl.

12. The compound of claim 11, wherein R₃, R₄ and R₅ are independently selected from –H, methyl, and ethyl.

13. The compound of claim 12, wherein R5 is –H.

14. The compound of claim 12, wherein R3 and R5 are –H, and R4 is selected from –H, methyl, and ethyl.

15. The compound of claim 12, wherein R₄ and R₅ are -H, and R₃ is selected from –H, methyl, and ethyl.

16. The compound of claim 12, wherein R₅ is H, and R₃ and R₄ are independently selected from methyl and ethyl.

17. The compound of claim 12, wherein R₃, R₄, and R₅ are hydrogen.

18. The compound of claim 12, wherein R4 is ethyl.

19. The compound of claim 18, wherein R3 and R5 are hydrogen.

20. The compound of claim 12, wherein the compound is a compound of Formula (III):

Formula (III) wherein R1 and R2 are independently selected from –H, halo, -NO2, -OH, -NH2, -NHR6, -NR6R7, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁-C₆)alkoxy, and substituted or unsubstituted (C₁-C₆)aromatic oxy, wherein R₆ and R₇ are independently selected from –H and (C1-C6)alkyl; R₄ is selected from –H and (C₁-C₆)alkyl; and Y is selected from substituted or unsubstituted (C₄-C₈)cycloalkyl.

21. The compound of claim 20, wherein R1 and R2 are independently selected from –H, halo, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₁-C₆)alkoxy, and substituted or unsubstituted (C1-C6)aromatic oxy.

22. The compound of claim 21, wherein R₁ and R₂ are independently selected from –H, -F,- OCH₃, -OBn, and -OCF₃.

23. The compound of claim 22, wherein Y is unsubstituted (C₃-C₈)cycloalkyl.

24. The compound of claim 23, wherein Y is unsubstituted C6-cycloalkyl.

25. The compound of claim 24, wherein the compound is

26. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carrier(s). 27. A method for treating a disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of the preceding claims or a pharmaceutical composition of claim 24. 28. The method of claim 27, wherein the disease is cancer. 29. The method of claim 27, wherein the cancer is a MYC-driven cancer. 30. The method of claim 27, wherein the cancer is selected from breast, liver, colorectal, AML, neuroblastoma, and lymphoma cancers. 31. The method of claim 30, wherein the breast cancer is TNBC.