Compounds and methods for treating cancer

Abstract

The present disclosure relates to compounds for treating cancer. The compounds may inhibit development of non-stem cancer cells into cancer-initiating cells.

Description

[0001] ATTY. DOCKET NO.: UCH-28927

[0002] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0003] COMPOUNDS AND METHODS FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U. S. Provisional Application No. 63 / 710,212, filed October 22, 2024, the contents of which are hereby incorporated by reference in their entireties.

[0005] GOVERNMENT SUPPORT

[0006] This invention was made with government support under CA200234 and CA211015, awarded by the National Institutes of Health. The government has certain rights in the invention.

[0007] BACKGROUND

[0008] Solid cancers are thought to be organized hierarchically with a small number of cancer-initiating cells (CICs; often also called “cancer stem cells’) at the apex of this hierarchy, able to repopulate and regrow the tumor, while their progeny lack these traits. It has been reported that breast-cancer initiating cells (BCICs) are relatively resistant to radiation. The radio resistance of BCICs has been independently confirmed by others and similar results have been reported for glioblastoma. This treatment resistance leads to a selective killing of non-stem cancer cells and thereby enrichment for CICs. However, selective killing of non-stem cancer cells alone cannot explain the magnitude of CIC enrichment by radiation. Indeed, it has been demonstrated that radiation not only spares CICs but also triggers a phenotype conversion of non-stem cancer cells into induced CICs (iCICs). Therefore, new treatments for cancer are needed.

[0009] SUMMARY OF THE INVENTION

[0010] In certain embodiments, the present disclosure provides compounds represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] ATTY. DOCKET NO.: UCH-28927

[0013] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0014] wherein:

[0015] RAis -NRjR2or -NR1C(O)R3; wherein

[0016] R1and R2are each independently H, alkyl, alkoxy, cycloalkyl, heterocyclyl, or phenyl;

[0017] each RMis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0018] R3is H, alkyl, alkoxy, cycloalkyl, heterocyclyl, or phenyl;

[0019] each RNis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0020] m is 0, 1, 2, 3, or 4; and

[0021] n is 0, 1, 2, 3, 4, or 5.

[0022] In certain embodiments, the present disclosure provides compounds represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0023]

[0024] wherein:

[0025] RAis halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxyl;

[0026] RBis halo, Ci-Ce haloalkyl, or Ci-Ce haloalkoxyl;

[0027] each RMis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0028] each RNis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0029] m is 0, 1, 2, 3, or 4;

[0030] n is 0, 1, 2, 3, 4, or 5; and

[0031] provided that RAand RBare not both Cl.

[0032] In certain embodiments, the present disclosure provides a method of treating cancer, comprising administering to the subject a compound of the present disclosure. ATTY. DOCKET NO.: UCH-28927

[0033] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0034] In certain embodiments, the present disclosure provides a method of inhibiting development of cancer-initiating cells from non-stem cancer cells, comprising administering to a subject a compound of the present disclosure.

[0035] Numerous embodiments are further provided that can be applied to any aspect of the present invention described herein.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1. Effects of compounds MHD001- MHD039 sphere forming capacity in glioblastoma. Patient-derived GBM cells of the classical TCGA subtype were treated with MHD001-039 at lOpM concentrations and irradiated with 0 or 4 Gy. Clonal sphere formation was quantified and expressed relative to unirradiated, DMSO-treated (solvent) controls. N=3 for all compounds. * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001, 2-way ANOVA. Figure 2. Effects of compounds MHD001- MHD039 sphere forming capacity in glioblastoma. Summary of data shown in Figure 1. Figure 2A: the effects of the 39 MHD compounds are shown in comparison to MXC017 and the solvent DMSO. Figure 2B: zoom-in view of the effects of MHD compound on sphere forming capacity.

[0038] Figure 3. Effects of MHD Compounds on Cancer Stem Cell Frequencies in GBM.

[0039] Patient-derived GBM cells of the classical TCGA subtype were treated with MHD001-MHD039 at lOpM concentrations, irradiated with 0 or 4 Gy and subjected to an Extreme Limiting Dilution Assay (ELD A). Cancer stem cell frequencies were calculated. N=3 for all compounds. * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001, 2-way ANOVA.

[0040] Figure 4. Clonogenic Survival Assays on Fibroblasts, Neuronal Human Astrocytes and Microglia. Normal murine fibroblast (NIH3T3), normal murine microglia cells (EOC 20) and normal human astrocytes (NHA) were plated at clonal densities. 24h later, cells either not treated (NC) or treated with solvent (DMSO), MXC017, MHD018, MHD025, or MHD024 at lOpM concentrations and irradiated with 0 or 4 Gy. 14 days later, colonies consisting of 50 cells or more were counted and expressed as the percentage of cells seeded (plating efficiency).

[0041] Figure 5. Dose-Response Characterization of MHD024 and MHD035 in the Nanomolar Range (Ix / week vs. 5x / week at 0 & 4Gy) in GBM cells. Representative pictures of patient-derived HK-374 GBM cells treated with nanomolar concentrations of MHD024 and ATTY. DOCKET NO.: UCH-28927

[0042] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0043] MHD035. The images show the reduction in sphere-formation in response to increasing drug doses.

[0044] Figure 6. Dose-Response Characterization of MHD024 and MHD035 in the Nanomolar Range (Ix / week vs. 5x / week at 0 & 4Gy). Quantification of sphere-formation (SFA) and cancer stem cell frequencies in HK-374 GBM cells after one- or five-time treatment with MHD024 or MHD035 alone or in combination with 4 Gy.

[0045] Figure 7. MXC017, MHD024 and MHD035 bind to and lock Vimentin in its fully assembled state. Figure 7A: Gel electrophoresis of cellular protein pull-down using MXC017 as a bait. Mass spectrometry identified the most prominent band (white rectangle) as vimentin. Figure 7B: MXC017 treatment of HK-374 cells does not change total vimentin protein levels Figure 7C: Confocal Immuno-fluoresence pictures of HK-374 cells treated with solvent or MXC017, with or without irradiation and stained against vimentin using a polyclonal antibody. Nuclei are counterstained. MXC017 does not affect total vimentin levels. Figure 7D: Same as in Figure 7C but stained with a monoclonal antibody again an epitope around Arg45 of vimentin, folded into the inner space of fully assembled vimentin showing that MXC017 locks vimentin in its fully assembled state. Figure 7E: In silico docking results indicate that MXC017, MHD024 and MHD35 bind to a pocket formed by the tetrameric protofibrils of vimentin.

[0046] Figure 8. Migration / Transwell Assay with MHD Compounds. Completed n=3. HK374 cells were serum-starved overnight for about 24h and seeded at 100K cells / well the next day. Conditions: Neg. Ctrl.: bottom & top chamber 1%FBS Pos. Ctrl.: bottom 10%FBS & top chamber 1% FBS Drug containing wells: bottom 10%FBS + drug & top 1%FBS. Images show representative pictures of migrated cells and the bar graph is the quantification of 3 independent experiments. The experiment is carried out to test if MHD024 or MHD035 affect the ability of cells to migrate through small pores, a feature related to the ability of cells to invade / metastasize. Both MHD024 and MHD035 eliminate the migratory capacity of the patient-derived GBM cells (HK-374).

[0047] Figure 9. Confocal Microscopy (Monoclonal AB against Vimentin, 6h & 24h time point, lOpM MHD024 & MHD035 on HK374 cells). Confocal Immuno-fluoresence pictures of HK-374 cells treated with solvent or MXC017, with or without irradiation and stained against vimentin using monoclonal antibody again an epitope around Arg45 of vimentin, folded into ATTY. DOCKET NO.: UCH-28927

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[0049] the inner space of fully assembled vimentin showing that MHD024 and MHD035 lock vimentin in its fully assembled state.

[0050] Figure 10. The Sphere Forming Capacities (SFCs) results of MHD Candidates vs.

[0051] Temozolomide in vitro on all GBM TCGA Types (Classical, Mesenchymal & Proneural). Sphere-forming assays (SFA) of patient-derived GBM cells in response to treatment with MHD024 or MHD035, with and without radiation. The effect is benchmarked against the effect of temozolomide (TMZ) at concentrations of TMZ reported for the brain or tumor tissue under TMZ treatment. Effects are shown for cells of 3 different TCGA glioblastoma subtypes (Classical subtype HK244 and HK390; Proneural subtype HK157 and HK308, Mesenchymal subtype HK217 and HK345).

[0052] Figure 11. The Stem Cell Frequencies and Extreme Limiting Dilution Analysis (ELDA) results of MHD Candidates vs. Temozolomide in vitro on all GBM TCGA Types (Classical, Mesenchymal & Proneural). The Stem Cell Frequencies estimate patient-derived GBM stem cells in response to treatment with MHD024 or MHD035, with and without radiation. The effect is benchmarked against the effect of temozolomide (TMZ) at concentrations of TMZ reported for the brain or tumor tissue under TMZ treatment. Effects are shown for cells of 3 different TCGA glioblastoma subtypes (Classical subtype HK244 and HK390; Proneural subtype HK157 and HK308, Mesenchymal subtype HK217 and HK345).

[0053] Figure 12. MHD Compounds in Prostate Cancer (Sphere Forming Capacities and Extreme Limiting Dilution Analysis). Effects of MXC017, MHD024 and MHD035 on sphere-formation and cancer stem cell frequencies in castration-resistant human (PC-3, DU-145) and murin (TRAMP-CI, TRAMP-C2) prostate cancer lines.

[0054] Figure 13. MHD Compounds in Prostate Cancer (Transwell / Migration Assay).

[0055] Transwell assay showing that MHD024 and MHD035 abolish the migratory capacity of DU-145 and PC-3 prostate cancer cells.

[0056] Figure 14. MHD Compounds in Pancreatic Cancer. Figure 14A: Effects of MXC017 and MHD019, MHD020, MHD024 or MHD035, with or without radiation on the cancer stem cell frequencies in human Mia Paca 2 and PANC-1 prostate cancer lines. Figure 14B: Effects of MHD024 or MHD035 on the migratory capacity of human Mia Paca 2 and PANC-1 prostate cancer lines (Transwell / Migration Assay). ATTY. DOCKET NO.: UCH-28927

[0057] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0058] Figure 15. MHD Compounds in Kaposi Sarcoma Effects of MXC017 and MHD019, MHD020, MHD024 or MHD035, with or without radiation on the cancer stem cell frequencies in murine Kaposi sarcoma cells (KP Sarcoma 3172R, an Orthotopic mouse cell line). Photographs show representative images of drug-treated sarcoma spheres.

[0059] Figure 16. MHD Compounds in mesothelioma Effects of MHD024 or MHD035 on the cancer stem cell frequencies in human mesothelioma lines.

[0060] DETAILED DESCRIPTION OF THE INVENTION

[0061] The present invention is based, at least in part, on the development of new chemical tools and therapeutics that target radiation-induced phenotype conversion. To this end, a series of compounds was designed and synthesized. A combination of high-throughput screening, cell biology, chemical biology, and structural biology was used to identify and validate small molecules that inhibit the conversion of non-stem cancer cells into induced cancer initiating cells (iCICs). Compounds that block the transition from non-stem cancer cells to iCICs were developed. These compounds prevented radiation-induced phenotype conversion of non-stem glioblastoma cells into glioma-initiating cells (GICs).

[0062] In certain embodiments, the present disclosure provides compounds represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] wherein:

[0065] RAis -NR1R2or -NR1C(O)R3; wherein

[0066] R1and R2are each independently H, alkyl, alkoxy, cycloalkyl, heterocyclyl, or phenyl;

[0067] each RMis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0068] R3is H, alkyl, alkoxy, cycloalkyl, heterocyclyl, or phenyl; ATTY. DOCKET NO.: UCH-28927

[0069] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0070] each RNis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0071] m is 0, 1, 2, 3, or 4; and

[0072] n is 0, 1, 2, 3, 4, or 5.

[0073] In certain embodiments, m is 0 and n is 0. In certain embodiments, RAis -NR1R2. In some such embodiments, R1and R2are each independently H or Ci-Ce alkyl.

[0074] In certain embodiments, RAis -NR1C(O)R3. In some such embodiments, R1and R3are each independently H or Ci-Ce alkyl.

[0075] In certain embodiments, RAis -NH2, -NH(CO)H, or -NH(CO)Me. In certain preferred embodiments, RAis -NH2.

[0076] In certain embodiments, the compound is selected from:

[0077]

[0078]

[0079] , a pharmaceutically acceptable salt thereof.

[0080] In certain embodiments, the present disclosure provides compounds represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0081]

[0082] ATTY. DOCKET NO.: UCH-28927

[0083] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0084] wherein:

[0085] RAis halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxyl;

[0086] RBis halo, Ci-Ce haloalkyl, or Ci-Ce haloalkoxyl;

[0087] each RMis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0088] each RNis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;

[0089] m is 0, 1, 2, 3, or 4;

[0090] n is 0, 1, 2, 3, 4, or 5; and

[0091] provided that RAand RBare not both Cl.

[0092] In certain embodiments, m is 0 and n is 0.

[0093] In certain embodiments, RAis halo, Ci-Ce haloalkyl, or Ci-Ce haloalkoxyl. In preferred embodiments, RAis fluoro, Ci-Ce fluoroalkyl or Ci-Ce fluoroalkoxyl. In particularly preferred embodiments, RAis fluoro or Ci-Ce fluoroalkyl. In most preferred embodiments, RAis -CF3.

[0094] In certain embodiments, RBis halo or Ci-Ce haloalkyl. In certain such embodiments, RBis fluoro, chloro or -CF3. In preferred embodiments, RBis chloro.

[0095] In certain embodiments, the compound is selected from:

[0096]

[0097] or a pharmaceutically acceptable salt thereof. ATTY. DOCKET NO.: UCH-28927

[0098] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0099] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0100] In certain embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound or a composition of present disclosure.

[0101] In certain embodiments, the method further comprises treating the subject with radiation. In further embodiments, the compound or composition is administered after the radiation. In other embodiments, the compound or composition is administered before the radiation. In yet other embodiments, the compound or composition is administered conjointly with the radiation.

[0102] In certain embodiments, the cancer is selected from multiple myeloma, prostate cancer, stomach cancer, bladder cancer, esophageal cancer, cervical cancer, liver cancer, kidney cancer, bone cancer, brain cancer, leukemia, head and neck cancer, oral cancer, pancreatic cancer, lung cancer, colon cancer, melanoma, breast cancer, ovarian cancer, glioblastoma, Kaposi sarcoma, and mesothelioma. In further embodiments, the cancer is selected from glioblastoma, breast cancer, prostate cancer, pancreatic cancer, Kaposi sarcoma, and mesothelioma. In yet further embodiments, wherein the cancer is glioblastoma or breast cancer.

[0103] In certain embodiments, the present disclosure provides a method of inhibiting development of cancer-initiating cells from non-stem cancer cells, comprising administering to a subject in need thereof a compound or a composition of the present disclosure.

[0104] In certain embodiments, the present disclosure provides a method of inhibiting conversion of non-stem cancer cells into cancer-initiating cells, comprising administering to a subject in need thereof a compound or composition of the present disclosure.

[0105] In certain embodiments, the method further comprises treating the subject with radiation. In further embodiments, the compound or composition is administered after the radiation. In other embodiments, the compound or composition is administered before the radiation. In yet other embodiments, the compound or composition is administered conjointly with the radiation.

[0106] In certain embodiments, the non-stem cancer cells are cancer cells from multiple myeloma, prostate cancer, stomach cancer, bladder cancer, esophageal cancer, cervical cancer, liver cancer, kidney cancer, bone cancer, brain cancer, leukemia, head and neck ATTY. DOCKET NO.: UCH-28927

[0107] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0108] cancer, oral cancer, pancreatic cancer, lung cancer, colon cancer, melanoma, breast cancer, ovarian cancer, glioblastoma, Kaposi sarcoma, or mesothelioma. In particular embodiments, the non-stem cancer cells are cancer cells from glioblastoma, breast cancer, prostate cancer, pancreatic cancer, Kaposi sarcoma, or mesothelioma. In preferred embodiments, the nonstem cancer cells are glioblastoma cells.

[0109] Pharmaceutical Compositions

[0110] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0111] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the ATTY. DOCKET NO.: UCH-28927

[0112] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0113] composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0114] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0115] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0116] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a ATTY. DOCKET NO.: UCH-28927

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[0118] cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U. S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0119] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0120] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0121] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0122] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, ATTY. DOCKET NO.: UCH-28927

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[0124] such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0125] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0126] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used ATTY. DOCKET NO.: UCH-28927

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[0128] include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0129] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0130] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0131] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0132] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0133] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0134] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0135] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by ATTY. DOCKET NO.: UCH-28927

[0136] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0137] dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0138] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraocular (such as intravitreal), intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0139] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and 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 coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0140] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0141] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having ATTY. DOCKET NO.: UCH-28927

[0142] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0143] poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0144] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0145] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0146] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0147] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0148] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0149] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical ATTY. DOCKET NO.: UCH-28927

[0150] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0151] composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0152] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0153] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0154] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0155] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0156] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, ATTY. DOCKET NO.: UCH-28927

[0157] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0158] IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxy -2-naphthoic acid, 2, 2-di chloroacetic acid, 2 -hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1, 2-di sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthal ene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acid salts.

[0159] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0160] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0161] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric ATTY. DOCKET NO.: UCH-28927

[0162] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0163] acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0164] Definitions

[0165] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[0166] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N. Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed ”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed ”, W. H. Freeman & Co., N. Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed ”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0167] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0168] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[0169] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). ATTY. DOCKET NO.: UCH-28927

[0170] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0171] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0172] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0173] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0174] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an ATTY. DOCKET NO.: UCH-28927

[0175] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0176] agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0177] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapies or therapeutic agents such that the second therapy or therapeutic agent is administered while the previously administered therapy or therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapies or therapeutic agents.

[0178] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0179] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0180] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. ATTY. DOCKET NO.: UCH-28927

[0181] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0182] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[0183] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups.

[0184] Preferably, the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Ce branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group may be optionally substituted.

[0185] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0186] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0187] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0188] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto.

[0189] Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0190] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0191] The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci-30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer. ATTY. DOCKET NO.: UCH-28927

[0192] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0193] Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0194] The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A Ci-ealkyl group, for example, contains from one to six carbon atoms in the chain.

[0195] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0196] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0197] The term “amide”, as used herein, refers to a group

[0198] 0

[0199] • 'R9

[0200] R10

[0201] wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0202] The terms “amine” and “amino” are art- recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

[0203] Rio

[0204]

[0205] wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0206] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0207] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. ATTY. DOCKET NO.: UCH-28927

[0208] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0209] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0210] The term “carbamate” is art-recognized and refers to a group

[0211]

[0212] wherein R9and R10independently represent hydrogen or a hydrocarbyl group.

[0213] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0214] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-IH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0215] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0216] The term “carbonate” is art-recognized and refers to a group -OCO2-. ATTY. DOCKET NO.: UCH-28927

[0217] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0218] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0219] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[0220] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.

[0221] Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[0222] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0223] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0224] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0225] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0226] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0227] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more ATTY. DOCKET NO.: UCH-28927

[0228] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0229] cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0230] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0231] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0232] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0233] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0234] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof. ATTY. DOCKET NO.: UCH-28927

[0235] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0236] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae

[0237]

[0238] wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0239] The term “sulfoxide” is art-recognized and refers to the group-S(O)-.

[0240] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0241] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0242] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is 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 “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0243] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. ATTY. DOCKET NO.: UCH-28927

[0244] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0245] The term “thioester”, as used herein, refers to a group -C(O)SR9or -SC(O)R9, wherein R9represents a hydrocarbyl.

[0246] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0247] The term “urea” is art-recognized and may be represented by the general formula

[0248]

[0249] wherein R9and R10independently represent hydrogen or a hydrocarbyl.

[0250] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0251] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0252] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0253] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.

[0254] Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. ATTY. DOCKET NO.: UCH-28927

[0255] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0256] Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0257] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0258] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0259] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[0260] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0261] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U. S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein ATTY. DOCKET NO.: UCH-28927

[0262] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0263] by reference. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0264] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0265] The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0266] CANCER

[0267] As described herein, the methods and compositions provided herein can be used for preventing or treating cancer.

[0268] Cancer, tumor, or hyperproliferative disease refer to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancer cells or non-stem cancer cells are often in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell. Cancers include, but are not limited to, B cell cancer, (e.g., multiple myeloma, Diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma, Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Mantle cell lymphoma (MCL), Marginal zone lymphomas, Burkitt lymphoma, Waldenstrom's macroglobulinemia, Hairy cell leukemia, Primary central nervous system (CNS) lymphoma, Primary intraocular lymphoma, the heavy chain diseases, such as, for example, alpha chain disease, gamma chain disease, and mu chain disease, benign monoclonal gammopathy, and immunocytic amyloidosis), T cell cancer (e.g., T-lymphoblastic lymphoma / leukemia, non-Hodgkin lymphomas, Peripheral T-cell lymphomas, Cutaneous T-cell lymphomas (e.g., mycosis fungoides, Sezary syndrome), Adult T-cell leukemia / lymphoma, Angioimmunoblastic T-cell lymphoma, Extranodal natural killer / T-cell lymphoma, Enteropathy-associated intestinal T- ATTY. DOCKET NO.: UCH-28927

[0269] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0270] cell lymphoma (EATL), Anaplastic large cell lymphoma (ALCL), Hodgkin lymphoma), melanomas, breast cancer, lung cancer, bronchus cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, cancer of hematologic tissues, and the like. Other non-limiting examples of types of cancers applicable to the methods encompassed by the present invention include human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, liver cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, bone cancer, brain tumor, testicular cancer, lung carcinoma, small cell lung carcinoma (SCLC), bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some embodiments, cancers are epithelial in nature and include but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, gynecologic cancers, renal cancer, laryngeal cancer, lung cancer, oral cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer. In other embodiments, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer. In still other embodiments, the epithelial cancer is non-small-cell lung cancer, nonpapillary renal cell carcinoma, cervical carcinoma, ovarian carcinoma (e.g., ATTY. DOCKET NO.: UCH-28927

[0271] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0272] serous ovarian carcinoma), or breast carcinoma. The epithelial cancers may be characterized in various other ways including, but not limited to, serous, endometrioid, mucinous, clear cell, Brenner, or undifferentiated.

[0273] Examples

[0274] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

[0275] General procedure (Synthesis):

[0276]

[0277] A mixture of the indole (0.50 mmol), diphenyl carbonate [(PhO)2CO (0.51 mmol)] and sodium carbonate (Na₂CO₃, 20 mol%) in anhydrous acetonitrile (0.7 mL) in a sealed vial was stirred at reflux under argon for 1 d. The reaction mixture was cooled, concentrated and purified by flash column chromatography on silica gel using 5% diethyl ether in hexane as eluent to afford the desired carbamate product. This was then mixed with the corresponding amine 1 or 2 (1 eq) and DBU (1.1 eq) in anhydrous THF (1.0 M) in a sealed vial. After stirring at 21 °C for 22 h, the mixture was purified by flash column chromatography on silica gel using 33% ethyl acetate in hexane as eluent to afford the desired urea product. MHD024-MHD026, MHD033, MHD035 and MHD038 were synthesized using General procedure.

[0278] NMR data for MHD024-MHD026, MHD033, MHD035, and MHD038:

[0279]

[0280] 5-amino-N-(4-(piperidin-l-ylsulfonyl)benzyl)-lH-indole-l-carboxamide (MHD024) ATTY. DOCKET NO.: UCH-28927

[0281] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0282] 1H NMR (500 MHz, CDCh; mixture of rotamers) 6 (ppm) 7.87 (d, J = 8.8 Hz, 0.8H), 7.76-7.67 (m, 1.66H), 7.56-7.46 (m, 1.65H), 7.44-7.33 (m, 0.9H), 7.22-7.11 (m, 0.61H), 6.99-6.80 (m, 1.62H), 6.79-6.62 (m, 1.15H), 6.59-6.42 (m, 0.8H), 6.37 (s, 0.26H), 5.91 (t, J= 5.6 Hz, 0.63H), 4.72 (d, J= 5.9 Hz, 2H), 3.08-2.89 (m, 4H), 1.76-1.58 (m, 4H), 1.46-1.33 (m, 2H).

[0283] 13C NMR (125 MHz, CDCh; mixture of rotamers) 6 (ppm) 152.1, 143.1, 141.9, 135.6, 131.4, 129.6, 129.3, 128.2, 128.0, 124.1, 120.8, 115.3, 114.8, 107.1, 106.1, 46.9, 44.1, 25.2, 23.4.

[0284] LRMS (ESI) m / z: [M+H]+Calcd for C21H24N4O3S: 412.2; Found 412.2.

[0285]

[0286] 5-acetamido-N-(4-(piperidin-l-ylsulfonyl)benzyl)-lH-indole-l-carboxamide (MHD025)

[0287] ¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.05 (d, J= 8.8 Hz, 1H), 7.92 (s, 1H), 7.75-7.64 (m, 2H), 7.56-7.48 (m, 2H), 7.44 (d, J= 3.6 Hz, 1H), 7.17(dd, J= 8.8, 2.0 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 6.21 (t, J= 5.7 Hz, 1H), 4.70 (d, J= 5.9 Hz, 2H), 2.97 (t, J= 5.4 Hz, 4H), 2.19 (s, 3H), 1.70-1.59 (m, 4H), 1.48-1.36 (m, 2H).

[0288] 13C NMR (125 MHz, CDCh) 6 (ppm) 168.4, 152.0, 143.0, 135.6, 132.7, 132.4, 130.5, 128.1, 128.0, 124.4, 117.7, 114.7, 114.7, 112.9, 107.8, 46.9, 44.2, 25.2, 24.6, 23.4.

[0289] LRMS (ESI) m / z: [M+H]+Calcd for C23H26N4O4S: 454.2; Found 454.2.

[0290]

[0291] 5-formamido-N-(4-(piperidin-l-ylsulfonyl)benzyl)-lH-indole-l-carboxamide (MHD026) ATTY. DOCKET NO.: UCH-28927

[0292] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0293] 1H NMR (500 MHz, CDCh; mixture of rotamers) 6 (ppm) 8.61 (d, J = 11.6 Hz, 0.19H), 8.37 (s, 0.27H), 8.20 (d, J= 8.8 Hz, 0.28H), 8.09 (d, J= 9.4 Hz, 0.28H), 8.05 (d, J = 8.8 Hz, 0.28H), 8.01-7.82 (m, 0.66H), 7.72-7.57 (m, 1.98H), 7.56-7.40 (m, 3.01H), 7.35-7.28 (m, 0.68H), 7.22-6.94 (m, 0.85H), 6.70-6.51 (m, 0.98H), 6.41-6.26 (m, 0.79H), 4.81-4.55 (m, 2H), 3.08-2.82 (m, 4H), 1.74-1.59 (m, 4H), 1.48-1.33 (m, 2H).

[0294] 13C NMR (125 MHz, CDCh; mixture of rotamers) 6 (ppm) 168.6, 162.8, 159.0, 152.14, 152.09, 143.16, 143.11, 135.4, 132.6, 131.6, 130.5, 127.93, 127.90, 124.9, 124.6,124.5, 117.8, 117.42, 117.37, 116.0, 115.0, 114.8, 113.0, 112.9, 111.9, 107.7, 107.4, 46.9, 44.2, 25.1, 23.4.

[0295] LRMS (ESI) m / z: [M+H]+Calcd for C22H24N4O4S: 440.2; Found 440.3.

[0296]

[0297] 5-fluoro-N-(4-(piperidin-l-ylsulfonyl)benzyl)-6-(trifluoromethyl)-lH-indole-l-carboxamide (MHD033)

[0298] ¹H NMR (500 MHz, CDCl₃; mixture of rotamers) δ (ppm) 8.62 (d, J = 6.2 Hz, 0.9H), 7.73 (d, J=.1 Hz, 0.92H), 7.47 (d, J= 8.4 Hz, 1.85H), 7.40-7.33 (m, 2.78H), 7.24-7.30 (m, 0.48H), 6.95-6.90 (m, 0.22H), 6.85-6.80 (m, 0.44H), 6.74 (t, J= 5.9 Hz, 0.88H), 6.67 (d, J= 3.3 Hz, 0.92H), 4.72 (d, J= 5.9 Hz, 2H), 3.02-2.80 (m, 4H), 1.70-1.58 (m, 4H), 1.50-1.34 (m, 2H).

[0299] 13C NMR (125 MHz, CDCh; mixture of rotamers) 6 (ppm) 155.7 (d, J= 244.9 Hz), 155.5, 151.8, 143.2, 134.7, 133.1 (d, J= 10.0 Hz), 131.1, 129.7, 127.8, 127.6, 127.2, 123.3 (q, J = 270.0 Hz), 120.7, 115.3, 114.6 (dd, J= 15.6, 15.6 Hz), 114.2 (d, J= 14.6 Hz), 107.7 (d, J= 22.8 Hz), 107.3, 107.2, 46.9, 43.9, 25.1, 23.4.

[0300] LRMS (ESI) m / z: [M+H]+Calcd for C22H21F4N3O4S: 483.1; Found 483.2. ATTY. DOCKET NO.: UCH-28927

[0301] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0302]

[0303] 6-chloro-N-(4-(piperidin-l-ylsulfonyl)benzyl)-5-(trifluoromethyl)-lH-indole-l-carboxamide(MHD035)

[0304] ¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.49 (s, 1H), 7.94 (s, 1H), 7.59 (d, J= 3.7 Hz, 1H), 7.54 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.5 Hz, 2H), 6.72 (dd, J= 3.7, 0.6 Hz, 1H), 6.53 (t, J= 6.0 Hz, 1H), 4.73 (d, J= 6.0 Hz, 2H), 3.04-2.85 (m, 4H), 1.67-1.58 (m, 4H), 1.47-1.33 (m, 2H).

[0305] 13C NMR (125 MHz, CDCh) 6 (ppm) 151.6, 142.9, 137.3, 135.1, 127.9, 127.8, 127.6, 125.3, 123.7 (q, 7= 210.6 Hz), 122.6, 122.3, 120.3 (dd, J= 17.5, 5.6 Hz), 118.0, 107.9, 46.9, 44.0, 25.1, 23.4.

[0306] LRMS (ESI) m / z: [M+H]+Calcd for C22H21CIF3N3O3S: 499.1; Found 499.1.

[0307]

[0308] 6-fluoro-N-(4-(piperidin-l-ylsulfonyl)benzyl)-5-(trifluoromethyl)-lH-indole-l-carboxamide (MHD038)

[0309] ¹H NMR (500 MHz, CDCl₃; mixture of rotamers) δ (ppm) 8.18 (d, J= 11.9 Hz, 0.94H), 7.82 (d, 7= 6.9 Hz, 0.95H), 7.62 (d, 7= 3.7 Hz, 0.95H), 7.48 (d, 7= 8.4 Hz, 2H), 7.38 (d, 7 = 8.3 Hz, 2H), 7.24-7.21 (m, 0.23H), 6.94-6.81 (m, 0.28H), 6.74-6.68 (m, 1.74H), 4.72 (d, 7 = 5.9 Hz, 2H), 3.00-2.80 (m, 4H), 1.72-1.50 (m, 4H), 1.48-1.35 (m, 2H).

[0310] 13C NMR (125 MHz, CDCh; mixture of rotamers) 6 (ppm) 157.6 (d, 7= 238.9 Hz), 156.6, 151.8, 143.2, 137.6 (d, 7= 12.2 Hz), 134.8, 129.7, 127.8, 127.7, 125.2, 125.1, 125.0, 123.2 (q, 7= 269.3 Hz), 120.7, 119.3 (t, 7= 5.0 Hz), 115.3, 113.8 (dd, 7= 15.4, 15.4 Hz), 107.8, 103.9 (d, 7= 27.2 Hz), 46.9, 43.8, 25.1, 23.3.

[0311] LRMS (ESI) m / z: [M+H]+Calcd for C22H21F4N3O4S: 483.1; Found 483.2. ATTY. DOCKET NO.: UCH-28927

[0312] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0313] Material & Methods

[0314] Cell Culture

[0315] Primary human glioma cell lines were established at UCLA as described (Hemmati et al., PNAS 2003; Characteristics of specific glioma sphere lines can be found in Laks et al., NeuroOncology 2016). Primary glioblastoma cells, PC-3, DU-145, Tramp-Cl, Tramp-C2 prostate cancer cell, Miapaca-2 and PANC-1 pancreatic cancer cell, Kaposi sarcoma cells 3172 R, and H2052 and MSTO-211H mesothelioma cells were propagated as spheres under serum -free conditions in T25 flasks in DMEM / F12, supplemented with B27, EGF, bFGF and heparin as described previously (Vlashi et al., Journal of the NCI, 2009, 101, 350-9). EOC 20 cells (female; sourced from C3H / HeJ mice) were obtained from ATCC (#CRL-2469, Manassas, VA). Cells were maintained under standard conditions in DMEM media / 10 % FBS supplemented with 20 % conditionedmedia from CSF-l-expressing LADMAC bone marrow cells (#CRL-2420, ATCC). Normal human astrocytes (#CC-2565, Lonza) andNH43T3 fibroblasts (#CRL-1685, ATCC) were cultured under standard conditions in DMEM supplemented with 10% FBS and 1% P / S. Mesothelioma cell lines MSTO-211H (biphasic histotype), NCI-H2052 (epithelial histotype), andNCI-H2452 (epithelial histotype) were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). Cell lines were cultured in log-growth phase in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco, Thermo Fisher Scientific, USA) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (10,000 U / mL, Gibco, Thermo Fisher Scientific, Waltham, MA, USA). Cells were propagated into MICs in non-treated plates with serum-free conditions (RPMI 1640 medium supplemented with SMI, epidermal growth factor (EGF), fibroblast growth factor 2 (bFGF), heparin, and 1% penicillin-streptomycin).

[0316] All cells were grown in a humidified atmosphere at 37°C with 5% CO2. The unique identity of all patient-derived specimen was confirmed by DNA fingerprinting (Laragen, Culver City, CA). All lines were routinely tested for mycoplasma infection (My coAlert, Lonza).

[0317] Irradiation

[0318] Cells were irradiated at room temperature using an experimental X-ray irradiator (Gulmay Medical Inc. Atlanta, GA) at a dose rate of 5.519 Gy / min for the time required to apply a prescribed dose. The X-ray beam was operated at 300 kV and hardened using a 4 mm Be, a 3 mm Al, and a 1.5 mm Cu filter and calibrated using NIST-traceable dosimetry. Corresponding controls were sham irradiated. ATTY. DOCKET NO.: UCH-28927

[0319] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0320] Reprogramming Assay

[0321] Primary glioblastoma cells were engineered to express a fusion protein of ZsGreen and the C-terminal degron of ornithine decarboxylase. This construct reports for lack of 26S proteasome activity and cells with low proteasome activity are enriched for cells with tumorinitiating properties. For reprogramming experiments, cells with low proteasome activity (ZsGreen-positive) were removed by FACS. ZsGreen-negative cells were treated and 5 days later the number of radiation-induced ZsGreen-positive cells was assessed by flow cytometry.

[0322] Sphere-forming Assay (SFA)

[0323] Cells were seeded under serum-free conditions into untreated plates in DMEM / FI 2 media, supplemented with 10 ml / 500 mL of B27 (Invitrogen), 0.145 U / ml recombinant insulin (Eli Lilly, Indiana), 0.68 U / mL heparin (Fresenius Kabi, Illinois), 20 ng / ml fibroblast growth factor 2 (bFGF, Sigma) and 20 ng / ml epidermal growth factor (EGF, Sigma). After 10 days in culture, spheres formed from singles cells were counted. Certain compounds tested in sphereforming assay according to the present disclosure are shown below.

[0324] Plating Efficiency Assay

[0325] Cells were plated at clonal density into 6-well plated, treated and incubated for 10 days, fixed with methanol, and stained with crystal violet. Colonies of more than 50 cells were counted and expressed as percent of cells plated.

[0326] Western Blotting

[0327] Patient-derived HK-374 spheres were dissociated and plated at the density of 1 x 10A6 cells / well in the ultra-low adhesion 6-well plates. The next day, the cells were treated with 10 pM Compound 2 (C2) or MXC017 or MXC021 or MXC032 or MXC035 or MXC040 or solvent control (DMSO), along with dimethyl oxalylglycine (DMOG) as the positive control. 15 minutes, 30 minutes and 1 hour after the drug treatment, the spheres were collected and lysed in 100 pl of ice-cold RIPA lysis buffer (10 mM Tris-HCl (pH 8.0), 1 mM EDTA, 1 % Triton X-100, 0.1 % Sodium Deoxy cholate, 0.1 % SDS, 140 mM NaCl, 1 mM PMSF) containing proteinase inhibitor (Thermo Fisher Scientific) and phosphatase inhibitor (Thermo Fisher Scientific). The protein concentration in each sample was determined by BCA protein assay (Therma Fisher Scientific) and samples were denaturated in 4X Laemmli sample buffer (Bio-Rad) containing 10% [3-mercaptoethanol for 10 minutes at 95°C. Equal amounts of protein were loaded onto 10% SDS-PAGE gels (IX Stacking buffer - 1.0 M Tris-HCl, 0.1% SDS, pH 6.8, IX Separating buffer - 1.5 M Tris-HCl, 0.4% SDS, pH 8.8) and were subjected to electrophoresis in IX Running buffer (12.5 mM Tris-base, 100 mM Glycine, 0.05% SDS), initially at 40 V for 30 minutes followed by ATTY. DOCKET NO.: UCH-28927

[0328] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0329] 80 V for two hours. Samples were then transferred onto 0.45 pM nitrocellulose membrane (BioRad) for two hours at 80 V. Membranes were blocked in IX TBST (20 mM Tris-base, 150 mM NaCl, 0.2% Tween-20) containing 5% milk or 5% bovine serum albumin (BSA) for 20 minutes and then washed with IX TBST followed by incubation with primary antibodies against HIF la (Cat # 36169S, 1: 1000, Cell Signaling), HIF2a (Cat # 7096S, 1: 1000, Cell Signaling) and GAPDH (Cat # ab9484, 1:5000, Abcam) in IX TBST containing 5% BSA overnight at 4°C with gentle rocking. Membranes were then washed three times for 5 minutes each with IX TBST and incubated with secondary antibodies, 1: 1000 anti -rabbit or anti -mouse horseradish peroxidase (HRP; Cell Signaling) in 5% BSA / TBST for two hours at room temperature with gentle rocking. Membranes were washed again three times for 5 minutes each with IX TBST. Pierce ECL Plus Western Blotting Substrate (Thermo Fisher Scientific) was added to each membrane and incubated at room temperature for 5 minutes. The blots were then scanned with Odyssey Fc Imaging system. GAPDH was used as a loading control.

[0330] Extreme Limiting Dilution Analysis (ELD A)

[0331] For in vitro Extreme Limiting Dilution Analysis (ELD A) cells were seeded into ultralow adhesion plates at 1024 cells to 1 cell per well in quadruplicates. The number of wells with at least one sphere per dilution step was recorded. Data were used to calculate stem cell frequences using the ELD A software package1.

[0332] 1. Y. Hu, G. K. Smyth, ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods 347, 70-78 (2009).

[0333] INCORPORATION BY REFERENCE

[0334] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0335] EQUIVALENTS

[0336] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. ATTY. DOCKET NO.: UCH-28927

[0337] UCLAREF. NO.: [UCLA 2021-286-6] WO

[0338] The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

ATTY. DOCKET NO.: UCH-28927UCLAREF. NO.: [UCLA 2021-286-6] WOWe claim:

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:wherein:RAis -NR1R2or -NR1C(O)R3; whereinR1and R2are each independently H, alkyl, alkoxy, cycloalkyl, heterocyclyl, or phenyl;each RMis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;R3is H, alkyl, alkoxy, cycloalkyl, heterocyclyl, or phenyl;each RNis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;m is 0, 1, 2, 3, or 4; andn is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein m is 0 and n is 0.

3. The compound of claim 1, wherein RAis -NR'R2.

4. The compound of any one of claims 1-3, wherein R1and R2are each independently H or Ci-Ce alkyl.

5. The compound of claim 1, wherein RAis -NR1C(O)R3.

6. The compound of any one of claims 1, 2, or 5, wherein R1and R3are each independently H or Ci-Ce alkyl.

7. The compound of claim 1, wherein RAis -NH2, -NH(CO)H, or -NH(CO)Me.

8. The compound of claim 7, wherein RAis -NH2.ATTY. DOCKET NO.: UCH-28927UCLAREF. NO.: [UCLA 2021-286-6] WO9. The compound of claim 1, selected from:

10. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof:wherein:RAis halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxyl;RBis halo, Ci-Ce haloalkyl, or Ci-Ce haloalkoxyl;each RMis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;each RNis independently halo, -OH, nitro, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, or Ci-Ce aminoalkyl;m is 0, 1, 2, 3, or 4;n is 0, 1, 2, 3, 4, or 5; andprovided that RAand RBare not both Cl.

11. The compound of claim 10, wherein m is 0 and n is 0.ATTY. DOCKET NO.: UCH-28927UCLAREF. NO.: [UCLA 2021-286-6] WO12. The compound of claim 10, wherein RAis halo, Ci-Ce haloalkyl, or Ci-Ce haloalkoxyl.

13. The compound of claim 12, wherein RAis Ci-Ce fluoroalkyl or Ci-Ce fluoroalkoxyl.

14. The compound of claim 12, wherein RAis fluoro or Ci-Ce fluoroalkyl.

15. The compound of claim 14, wherein RAis -CF3.

16. The compound of any one of claims 10-15, wherein RBis halo or Ci-Ce haloalkyl.

17. The compound of claim 16, wherein RBis fluoro, chloro or -CF3.

18. The compound of claim 17, wherein RBis chloro.

19. The compound of claim 10, selected from:

20. A pharmaceutical composition comprising a compound of any one of claims 1-19 and a pharmaceutically acceptable excipient.

21. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-19 or a composition of claim 20.

22. The method of claim 21, further comprising treating the subject with radiation.

23. The method of claim 22, wherein the compound or composition is administered after the radiation.ATTY. DOCKET NO.: UCH-28927UCLAREF. NO.: [UCLA 2021-286-6] WO24. The method of claim 22, wherein the compound or composition is administered before the radiation.

25. The method of claim 22, wherein the compound or composition is administered conjointly with the radiation.

26. The method of any one of claims 21-25, wherein the cancer is selected from multiple myeloma, prostate cancer, stomach cancer, bladder cancer, esophageal cancer, cervical cancer, liver cancer, kidney cancer, bone cancer, brain cancer, leukemia, head and neck cancer, oral cancer, pancreatic cancer, lung cancer, colon cancer, melanoma, breast cancer, ovarian cancer, glioblastoma, Kaposi sarcoma, and mesothelioma.

27. The method of any one of claims 21-26, wherein the cancer is selected from glioblastoma, breast cancer, prostate cancer, pancreatic cancer, Kaposi sarcoma, and mesothelioma.

28. The method of any one of claims 21-27, wherein the cancer is glioblastoma or breast cancer.

29. A method of inhibiting development of cancer-initiating cells from non-stem cancer cells, comprising administering to a subject in need thereof a compound of any one of claims 1-19 or a composition of claim 20.

30. A method of inhibiting conversion of non-stem cancer cells into cancer-initiating cells, comprising administering to a subject in need thereof a compound of any one of claims 1-19 or a composition of claim 20.

31. The method of claim 29 or 30, further comprising treating the subject with radiation.

32. The method of claim 31, wherein the compound or composition is administered after the radiation.

33. The method of claim 31, wherein the compound or composition is administered before with the radiation.

34. The method of claim 31, wherein the compound or composition is administered conjointly with the radiation.ATTY. DOCKET NO.: UCH-28927UCLAREF. NO.: [UCLA 2021-286-6] WO35. The method of any one of claims 29-34, wherein the non-stem cancer cells are cancer cells from multiple myeloma, prostate cancer, stomach cancer, bladder cancer, esophageal cancer, cervical cancer, liver cancer, kidney cancer, bone cancer, brain cancer, leukemia, head and neck cancer, oral cancer, pancreatic cancer, lung cancer, colon cancer, melanoma, breast cancer, ovarian cancer, glioblastoma, Kaposi’s sarcoma, or mesothelioma.

36. The method of any one of claims 29-35, wherein the non-stem cancer cells are cancer cells from glioblastoma, breast cancer, prostate cancer, pancreatic cancer, Kaposi’s sarcoma, or mesothelioma.

37. The method of any one of claims29-36, wherein the non-stem cancer cells are glioblastoma cells.

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