Trdmt1 inhibitors

Abstract

The invention provides compounds, pharmaceutical compositions, and methods of use for the purpose of inhibiting TRDMT1 activity within a cell.

Description

[0001] TRDMT1 INHIBITORS

[0002] BACKGROUND OF THE INVENTION

[0003] Cancer drugs targeting the DNA damage response (DDR), including DNA-damaging drugs, such as cisplatin, bleomycin, or Mitomycin C, and DNA repair inhibitors, such as PARPi, ATRi, or Topli, kill cancer cells by exploiting their DNA repair defects or genomic instability. These DDR-targeted drugs directly or indirectly induce DNA double-strand breaks (DSBs), a lethal form of DNA damage. Despite the efficacy of these drugs in the clinic, drug resistance is a common problem. Biomarkers of resistance to DDR- targeted drugs and strategies to overcome the resistance are much needed for improving cancer therapy. Homologous Recombination (HR) is one of the DNA repair pathways critical for repairing DSBs. Breast, ovarian, and some other cancers with BRCAI / 2 mutations are defective in HR and highly sensitive to PARPi. Unfortunately, only around 10% of cancer patients carry BRCAI / 2 mutations, presenting a challenge to predicting the response of the majority of cancer patients to PARPi and other DDR-targeted drugs. Overall, the lack of biomarkers for sensitivity or resistance to DDR-targeted drugs has been a major obstacle for the treatment of cancer patients. Moreover, both preexisting and acquired resistance to DDR-targeted drugs also limit the efficacy of these drugs in patients. As a result, there is a need for better methods to identify and treat patients suffering from cancer that can benefit from cancer drugs that target DDR.

[0004] SUMMARY OF THE INVENTION

[0005] In one aspect, the invention provides a compound having the structure of formula I:

[0006] Formula I, wherein Ri is alkoxy or heteroalkyl, R2 is halo, and Ar is an unsubstituted or a substituted heteroaryl, or a pharmaceutically acceptable salt thereof. In some embodiments, Ar is one some embodiments, R2 is fluoro. In some embodiments, R1 is methoxy or 2-methoxyethyoxy. In some embodiments, the compound has a structure of: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has a structure of: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has a structure of: or a pharmaceutically acceptable salt thereof. In a related aspect, the invention provides a pharmaceutical composition including compound of formula I or any of the above mentioned compounds and a pharmaceutically acceptable excipient, carrier or diluent. In a related aspect, the invention provides a method of inhibiting TRNA Aspartic Acid Methyltransferase 1 (TRDMT1) enzyme activity in a cell by contacting the cell with any of the above mentioned compounds or the pharmaceutical composition containing the compounds. In some embodiments, the cell is a cancer cell, and the method further includes contacting the cell with a DNA damaging agent.

[0007] In another aspect, the invention provides a compound having the structure of Formula II:

[0008] Formula II, wherein R is selected from a group consisting of: pharmaceutically acceptable salt thereof.

[0009] In another aspect, the invention provides a compound having the structure of Formula III:

[0010] Formula III, wherein each of Xi or X2 is individually -C- or -N-, and wherein at least one of Xi or X2 is -C-, or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the invention provides a compound of Formula IV: , , or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the invention provides a compound of Formula V:

[0013] Formula V, wherein each of Ri, R2, and R3, is each individually -H, halo, heteroalkyl, or alkoxy, and wherein at least one of R1, R2, and R3 is halo and at least one of R1, R2, and Rs is -H, at least two of R1, R2, and R3 is -H, or R2 and R3, together with the atoms to which each is attached, join to form a 5-member heterocycle, or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the invention provides a compound having the structure of any one of the compounds of Table 4 or Table 8, or a pharmaceutically acceptable salt thereof. In a related aspect, the invention provides a pharmaceutical composition including the compound of Formula II, Formula III, Formula IV, Formula V, or any one of the compounds of Table 4 or Table 8, and a pharmaceutically acceptable excipient, carrier, or diluent. In another aspect, the invention provides a method for inhibiting enzymatic activity in a cell by contacting the cell with a compound having the structure of Formula II, Formula III, Formula IV, Formula V, any one of the compounds of Table 4 or Table 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the compound having the structure having the structure of Formula II, Formula III, Formula IV, Formula V, or any one of the compounds of Table 4 or Table 8. In some embodiments, the enzymatic activity is TRDMT1 activity, and the method further comprises contacting the cell with a DNA damaging agent.

[0015] In another aspect, the invention provides inhibiting TRDMT1 enzymatic activity in a cell by contacting the cell with any of compounds 1-46, 53, 55, 58, 59, and 61 in an amount sufficient to inhibit the TRDMT1 enzymatic activity.

[0016] DEFINITIONS

[0017] By “about” or “approximately” is meant ±10% of a recited value.

[0018] By “alkenyl” is meant an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-Ci2-alkenyl, C2-Cio-alkenyl, and C2-Ce-alkenyl, respectively.

[0019] By “alkyl” is meant a straight-chain or branched alkyl radical in all of its isomeric forms, such as a straight or branched group of 1 -12, 1 -10, or 1 -6 carbon atoms, referred to herein as C1-C12 alkyl, C 1 -C 1 o-al ky I , and Ci-Ce-alkyl, respectively. Representative alkoxyl groups include methyl, ethyl, tert-butyl and the like.

[0020] By “alkynyl” is meant an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-Ci2-alkynyl, C2-Cio-alkynyl, and C2-Ce-alkynyl, respectively.

[0021] By “alkoxyl” or “alkoxy” is meant an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, tert-butoxy and the like.

[0022] By “amide” or “amido” is meant a radical of the form — R1C(O)N(R2) — , — R1C(O)N(R2)R3— , — C(O)NR2R3, or — C(O)NH2, wherein R1, R2and R3are each independently alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.

[0023] By “amine” and “amino” is meant both unsubstituted and substituted amines, wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl.

[0024] By “aryl” is meant a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. By “aryl” includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and / or aryls. Unless specified otherwise, the aromatic ring may be substituted at one or more ring positions with, for example, , alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amino, aryl, carboxy, cycloalkyl, ester, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, sulfonamido, sulfonyl or the like. In certain other embodiments, the aromatic ring is not substituted, e.g., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.

[0025] By “carboxy” is meant a radical — COOH or its corresponding salts, e.g. — COONa, etc.

[0026] By “cycloalkyl” is meant a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amino, aryl, carboxy, cycloalkyl, ester, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, sulfonamido, sulfonyl. In certain embodiments, the cycloalkyl group is not substituted, e.g., it is unsubstituted.

[0027] By “effective amount” is meant the amount or dose of the compound that provides the desired effect. An effective amount may be provided as a single or multiple doses to the subject. The disclosed methods may include administering an effective amount of the disclosed compounds (e.g., as present in a pharmaceutical composition) for treating a cell proliferative disease or disorder, such as a cancer.

[0028] By “ester” is meant a -R1C(O)OR2-, wherein R1and R2are each independently alkoxy, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroalkyl, heteroaryl, or heterocyclyl.

[0029] By “ether” is meant two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of — O-alkyl, — O-alkenyl, — O-alkynyl, and the like.

[0030] By “haloalkyl” is meant an alkyl group that is substituted with at least one halogen. For example, — CH2F, — CHF2, — CF3, — CH2CF3, — CF2CF3, and the like.

[0031] By “halogen” or “halo” is meant a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0032] By “heteroalkyl” is meant an “alkyl” group in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). One type of heteroalkyl group is an “alkoxyl” group.

[0033] By “heteroaryl” is meant an aromatic 3 to 10 member ring structure, alternatively 3 to 7 member rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl is substituted at one or more ring positions , alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amino, aryl, carboxy, cycloalkyl, ester, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, sulfonamido, sulfonyl, or the like. In certain other embodiments, the aromatic ring is not substituted, e.g., it is unsubstituted.

[0034] By “heterocyclyl” and “heterocyclic group” is meant a saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3-to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in the heterocyclyl group can be specified using 5 Cx-Cx nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-C7 heterocyclyl group refers to a saturated or partially unsaturated 3- to 7- membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The designation “C3-C7” indicates that the heterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position. In certain embodiments, the heterocyclyl is substituted at one or more positions with , alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amino, aryl, carboxy, cycloalkyl, ester, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, sulfonamido, sulfonyl, or the like. In certain other embodiments, the heterocyclyl is not substittued.

[0035] By “hydroxyl” or “hydroxy” is meant a -OH group.

[0036] The terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of’ should be interpreted as being “closed” transitional terms that do not permit the inclusion additional components other than the components recited in the claims. The term “consisting essentially of’ should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.

[0037] The term “pharmaceutically acceptable salt” refer to salts of the compounds which are substantially nontoxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds as disclosed herein with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. It will be appreciated by the skilled reader that most or all of the compounds as disclosed herein are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids or bases. The particular counter-ion forming a part of any salt of a compound disclosed herein may not be critical to the activity of the compound, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. Undesired qualities may include undesirably solubility or toxicity.

[0038] By “subject,” “patient,” or “individual” is meant an animal, which may be a human or non-human animal, in need of treatment. A “subject in need of treatment” may include a subject having a disease, disorder, or condition that is responsive to therapy with a sensitizing agent in combination with a DNA damaging agent. In some embodiments, the patent may be have a disease, disorder, or condition that is responsive to therapy with the RNA methyltransferase inhibitor alone or in combination with a DNA damaging agent. For example, a “subject in need of treatment” may include a subject having a cell proliferative disease, disorder, or condition such as cancer. In some embodiments, the cancer may be a breast cancer, an ovarian cancer, an esophageal cancer, a stomach cancer, a colon cancer, a lung cancer, a skin cancer, a prostate cancer, a head and neck cancer, a bone cancer, a kidney cancer, a urinary tract cancer, a bladder cancer, a pancreatic cancer, a pediatric cancer, or a blood cancer.

[0039] By “sulfonamido” is meant a -S(O)(O)NR1R2, wherein R1and R2are each independently alkoxy, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroalkyl, heteroaryl, or heterocyclyl. By “sulfonyl” is meant a -RS(O)(O)R1, wherein R1is alkoxy, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalky I, heteroalkyl, heteroaryl, or heterocyclyl.

[0040] By “treating” or “to treat” is meant to alleviate symptoms.

[0041] The terms “sensitizer” or “sensitizing agent” is any compound or composition that improves or increases the activity, decreases resistance to, or improves a therapeutic outcome of another compound or composition when used in combination with the sensitizer.

[0042] BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 is a depiction of the experimental design for the structure-activity relationship (SAR) optimization design for the core substituents.

[0044] FIG. 2 is a depiction of the experimental design for the SAR optimization design for the top rings.

[0045] FIG. 3 is a depiction of the experimental design for the SAR optimization design for the sulfone group.

[0046] FIG. 4 is a depiction of the experimental design for the SAR optimization design for various miscellaneous modification experiments.

[0047] FIG. 5 is a graph illustrating the IC50 analysis for the compounds of interest from the first round of SAR optimizations.

[0048] FIG. 6 is a graph illustrating the frequency of cells found with foci post treatment with compounds from the second round of SAR optimization and a DNA damaging agent.

[0049] FIG. 7 is a graph illustrating the IC50 analysis for the compounds of interest from the second round of SAR optimizations.

[0050] FIG. 8 provides a chemical synthesis pathway of compound 7.

[0051] FIG. 9 provides a chemical synthesis pathway of compound 53.

[0052] FIG. 10 provides a chemical synthesis pathway of compound 61.

[0053] DETAILED DESCRIPTION

[0054] The invention provides compounds, pharmaceutical compositions, and methods of use thereof to treat patients suffering from a cancer that can benefit from compounds affecting the DNA damage response (DDR). In one aspect, the invention provides compounds that inhibit TRNA Aspartic Acid Methyltransferase 1 (TRDMT1) activity within a cell. Exemplary compounds are found below and within the Examples. In another aspect, the invention provides pharmaceutical composition of the compounds, or their pharmaceutically acceptable salts, for use in treatment. In another aspect, the invention provides the methods of use of the compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions including the compounds or their pharmaceutically acceptable salts for treating of a subject. Compounds

[0055] The present invention features compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or any one of the compounds of Table 4 or Table 8, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds have the structure of compounds 1-46, 53, 55, 58, 59, and 61. Exemplary synthesis of the compounds is disclosed in US 20240066033 A1 , incorporated hereby reference, and further exemplary synthesis procedure for compound 7, 53, and 61 is discussed below in Example 4, 5 and 6, respectively.

[0056] Pharmaceutical Compositions

[0057] The compounds disclosed and utilized in the methods disclosed herein may be formulated as pharmaceutical compositions that include an effective amount of one or more RNA methyltransferases as disclosed herein and one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0058] The compounds for use according to the methods disclosed herein may be administered as a single compound or a combination of compounds. For example, an RNA methyltransferase inhibitor may be administered as a single compound or in combination with another compound that treats cancer or that has a different pharmacological activity. In some embodiments, the pharmaceutical composition may further include an effective amount of a DNA damaging agent. In other embodiments, the pharmaceutical composition comprising the effective amount of RNA methyltransferase inhibitor may be intended for coadministration with a second pharmaceutical composition comprising the effective amount of DNA damaging agent.

[0059] The pharmaceutical composition may include the compound in a range of about 0.1 mg to about 2000 mg. The pharmaceutical composition may be administered to provide the compound at a dose of about 0.01 mg / kg to about 100 mg / kg body weight. In some embodiments, after the pharmaceutical composition is administered to a patient (e.g., after about 1 , 2, 3, 4, 5, or 6 hours post-administration), the concentration of the compound at the site of action is about 2 pM to about 10 pM.

[0060] The compounds utilized in the methods disclosed herein may be formulated as a pharmaceutical composition in solid dosage form, although any pharmaceutically acceptable dosage form can be utilized. Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form can be, for example, a fast melt dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, mixed immediate release and controlled release dosage form, or a combination thereof.

[0061] The compounds utilized in the methods disclosed herein may be formulated as a pharmaceutical composition that includes a carrier. For example, the carrier may be selected from the group consisting of proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, and starch- gelatin paste.

[0062] The compounds utilized in the methods disclosed herein may be formulated as a pharmaceutical composition that includes one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, and effervescent agents.

[0063] Suitable diluents may include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose® DCL21 ; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.

[0064] Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.

[0065] Pharmaceutical compositions comprising the compounds may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), or pulmonary route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Examples of pharmaceutical compositions for oral administration include capsules, syrups, concentrates, powders and granules.

[0066] The compounds employed in the compositions and methods disclosed herein may be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating the compounds are considered to be embodiments of the compositions disclosed herein. Such compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions. Such pharmaceutical compositions contain an effective amount of a disclosed compound, which effective amount is related to the dose of the compound to be administered. Each dosage unit may contain the dose of a given compound or each dosage unit may contain a fraction of the dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given. The pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.

[0067] DNA Damaging Agents

[0068] The present invention feature the use of DNA damaging agents in conjunction with the TRDMT1 inhibitor compounds discussed above. The DNA damaging agents may include poly(ADP-ribose) polymerase (PARP) inhibitors (e.g., olaparib, rucaparib, niraparib, or talazoparib), ATM serine / threonine kinase (ATM) inhibitors, ATR Serine / threonine-protein kinase (ATR) inhibitors, radiotherapy and radiomimetics (e.g., ionizing radiation or bleomycin), monofunctional alkylators (e.g., alkyl sulphonates, nitrosourea compounds, or temozolomide), bifunctional alkylators (e.g., nitrogen mustard, Mitomycin C, or Cisplatin), antimedtabolites (e.g., 5-Fluorouracil (5FU), thiopurines, or folate analogs), topoisomerase inhibitors, including topoisomerase I (Topo I) and II (Topo II) inhibitors (e.g., Camptothecins (Topo I), Etoposide (Topo II), anthracyclines, such as Doxorubicin, Epirubicin, or Daunorubicin (Topo II)), replication inhibitors (e.g., Aphidicolin or Hydroxyurea), and the like. In some embodiments, the DNA damaging agent is KillerRed (KR), which is a light-excitable and superoxide-releasing chromophore. In some embodiments, the DNA damaging agent is H2O2.

[0069] Subject in Need of Treatment

[0070] The compounds or pharmaceutical compositions thereof may be administered to a subject in need of a treatment. In some embodiments, the subject in need of a treatment may include a subject having a disease, disorder, or condition. In some embodiments, the condition may be cancer. In some embodiments the cancer may be a breast cancer, an ovarian cancer, an esophageal cancer, a stomach cancer, a colon cancer, a lung cancer, a skin cancer, a prostate cancer, a head and neck cancer, a bone cancer, a kidney cancer, a urinary tract cancer, a bladder cancer, a pancreatic cancer, a pediatric cancer, or a blood cancer.

[0071] In some embodiments, the disease or disorder may be associated with the overexpressed TRDMT1 protein or that is in need of disruption or inhibition of TRDMT1 . In some embodiments, the subject in need of treatment has a cancer associated with upregulated TRDMT1 expression or TRDMT1 activity. A cancer associated with upregulated TRDMT1 expression or TRDMTI activity is a cancer or sample thereof that exhibits statistically elevated levels of TRDMT1 expression or TRDMT1 activity when compared to cancerous or non-cancerous samples that exhibit normal or near normal levels. In some embodiments, the cancer may be a cancer associated with upregulated TRDMT1 expression or upregulated TRDMT1 activity. Exemplary cancers that may have upregulated TRDMT1 expression or upregulated TRDMT1 activity include breast cancer, ovarian cancer, esophageal cancer, stomach cancer, and colon cancer.

[0072] Method of Treatment

[0073] The compounds and pharmaceutical compositions described herein may be used for methods of treatment. In particular, the compounds and pharmaceutical compositions may be used for methods of treatment of a cancer. In some embodiments, the methods of treatment may include the administration of a sensitizing agent, such as the compounds or pharmaceutical compositions including the compound, in combination with the administration of a DNA damaging agent. Use of the sensitizing agent may overcome resistance to treatment with the DNA damaging agent alone. In other embodiments, the methods of treatment may include administration of the compound or a pharmaceutical composition containing the compound alone.

[0074] In some embodiments, the method of treating a cancer include treating a breast cancer, an ovarian cancer, an esophageal cancer, a stomach cancer, a colon cancer, a lung cancer, a skin cancer, a prostate cancer, a head and neck cancer, a bone cancer, a kidney cancer, a urinary tract cancer, a bladder cancer, a pancreatic cancer, a pediatric cancer, or a blood cancer.

[0075] In some embodiments, the compounds of the present invention are effective in inhibiting the activity of an RNA methyltransferase such as TRMDT1 . This allows for the sensitization of subjects or cells to DNA damaging agents. As a result, the RNA methyltransferase inhibitors are effective for use in methods for the treatment of cancer, inhibiting the growth or proliferation of cells, or for the killing of cells when combined with a DNA damaging agent

[0076] In some embodiments, the method of treatment includes determination of an effective amount of the compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound that should be administered. An effective amount can be determined by one skilled in the art by using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[0077] In some embodiments, the method of treatment includes administering an effective amount of a compound or pharmaceutical composition including the compound. In some embodiments, the effective amount may contain from about 0.01 mg / kg to about 100 mg / kg of the compound, or pharmaceutically acceptable salt thereof, for a dose.

[0078] In some embodiments, the method of treatment includes administering an effective amount of a compound or pharmaceutical compositions including a compound of the present disclosure in an amount that is effective in decreasing tumor volume. In some embodiments, tumor volume may decrease by at least 5% (e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%).

[0079] In some embodiments, the method of treatment includes administering an effective amount of a compound or pharmaceutical compositions including a compound of the present disclosure in an amount that is effective in killing cancerous cells. In some embodiments, at least 5% (e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) of cancerous cells may be killed.

[0080] In some embodiments, the method of treatment includes administering an effective amount of a compound or pharmaceutical compositions including a compound of the present disclosure in an amount that is effective in inhibiting the growth or proliferation cancerous cells. In some embodiments, growth or proliferation of cancerous cells are inhibited by at least 5% (e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) when compared to an untreated control.

[0081] In some embodiments, the method of treatment includes administering an effective amount of a compound or pharmaceutical compositions including a compound of the present disclosure in an amount that is effective in increasing the rate of survival or prolonging survival of subjects in comparison to comparable subjects that are not administered the treatment. In some embodiments, the rate of survival may increase by at least 5% (e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%). In some embodiments, the survival may be prolonged by at least 5% (e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%). EXAMPLES

[0082] The invention will be further described by the following non-limiting examples.

[0083] Example 1 : Structure-Activity Relationship (SAR) Optimization of Target Molecules.

[0084] To test the relationship between TRDMT1 inhibition activity and the structure of YW-1842 (Formula I), SAR optimization was conducted on the YW-1842 molecule previously shown to have TRDMT1 inhibitor activity.

[0085] Formula I

[0086] The SAR optimization was conducted in four separate trials by comparing an equal molar amount of derivative molecules against the IC50 dosage of YW-1842, and monitoring survival rate of the U2OS SCE GFP-TRDMT1 stable cells post exposure to radiation and DNA damaging agents (e.g., H2O2, KR). Results of the SAR optimization for core substituent exploration (Table 1), top ring exploration (Table 2), sulfone exploration (Table 3), and miscellaneous exploration (Table 4) are reproduced below.

[0087] Core Substituent SAR Exploration

[0088] The effect on the core structure of substitution of YW-1842 was explored by testing molecules having the structures shown in FIG. 1 and summarized in Table 1.

[0089] Table 1 : Core substituent SAR optimization of YW-1842.

[0090]

[0091] Of the tested compounds, compounds 7 and 11 showed the most TRDMTI inhibition activity, as evidenced by the lowest cell survival rate.

[0092] Top Ring SAR Exploration The effect on the top ring (Ri in FIG. 2) substitution of YW-1842 was explored by testing molecules having the structures shown in FIG. 2 and summarized in Table 2.

[0093] Table 2: Top ring substitution SAR optimization of YW-1842.

[0094] Of the tested compounds, compounds 18, 19, 22, 25 showed the most TRDMT1 inhibition activity, as evidenced by the lowest cell survival rate.

[0095] Sulfone SAR Exploration The effect of Sulfone group (R in FIG. 3) substitution of YW-1842 was explored by testing molecules having the structures shown in FIG. 3 and summarized in Table 3.

[0096] Table 3: Sulfone group substitution SAR optimization of YW-1842.

[0097] Of the tested compounds, compound 30 showed the most TRDMTI inhibition activity, as evidenced by the lowest cell survival rate.

[0098] Miscellaneous SAR Exploration The effect of miscellaneous substitutions of YW-1842 was explored by testing molecules having the structures shown in FIG. 4 and summarized in Table 4. Table 4: Miscellaneous substitution SAR optimization of YW-1842.

[0099]

[0100] Of the tested compounds, none showed greater TRDMT1 inhibition activity compared to YW-1842.

[0101] Example 2: Pharmacokinetic and Pharmacodynamic Studies of Molecules of Interest.

[0102] Of the compounds identified in Example 1 , compounds 7, 11 , 18, 19, 22, and 30 were chosen to determine their pharmacokinetic (PK) and pharmacodynamic (PD) values and compare these values to that of YW-1842. To determine the PK / PD values of the compounds of interest, solutions of the compounds of interest were produced in the following manner, exemplified using YW-1842: For intravenously (IV) exposure, 1 .34 mg of YW-1842 was dissolved in 0.335 mL of DMSO. The solution was then vortexed and sonicated to assist in dissolution of the compound. To this solution, 0.335 mL of 2- hydroxyethyl 12-hydroxyoctadecanoate (Solutol-HS-15©) was added, and the solution further vortexed and sonicated, to assist with dissolution. Finally, 6.030 mL of saline was added to the mixture, with vertexing and sonication, to yield a final solution of 0.2 mg / ml (0.406 pM) YW-1842 in a solution containing 5% Solutol-HS-15© and 5% DMSO by volume. For oral administration, 1.29 mg of YW-1842 was dissolved in 1 .29 mL of 1% microcrystalline cellulose in 50% sucrose solution. The mixture was vortexed and sonicated to result in a suspension of YW-1842 with a concentration of 1 mg / mL (2.03 mM). These solutions were then administered to mice, either orally or through IV. The resulting PK / PD data is shown in Table 5 (oral exposure) and Table 6 (IV exposure).

[0103] Table 5. PK / PD data for oral administration of compounds of interest. Table 6. PK / PD data for oral administration of compounds of interest

[0104] Furthermore, of the compounds tested above, compounds 7, 11 , 18, and 30 were selected to determine their IC50 values (See FIG. 5). The IC50 values were determined using U2OS SCE stable cells which were transfected with 1 pg of GFP-TRDMT1 and 1 pg of TA-KR (transcription activator - KillerRed) for 24 hours. These cells were then given the compounds of interest and exposed to light for 20 minutes, causing KR to release a superoxide. The cells were then allowed to rest for 20 minutes, prior to reading of the results. The results of the calculated IC50 values of compounds 7, 11 , 18, 30 and YW-1842 is summarized in Table 7.

[0105] Table 7. Calculated IC50 values for compounds of interest.

[0106] Of the above tested compounds, compound 7 was determined to show the most promising results based on PD / PK data for oral and IV administration, as well as the calculated IC50 values (see Table 5, Table 6, and Table 7), due to its long half-life during both oral and IV administration, and an IC50 value within the same order of magnitude as YK-1842. Thus, compound 7, along with compound 11 , 18, and 30, were used as a basis for further SAR optimizations discussed below.

[0107] Example 3: Further SAR Optimization of Molecules of Interest.

[0108] Compounds determined to be of interest in Examples 1 and 2 (e.g., compounds 7, 11 , 18, and 30) were further subjected to SAR optimization by synthesizing derivative compounds (compounds 47-75) and their activity was tested in U2OS SCE stable cells which were transfected with 1 pg of GFP-TRDMT 1 and 1 pg of TA-KR (transcription activator - KillerRed) for 24 hours. These cells were then given the compounds of interest and exposed to light for 20 minutes, causing KR to release a superoxide. The cells were then allowed to rest for 20 minutes, prior to reading of the results. The frequency of foci was then determined in these cells and compared to that of the previously known inhibitor, YW-1842 (See FIG. 6). Of these compounds, 5 were identified (Compounds 53, 55, 58, 59, and 61 , See Table 8), 4 were used for further PD / PK analysis (Compounds 53, 55, 58, and 59), compound 61 was omitted due to poor solubility.

[0109] Table 8. Compounds of Interest After Second Round of SAR Analysis Next, the IC50 values of the 4 compounds (Compounds 53, 55, 58, and 59) was determined using U2OS SCE TRDMT 1 KO cells transfected with 1 pg GFP-TRDMT 1 and 1 pg TA-KR for 2 hours. The cells were given two concentrations of the compounds of interest (1 pM and 2.5 pM). The cells were exposed to light for 15 minutes, to activate KR and to release the superoxide, followed by 40 minutes of rest. After the rest period, the frequency of foci positive cells were determined and the IC50 value calculated (see FIG. 7). Example 4: Synthesis of Compound 7.

[0110] An exemplary synthesis pathway for the production of compounds used in the SAR optimization is demonstrated in FIG. 8 using Compound 7, and described below in detail.

[0111] Step 1 : To a solution of 7-0 (1 .0 g, 4.35 mmol, 1 .0 eq) in ethyl alcohol (20 mL) was added Pd / C (0.1 g, 10 wt%) under argon atmosphere. The mixture was purged with H2 three times, and then stirred at 25 °C for 6 hours under H2 (15 psi). Four additional vials were set up as described above and five reaction mixtures were combined. LCMS showed formation of the desired product. The combined reaction mixture was filtered with celite and the filtrate was concentrated under reduced pressure to obtain 7-1 (3.6 g, 80% yield) as a white solid.1H NMR: (400 MHz, DMSO-cfe) 5 ppm 7.34 (d, J = 9.9 Hz, 1 H), 6.64 (d, J = 13.6 Hz, 1 H), 6.54 (s, 2 H), 3.78 (s, 3 H), 3.72 (s, 3 H).19F NMR: (376 MHz, DMSO-cfe) -125.814 5 ppm. LCMS (ESI+): m / z 200.3 [MH]+.

[0112] Step 2: A mixture of 7-1 (1 g, 5.02 mmol, 1 .0 equiv) and urea (2.11 g, 35.1 mmol, 7.0 equiv) was stirred at 160 °C for 12 hours. LCMS showed formation of the desired product. The reaction mixture was diluted with water (2 mL) and stirred at 100 °C for 1 hour. The suspension was filtered, and the filter cake was washed with water (1 mL), dried in vacuum to obtain 7-2 (700 mg, 66% yield) as a gray solid.1H NMR: (400 MHz, DMSO-cfe) 5 ppm 11.49 - 10.97 (m, 2 H), 7.50 (d, J = 9.0 Hz, 1 H), 6.97 (d, J = 11.6 Hz, 1 H), 3.87 (s, 3 H).19F NMR: (376 MHz, DMSO-cfe) -123.689 5 ppm. LCMS (ESI-): m / z 208.9 [M-H]-.

[0113] Step 3: To a solution of 7-2 (500 mg, 2.38 mmol, 1 .0 equiv) in phosphoryl trichloride (2.5 mL) was added diisopropylethylamine (307 mg, 2.38 mmol, 414 pL, 1.0 equiv). The mixture was stirred at 110 °C for 6 hours. TLC (petroleum ether / ethyl acetate= 3 / 1 , Rf = 0.4) indicated the reaction was completed.

[0114] LCMS showed formation of the desired product. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 3 / 1 , Rf = 0.4) to obtain 7-3 (300 mg, 46% yield) as a white solid.1H NMR: (400 MHz, DMSO-cfe) 5 ppm 8.00 (d, J = 11.5 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 4.09 (s, 3 H).19F NMR: (376 MHz, DMSO-cfe) -117.378 5 ppm.

[0115] LCMS (ESI+): m / z 247.1 [MH]+.

[0116] Step 4: To a mixture of 7-3 (400 mg, 1.62 mmol, 1.0 equiv) and 1-2 (272 mg, 1.29 mmol, 0.8 equiv) in dioxane (4.8 mL) and water (2.4 mL) were added potassium carbonate (671 mg, 4.86 mmol, 3.0 equiv) and [1 ,1-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (59.2 mg, 81.0 pmol, 0.05 equiv). The mixture was stirred at 100 °C for 12 hours under nitrogen atmosphere. TLC (petroleum ether / ethyl acetate= 3 / 1 , Rf = 0.6) indicated the reaction was completed. LCMS showed formation of the desired product. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 3 / 1 , Rf = 0.6) to obtain 7-4 (380 mg, 75% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-cfe) 5 ppm 8.49 (s, 1 H), 7.90 (d, J = 11 .8 Hz, 1 H), 7.85 (dd, J = 2.8, 4.8 Hz, 1 H), 7.79 - 7.72 (m, 2 H), 4.03 (s, 3 H).19F NMR: (376 MHz, DMSO-cfe) -119.787 5 ppm. LCMS (ESI+): m / z 295.2 [MH]+.

[0117] Step 5: A mixture of 7-4 (200 mg, 679 pmol, 1 .0 equiv), 1-4 (151 mg, 679 pmol, 1 .0 equiv) and phenol (192 mg, 2.04 mmol, 179 pL, 3.0 equiv) was stirred at 140 °C for 4 hours. LCMS showed formation of the desired product. The mixture was cooled to 20 °C, diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)- ACN]; gradient:38%-68% B over 10 min) to obtain Set-1-007 (20.5 mg, 6% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-cfe) 6 ppm 9.44 (s, 1 H), 8.69 - 8.63 (m, 1 H), 8.53 (s, 1 H), 8.14 (d, J = 8.4 Hz,

[0118] 2 H), 7.99 - 7.93 (m, 4 H), 7.91 (dd, J = 2.8, 4.9 Hz, 1 H), 7.86 (d, J = 9.0 Hz, 1 H), 4.06 (s, 3 H), 3.25 (s,

[0119] 3 H).19F NMR: (376 MHz, DMSO-cfe) -120.477 5 ppm. LCMS (ESI+): m / z 481.2 [MH]+.

[0120] Example 5: Synthesis of Compound 53.

[0121] An example synthesis pathway for the production of compounds used in the second SAR optimization is demonstrated in FIG. 9 using Compound 53 and described below in detail.

[0122] Step 1 : To a stirred solution of 2-fluoro-4-nitrophenol (1) (7 g, 44.6 mmol) and 1-bromo-2- methoxyethane (2) (7.44 g, 53.52 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (12.33 g, 89.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was allowed to cool down to room temperature and then poured into ice water (300 mL). The mixture was extracted with ethyl acetate (100 mL x3). The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro- 1-(2-methoxyethoxy)-4- nitrobenzene (3) (9.36 g, yield: 85%) as a yellow solid. MS (ESI+): m / z = 216.1 [M+H]+.

[0123] Step 2: To a stirred solution of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (3) (9.36 g, 43.5 mmol) in methanol (200 mL) was added Pd / C (600 mg). The reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction was filtered and the filtrate was concentrated. The crude reaction mixture was purified by silica-gel column chromatography (petroleum ether / ethyl acetate from 30 / 1 to 3 / 1) to give 3-fluoro-4-(2- methoxyethoxy)aniline (4) (8 g, yield: 91 %) as a yellow oil. MS (ESI+): m / z = 186.1 [M+H]+.

[0124] Step 3: To a stirred solution of 3-fluoro-4-(2-methoxyethoxy)aniline (4) (7.5 g, 40.5 mmol) in N, N- dimethylformamide (200 mL) was added A / -bromosuccinimide (8.65 g, 48.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was collected, which was diluted with water (300 mL) and extracted with te / Y-butyl methyl ether (100 mL x3). The combined organic layers were concentrated and purified by silica-gel column chromatography (petroleum ether / ethyl acetate from 40 / 1 to 3 / 1) to give 2-bromo-5-fluoro-4-(2- methoxyethoxy)aniline (5) (5.9 g, yield: 55%) as a brown oil. MS (ESI+): m / z =264.0 [M+H]+.

[0125] Step 4: To a stirred solution of 2-bromo-5-fluoro-4-(2-methoxyethoxy)aniline (5) (2.93 g, 11.1 mmol) and triethylamine (4.05 g, 40 mmol) in methanol (50 mL) was added Pd(PPh3)2Cl2 (0.78 g, 1.1 mmol). The reaction mixture was degassed and backfilled with CO three times. The mixture was stirred at 100°C for 16 hours under CO. The reaction mixture was filtered, and the filtrate was concentrated, which was diluted with water and extracted with ethyl acetate (50 mL x3). The combined organic layers were concentrated and purified by silica-gel column chromatography (petroleum ether / ethyl acetate from 50 / 1 to 4 / 1) to give methyl 2-amino-4-fluoro-5-(2- methoxyethoxy)benzoate (6) (2.2 g, yield: 68%) as a yellow oil. MS (ESI+): m / z = 509.1 [2M+Na]+. Step 5: To a suspension of methyl 2-amino-4-fluoro-5-(2-methoxyethoxy)benzoate (6) (2.36 g, 9.7 mmol) in tetra hydrofuran (44 mL) cooled to 0°C was added 2,2,2- trichloroethanecarbonyl isocyanate (7) (2.19 g, 11.6 mmol). The mixture was stirred at room temperature for 30 minutes. Solvent was removed and the residue was suspended in methanol (40 mL). The mixture was cooled to 0°C and treated with ammonia (7M in methanol, 9 mL). The mixture was stirred at room temperature for 16 hours. The mixture was filtered. The filter cake was washed with methanol and dried in vacuo to give 7-fluoro-6-(2- methoxyethoxy)quinazoline-2,4(1 / 7,3 / - / )-dione (8) (2.1 g, yield: 73%) as a white solid. MS (ESI+): m / z = 255.1 [M+H]+.

[0126] Step 6: To a solution of 7-fluoro-6-(2-methoxyethoxy)quinazoline-2,4(1 H,3H)-dione (8) (187 mg, 0.7 mmol) in phosphorus oxychloride (4 mL) was added N,N-diisopropylethylamine (95 mg, 0.7 mmol) at 0°C. The mixture was stirred at 110°C for 5 hours. After reaction completion, the mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (35 mLx3). The organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by silica-gel column chromatography (petroleum ether / ethyl acetate from 20 / 1 to 1 / 1) to give 2,4- dichloro-7-fluoro-6-(2- methoxyethoxy)quinazoline (9) (187 mg, yield: 87%) as a yellow solid. MS (ESI+): m / z = 291.0 [M+H]+.

[0127] Step 7: To a stirred solution of 2,4-dichloro-7-fluoro-6-(2-methoxyethoxy)quinazoline (9) (187 mg, 0.6 mmol), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1 ,3,2-dioxaborolane (10) (121 mg, 0.6 mmol) and potassium carbonate (178 mg, 1.3 mmol) in dioxane / water (4 mL / 1 mL) was added Pd(PPhs)4 (37 mg, 0.03 mmol) under N2. The mixture was degassed and backfilled with N2 for three times. The reaction mixture was stirred at 85°C for 16 hours. After cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x3). The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by silica-gel column chromatography (petroleum ether / ethyl acetate from 20 / 1 to 1 / 1) to give 2-chloro-7- fluoro-6-(2-methoxyethoxy)-4-(thiophen-3-yl)quinazoline (11) (126 mg, yield: 58%) as a yellow solid. MS (ESI+): m / z = 339.0 [M+H]+.

[0128] Step 8: To a stirred solution of 2-chloro-7-fluoro-6-(2-methoxyethoxy)-4-(thiophen-3-yl)quinazoline (11) (56 mg, 0.17 mmol), 4-(4-methanesulfonylphenyl)-1 H-pyrazole (12) (55 mg, 0.25 mmol), cesium carbonate (108 mg, 0.33 mmol) in 1.4-dioxane (5 mL) was added RuPhos (15 mg, 0.03 mmol) and RuPhos-Pd-G3 (14 mg, 0.02 mmol) at room temperature under N2. The reaction mixture was stirred at 100°C for 16 hours. After cooled to room temperature, the reaction was filtered and the filtrate was concentrated, which was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep- TLC (dichloromethane / methanol = 50 / 1) to give 7-fluoro- 6-(2-methoxyethoxy)-2-(4- (4-(methylsulfonyl)phenyl)-1 / 7-pyrazol-1-yl)-4-(thiophen-3-yl)quinazoline (compound 53) (13.5 mg, yield: 15%) as a yellow solid. MS (ESI+): m / z = 525.0 [M+H]+.1H NMR: (DMSO-cfe, 400 MHz) 5 9.42 (s, 1 H), 8.61-8.60 (m, 1 H), 8.51 (s, 1 H), 8.12 (d, J = 4.2 Hz, 2H), 7.97-7.86 (m, 6H), 4.41 (t, J = 4.0 Hz, 2H), 3.78 (t, J = 4.0 Hz, 2H), 3.35 (s, 3H), 3.24 (s, 3H). Example 6: Synthesis of Compound 61.

[0129] An example synthesis pathway for the production of compounds used in the second SAR optimization is demonstrated in FIG. 10, using Compound 61 and described below in detail.

[0130] Step 1 : To a mixture of 2,4-dichloro-7-fluoro-6-methoxyquinazoline (1) (2.0 g, 8.13 mmol) in N, N- dimethylformamide (30 mL) was added tributyl(1 -ethoxyvinyl)stannane (2) (3.5 g, 9.76 mmol) and Pd(PPh3)2Cl2 (285 mg, 0.41 mmol). The mixture was stirred at 60°C under nitrogen atmosphere for 12 hours. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluted with ethyl acetate in petroleum ether from 0% to 10% to give 2-chloro-4-(1-ethoxyvinyl)-7-fluoro-6-methoxyquinazoline (3) (2.1 g, 7.45 mmol, 92% yield) as a yellow solid. MS (ESI+): m / z 283.2 [M+H]+.

[0131] Step 2: To a mixture of 2-chloro-4-(1-ethoxyvinyl)-7-fluoro-6-methoxyquinazoline (3) (2.1 g, 7.45 mmol) in tetra hydrofuran (20 mL) was added HCI (2N) (10 mL, 2 N). The mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound 1 -(2-chloro-7-fluoro-6- methoxyquinazolin-4-yl)ethan-1-one (4) (1.7 g crude) as a yellow solid. MS (ESI+): m / z 255.0 [M+H]+.

[0132] Step 3: To a solution of phenyl-A3-iodanediyl diacetate (5) (380 mg, 1.18 mmol) in acetonitrile (20 mL) was added trifluoromethanesulfonic acid (1.1 g, 7.08 mmol). The mixture was stirred at 0°C for 1 h, then 1-(2-chloro-7-fluoro-6-methoxyquinazolin-4-yl)ethan-1-one (4) (200 mg, 0.79 mmol) was added. The mixture was stirred at 80°C for 5 hours. The mixture was quenched by water (20 mL) and extracted with dichloromethane (20 mL x2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography eluted with ethyl acetate in petroleum ether from 0% to 50% to give the crude compound 5-(2-chloro-7-fluoro-6- methoxyquinazolin-4-yl)-2-methyloxazole (6) (130 mg, yield: 56%) as a yellow solid. MS (ESI+): m / z 294.20 [M+H]+.

[0133] Step 4: To a mixture of 5-(2-chloro-7-fluoro-6-methoxyquinazolin-4-yl)-2-methyloxazole (6) (130 mg, 0.44 mmol) in te / Y-butanol (15 mL) was added 4-(4-methanesulfonylphenyl)- 1 / 7-pyrazole (7) (117 mg, 0.53 mmol), ABuXPhos (35 mg, 0.08 mmol), potassium phosphate (187 mg, 0.88 mmol) and tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol). The mixture was stirred at 90°C under nitrogen atmosphere for 12 hours. The mixture was diluted and filtered. The filtrate was concentrated to give a residue, which was purified by flash column chromatography (gradient elution, 0% to 3%, methanol in dichloromethane) to give 5-(7-fluoro-6-methoxy-2-(4-(4- (methylsulfonyl)phenyl)-1 / 7-pyrazol-1- yl)quinazolin-4-yl)-2-methyloxazole (Compound 61) (30 mg, yield: 14 %) as a yellow solid. MS (ESI+): m / z 480.0 [M+H]+.1H NMR: (400 MHz, DMSO-cfe) 5 9.46 (d, J = 0.4 Hz, 1 H), 8.55 (s, 1 H), 8.52 (d, J = 0.8 Hz, 1 H), 8.19-8.13 (m, 3H), 7.98-7.89 (m, 3H), 4.12 (s, 3H), 3.26 (s, 3H), 2.72 (s, 3H).

Claims

CLAIMS1 . A compound having the structure of Formula I:Formula I, wherein:R1 is alkoxy or heteroalkyl;R2 is halo; andAr is unsubstituted or substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Ar is one of:

3. The compound of claim 1 or 2, wherein R2 is fluoro.

4. The compound of any one of claims 1 -3, wherein R1 is methoxy or 2-methoxyethoxy.

5. The compound of any one of claims 1 -4, wherein the compound has the structure of:or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 -4, wherein the compound has the structure of:or a pharmaceutically acceptable salt thereof.The compound of any one of claims 1 -4, wherein the compound has the structure of:or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound of any one of claims 1 -7 and a pharmaceutically acceptable excipient, carrier, or diluent.

9. A method of inhibiting TRNA Aspartic Acid Methyltransferase 1 (TRDMT1) enzymatic activity in a cell by contacting the cell with a compound of any one of claims 1 -7 or the pharmaceutical composition of claim 8.

10. The method of claim 9, wherein the cell is a cancer cell and the method further comprises contacting the cell with a DNA damaging agent.

11. A compound having the structure of Formula II:Formula II wherein:R is selected from a group consisting of:or a pharmaceutically acceptable salt there of.

12. A compound having the structure of Formula III:Formula III wherein: each of Xi or X2 is individually -C- or -N-; and wherein at least one of Xi or X2 is -C-; or a pharmaceutically acceptable salt thereof.

13. A compound having the structure of Formula IV:Formula IV, wherein:or a pharmaceutically acceptable salt thereof.

14. A compound having the structure of Formula V:Formula V, wherein: each of Ri, R2, and R3, is each individually -H, halo, heteroalkyl, or alkoxy; andwherein at least one of Ri, R2, and R3 is halo and at least one of R1, R2, and Rs is -H; at least two of R1, R2, and R3 is -H; or R2 and R3, together with the atoms to which each is attached, join to form a 5-member heterocycle; or a pharmaceutically acceptable salt thereof.

15. A compound having the structure of any one of the compounds of Table 4 or Table 8, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound of any one of claims 11 -15 and a pharmaceutically acceptable excipient, carrier, or diluent.

17. A method of inhibiting enzymatic activity in a cell by contacting the cells with a compound of any one of claims 11 -15 or the pharmaceutical composition of claim 16.

18. The method of claim 17, wherein the enzymatic activity is TRDMT1 activity and the method further comprises contacting the cell with a DNA damaging agent.

19. A method of inhibiting TRDMT1 enzymatic activity in a cell by contacting the cell with any of compounds 1 -46, 53, 55, 58, 59, and 61 in an amount sufficient to inhibit the TRDMT1 enzymatic activity.

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