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WO2025129032A1 - Chd1l inhibitors for treating cancer - Google Patents

Chd1l inhibitors for treating cancer Download PDF

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Publication number
WO2025129032A1
WO2025129032A1 PCT/US2024/060084 US2024060084W WO2025129032A1 WO 2025129032 A1 WO2025129032 A1 WO 2025129032A1 US 2024060084 W US2024060084 W US 2024060084W WO 2025129032 A1 WO2025129032 A1 WO 2025129032A1
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Prior art keywords
alkyl
compound
nhc
alkylene
halogen
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PCT/US2024/060084
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French (fr)
Inventor
Daniel V. Labarbera
Qiong ZHOU
Paul AWOLADE
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University of Colorado System
University of Colorado Colorado Springs
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University of Colorado System
University of Colorado Colorado Springs
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Publication of WO2025129032A1 publication Critical patent/WO2025129032A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • CRC Colorectal Cancer
  • CRC Colorectal Cancer
  • FIG.1 shows a workflow for CHD1L inhibitor discovery.
  • CHD1Li are selected from either HTS hits or analogs developed. They are then subjected to different in vitro assays in the “testing funnel” to filter out the less promising hits or analogs.
  • FIGs.2A-2B show top hits exhibiting dose-dependent inhibition of CHD1L and tumor organoid viability.
  • SEM standard error of the mean
  • FIG.4A-4B show CHD1Li Inhibit CSC Stemness in CRC cells.
  • FIG.4B shows a representative images (25 stitched fields of view on 10x air objective) of 2D SW620-GFP+ colonies treated with CHD1Li for 10 days at 0.25-8 ⁇ M and stained with Hoechst dye for imaging. All images were obtained using the Opera Phenix.
  • FIGs.5A-5E show predicted fl-CHD1L allosteric binding site and binding poses of hit CHD1Li.
  • FIG.5A depicts fl-CHD1L structure showing the most plausible CHD1Li binding site.
  • the domain architecture is depicted in cartoon representation as N-ATPase, C-ATPase, macro domain and linker region.
  • FIG.5B-5E depict the 3D representation of the predicted binding pose for the CHD1Li as indicated.
  • the non-bonded interactions are depicted as hydrogen bond, pi-cation, and pi-pi stacking.
  • FIG.6A (left) illustrates a graph showing the root mean square distance in nanometers (nm) as a function of time in nanoseconds (ns) for CHD1L_CA and CHD1L C-ATPase allosteric site.
  • FIG.6A illustrates CHD1L inhibitor Compound 9 in the allosteric pocket or binding site as a 2-D representation of protein-ligand contacts over the 500 ns simulation period.
  • FIG.6B (left) illustrates a graph showing the root mean square distance in nanometers (nm) as a function of time in nanoseconds (ns) for CHD1L_CA and CHD1L C-ATPase allosteric site.
  • FIG.6B (right) illustrates CHD1L inhibitor Compound 4 in the allosteric pocket or binding site as a 2-D representation of protein-ligand contacts over the 500 ns simulation period.
  • FIG.7 shows a schematic summary of mechanism of CHD1Li actions.
  • FIGs.8A-8B show predicted binding interaction of two example compounds of CHD1L inhibitors (CHD1Li), compound 25 and compound 42, respectively.
  • FIG.9A illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 30) concentration (in ⁇ M), where the IC 50 was determined to be about 1.75 ⁇ M.
  • FIG.9B illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 32) concentration (in ⁇ M), where the IC 50 was determined to be about 1.75 ⁇ M.
  • FIG.9C illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 33) concentration (in ⁇ M), where the IC 50 was determined to be about 1.75 ⁇ M.
  • SEM standard error of the mean
  • FIGs.10A-10C show plots demonstrating CHD1L trapping of example compounds disclosed herein visualizing the correlation between CHD1L trapping and 20-hour treatment with the example compound at different concentrations in the SUM149PT cancer cell line.
  • the data has been derived from two independent experiments, with the mean value indicated, and a standard deviation of 3 samples.
  • FIG.10A illustrates a graph of CHD1L trapping as a function of Compound 30 concentration (after 20-hour treatment with Compound 30).
  • FIG.10B illustrates a graph of CHD1L trapping as a function of Compound 32 concentration (after 20- hour treatment with Compound 32).
  • FIG.10C illustrates a graph of CHD1L trapping as a function of Compound 33 concentration (after 20-hour treatment with Compound 33).
  • FIG. 11A illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 30 (in ⁇ M), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown.
  • FIG.11B illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 32 (in ⁇ M), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown.
  • FIG.11C illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 33 (in ⁇ M), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown.
  • DETAILED DESCRIPTION DEFINITIONS [0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0020] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
  • an agent includes a plurality of such agents
  • the cell includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.
  • ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
  • C1-Cx includes C1-C2, C1-C3... C1-Cx.
  • a group designated as “C 1 -C 4 ” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl- 1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl.
  • an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , - SR a , -OC(O)R a , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, - N(R a )C(O)OR f , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR f (where t is 1 or 2), -S(O)tOR a (where
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 -hybridized carbon or an sp 3 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R f , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , - C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-N(R a )2, -N(R a )C(O)R f , - N(R a )S(O)tR f (where t is 1 or 2), -S(O)t
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp 3 -hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • optionally substituted alkyl means either “alkyl” or “substituted alkyl” as defined above.
  • an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.).
  • substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • substitution or substitution patterns e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • phrases “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.
  • pharmaceutically acceptable excipient or “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.
  • the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist.
  • tautomeric equilibrium includes: [0054]
  • the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (S)- configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • 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.
  • pharmaceutically acceptable excipient or “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.
  • 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, corn 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 eth
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • determining means determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • subject can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • the term “in vivo” is used to describe an event that takes place in a subject’s body.
  • the term “ex vivo” is used to describe an event that takes place outside of a subject’s body.
  • ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject.
  • An example of an ex vivo assay performed on a sample is an “in vitro” assay.
  • the term “in vitro” is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained.
  • In vitro assays can encompass cell-based assays in which living or dead cells are employed.
  • In vitro assays can also encompass a cell-free assay in which no intact cells are employed.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
  • Chromodomain Helicase DNA Binding Protein 1 Like (also known as amplified in liver cancer 1, ALC1) is an oncogene that promotes tumor progression, metastasis, and multidrug resistance (MDR) in many cancers such as lung cancer, breast cancer, and colorectal cancer (CRC).
  • CHD1L is an oncogene and its amplification and overexpression in patients is a marker of metastatic cancer, poor prognosis, low survival, and multidrug resistance (MDR).
  • CHD1L functions at the interface of malignant gene expression and tumor cell survival.
  • CRC is the third most prevalent cancer diagnosed each year and CRC patients have the second highest mortality rate worldwide.
  • CHD1L is an oncogene overexpressed in many cancer types. Elevated CHD1L expression may be a biomarker for poor prognosis, poor survival, and metastasis in various cancers, including CRC.
  • CHD1L is influenced by key cancer-driving pathways, including Wnt/ ⁇ -catenin, PI3K/AKT, and Ras/MAPK. Its diverse roles encompass regulating malignant gene expression, cell plasticity and stemness via epithelial-mesenchymal transition (EMT), cell survival, and metastatic potential. Given the critical role of CHD1L in tumor progression, metastasis, and drug resistance, the identification of CHD1L inhibitors (CHD1Li) could lead to effective targeted therapies for CRC and other cancers. [0073] Presented herein are CHD1L inhibitors (CHD1Li) that display potent antitumor activity through allosteric inhibition of CHD1L ATPase, which induces programmed cell death.
  • CHD1Li CHD1L inhibitors
  • the present disclosure provides a compound having a structure of Formula (I): Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is selected from -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, and -(C 1 -C 6 alkylene)-NH 2 , 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-
  • the 3- to 9-membered carbocycle and 3- to 9-membered heterocycle are optionally substituted with one or more R b ;
  • R 1 is -H. In some embodiments, R 1 is -(C1-C6 alkyl). In some embodiments, R 1 is -(C 2 -C 6 alkenyl). In some embodiments, R 1 is -(C 2 -C 6 alkynyl). In some embodiments, R 1 is halogen. In some embodiments, R 1 is -(C 1 -C 6 haloalkyl). In some embodiments, R 1 is -OH. In some embodiments, R 1 is -O(C1-C6 alkyl). In some embodiments, R 1 is -NH2. In some embodiments, R 1 is -NH(C1-C6 alkyl).
  • R b is C 3 -C 9 heterocycle.
  • L 1 is -NH-*.
  • L 1 is . 1 some embodiments, L is .
  • R 3 is .
  • Y is S.
  • Y is N.
  • W is N.
  • W is C.
  • R 1 is pyrrolyl. In some embodiments, R 1 is tetrahydropyrrolyl. In some embodiments, R 1 is thiophenyl.
  • the compound having a structure of Formula (I) is selected from , and .
  • the compound has a structure of Formula (III-A): , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is selected from phenyl, pyridinyl, pyrimidinyl, furanyl, and thiophenyl, and wherein Ring A is optionally substituted with one or more R b .
  • R 1 is -C(CH 3 ) 3 . In some embodiments, R 1 is -phenyl. In some embodiments, R 1 is pyridinyl. In some embodiments, R 1 is pyrimidinyl. In some embodiments, R 1 is furanyl. In some embodiments, R 1 is thiophenyl. In some embodiments, R 1 is pyrazolyl. In some embodiments, R 1 is pyrrolyl. In some embodiments, R 1 is tetrahydropyrrolyl. In some embodiments, R 1 is thiophenyl. In some embodiments, R 1 is optionally substituted with one or more R a .
  • the compound of Formula (III-B) is selected from: , , , , , , and , or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0103] In some embodiments, the compound is selected from:
  • the compound of Formula (V) is: 11: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 12: 3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 13: 5-ethyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-ol; 14: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine; 15: 5-ethyl-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7-ol; 16: 3-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol;
  • the present disclosure also provides a compound of Formula (IV): Formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Ring B is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more R b ; R a and R b are each independently selected at each occurrence from -(C 1 -C 6 alkyl), -(C 2 -C 6 alkenyl), -(C 2 -C 6 alkynyl), -OH, -O(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NH
  • Ring B is a 3- to 9-membered carbocycle. In some embodiments, Ring B is a 3- to 9-membered heterocycle. In some embodiments, Ring B is a 3- membered heterocycle. In some embodiments, Ring B is a 4-membered heterocycle. In some embodiments, Ring B is a 5-membered heterocycle. In some embodiments, Ring B is a 6- membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has a oxygen atom. In some embodiments, the heterocycle has one nitrogen atom and one oxygen atom. [0107] In some embodiments, when Ring B is , then R x is other than pyridinyl. [0108] In some embodiments, when Ring B is and R x is pyridinyl, then R x is substituted with one or more R n .
  • R x is -(C1-C6 alkyl). In some embodiments, R x is -(C2-C6 alkenyl). In some embodiments, R x is -(C2-C6 alkynyl). In some embodiments, R x is -OH. In some embodiments, R x is -O(C 1 -C 6 alkyl). In some embodiments, R x is -(C1-C6 alkylene)-OH. In some embodiments, R x is -NH2. In some embodiments, R x is - NH(C 1 -C 6 alkyl). In some embodiments, R x is -N(C 1 -C 6 alkyl) 2 .
  • R x is C3-C9 heterocycle.
  • when two or more R x are taken together with the C atom to which they are bound to form n is an integer from 1 to 5.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • n is 5.
  • R n is - (C 1 -C 6 alkyl). In some embodiments, R n is -(C 2 -C 6 alkenyl). In some embodiments, R n is -(C 2 -C 6 alkynyl). In some embodiments, R n is -OH. In some embodiments, R n is -O(C1-C6 alkyl). In some embodiments, R n is -(C1-C6 alkylene)-OH. In some embodiments, R n is -NH2. In some embodiments, R n is -NH(C 1 -C 6 alkyl). In some embodiments, R n is -N(C 1 -C 6 alkyl) 2 .
  • the present disclosure provides a method of treating a proliferative disease comprising administering a compound having a structure of Formula (V) to a subject in need thereof, the compound having a structure of Formula (V): Formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is selected from -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl) 2 , -(C 1 -C 6 alkylene)-OH, and -(C 1 -C 6 alkyl
  • R 1 is -H. In some embodiments, R 1 is -(C1-C6 alkyl). In some embodiments, R 1 is -(C2-C6 alkenyl). In some embodiments, R 1 is -(C2-C6 alkynyl). In some embodiments, R 1 is halogen. In some embodiments, R 1 is -(C 1 -C 6 haloalkyl). In some embodiments, R 1 is -OH. In some embodiments, R 1 is -O(C1-C6 alkyl). In some embodiments, R 1 is -NH2. In some embodiments, R 1 is -NH(C1-C6 alkyl).
  • R 1 is -NH(C1- C 6 alkyl) 2 . In some embodiments, R 1 is -(C 1 -C 6 alkylene)-OH. In some embodiments, R 1 is -(C 1 - C 6 alkylene)-NH 2 . [0117] In some embodiments, R 1 is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle. In some embodiments, R 1 is phenyl, pyridinyl, pyrimidyl, furanyl, thiophenyl, naphthyl, or indolyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is pyridinyl.
  • Ring A is pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is furanyl. In some embodiments, Ring A is thiophenyl. In some embodiments, Ring A is substituted with at least one R b .
  • the administering the compound of any one of Formulas (V)- (IX) reduces an average tumor cell size by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In some embodiments, administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by 20% to 80%, 40% to 90%, 60% to 100%, 30% to 80%, or 50% to 90%, including all values and sub ranges in between.
  • the proliferative disease comprises a T cell factor (TCF)-driven cancer.
  • the method comprises inhibiting chromatin helicase DNA- binding protein 1-like (CHD1L).
  • the inhibiting of CHD1L comprises determining a loss of ATPase activity.
  • the determining comprises performing an ATPase activity assay.
  • the method comprises trapping CHD1L onto chromatin.
  • the trapping comprises increasing an amount of CHD1L by 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold.
  • the trapping comprises increasing an amount of CHD1L by at most 1-fold, at most 2-fold, at most 3-fold, at most 4-fold, at most 5-fold, at most 6-fold, at most 7-fold, at most 8-fold, at most 9-fold, or at most 10-fold.
  • the TCF-driven cancer comprises colorectal cancer or metastatic colorectal cancer.
  • the present disclosure provides a method of reducing catalytic activity of a CHD1L.
  • the method comprises contacting the CHD1L with a compound of any one of Formulas (I)-(IX).
  • the catalytic activity of the CHD1L is an ATPase activity.
  • the catalytic activity of the CHD1L is reduced by about 10% to about 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • the catalytic activity of the CHD1L is reduced by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, or at most 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by 20% to 70%, 40% to 90%, 60% to 80%, 30% to 80%, or 50% to 90%, including all values and sub ranges in between. [0155] In some embodiments, the catalytic activity is measured by an ATPase assay. [0156] In some embodiments, the compound is selected from: ,
  • the method comprises binding a CHD1L inhibitor to an allosteric binding site of CHD1L.
  • binding a CHD1L inhibitor comprises binding the CHD1L inhibitor to a CHD1L having at least about 70% sequence identity to SEQ ID NO: 1.
  • binding a CHD1L inhibitor comprises exposing the CHD1L inhibitor to a lysine in the allosteric binding site. In some instances, the lysine is lysine-273 (K273).
  • binding a CHD1L inhibitor comprises exposing the CHD1L inhibitor to a tyrosine in the allosteric binding site.
  • the glutamate is tyrosine 480 (Y480).
  • the CHD1L comprises any one of SEQ ID NOs: 1-39.
  • the CHD1L comprises a sequence selected from Table 3. Table 3. CHD1L Sequences.
  • Cell Culture –cells were grown within RPMI 1640 media (Gibco, Ref#: 11875-093) containing 5% fetal bovine serum (Gibco, Ref#: 10437028) in 10 cm tissue culture coated dishes (Fisher Scientific, Ref#: FB012924). Cells were stored in a 37°C humidified incubator at 5% CO 2 for growth. Cells were split by aspirating media from the plate, washing with 5 mL of Phosphate Buffer Solution (PBS) 1X pH 7.4 (Gibco, Ref#: 10010-023), followed by addition of 0.25% Trypsin (Life Technologies, Ref#: 25200072) in media, prior to incubation for 6 minutes.
  • PBS Phosphate Buffer Solution
  • EMT Dual Reporter Assay The EMT dual reporter assay was performed. SW620- GFP+ cells were plated as 3D organoids and treated with 0-40 ⁇ M of CHD1Li as described above.
  • the 100 ⁇ L reaction solution consisted of 0.5 mg/mL microsomes, phosphate buffer pH 7.4 (44 mM KH2PO4, 56 mM K2HPO4), 1.94 mg/mL UDPGA (Sigma Aldrich, Ref# U6751), 25 ⁇ g alamethicin (Sigma-Aldrich, A4665), 1 mM MgCl2, 1 mM NADPH (Sigma-Aldrich, Ref# 481973-50MG), 1% DMSO, and 10 ⁇ M of either CHD1Li or testosterone (Sigma, T1500-1G) for control tubes.
  • the mass spectrometer was operated in the ESI+ mode and all settings were optimized by manually tuning to infused standard solutions.
  • Global mass spectrometer parameter settings were selected to give the highest average sensitivity for all compounds of interest.
  • Global mass spectrometer settings are as follows: curtain gas, 40 psi; collision gas, high; ion spray voltage, 4500 V; source temperature, 700°C; ion source gas 1 and 2, 50 psi; entrance potential, 10 V; and collision cell exit potential, 14 V.
  • the collision energy (CE) and declustering potential (DP) were optimized separately for each compound.
  • Data was collected using the multiple reaction monitoring (MRM) mode. Quantitation was performed using an external calibration curve for each compound.
  • Analytical separation was achieved with a Phenomenex kinetex C18 column [2.1 x 100 mm, 2.6 ⁇ m]. The column was held at 40°C and eluted at 0.6 mL/min with a gradient of 0.1% formic acid (A) and 0.1% formic acid in 9:1 acetonitrile:water (B) with a total runtime of 10 minutes. Chromatographic separation was achieved with a linear gradient (time, % of solvent B): 0-0.5 min, 5% B; 0.5-4.5 min, 5-55% B; 4.5-6.5 min, 55-94% B; 6-7 min, 94-5% B; and then isocratic for 3 minutes at 5% B to re-equilibrate the column.
  • the 3D low energy conformation of hit compounds 8- 11 was created with the LigPrep module. Ligands ionization and tautomeric states were generated using Epik at pH 7.0 ⁇ 2.0.
  • the 3D model of fl-CHD1L (UniProt# Q86WJ1) in the active state was downloaded from AlphaFold database and processed using the protein preparation workflow. A reliability check of the minimized protein structure was conducted prior to its use for further calculations. [0171] Binding Site Elucidation.
  • the minimized fl-CHD1L structure was characterized for potential druggable sites using the SiteMap module. The minimum site points per site were set at 15 while using a more restrictive requirement for hydrophobicity to exclude sites occupying free space.
  • the returned sites were ranked based on the site score, drugability score, size, and volume.
  • ⁇ Gbind Molecular Docking and Binding Free Energy ( ⁇ Gbind) Estimation.
  • the minimized structures of hit CHD1Li 8-11 and fl-CHD1L were used as inputs for molecular docking calculations using the induced-fit docking (IFD) protocol at the best site identified from SiteMap calculations.
  • the receptor grid box was defined as the centroid of amino acid residues bordering the selected binding site with an inner and outer box size of 10 and 30 ⁇ , respectively.
  • the ligand ring conformations were sampled at 2.5 kcalmol-1, followed by a short minimization of the protein structure to RMSD 0.18 ⁇ and Prime refinement of residues within 5 ⁇ of binding site.
  • Ligands were then redocked into receptor structures within 30 kcalmol-1 using extra- precision Glide docking.
  • the ⁇ Gbind for the resulting CHD1L complexes were estimated using Prime molecular mechanics/generalized Born surface area (MM/GBSA) module.
  • MM/GBSA generalized Born surface area
  • VSGB variable- dielectric generalized Born model
  • All atoms of binding site residues were minimized during the calculation to account for ligand-induced conformational changes.
  • the best pose for each hit compound was determined using the docking score, glide model, glide energy, IFD score and ⁇ Gbind.
  • MD Molecular Dynamics
  • a non-linear regression model was used to create a logarithmic curve to model the inhibitor vs response variable slope and calculate the half maximal inhibitory concentration (IC50) of each compound within a 95% confidence interval. Normalization to control and EC2-fold calculations were performed in Microsoft Excel for MacOS (version 16.76) [0176] Results [0177] Hits were reexamined for their potential as CHD1Li using a tailored hit-to-lead validation schema to prioritize additional hits as leads for further optimization (FIG.1). Compound 6 was used as reference and positive control and is described at PCT Pub. No. WO 2021/195279 A1, the entirety of which is incorporated by this reference.
  • the compounds were first tested against the cat-CHD1L recombinant enzyme ATPase assay to confirm inhibitory activity and eliminate false positives from the HTS. Once confirmed as hits, they are tested for their ability to induce cytotoxicity or inhibit or reverse EMT, using CRC tumor organoids models. [0178] Select hits were next examined for their ability to inhibit CSC stemness, using the clonogenic colony formation assay.
  • the mesenchymal phenotype of SW620 cells was selected for the cell-based assays in this validation scheme since it displays enhanced tumorigenic properties, including multidrug resistance and CSC stemness. Therefore, this phenotype has the highest potential for colony formation, metastasis, and represents an aggressive CRC tumor cell model .
  • CHD1L Enzyme Inhibition – confirmed hits from primary HTS were re-evaluated for their dose dependent inhibition of cat-CHD1L ATPase.
  • Compounds 32-36 were deprioritized due to their limited potency with inhibition concentration 50% (IC50) values >20 ⁇ M. All the other compounds displayed relatively potent CHD1L inhibition with IC50 ⁇ 15 (Table 4).
  • Hit compounds 8-11 displayed similar inhibitory activity compared to Compound 6 and were prioritized for further validation (Table 4 and FIG.2A).

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Abstract

Provided are compounds and methods for the treatment of cancer.

Description

CHD1L INHIBITORS FOR TREATING CANCER CROSS REFERENCE [0001] This application claims the benefit of U.S. provisional application serial no. 63/610,987, filed December 15, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 65194-705601.xml, created December 12, 2024, which is 69,376 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0003] This disclosure was made with government support under R01-CA251361-01 awarded by the National Cancer Institute of the National Institutes of Health. The government has certain rights in the disclosure. BACKGROUND [0004] Colorectal Cancer (CRC) is the third leading type of cancer and the second most common cause of cancer-related deaths worldwide. Age has historically been the main risk factor for CRC, with the average diagnostic age exceeding 50 years. However, the age group at risk for CRC is shifting, as early onset disease is becoming increasingly prevalent, with rates increasing from 11% to 20% in the past 25 years. Although recent advances in preventive screening have increased detection and therefore the success of treatments, 22% of CRC patients are not diagnosed until stage IV, and the vast majority of these patients receive chemotherapy as palliative care. BRIEF SUMMARY [0005] Colorectal Cancer (CRC) is the third leading type of cancer and the second most common cause of cancer-related deaths worldwide. Age has historically been the main risk factor for CRC, with the average diagnostic age exceeding 50 years. However, the age group at risk for CRC is shifting, as early onset disease is becoming increasingly prevalent, with rates increasing from 11% to 20% in the past 25 years. Although recent advances in preventive screening have increased detection and therefore the success of treatments, 22% of CRC patients are not diagnosed until stage IV, and the vast majority of these patients receive chemotherapy as palliative care. BRIEF DESCRIPTION OF THE DRAWINGS [0006] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: [0007] FIG.1 shows a workflow for CHD1L inhibitor discovery. CHD1Li are selected from either HTS hits or analogs developed. They are then subjected to different in vitro assays in the “testing funnel” to filter out the less promising hits or analogs. Highly promising compounds are advanced for further testing and the most promising (leads) are taken through in vivo testing or used as structural templates for lead optimization using medicinal chemistry. Results from all tests are analyzed for existing SAR to design new analogs and improve efficacy. [0008] FIGs.2A-2B show top hits exhibiting dose-dependent inhibition of CHD1L and tumor organoid viability. FIG.2A is a graphical representation of dose-response inhibition of the cat- CHD1L enzyme by top CHD1Li (N=2). Each data point is averaged from 2 experiments performed in quadruplicate and error bars are the calculated standard error of the mean (SEM). GIF.2B is a graphical representation of dose-response cytotoxicity induced by top CHD1Li (N=3) in SW620-GFP+ tumor organoids. Each data point is averaged from 3 experiments performed in triplicate and error bars are the calculated standard error of the mean (SEM). [0009] FIGs.3A-3B show CHD1Li Modulates EMT. FIG.3A is a graphical representation of EMT reversal by each of the top HTS hits (N=3) Each data point is the average of 3 experiments performed in triplicate and error bars are the calculated standard error of the mean (SEM). FIG. 3B is a representative fluorescent images (10x air objective) of 3D SW620-GFP+ tumor organoids treated with CHD1Li for 72 hours at concentrations of 0-40 μM. All images obtained using Opera Phenix using the RFP and GFP channel. [0010] FIGs.4A-4B show CHD1Li Inhibit CSC Stemness in CRC cells. FIG.4A shows a graphical representation of dose-response inhibition of CSC stemness by the top HTS hits (N=2) Error bars are the calculated standard error of the mean (SEM) of 2 experiments performed in triplicate. FIG.4B shows a representative images (25 stitched fields of view on 10x air objective) of 2D SW620-GFP+ colonies treated with CHD1Li for 10 days at 0.25-8 μM and stained with Hoechst dye for imaging. All images were obtained using the Opera Phenix. [0011] FIGs.5A-5E show predicted fl-CHD1L allosteric binding site and binding poses of hit CHD1Li. FIG.5A depicts fl-CHD1L structure showing the most plausible CHD1Li binding site. The domain architecture is depicted in cartoon representation as N-ATPase, C-ATPase, macro domain and linker region. The proposed C-ATPase allosteric binding site is marked with a red ellipse while the ATP binding site is depicted by the bound ADP shown in CPK representation. FIGs.5B-5E depict the 3D representation of the predicted binding pose for the CHD1Li as indicated. The non-bonded interactions are depicted as hydrogen bond, pi-cation, and pi-pi stacking. [0012] FIG.6A (left) illustrates a graph showing the root mean square distance in nanometers (nm) as a function of time in nanoseconds (ns) for CHD1L_CA and CHD1L C-ATPase allosteric site. FIG.6A (right) illustrates CHD1L inhibitor Compound 9 in the allosteric pocket or binding site as a 2-D representation of protein-ligand contacts over the 500 ns simulation period. [0013] FIG.6B (left) illustrates a graph showing the root mean square distance in nanometers (nm) as a function of time in nanoseconds (ns) for CHD1L_CA and CHD1L C-ATPase allosteric site. FIG.6B (right) illustrates CHD1L inhibitor Compound 4 in the allosteric pocket or binding site as a 2-D representation of protein-ligand contacts over the 500 ns simulation period. [0014] FIG.7 shows a schematic summary of mechanism of CHD1Li actions. [0015] FIGs.8A-8B show predicted binding interaction of two example compounds of CHD1L inhibitors (CHD1Li), compound 25 and compound 42, respectively. [0016] FIG.9A-9C show dose-response inhibition of the cat-CHD1L enzyme by three example CHD1Li (N=2), compound 30, compound 32, and compound 33, respectively. FIG.9A illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 30) concentration (in μM), where the IC50 was determined to be about 1.75 μM. FIG.9B illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 32) concentration (in μM), where the IC50 was determined to be about 1.75 μM. FIG.9C illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 33) concentration (in μM), where the IC50 was determined to be about 1.75 μM. Each data point was averaged from two experiments performed in quadruplicate and error bars are the calculated standard error of the mean (SEM). [0017] FIGs.10A-10C show plots demonstrating CHD1L trapping of example compounds disclosed herein visualizing the correlation between CHD1L trapping and 20-hour treatment with the example compound at different concentrations in the SUM149PT cancer cell line. The data has been derived from two independent experiments, with the mean value indicated, and a standard deviation of 3 samples. FIG.10A illustrates a graph of CHD1L trapping as a function of Compound 30 concentration (after 20-hour treatment with Compound 30). FIG.10B illustrates a graph of CHD1L trapping as a function of Compound 32 concentration (after 20- hour treatment with Compound 32). FIG.10C illustrates a graph of CHD1L trapping as a function of Compound 33 concentration (after 20-hour treatment with Compound 33). [0018] FIGs.11A-11C present the three-dimensional cytotoxicity of the compound disclosed herein across five different cancer cell lines including HCT116, SW620, MDA-MB-231, SUM149PT, and Miapaca-2. These plots demonstrate tumor organoid viability (%) versus the concentrations of the compound used. The treatments lasted for 72 hours, with a standard error of the mean (SEM) provided for each data set. Each data point represents an average of either 2 or 3 independent experiments, with each experiment consisting of three replicates (n=3). FIG. 11A illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 30 (in μM), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown. FIG.11B illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 32 (in μM), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown. FIG.11C illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 33 (in μM), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown. DETAILED DESCRIPTION DEFINITIONS [0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0020] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. [0021] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. [0022] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0023] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below: [0024] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl. [0025] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl- 1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl, a C1-C9 alkyl, a C1-C8 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0026] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2-hybridized carbon or an sp3-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, - N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and - S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0027] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp3-hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, - N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, - N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0028] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0029] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkenylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), - S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0030] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkynylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0031] “Alkoxy” or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula –O–alkyl, where alkyl is an alkyl chain as defined above. [0032] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms unless otherwise specified (i.e., from 6 to 18 carbon atoms), where at least one of the rings in the ring system is fully unsaturated, (i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory). The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In some embodiments, the aryl is a C6-C10 aryl. In some embodiments, the aryl is a phenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf (where t is 1 or 2), -Rb- S(O)tORa (where t is 1 or 2), -Rb-S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain. [0033] An “arylene” refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group. The arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the arylene is a phenylene. Unless stated otherwise specifically in the specification, an arylene group is optionally substituted as described above for an aryl group. [0034] “Cycloalkyl” or “carbocycle” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged ring systems, and/or spirocyclic ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6- membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O- Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf (where t is 1 or 2), - Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain. [0035] A “cycloalkylene” refers to a divalent radical derived from a “cycloalkyl” group as described above linking the rest of the molecule to a radical group. The cycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a cycloalkylene group is optionally substituted as described above for a cycloalkyl group. [0036] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0037] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [0038] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. [0039] “Haloalkoxy” or “haloalkoxyl” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. [0040] “Fluoroalkoxy” or “fluoroalkoxyl” refers to an alkoxy radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and the like. [0041] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, 2,3,4,5,6- pentahydroxyhexyl, and the like. [0042] “Heterocycloalkyl” or “heterocycle” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), bridged ring systems, and/or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, the term “heterocycloalkyl” is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb- ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb- S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain. [0043] “N-heterocycloalkyl” refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical. An N- heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals. [0044] “C-heterocycloalkyl “ refers to a heterocycloalkyl radical as defined above and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical. A C-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals. [0045] A “heterocycloalkylene” refers to a divalent radical derived from a “heterocycloalkyl” group as described above linking the rest of the molecule to a radical group. The heterocycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heterocycloalkylene group is optionally substituted as described above for a heterocycloalkyl group. [0046] “Heteroaryl” refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6- membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. The heteroatom(s) in the heteroaryl radical is optionally oxidized. The carbon atom(s) in the heteroaryl is optionally oxidized. Two non-limiting examples of heteroaryl radicals that are oxidized and are encompassed by the term heteroaryl are pyridone and pyridine N-oxide. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O- Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf (where t is 1 or 2), - Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain. [0047] A “heteroarylene” refers to a divalent radical derived from a “heteroaryl” group as described above linking the rest of the molecule to a radical group. The heteroarylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heteroarylene group is optionally substituted as described above for a heteroaryl group. [0048] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. [0049] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. [0050] 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. [0051] The phrase “pharmaceutically acceptable excipient” or “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. Further Forms of Compounds [0052] Furthermore, in some embodiments, the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. [0053] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000016_0001
[0054] In some situations, the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (S)- configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. [0055] The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. [0056] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)”. Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”. [0057] 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. [0058] The phrase “pharmaceutically acceptable excipient” or “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, corn 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. [0059] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. [0060] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context. [0061] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease. [0062] The term “in vivo” is used to describe an event that takes place in a subject’s body. [0063] The term “ex vivo” is used to describe an event that takes place outside of a subject’s body. An ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject. An example of an ex vivo assay performed on a sample is an “in vitro” assay. [0064] The term “in vitro” is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass a cell-free assay in which no intact cells are employed. [0065] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made. [0066] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution. [0067] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [0068] Chromodomain Helicase DNA Binding Protein 1 Like (CHD1L) (also known as amplified in liver cancer 1, ALC1) is an oncogene that promotes tumor progression, metastasis, and multidrug resistance (MDR) in many cancers such as lung cancer, breast cancer, and colorectal cancer (CRC). CHD1L is an oncogene and its amplification and overexpression in patients is a marker of metastatic cancer, poor prognosis, low survival, and multidrug resistance (MDR). CHD1L functions at the interface of malignant gene expression and tumor cell survival. [0069] CRC is the third most prevalent cancer diagnosed each year and CRC patients have the second highest mortality rate worldwide. Early detection, surgery, and chemo/targeted therapy such as FOLFIRI, FOLFOX, and Avastin have minimally improved CRC overall survival. Despite the emergence of targeted therapies such as Avastin, which have not proven effective alone, chemotherapy is still the safer, more effective and affordable treatment for CRC. Chemotherapy will remain a frontline treatment for the foreseeable future. Still, only about half of CRC patients respond to FOLFIRI-based chemotherapy and almost all display MDR at some point in the treatment. This poor response rate is attributed to the high tumor heterogeneity of CRC. In addition, CHD1L expression is upregulated in stage IV metastatic CRC (mCRC) patients. Surgery is not typical for mCRC, and chemo/targeted therapy is the standard of care, yet these therapies are ineffective, evidenced by a low 11% 5-year overall survival. [0070] Age has historically been the main risk factor for CRC, with the average diagnostic age exceeding 50 years. However, the age group at risk for CRC is shifting, as early onset disease is becoming increasingly prevalent, with rates increasing from 11% to 20% in the past 25 years. Although recent advances in preventive screening have increased detection and therefore the success of treatments, 22% of CRC patients are not diagnosed until stage IV, and the vast majority of these patients receive chemotherapy as palliative care. [0071] The most effective therapy for early-stage CRC is currently surgical resection, while 5- fluorouracil (5-FU) based combination chemotherapy is the first-line standard of care for both metastatic and surgically resectable CRC. Despite the efficacy of surgical intervention at early stages, chemotherapy is the standard of care for advanced disease. Thus, an unmet need exists for targeted antitumor agents that can effectively combat tumor progression and metastasis while synergizing with chemotherapy and targeted therapies. [0072] CHD1L is an oncogene overexpressed in many cancer types. Elevated CHD1L expression may be a biomarker for poor prognosis, poor survival, and metastasis in various cancers, including CRC. CHD1L is influenced by key cancer-driving pathways, including Wnt/β-catenin, PI3K/AKT, and Ras/MAPK. Its diverse roles encompass regulating malignant gene expression, cell plasticity and stemness via epithelial-mesenchymal transition (EMT), cell survival, and metastatic potential. Given the critical role of CHD1L in tumor progression, metastasis, and drug resistance, the identification of CHD1L inhibitors (CHD1Li) could lead to effective targeted therapies for CRC and other cancers. [0073] Presented herein are CHD1L inhibitors (CHD1Li) that display potent antitumor activity through allosteric inhibition of CHD1L ATPase, which induces programmed cell death. Moreover, inhibition of CHD1L does not cause DNA damage or acute toxicity in mice. [0074] Provided herein are compounds. In some embodiments, the compounds are CHD1Li. Further provided herein are therapeutic compositions comprising a CHD1Li and a therapeutic agent. CHD1L inhibitors (CHD1Li) are used as targeted therapies for the treatment of multiple cancer types, including CRC. CHD1Li are effective antitumor agents that synergize with broadly used standard of care chemotherapy and targeted therapy. [0075] In some aspects, provided herein are methods of treating a cancer, such as colorectal cancer (CRC). [0076] In some aspects, provided herein are methods of treating a cancer comprising administering a CHD1L inhibitor. In some embodiments, the CHD1L inhibitor is selected from Table 1 and Table 2. Table 1. Compounds of Formulas (I)-(III).
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Table 2. Compounds of Formula (IV) and others.
Figure imgf000027_0002
Figure imgf000028_0002
COMPOUNDS [0077] In certain aspects, the present disclosure provides a compound having a structure of Formula (I):
Figure imgf000028_0001
Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is selected from -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, and -(C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Ra; R2 is H or C1-C6 alkyl; L1 is absent or is selected from -CH2-*, -O-*, -C(=O)-*, -NH-*, -NHC(=O)-*, , and , wherein * indicates a bo 3
Figure imgf000029_0001
Figure imgf000029_0002
nd to R ; R3 is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, - C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, C3-C9 carbocycle, and C3-C9 heterocycle. In some embodiments, the 3- to 9-membered carbocycle and 3- to 9-membered heterocycle are optionally substituted with one or more Rb; X is selected from =O, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and halogen; Ra and Rb are each independently selected at each occurrence from -(C2-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, - CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, - C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9- membered carbocycle, and 3- to 9-membered heterocycle; wherein: when R1 is phenyl and Ra is -F, Rb is other than -F or -Br, when R1 is -H or phenyl, R3 is other than fluorophenyl, or when R1 is -C(CH3)3, R3 is other than chloro, phenyl, or phenyl substituted with methyl, fluoro, or chloro. [0078] In some embodiments, R1 is -H. In some embodiments, R1 is -(C1-C6 alkyl). In some embodiments, R1 is -(C2-C6 alkenyl). In some embodiments, R1 is -(C2-C6 alkynyl). In some embodiments, R1 is halogen. In some embodiments, R1 is -(C1-C6 haloalkyl). In some embodiments, R1 is -OH. In some embodiments, R1 is -O(C1-C6 alkyl). In some embodiments, R1 is -NH2. In some embodiments, R1 is -NH(C1-C6 alkyl). In some embodiments, R1 is -NH(C1- C6 alkyl)2. In some embodiments, R1 is -(C1-C6 alkylene)-OH. In some embodiments, R1–(C1-C6 alkylene)-NH2. [0079] In some embodiments, R1 is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle. In some embodiments, R1 is phenyl, pyridinyl, pyrimidyl, pyrazolyl, furanyl, and thiophenyl. In some embodiments, R1 is substituted with one or more Ra. [0080] In some embodiments, R2 is H. In some embodiments, R2 is C1-C6 alkyl. [0081] In some embodiments, L1 is absent. In some embodiments, L1 is -CH2-*. In some embodiments, L1 is -O-*. In some embodiments, L1 is -C(=O)-*. In some embodiments, L1 is - NH-*. In some embodiments, L1 is -NHC(=O)-*. In some embodiments, L1 is
Figure imgf000030_0001
1
Figure imgf000030_0002
. In some embodiments, L is . [0082] In some embodiments, R3 is -(C1-C6 alkyl). In some embodiments, R3 is -(C2-C6 alkenyl). In some embodiments, R3 is -(C2-C6 alkynyl). In some embodiments, R3 is -OH. In some embodiments, R3 is -O(C1-C6 alkyl). In some embodiments, R3 is -(C1-C6 alkylene)-OH. In some embodiments, R3 is -NH2. In some embodiments, R3 is -NH(C1-C6 alkyl). In some embodiments, R3 is -N(C1-C6 alkyl)2. In some embodiments, R3 is -(C1-C6 alkylene)-NH2. In some embodiments, R3 is -NHC(=O)(C1-C6 alkyl). In some embodiments, R3 is -NO2. In some embodiments, R3 is -CN. In some embodiments, R3 is -SCN. In some embodiments, R3 is -SH. In some embodiments, R3 is -S(C1-C6 alkyl). In some embodiments, R3 is halogen. In some embodiments, R3 is -C(=O)OH. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, R3 is -C(=O)N(C1-C6 alkyl)2. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, R3 is -C(=O)NH2. In some embodiments, R3 is -C(=O)NH(C1-C6 alkyl). In some embodiments, R3 is -C(=O)N(C1-C6 alkyl)2. In some embodiments, R3 is -(C1-C6 alkyl)- NHC(=O)NH2. In some embodiments, R3 is C3-C9 carbocycle. In some embodiments, R3 is C3- C9 heterocycle. [0083] In some embodiments, X is =O. In some embodiments, X is -OH. In some embodiments, X is -NH2. In some embodiments, X is -NH(C1-C6 alkyl). In some embodiments, X is -N(C1-C6 alkyl)2. In some embodiments, X is halogen. [0084] In some embodiments, the compound is not 5-(tert-butyl)-3-(4- fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one. In some embodiments, R3 is substituted with at least one Rb. In some embodiments, L1 is absent. [0085] In some embodiments, the compound has the structure of Formula (II):
Figure imgf000031_0001
Formula (II), wherein Ring A is selected from phenyl, pyridinyl, pyrimidyl, furanyl, and thiophenyl, and wherein Ring A is optionally substituted with one or more Rb. In some embodiments, each Rb is independently selected at each occurrence from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, and 3- to 9-membered heterocycle. In some embodiments, Rb is -(C1-C6 alkyl). In some embodiments, Rb is -(C2-C6 alkenyl). In some embodiments, Rb is -(C2-C6 alkynyl). In some embodiments, Rb is -OH. In some embodiments, Rb is -O(C1-C6 alkyl). In some embodiments, Rb is -(C1-C6 alkylene)-OH. In some embodiments, Rb is -NH2. In some embodiments, Rb is - NH(C1-C6 alkyl). In some embodiments, Rb is -N(C1-C6 alkyl)2. In some embodiments, Rb is - (C1-C6 alkylene)-NH2. In some embodiments, Rb is -NHC(=O)(C1-C6 alkyl). In some embodiments, Rb is -NO2. In some embodiments, Rb is -CN. In some embodiments, Rb is -SCN. In some embodiments, Rb is -SH. In some embodiments, Rb is -S(C1-C6 alkyl). In some embodiments, Rb is halogen. In some embodiments, Rb is -C(=O)OH. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is -C(=O)NH2. In some embodiments, Rb is -C(=O)NH(C1-C6 alkyl). In some embodiments, Rb is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is -(C1-C6 alkyl)-NHC(=O)NH2. In some embodiments, Rb is C3-C9 carbocycle. In some embodiments, Rb is C3-C9 heterocycle. [0086] In some embodiments, L1 is selected from -NH-*, -NHC(=O)-*,
Figure imgf000032_0001
,
Figure imgf000032_0002
and , wherein * indicates a bond to R3 . In some embodiments, L1 is -NH-*. In some embodiments, L1 is -NHC(=O)-*. In some embodiments, L1 is
Figure imgf000032_0003
. 1
Figure imgf000032_0004
some embodiments, L is . [0087] In some embodiments, R3 is
Figure imgf000032_0005
. In some embodiments, Y is S. In some embodiments, Y is N. In some embodiments, W is N. In some embodiments, W is C. [0088] In some embodiments, Y is S, W is N, and Rb is halogen. [0089] In some embodiments, L1-R3 is selected from
Figure imgf000032_0006
,
Figure imgf000032_0007
, and
Figure imgf000032_0008
[0090] In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CH(CH3)2. In some embodiments, R1 is -C(CH3)3. In some embodiments, R1 is -phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidinyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is pyrazolyl. In some embodiments, R1 is pyrrolyl. In some embodiments, R1 is tetrahydropyrrolyl. In some embodiments, R1 is thiophenyl. [0091] In some embodiments, the compound having a structure of Formula (I) is selected from
Figure imgf000033_0003
Figure imgf000033_0004
, and
Figure imgf000033_0005
. [0092] In some embodiments, the compound has a structure of Formula (III-A):
Figure imgf000033_0001
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is selected from phenyl, pyridinyl, pyrimidinyl, furanyl, and thiophenyl, and wherein Ring A is optionally substituted with one or more Rb. [0093] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is furanyl. In some embodiments, Ring A is thiophenyl. [0094] In some embodiments, L1 is selected from -NH-*, -NHC(=O)-*, , and
Figure imgf000033_0006
Figure imgf000033_0002
, wherein * indicates a bond to R5. In some embodiments, L1 is -NH-*. In some embodiments, L1 is -NHC(=O)-*. In some embodiments, L1 is
Figure imgf000034_0002
In some
Figure imgf000034_0001
embodiments, L1 is . [0095] In some embodiments, R1 is selected from -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, and thiophenyl. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CH(CH3)2. In some embodiments, R1 is -C(CH3)3. In some embodiments, R1 is -phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidinyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is pyrazolyl. In some embodiments, R1 is pyrrolyl. In some embodiments, R1 is tetrahydropyrrolyl. In some embodiments, R1 is thiophenyl. [0096] In some embodiments, R1 is phenyl substituted with one or more halogens. In some embodiments, the halogen is chloro. In some embodiments, R1 is phenyl substituted with one or more -Cl. [0097] In some embodiments, the compound of Formula (III-A) is selected from
Figure imgf000034_0003
, , , and
Figure imgf000034_0004
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0098] In some embodiments, the compound has a structure of Formula (III-B):
Figure imgf000035_0001
Formula (III-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0099] In some embodiments, R1 is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle, or a 3- to 9-membered heterocycle. In some embodiments, the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Ra. [0100] In some embodiments, R1 is -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CH(CH3)2. In some embodiments, R1 is -C(CH3)3. In some embodiments, R1 is -phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidinyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is pyrazolyl. In some embodiments, R1 is pyrrolyl. In some embodiments, R1 is tetrahydropyrrolyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is optionally substituted with one or more Ra. [0101] In some embodiments, Ra is selected from -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1- C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, and -(C1-C6 alkyl)-NHC(=O)NH2. [0102] In some embodiments, the compound of Formula (III-B) is selected from:
Figure imgf000035_0002
,
Figure imgf000036_0002
, , ,
Figure imgf000036_0003
, , and
Figure imgf000036_0004
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0103] In some embodiments, the compound is selected from:
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000037_0002
, and
Figure imgf000037_0003
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0104] In some embodiments, the compound of Formula (V) is: 11: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 12: 3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 13: 5-ethyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-ol; 14: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine; 15: 5-ethyl-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7-ol; 16: 3-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol; 17: 5-(tert-butyl)-7-chloro-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine; 18: 3-(4-fluorophenyl)-5-isopropylpyrazolo[1,5-a]pyrimidin-7(4H)-one; 19: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine; 20: 3-(4-fluorophenyl)-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one; 21: 3-(4-fluorophenyl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 22: 5-(tert-butyl)-3-(4-fluorophenyl)-4-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one; 23: 5-(tert-butyl)-3-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyrimidin-7-amine; 24: 5-(tert-butyl)-3-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 25: 5-(tert-butyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 26: 3-(4-chlorophenyl)-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one; 27: 5-(tert-butyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 28: 5-(tert-butyl)-3-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 29: 3-(4-aminophenyl)-5-(tert-butyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 30: 5-(4-chlorophenyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 31: 3,5-bis(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 32: 3-(4-bromophenyl)-5-(tert-butyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 33: 5-(tert-butyl)-3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 34: 5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 35: 3-(4-(tert-butyl)phenyl)-5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 36: 5-(tert-butyl)-3-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 37: 5-(tert-butyl)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 38: N-(5-(tert-butyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-4-fluorobenzamide; 39: 3-(4-bromophenyl)-5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 40: N-(4-(5-(tert-butyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-4-chloro-1H- pyrrole-2-carboxamide; 41: 5-(tert-butyl)-3-chloropyrazolo[1,5-a]pyrimidin-7(4H)-one; 42: N-(4-(5-(tert-butyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-2- chlorothiazole-5-carboxamide; 43: 5-(tert-butyl)-3-((4-chlorophenyl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 44: 5-(chloromethyl)-3-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 45: 3-(4-chlorophenyl)-5-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 46: N-(4-(5-(tert-butyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)phenyl)acetamide; 47: 5-(tert-butyl)-3-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; or 48: N-(3-(5-(tert-butyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-2- chlorothiazole-5-carboxamide. [0105] In certain aspects, the present disclosure also provides a compound of Formula (IV):
Figure imgf000039_0001
Formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Ring B is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Rb; Ra and Rb are each independently selected at each occurrence from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, - CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, - C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9- membered carbocycle, and 3- to 9-membered heterocycle; Rx is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, and 3- to 9-membered heterocycle, or two Rx are taken together with the C atom to which they are bound to form a 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, wherein each 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Rn, wherein Rn is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, - O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), - halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1- C6 alkyl)2, and -(C1-C6 alkyl)-NHC(=O)NH2; m is an integer from 0 to 4; and n is an integer from 0 to 5. [0106] In some embodiments, Ring B is a 3- to 9-membered carbocycle. In some embodiments, Ring B is a 3- to 9-membered heterocycle. In some embodiments, Ring B is a 3- membered heterocycle. In some embodiments, Ring B is a 4-membered heterocycle. In some embodiments, Ring B is a 5-membered heterocycle. In some embodiments, Ring B is a 6- membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has a oxygen atom. In some embodiments, the heterocycle has one nitrogen atom and one oxygen atom. [0107] In some embodiments, when Ring B is , then Rx is other than pyridinyl. [0108] In some embodiments, when Ring B is
Figure imgf000040_0001
and Rx is pyridinyl, then Rx is substituted with one or more Rn. [0109] In some embodiments, when Ring B is
Figure imgf000040_0002
and Rx is phenyl, then Rn is other than methoxy. [0110] In some embodiments, when Ring B is
Figure imgf000040_0003
and Rx is phenyl, then Rn is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -(C1-C6 alkylene)-OH, -NH2, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, and -(C1-C6 alkyl)-NHC(=O)NH2. [0111] In some embodiments, Rx is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, and 3- to 9-membered heterocycle. In some embodiments, Rx is -(C1-C6 alkyl). In some embodiments, Rx is -(C2-C6 alkenyl). In some embodiments, Rx is -(C2-C6 alkynyl). In some embodiments, Rx is -OH. In some embodiments, Rx is -O(C1-C6 alkyl). In some embodiments, Rx is -(C1-C6 alkylene)-OH. In some embodiments, Rx is -NH2. In some embodiments, Rx is - NH(C1-C6 alkyl). In some embodiments, Rx is -N(C1-C6 alkyl)2. In some embodiments, Rx is - (C1-C6 alkylene)-NH2. In some embodiments, Rx is -NHC(=O)(C1-C6 alkyl). In some embodiments, Rx is -NO2. In some embodiments, Rx is -CN. In some embodiments, Rx is -SCN. In some embodiments, Rx is -SH. In some embodiments, Rx is -S(C1-C6 alkyl). In some embodiments, Rx is halogen. In some embodiments, Rx is -C(=O)OH. In some embodiments, Rx is -C(=O)O(C1-C6 alkyl). In some embodiments, Rx is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rx is -C(=O)O(C1-C6 alkyl). In some embodiments, Rx is -C(=O)NH2. In some embodiments, Rx is -C(=O)NH(C1-C6 alkyl). In some embodiments, Rx is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rx is -(C1-C6 alkyl)-NHC(=O)NH2. In some embodiments, Rx is C3-C9 carbocycle. In some embodiments, Rx is C3-C9 heterocycle. [0112] In some embodiments, when two or more Rx are taken together with the C atom to which they are bound to form
Figure imgf000041_0001
n is an integer from 1 to 5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [0113] In some embodiments, Rn is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, and -(C1-C6 alkyl)-NHC(=O)NH2. In some embodiments, Rn is - (C1-C6 alkyl). In some embodiments, Rn is -(C2-C6 alkenyl). In some embodiments, Rn is -(C2-C6 alkynyl). In some embodiments, Rn is -OH. In some embodiments, Rn is -O(C1-C6 alkyl). In some embodiments, Rn is -(C1-C6 alkylene)-OH. In some embodiments, Rn is -NH2. In some embodiments, Rn is -NH(C1-C6 alkyl). In some embodiments, Rn is -N(C1-C6 alkyl)2. In some embodiments, Rn is -(C1-C6 alkylene)-NH2. In some embodiments, Rn is -NHC(=O)(C1-C6 alkyl). In some embodiments, Rn is -NO2. In some embodiments, Rn is -CN. In some embodiments, Rn is -SCN. In some embodiments, Rn is -SH. In some embodiments, Rn is -S(C1- C6 alkyl). In some embodiments, Rn is halogen. In some embodiments, Rn is -C(=O)OH. In some embodiments, Rn is -C(=O)O(C1-C6 alkyl). In some embodiments, Rn is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rn is -C(=O)O(C1-C6 alkyl). In some embodiments, Rn is - C(=O)NH2. In some embodiments, Rn is -C(=O)NH(C1-C6 alkyl). In some embodiments, Rn is - C(=O)N(C1-C6 alkyl)2. In some embodiments, Rn is -(C1-C6 alkyl)-NHC(=O)NH2. [0114] In some embodiments, the compound is selected from:
Figure imgf000042_0002
Figure imgf000042_0003
, and
Figure imgf000042_0004
or a pharmaceutically acceptable salt, tautomer, or solvate thereof. METHODS [0115] In certain aspects, the present disclosure provides a method of treating a proliferative disease comprising administering a compound having a structure of Formula (V) to a subject in need thereof, the compound having a structure of Formula (V):
Figure imgf000042_0001
Formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is selected from -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, and -(C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Ra; R2 is H or C1-C6 alkyl; L1 is absent or is selected from -CH2-*, -O-*, -C(=O)-*, -NH-*, -NHC(=O)-*, , and
Figure imgf000042_0006
, wherein * indicates a bond to R3;
Figure imgf000042_0005
R3 is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, - C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, C3-C9 carbocycle, or C3-C9 heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle are optionally substituted with one or more Rb; X is -H, =O, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or halogen; Ra and Rb are each independently selected at each occurrence from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, - CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, - C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9- membered carbocycle, and 3- to 9-membered heterocycle. [0116] In some embodiments, R1 is -H. In some embodiments, R1 is -(C1-C6 alkyl). In some embodiments, R1 is -(C2-C6 alkenyl). In some embodiments, R1 is -(C2-C6 alkynyl). In some embodiments, R1 is halogen. In some embodiments, R1 is -(C1-C6 haloalkyl). In some embodiments, R1 is -OH. In some embodiments, R1 is -O(C1-C6 alkyl). In some embodiments, R1 is -NH2. In some embodiments, R1 is -NH(C1-C6 alkyl). In some embodiments, R1 is -NH(C1- C6 alkyl)2. In some embodiments, R1 is -(C1-C6 alkylene)-OH. In some embodiments, R1 is -(C1- C6 alkylene)-NH2. [0117] In some embodiments, R1 is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle. In some embodiments, R1 is phenyl, pyridinyl, pyrimidyl, furanyl, thiophenyl, naphthyl, or indolyl. In some embodiments, R1 is phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is naphthyl. In some embodiments, R1 is or indolyl. [0118] In some embodiments, R2 is H. In some embodiments, R2 is C1-C6 alkyl. In some embodiments R2 is methyl. [0119] In some embodiments, L1 is absent. In some embodiments, L1 is -CH2-*. In some embodiments, L1 is -O-*. In some embodiments, L1 is -C(=O)-*. In some embodiments, L1 is - NH-*. In some embodiments, L1 is -NHC(=O)-*. In some embodiments, L1 is
Figure imgf000044_0001
1
Figure imgf000044_0002
. In some embodiments, L is . [0120] In some embodiments, R3 is -(C1-C6 alkyl). In some embodiments, R3 is -(C2-C6 alkenyl). In some embodiments, R3 is -(C2-C6 alkynyl). In some embodiments, R3 is -OH. In some embodiments, R3 is -O(C1-C6 alkyl). In some embodiments, R3 is -(C1-C6 alkylene)-OH. In some embodiments, R3 is -NH2. In some embodiments, R3 is -NH(C1-C6 alkyl). In some embodiments, R3 is -N(C1-C6 alkyl)2. In some embodiments, R3 is -(C1-C6 alkylene)-NH2. In some embodiments, R3 is -NHC(=O)(C1-C6 alkyl). In some embodiments, R3 is -NO2. In some embodiments, R3 is -CN. In some embodiments, R3 is -SCN. In some embodiments, R3 is -SH. In some embodiments, R3 is -S(C1-C6 alkyl). In some embodiments, R3 is halogen. In some embodiments, R3 is -C(=O)OH. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, R3 is -C(=O)N(C1-C6 alkyl)2. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, R3 is -C(=O)NH2. In some embodiments, R3 is -C(=O)NH(C1-C6 alkyl). In some embodiments, R3 is -C(=O)N(C1-C6 alkyl)2. In some embodiments, R3 is -(C1-C6 alkyl)- NHC(=O)NH2. In some embodiments, R3 is C3-C9 carbocycle. In some embodiments, R3 is 3- to 9-membered heterocycle. [0121] In some embodiments, X is =O. In some embodiments, X is -OH. In some embodiments, X is -NH2. In some embodiments, X is -NH(C1-C6 alkyl). In some embodiments, X is -N(C1-C6 alkyl)2. In some embodiments, X is halogen. [0122] In some embodiments, the compound is not 5-(tert-butyl)-3-(4- fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one. [0123] In some embodiments, R3 is substituted with at least one Rb. In some embodiments, L1 is absent. [0124] In some embodiments, the compound has the structure of Formula (VI):
Figure imgf000044_0003
Formula (VI), wherein Ring A is phenyl, pyridinyl, pyrimidyl, furanyl, thiophenyl, and wherein Ring A is optionally substituted with one or more Rb. [0125] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is furanyl. In some embodiments, Ring A is thiophenyl. In some embodiments, Ring A is substituted with at least one Rb. In some embodiments, each Rb is independently selected at each occurrence from -(C1- C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, - NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1- C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, and 3- to 9-membered heterocycle. In some embodiments, Rb is - (C1-C6 alkyl). In some embodiments, Rb is -(C2-C6 alkenyl). In some embodiments, Rb is -(C2-C6 alkynyl). In some embodiments, Rb is -OH. In some embodiments, Rb is -O(C1-C6 alkyl). In some embodiments, Rb is -(C1-C6 alkylene)-OH. In some embodiments, Rb is -NH2. In some embodiments, Rb is -NH(C1-C6 alkyl). In some embodiments, Rb is -N(C1-C6 alkyl)2. In some embodiments, Rb is -(C1-C6 alkylene)-NH2. In some embodiments, Rb is -NHC(=O)(C1-C6 alkyl). In some embodiments, Rb is -NO2. In some embodiments, Rb is -CN. In some embodiments, Rb is -SCN. In some embodiments, Rb is -SH. In some embodiments, Rb is -S(C1- C6 alkyl). In some embodiments, Rb is halogen. In some embodiments, Rb is -C(=O)OH. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is - C(=O)NH2. In some embodiments, Rb is -C(=O)NH(C1-C6 alkyl). In some embodiments, Rb is - C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is -(C1-C6 alkyl)-NHC(=O)NH2. In some embodiments, Rb is C3-C9 carbocycle. In some embodiments, R3 is 3- to 9-membered heterocycle. [0126] In some embodiments, R1 is H. In some embodiments, the compound is
Figure imgf000045_0001
. [0127] In some embodiments, L1 is selected from -NH-*, -NHC(=O)-*,
Figure imgf000046_0001
, and
Figure imgf000046_0002
, wherein * indicates a bond to R3 . In some embodiments, L1 is -NH-*. In some embodiments, L1 is -NHC(=O)-*. In some embodiments, L1 is
Figure imgf000046_0005
. In some 1
Figure imgf000046_0003
embodiments, L is . [0128] In some embodiments, R3 is
Figure imgf000046_0004
. In some embodiments, Y is S. In some embodiments, Y is N. In some embodiments, W is N. In some embodiments, W is C. In some embodiments, Y is S, W is N, and Rb is halogen. In some embodiments, L1-R3 is selected from
Figure imgf000046_0006
Figure imgf000046_0007
, and
Figure imgf000046_0008
[0129] In some embodiments, R1 is selected from -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, and thiophenyl. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CH(CH3)2. In some embodiments, R1 is -C(CH3)3. In some embodiments, R1 is -phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidinyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is pyrazolyl. In some embodiments, R1 is pyrrolyl. In some embodiments, R1 is tetrahydropyrrolyl. In some embodiments, R1 is thiophenyl. [0130] In some embodiments, the compound of Formula (V) is selected from
Figure imgf000047_0001
, , ,
Figure imgf000047_0002
, and
Figure imgf000047_0003
. [0131] In some embodiments, the compound is of Formula (VII):
Figure imgf000047_0004
Formula (VII), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is selected from phenyl, pyridinyl, pyrimidinyl, furanyl, and thiophenyl, wherein Ring A is optionally substituted with one or more Rb, and X is =O or -OH. [0132] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is furanyl. In some embodiments, Ring A is thiophenyl. [0133] In some embodiments, L1 is selected from -NH-*, -NHC(=O)-*,
Figure imgf000048_0001
, and
Figure imgf000048_0002
, wherein * indicates a bond to R5. In some embodiments, L1 is -NH-*. In some embodiments, L1 is -NHC(=O)-*. In some embodiments, L1 is
Figure imgf000048_0003
. In some 1
Figure imgf000048_0004
embodiments, L is . [0134] In some embodiments, R1 is selected from hydrogen, -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, and thiophenyl. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CH(CH3)2. In some embodiments, R1 is -C(CH3)3. In some embodiments, R1 is -phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidinyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is pyrazolyl. In some embodiments, R1 is pyrrolyl. In some embodiments, R1 is tetrahydropyrrolyl. In some embodiments, R1 is thiophenyl. [0135] In some embodiments, R1 is H. [0136] In some embodiments, R1 is phenyl or pyridinyl. In some embodiments, R1 is phenyl or pyridinyl substituted with one or more halogen. In some embodiments, the halogen is chloro. [0137] In some embodiments, Rb is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, and 3- to 9-membered heterocycle. In some embodiments, Rb is -(C1-C6 alkyl). In some embodiments, Rb is -(C2-C6 alkenyl). In some embodiments, Rb is -(C2-C6 alkynyl). In some embodiments, Rb is -OH. In some embodiments, Rb is -O(C1-C6 alkyl). In some embodiments, Rb is -(C1-C6 alkylene)-OH. In some embodiments, Rb is -NH2. In some embodiments, Rb is - NH(C1-C6 alkyl). In some embodiments, Rb is -N(C1-C6 alkyl)2. In some embodiments, Rb is - (C1-C6 alkylene)-NH2. In some embodiments, Rb is -NHC(=O)(C1-C6 alkyl). In some embodiments, Rb is -NO2. In some embodiments, Rb is -CN. In some embodiments, Rb is -SCN. In some embodiments, Rb is -SH. In some embodiments, Rb is -S(C1-C6 alkyl). In some embodiments, Rb is halogen. In some embodiments, Rb is -C(=O)OH. In some embodiments, R3 is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is -C(=O)NH2. In some embodiments, Rb is -C(=O)NH(C1-C6 alkyl). In some embodiments, Rb is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is -(C1-C6 alkyl)-NHC(=O)NH2. In some embodiments, Rb is C3-C9 carbocycle. In some embodiments, R3 is C3-C9 heterocycle. [0138] In some embodiments, Rb is selected from -(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), -(C1- C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, phenyl, thiazolyl, pyrazolyl, and furanyl. In some embodiments, Rb is - (C1-C6 alkyl). In some embodiments, Rb is -OH. In some embodiments, Rb is -O(C1-C6 alkyl). In some embodiments, Rb is -(C1-C6 alkylene)-OH. In some embodiments, Rb is -NH2. In some embodiments, Rb is -NH(C1-C6 alkyl). In some embodiments, Rb is -N(C1-C6 alkyl)2. In some embodiments, Rb is -NHC(=O)H. In some embodiments, Rb is -NHC(=O)(C1-C6 alkyl). In some embodiments, Rb is -NO2. In some embodiments, Rb is halogen. In some embodiments, Rb is - C(=O)OH. In some embodiments, Rb is -C(=O)O(C1-C6 alkyl). In some embodiments, Rb is - C(=O)NH2. In some embodiments, Rb is -C(=O)NH(C1-C6 alkyl). In some embodiments, Rb is - C(=O)N(C1-C6 alkyl)2. In some embodiments, Rb is phenyl. In some embodiments, Rb is thiazolyl. In some embodiments, Rb is pyrazolyl. In some embodiments, Rb is furanyl. [0139] In some embodiments, the compound having a structure of Formula (VII) is selected
Figure imgf000049_0001
,
Figure imgf000050_0001
Figure imgf000051_0002
, , ,
Figure imgf000051_0003
, or
Figure imgf000051_0004
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0140] In some embodiments, the compound has a structure of Formula (IX):
Figure imgf000051_0001
Formula (IX), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0141] In some embodiments, R1 is selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1- C6 alkyl)2, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle, and a 3- to 9-membered heterocycle. In some embodiments, the 3- to 9-membered carbocycle or 3- to 9- membered heterocycle is optionally substituted with one or more Ra. In some embodiments, R1 is -(C1-C6 alkyl). In some embodiments, R1 is -(C2-C6 alkenyl). In some embodiments, R1 is - (C2-C6 alkynyl). In some embodiments, R1 is halogen. In some embodiments, R1 is -(C1-C6 haloalkyl). In some embodiments, R1 is -OH. In some embodiments, R1 is -O(C1-C6 alkyl). In some embodiments, R1 is -(C1-C6 alkylene)-OH. In some embodiments, R1 is -NH2. In some embodiments, R1 is -NH(C1-C6 alkyl). In some embodiments, R1 is -N(C1-C6 alkyl)2. In some embodiments, R1 is -(C1-C6 alkylene)-NH2. In some embodiments, R1 is C3-C9 carbocycle. In some embodiments, R1 is C3-C9 heterocycle. [0142] In some embodiments, R1 is selected from -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, and thiophenyl. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CH(CH3)2,. In some embodiments, R1 is -C(CH3)3. In some embodiments, R1 is -phenyl. In some embodiments, R1 is pyridinyl. In some embodiments, R1 is pyrimidinyl. In some embodiments, R1 is furanyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is pyrazolyl. In some embodiments, R1 is pyrrolyl. In some embodiments, R1 is tetrahydropyrrolyl. In some embodiments, R1 is thiophenyl. In some embodiments, R1 is optionally substituted with one or more Ra. [0143] In some embodiments, Ra is selected from -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1- C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, and -(C1-C6 alkyl)-NHC(=O)NH2. In some embodiments, Ra is -OH. In some embodiments, Ra is -O(C1-C6 alkyl). In some embodiments, Ra is -(C1-C6 alkylene)-OH. In some embodiments, Ra is -NH2. In some embodiments, Ra is -NH(C1-C6 alkyl),. In some embodiments, Ra is -N(C1-C6 alkyl)2. In some embodiments, Ra is -(C1-C6 alkylene)-NH2. In some embodiments, Ra is -NHC(=O)H,. In some embodiments, Ra is -NHC(=O)(C1-C6 alkyl). In some embodiments, Ra is -NO2. In some embodiments, Ra is -CN. In some embodiments, Ra is -SCN. In some embodiments, Ra is -SH. In some embodiments, Ra is -S(C1-C6 alkyl). In some embodiments, Ra is halogen. In some embodiments, Ra is -C(=O)OH. In some embodiments, Ra is -C(=O)O(C1-C6 alkyl). In some embodiments, Ra is -C(=O)NH2. In some embodiments, Ra -C(=O)NH(C1-C6 alkyl). In some embodiments, Ra is -C(=O)N(C1-C6 alkyl)2. In some embodiments, Ra is -(C1-C6 alkyl)- NHC(=O)NH2. [0144] In some embodiments, the compound of Formula (IX) is selected from: ,
Figure imgf000052_0001
,
Figure imgf000053_0001
, , and
Figure imgf000053_0002
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0145] In some aspects, the present disclosure provides a method of treating a proliferative disease or disorder comprising administering a compound of any one of Formulas (I)-(IV) to a subject in need thereof. [0146] In additional aspects, the present disclosure provides a method of decreasing tumor cell viability comprising administering to the tumor cell a compound of any one of Formulas (I)- (IX). [0147] In some embodiments, the method comprises measuring an average tumor cell size. [0148] In some embodiments, administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by about 10% to about 100%. In some embodiments, the administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, the administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In some embodiments, the administering the compound of any one of Formulas (V)- (IX) reduces an average tumor cell size by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In some embodiments, administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by 20% to 80%, 40% to 90%, 60% to 100%, 30% to 80%, or 50% to 90%, including all values and sub ranges in between. [0149] In some embodiments, the proliferative disease comprises a T cell factor (TCF)-driven cancer. [0150] In some embodiments, the method comprises inhibiting chromatin helicase DNA- binding protein 1-like (CHD1L). [0151] In some embodiments, the inhibiting of CHD1L comprises determining a loss of ATPase activity. In some embodiments, the determining comprises performing an ATPase activity assay. [0152] In some embodiments, the method comprises trapping CHD1L onto chromatin. In some embodiments, the trapping comprises increasing an amount of CHD1L by 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold. In some embodiments, the trapping comprises increasing an amount of CHD1L by about 1-fold, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold. In some embodiments, the trapping comprises increasing an amount of CHD1L by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold. In some embodiments, the trapping comprises increasing an amount of CHD1L by at most 1-fold, at most 2-fold, at most 3-fold, at most 4-fold, at most 5-fold, at most 6-fold, at most 7-fold, at most 8-fold, at most 9-fold, or at most 10-fold. [0153] In some embodiments, the TCF-driven cancer comprises colorectal cancer or metastatic colorectal cancer. [0154] In additional aspects, the present disclosure provides a method of reducing catalytic activity of a CHD1L. In some embodiments, the method comprises contacting the CHD1L with a compound of any one of Formulas (I)-(IX). In some embodiments, the catalytic activity of the CHD1L is an ATPase activity. In some embodiments, the catalytic activity of the CHD1L is reduced by about 10% to about 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, or at most 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by 20% to 70%, 40% to 90%, 60% to 80%, 30% to 80%, or 50% to 90%, including all values and sub ranges in between. [0155] In some embodiments, the catalytic activity is measured by an ATPase assay. [0156] In some embodiments, the compound is selected from: ,
Figure imgf000054_0001
,
Figure imgf000055_0001
, , ,
Figure imgf000056_0001
, an ,
Figure imgf000056_0003
Figure imgf000056_0002
d or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0157] In certain aspects, provided herein are methods of treating a cancer. In some embodiments, the method comprises binding a CHD1L inhibitor to an allosteric binding site of CHD1L. In some embodiments, binding a CHD1L inhibitor comprises binding the CHD1L inhibitor to a CHD1L having at least about 70% sequence identity to SEQ ID NO: 1. In some embodiments, binding a CHD1L inhibitor comprises exposing the CHD1L inhibitor to a lysine in the allosteric binding site. In some instances, the lysine is lysine-273 (K273). In some embodiments, binding a CHD1L inhibitor comprises exposing the CHD1L inhibitor to a tyrosine in the allosteric binding site. In some instances, the glutamate is tyrosine 480 (Y480). In some embodiments, the CHD1L comprises any one of SEQ ID NOs: 1-39. In some embodiments, the CHD1L comprises a sequence selected from Table 3. Table 3. CHD1L Sequences.
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
EXAMPLES Example 1: Compounds for treating colorectal cancer (CRC) [0158] Chromodomain helicase DNA-binding protein 1 like (CHD1L) is an oncogene that promotes tumor progression, metastasis, and multidrug resistance. CHD1L expression is indicative of poor outcomes and low survival in cancer patients with various cancer types. A set of CHD1L inhibitors (CHD1Li) discovered from high-throughput screening were evaluated using enzyme inhibition, 3D tumor organoid cytotoxicity and mechanistic assays. The structurally distinct Compounds 8-11 emerged as hits with promising bioactivity by targeting CHD1L. CHD1Li were further examined for their stability in human and mouse liver microsomes, which showed compounds 9 and 11 to be the most metabolically stable. Additionally, molecular modelling studies of CHD1Li with the target protein shed light on key pharmacophore features driving CHD1L binding. Taken together, these results expand the chemical space of CHD1Li as a potential targeted therapy for colorectal cancer and other cancers. [0159] Methods [0160] Cell Line – the immortalized colorectal cancer cell line SW620 was purchased from American Type Culture Collection (ATCC) (Manassas, VA). The cell line was STR profiled and tested for bacteria or mycoplasma contamination prior to use. SW620 cells were transfected with a dual-reporter plasmid and sorted according to their mesenchymal or epithelial phenotype. All cell-based assays described herein were performed using the isolated mesenchymal phenotype (SW620-GFP+). The cells were stored in a liquid nitrogen tank until needed, when they were then thawed and passaged twice before use. [0161] Cell Culture –cells were grown within RPMI 1640 media (Gibco, Ref#: 11875-093) containing 5% fetal bovine serum (Gibco, Ref#: 10437028) in 10 cm tissue culture coated dishes (Fisher Scientific, Ref#: FB012924). Cells were stored in a 37°C humidified incubator at 5% CO2 for growth. Cells were split by aspirating media from the plate, washing with 5 mL of Phosphate Buffer Solution (PBS) 1X pH 7.4 (Gibco, Ref#: 10010-023), followed by addition of 0.25% Trypsin (Life Technologies, Ref#: 25200072) in media, prior to incubation for 6 minutes. The trypsin was neutralized with 4 mL of growth media. [0162] Catalytic Enzyme Assay – The catalytic enzyme assay was performed. A reaction mixture was prepared at the concentrations of 100 nM of the catalytic domain of CHD1L (cat- CHD1L) and 200 nM/L of c-Myc DNA or mononucleosome (Active Motif, Ref#: 81770) in buffer (50 mM Tris pH 7.5, 50 mM NaCl, 1 mM DTT, 5% glycerol). ATP was added at a concentration of 10 µM to begin the reaction, bringing the total reaction volume to 10 µL. After initiation, the reaction was allowed to proceed for 1 hour while incubated at 37°C. Then, 500 nM/L of Phosphate sensor was added to the reaction to quantify the ATPase activity of the enzyme. An Envision plate reader (Revvity, Waltham, MA) was used to measure the excitation at 430 nm and the emission at 450 nm of the phosphate sensor. The fluorescence generated from this reaction was compared to a standard inorganic phosphate curve to calculate the enzyme kinetics. All statistical analysis was performed using GraphPad Prism. [0163] Tumor Organoid Culture – SW620-GFP+ cells were used to grow 3D tumor organoids. After cell lines were split, they were counted by creating a 1:1 ratio mixture of cell suspension and Trypan Blue (Sigma-Aldrich, Ref#: T8154-20ML). This solution was analyzed and counted using a Bio-Rad TC20 automated cell counter (Bio-Rad, Hercules, CA).2,000 cells in 100 μL of growth media were added to each well in a 96-well clear, round bottom ultra-low attachment (ULA) well plates (Corning, Ref # 7007). Plates were spun at 1000 RPM for 15 minutes at 25°C to aggregate the cells.25 μL of 10% Matrigel (Corning, Ref# 356231) in growth media was added to each well for a final concentration of 2% Matrigel.100 μL of PBS 1X pH 7.4 (Gibco, Ref#: 10010-023) was added to the spaces between wells within the plate to reduce evaporation. The plates were incubated at 37°C for 72 hours to grow tumor organoids in each well. [0164] 3D Cytotoxicity Assay – The CHD1Li were tested at seven different concentrations to determine their cytotoxic effect on SW620-GFP+ tumor organoids. Compounds were dissolved in DMSO (Sigma-Aldrich, Ref #34869) to make a 10 mM stock solution and stored at -80˚C. After thawing, the stock was diluted with growth media and serially diluted before addition to cells in a 1:6 ratio. After 72 hours of growth, cells were treated with CHD1Li in triplicates or quadruplicates at final concentrations ranging from 0.625 μM to 40 μM in 0.4% DMSO. The plate was incubated at 37°C for 72 hours before harvesting. During harvesting, the organoids were transferred to a white, flat bottom 96-well plate (Greiner, Ref#:655083) and treated with 35 μL of 3D Cell Titer Glo (Promega, Ref#: G7572). The plates were then placed on an orbital shaker at 400 RPM for 45 minutes before they were analyzed using the Envision plate reader. These experiments were conducted on 2 to 3 separate instances on different days to determine result repeatability. [0165] EMT Dual Reporter Assay – The EMT dual reporter assay was performed. SW620- GFP+ cells were plated as 3D organoids and treated with 0-40 µM of CHD1Li as described above. The Opera Phenix HCS System (Revvity) was used to perform high content imaging and analysis of the 3D organoids. This imaging was performed on SW620-GFP+ organoids prior to harvesting for the cytotoxicity assay. [0166] CSC Stemness Clonogenic Assay – The CSC stemness assay was performed. SW620- GFP+ Cells were plated at 300 cells/well in 96 well clear, flat bottom, black plates and allowed to attach overnight. The following day, cells were treated with CHD1Li or DMSO control at concentrations ranging from 0.25 to 8 µM in media. The vehicle and treatments were refreshed with 25 µL of treatment or vehicle on days 5 and 8. On day 9, cells were imaged with the Opera Phenix HCS system. Prior to imaging, the colonies were stained with 25 µL of 0.67 µg/mL Hoechst 33342 (Life Technologies, Ref#: H3570) in PBS and incubated for 15 minutes at 37°C. The images were analyzed using the Harmony 5.1 software to count colony number, area, and confluence. [0167] Microsomal Assay – The microsomal stability of hit CHD1Li 8-11 was evaluated in CD-1 mouse microsomes (Gibco, Ref#: MSMCPL) and human microsomes (Gibco, Ref#: HMMCPL). At the final concentrations, the 100 µL reaction solution consisted of 0.5 mg/mL microsomes, phosphate buffer pH 7.4 (44 mM KH2PO4, 56 mM K2HPO4), 1.94 mg/mL UDPGA (Sigma Aldrich, Ref# U6751), 25 µg alamethicin (Sigma-Aldrich, A4665), 1 mM MgCl2, 1 mM NADPH (Sigma-Aldrich, Ref# 481973-50MG), 1% DMSO, and 10 µM of either CHD1Li or testosterone (Sigma, T1500-1G) for control tubes. All the reaction components except NADPH were pre-incubated for 5 minutes at 37°C on a heat block. The reactions were activated by adding NADPH and incubated at 37°C for the remainder of the reaction. At time points 0, 5, 15, 30, 45, and 60 minutes, 100 µL of the reaction solution was removed and mixed with acetonitrile at a 1:1 ratio to halt the reaction. Samples from each time point were centrifuged at 3000 RPM for 5 minutes and the supernatant was sampled for mass spectrometry analysis. [0168] Mass Spectrometry Analysis – a Prominence HPLC (Shimadzu, Kyoto, Japan) coupled to a QTrap 4500 mass spectrometer (AB Sciex, Farmingham, MA) was used for this analysis. The mass spectrometer was operated in the ESI+ mode and all settings were optimized by manually tuning to infused standard solutions. Global mass spectrometer parameter settings were selected to give the highest average sensitivity for all compounds of interest. Global mass spectrometer settings are as follows: curtain gas, 40 psi; collision gas, high; ion spray voltage, 4500 V; source temperature, 700°C; ion source gas 1 and 2, 50 psi; entrance potential, 10 V; and collision cell exit potential, 14 V. The collision energy (CE) and declustering potential (DP) were optimized separately for each compound. Data was collected using the multiple reaction monitoring (MRM) mode. Quantitation was performed using an external calibration curve for each compound. Analytical separation was achieved with a Phenomenex kinetex C18 column [2.1 x 100 mm, 2.6 µm]. The column was held at 40°C and eluted at 0.6 mL/min with a gradient of 0.1% formic acid (A) and 0.1% formic acid in 9:1 acetonitrile:water (B) with a total runtime of 10 minutes. Chromatographic separation was achieved with a linear gradient (time, % of solvent B): 0-0.5 min, 5% B; 0.5-4.5 min, 5-55% B; 4.5-6.5 min, 55-94% B; 6-7 min, 94-5% B; and then isocratic for 3 minutes at 5% B to re-equilibrate the column. The first 3 minutes of eluent was diverted to waste to reduce contamination of the front end of the mass spectrometer. Calibration curves were prepared from the stock standard solutions. Serial dilutions of stock standards were prepared in DMSO. Calibration standards were prepared in 20% DMSO in water. Calibration curves typically contained 25 fmols – 3 pmols on column for testosterone, and 25 fmols – 2 pmols on column for Compounds 8-11. [0169] Molecular Modeling – all calculations were performed using the Schrödinger molecular modeling suite (version 2022-2) and OPLS4 force field. [0170] Ligand and Protein Preparation. The 3D low energy conformation of hit compounds 8- 11 was created with the LigPrep module. Ligands ionization and tautomeric states were generated using Epik at pH 7.0^2.0. The 3D model of fl-CHD1L (UniProt# Q86WJ1) in the active state was downloaded from AlphaFold database and processed using the protein preparation workflow. A reliability check of the minimized protein structure was conducted prior to its use for further calculations. [0171] Binding Site Elucidation. The minimized fl-CHD1L structure was characterized for potential druggable sites using the SiteMap module. The minimum site points per site were set at 15 while using a more restrictive requirement for hydrophobicity to exclude sites occupying free space. The returned sites were ranked based on the site score, drugability score, size, and volume. [0172] Molecular Docking and Binding Free Energy (ΔGbind) Estimation. The minimized structures of hit CHD1Li 8-11 and fl-CHD1L were used as inputs for molecular docking calculations using the induced-fit docking (IFD) protocol at the best site identified from SiteMap calculations. The receptor grid box was defined as the centroid of amino acid residues bordering the selected binding site with an inner and outer box size of 10 and 30 Å, respectively. The ligand ring conformations were sampled at 2.5 kcalmol-1, followed by a short minimization of the protein structure to RMSD 0.18 Å and Prime refinement of residues within 5 Å of binding site. Ligands were then redocked into receptor structures within 30 kcalmol-1 using extra- precision Glide docking. [0173] Subsequently, the ΔGbind for the resulting CHD1L complexes were estimated using Prime molecular mechanics/generalized Born surface area (MM/GBSA) module. The variable- dielectric generalized Born model (VSGB), which uses water as an implicit solvent, was selected as the solvation model. All atoms of binding site residues were minimized during the calculation to account for ligand-induced conformational changes. The best pose for each hit compound was determined using the docking score, glide model, glide energy, IFD score and ΔGbind. [0174] Molecular Dynamics (MD) Simulation. MD simulations were conducted. The requisite model systems for Compounds 9 and 11 were created using the system builder. Each system was solvated with SPC solvent models in an orthorhombic box with 10 Å periodic boundary conditions on all sides. System neutralization was achieved with NaCl salt at ~50 mM. The Desmond MD simulation was performed over a total of 500 ns simulation period using the NPT ensemble at constant temperature (300 K) and pressure (1.01 bar). Simulation trajectories were recorded at 500 ps intervals and using relevant Python scripts. [0175] Statistical Analysis – statistical analysis and graphs were executed in GraphPad Prism 10 for MacOS (version 10.0.2). A non-linear regression model was used to create a logarithmic curve to model the inhibitor vs response variable slope and calculate the half maximal inhibitory concentration (IC50) of each compound within a 95% confidence interval. Normalization to control and EC2-fold calculations were performed in Microsoft Excel for MacOS (version 16.76) [0176] Results [0177] Hits were reexamined for their potential as CHD1Li using a tailored hit-to-lead validation schema to prioritize additional hits as leads for further optimization (FIG.1). Compound 6 was used as reference and positive control and is described at PCT Pub. No. WO 2021/195279 A1, the entirety of which is incorporated by this reference. The compounds were first tested against the cat-CHD1L recombinant enzyme ATPase assay to confirm inhibitory activity and eliminate false positives from the HTS. Once confirmed as hits, they are tested for their ability to induce cytotoxicity or inhibit or reverse EMT, using CRC tumor organoids models. [0178] Select hits were next examined for their ability to inhibit CSC stemness, using the clonogenic colony formation assay. The mesenchymal phenotype of SW620 cells (SW620- GFP+) was selected for the cell-based assays in this validation scheme since it displays enhanced tumorigenic properties, including multidrug resistance and CSC stemness. Therefore, this phenotype has the highest potential for colony formation, metastasis, and represents an aggressive CRC tumor cell model . Finally, top hits from these experiments were evaluated for their metabolic stability in mouse liver microsomes. The results from the hit-to-lead validation experiments are summarized in Table 4. [0179] Workflow – 30 compounds were examined for their potential as CHD1Li using a tailored hit-to-lead validation schema to prioritize additional hits as leads for further optimization. Compound 6 was used as a control. The compounds were first tested against the cat-CHD1L recombinant enzyme ATPase assay to confirm inhibitory activity and eliminate false positives from the HTS. Once confirmed as hits, they are tested for their ability to induce cytotoxicity or inhibit or reverse EMT, using CRC tumor organoids models. [0180] Promising hits were next examined for their ability to inhibit CSC stemness, using the clonogenic colony formation assay. The mesenchymal phenotype of SW620 cells (SW620- GFP+) was selected for the cell-based assays in this validation scheme since it displays enhanced tumorigenic properties, including multidrug resistance and CSC stemness. Therefore, this phenotype has the highest potential for colony formation, metastasis, and represents an aggressive CRC tumor cell model. Finally, top hits from these experiments were evaluated for their metabolic stability in mouse liver microsomes. The results from the hit-to-lead validation experiments are summarized in Table 4. Table 4. Hit to lead validation results.
Figure imgf000080_0001
Figure imgf000081_0001
[0181] CHD1L Enzyme Inhibition – confirmed hits from primary HTS were re-evaluated for their dose dependent inhibition of cat-CHD1L ATPase. Compounds 32-36 were deprioritized due to their limited potency with inhibition concentration 50% (IC50) values >20 μM. All the other compounds displayed relatively potent CHD1L inhibition with IC50 <15 (Table 4). Hit compounds 8-11 displayed similar inhibitory activity compared to Compound 6 and were prioritized for further validation (Table 4 and FIG.2A). [0182] 3D Cytotoxicity – as a measure of antitumor activity, hits were prioritized for their ability to induce cytotoxicity using SW620 tumor organoids cultured uniformly in 96-well plates. Despite the promising IC50 values for inhibition of CHD1L ATPase, many compounds in the screen showed poor cytotoxicity even at a high dose of 40 μM, which is likely due to unfavorable physicochemical properties (Table 4). For example, compounds 18 and 20 were poorly soluble in DMSO and aqueous solutions likely prohibiting cellular activity. However, compounds 8-11 displayed relatively good cytotoxicity with IC50 <30 μM further validating their selection as hits (FIG.2B). Notably, compound 11 exhibited the best cell based activity with an IC50 of 3.3 μM, which is comparable to Compound 6 but up to 9-fold greater than hit compounds 8-10 (FIG.2B). The cellular activity of compound 11 is likely facilitated due to its better physicochemical properties i.e., molecular weight, lipophilicity, and aqueous solubility. [0183] EMT Reversal – CHD1Li exhibited dose-dependent inhibition or reversal of EMT in CRC tumor organoids. EMT inhibition or reversal was evaluated using a fluorescent dual- reporter plasmid, measuring downregulation of mesenchymal biomarker vimentin with concomitant upregulation of the epithelial biomarker E-cadherin (FIG.3). Partial effects or inhibition of EMT was observed with some CHD1Li such as Compounds 8 and 10, while Compounds 9 and 11 effectively reversed EMT (FIG.3A). Compound 11 displayed the most potent reversion of EMT, which led to tumor organoid killing at higher doses (FIG.3). This suggests that Compound 11 may be effective at reducing the metastatic potential of aggressive mesenchymal tumor cells. [0184] Inhibition of CHD1L-mediated CSC Stemness – complementary to CHD1Li effects on EMT, the clonogenic assay was used to evaluate the CHD1Li’s ability to inhibit CSC stemness. The IC50 of stemness for all compounds ranged between nM to low μM (Table 4) with the most potent CHD1Li being compound 9 and 11 (FIG.4A & B). However, 11 superior and 3-fold more potent compared Compound 6, and this is also consistent with its ability to reverse EMT (FIG.3). Mesenchymal cells expressing vimentin possess enhanced CSC stemness, which facilitates cell survival and increased invasion and metastatic potential. As such, the compounds that only induced partial EMT reversal had reduced potency against stemness compared to compound 11. [0185] Microsomal Stability – a knowledge of metabolic stability is an important step during early-stage drug development for lead prioritization. A correlation between in vitro microsomal stability and in vivo pharmacokinetics and efficacy for CHD1Li was observed. In vitro evaluation of hit CHD1Li 8-11 stability towards biotransformation showed that Compounds 9 and 11 were the most stable when exposed to human and mouse microsomes with half-lives of ~100 minutes. Compounds 9 and 11 also exhibited up to 16-fold superior stability compared to Compounds 8 and10 (Table 4). The poor stability in Compounds 8 and 10 are attributed to the S-methyl unit as shown by the mass transition analysis. Sterically unhindered S-methyl units are considered as metabolic soft spots due to their vulnerability to cytochrome P450-mediated oxidative metabolism. Hence, optimization studies for these CHD1Li should focus on addressing the thiomethyl functionalities. Similarly, the ability of Compound 11 to exist as either the pyrimidinol or pyrimidinone tautomer requires attention to avoid idiosyncratic toxicity outcomes. [0186] In Silico CHD1L Binding Studies: Binding Site Elucidation – an AI generated homology model retrieved from the AlphaFold database to improve the accuracy of our predicted CHD1Li complexes was used. [0187] Structural analysis of the apo AlphaFold homology model before and after protein preparation provided a full length (fl)-CHD1L structure in an active conformation with improved protein packing and without missing loops, steric clashes, or unusual B-factors. More importantly, SiteMap calculations returned five potential binding sites, including the ATP binding site, a large allosteric site on the macro domain, two shallow sites on the N-ATPase domain, and the identified CHD1Li allosteric binding site on the C-ATPase domain. Again, the C-ATPase allosteric site had the highest drugability score (1.039) and site score (1.016) overall, confirming it as the most plausible binding site (FIG.5A). [0188] CHD1Li Target Interaction – to gain molecular level insight on the possible target interaction profile of hit Compounds 8-11 and identify the corresponding pharmacophore features furnishing enzyme inhibition, the compounds were docked at the C-ATPase allosteric site using the IFD protocol. The higher docking and IFD scores for Compounds 8 and 10 suggests that they bind more tightly to the target compared to Compounds 9 and 11. The MM/GBSA binding free energy, which is often a more accurate descriptor of native poses, is also higher for Compounds 8 and 10 as compared to Compounds 9 and 11. The result agrees with the enzymatic data, which showed Compound 8 and 10 as more potent CHD1Li than Compound 9 and 11 (FIG.2). Nevertheless, the weaker cell-based potencies of Compound 8-10 as compared to Compound 11 despite their potent CHD1L inhibition can be attributed to structural features limiting cell membrane permeability. For instance, with a calculated pKa of 7.12 and a protonated imidazole nitrogen, Compound 9 will exist at an ~50:50% ratio of ionized and neutral forms at physiological pH likely impacting its cell activity and potency due to limited diffusion into cells of the ionized form. [0189] Analysis of the docked complexes showed the CHD1Li structural features favoring target binding (FIG.5B-E). Compound 8 formed strong H-bond interactions (within 3 Å) with Asn 491 and Lys 273 via its urea and thiadiazole units, and other H-bond interactions with Ser 441 and Arg 468 via the 3,5-dimethoxy unit (FIG.5B). The pi-cation interactions of electron- rich phenyl and thiophene rings with Lys 273 and Arg 468, and the hydrophobic contacts with Lys 263, Glu 275, and Pro 445 presumably stabilized the ligand in the allosteric binding site. Although Compound 10 (FIG.5C) only formed pi-pi stacking and H-bond interactions with Phe 438 and Tyr 480, respectively, the hydrophobic propyl linker allowed a robust network of hydrophobic contacts to favor high CHD1L affinity comparable to Compound 8. On the other hand, the similar enzyme inhibition of Compounds 9 and 11 is justified by their identical pi-pi stacking interaction with Tyr 480 (FIG.5D and E). Moreover, Compound 9 featured an H-bond with Lys-273 while Compound 10 interacted similarly with Tyr 480. These results suggest that a combination of H-bond acceptors and hydrophobic groups favor CHD1L binding. Thus, Compounds 9 and 11 can be optimized by incorporating pharmacophore features that favor these desired interactions. This is supported by Compound 8, the most potent hit, having the highest number of H-bond acceptors and overall interactions with CHD1L (FIG.5B), and the most stable target complexation. [0190] Molecular Dynamics Simulation – having established the possible protein-ligand interactions, a 500 ns long MD simulation for Compounds 9 and 11 was conducted. The goal was to analyze the time-dependent evolution of these interactions and determine ligand stability in terms of root-mean square deviation (RMSD) from the reference structure, i.e., the IFD pose. MD simulation is crucial to comprehensively account for the structural flexibility and ligand- induced conformational changes in a drug-target model system beyond IFD. [0191] The convergence of CHD1Li 9 at an average RMSD of 0.8 nm within the first 10 ns and the preservation over the entire 500 ns simulation period indicates a highly stable complexation without the ligand diffusing away from the allosteric binding pocket (FIG.6A). Compound 11 also had sustained binding site residence, which is inferable from the H-bond interaction with the amide oxygen atom of Tyr 480 which occurred for 94% or 470 ns (FIG. 6B). This interaction and others shown in FIG.6B (right panel) further corroborate the idea that H-bond acceptors and hydrophobic pharmacophores might be beneficial to tight CHD1L binding. [0192] Discussion [0193] CHD1L functions at the interface of tumor progression and tumor cell survival, particularly by promoting malignant gene expression, cell cycle progression, inhibition of programed cell death, and promoting the increased invasion and metastatic potential, all of which contribute to multidrug resistance of chemotherapy and targeted therapy in the clinic. Many of these tumorigenic properties have been linked to CHD1L’s role in EMT, where CRC cells gain CSC stemness. Hence, CHD1L inhibition can reduce tumor viability, reverse EMT, and decrease CSC stemness in CRC and potentially other cancers. [0194] Compound 11 is particularly noteworthy as it potently inhibits the target resulting in, EMT reversal, inhibition of stemness, and tumor cell death in metastatic CRC cells and tumor organoids. Furthermore, Compound 11 was stable to metabolic degradation in human and mouse microsomes. In addition to antitumor properties, a small molecule drug capable of eliciting inhibitory effects on tumor progression is desirable for treating aggressive cancers, as it can prevent drug resistance, tissue invasion and metastasis. Example 2: Synthesis of Compounds of Formulas (I)-(III). [0195] General synthesis protocol
Figure imgf000084_0001
[0196] 5 mmol of the selected phenylacetonitrile (Compound 1) was refluxed in excess dimethylformamide dimethyl acetal (DMF-DMA) at 90ºC, monitored by thin layer chromatography (TLC) until completion, which typically occurred within a 1-3 hour timeframe. The resultant reaction mixture was concentrated in vacuo, yielding corresponding dimethylaminoacrylonitrile (Compound 2). Compound 2 was subsequently dissolved in 25 mL of absolute ethanol, treated with 20 mmol hydrazine hydrate, and refluxed at 85ºC. Confirmation of completion was achieved through TLC. The completed reaction mixture was subjected to purification using a CombiFlash NextGen 300+ flash chromatography system with either a hexane-ethyl acetate or chloroform-methanol solvent system, yielding 5-aminopyrazoles (Compound 3) at a 60-85% yield. Subsequently, Compound 3 (6 mmol) was added to 30 mL of absolute ethanol with a few drops of concentrated HCl and 18 mmol of the selected ketoester, then refluxed at 90ºC overnight. The resulting precipitate was filtered and dried in vacuo while being washed with cold ethanol to yield crude pyrazolopyrimidinones (Compound 4). The purification of Compound 4 using flash chromatography led to the final compound (Compound 11) at a yield rate ranging from 45-82%. [0197] Compounds 12 to 48 were synthesized according to the same procedure. [0198] AMDE (Absorption, Distribution, Metabolism, and Excretion) data of example compounds [0199] ADME properties of example compounds disclosed herein can influence the compound's efficacy, dosing, potential side effects, and overall safety profile. The 2D structure of each CHD1Li compound was created using the 2D sketcher and converted to a low-energy 3D model using the LigPrep module (a module in the Schrödinger software suite used for the preparation of small-molecule 3D structures for further analyses) under the OPLS4 (Optimized Potentials for Liquid Simulations) force field. Subsequently, the 3D models were used as inputs in the QikProp module (another module in the Schrödinger software suite that is designed to predict the physicochemical properties and pharmaceutical relevancy of organic molecules) to calculate the ADME properties. [0200] The ADME data of the example compound would provide insights into how it is likely to behave in the body and its potential as a therapeutic agent. The ADME properties of example compounds are listed in Table 5. Table 5. ADME data of example compounds.
Figure imgf000085_0001
[0201] CHD1L Enzyme Inhibition confirmed hits from primary HTS were re-evaluated for their dose dependent inhibition of cat-CHD1L ATPase. Compounds 11-47 displayed relatively potent CHD1L inhibition with IC50 <5 (Table 6 and FIGs.9A-9C). Table 6. Hit to lead validation results of compounds 11-47.
Figure imgf000086_0001
[0202] CHD1L trapping – The ability of the compounds described herein to inhibit CHD1L ATPase activity and consequently trap the protein onto chromatin was examined in SUM194PT cells, as a way to further establish the compounds’ on-target effects. FIGs 10A-10C shows that the representative CHD1Li 30, 32 and 33 effectively traps CHD1L in a dose-dependent manner. [0203] 3D Cytotoxicity – The cell viability of five cancer cell phenotypes upon treatment with CHD1Li 11-47 was also assessed in 3D tumor organoids over a 72 hr time course. The data in Table 6 shows that majority of the tested compounds display single-agent cytotoxicity against the cancer cell lines. Notably, CHD1Li 30, 32 and 33 showed a dose-dependent low micromolar cytotoxicity (IC50 < 4 μM) against colon and breast cancer cells, SW620 and MDA-MB-231, respectively (FIGs 11A-11C). Example 3: Compounds of Formula (IV) and others [0204] General synthesis protocol
Figure imgf000087_0001
[0205] Step 1: 2-chlorobenzo[d]thiazole (Compound 1) (8.0 mmol) was heated in excess propanolamine at 130ºC overnight. After confirming completion of the reaction via TLC analysis, the reaction mixture was concentrated until dryness was achieved. The residue was then dissolved in water (300 mL), made alkaline with saturated NaHCO3 and extracted using ethyl acetate (70 mLx3). Post extraction, the combined ethyl acetate extracts were dried over anhydrous Na2SO4 and concentrated in vacuo, yielding 3-(benzo[d]thiazol-2-ylamino)propan-1- ols (2) in quantitative yields. [0206] Step 2: 300 mg of the propanol intermediate (Compound 2) was dissolved in chloroform (13 mL), followed by the addition of thionyl chloride (1.5 mL) and catalytic amounts of DMF, dropwise. The solution was then refluxed at 70ºC for 4 h, concentrated in vacuo, and the residue washed with diethylether and NaHCO3 solution. Further steps included ethyl acetate (EtOAc) extraction and concentration of the Na2SO4-dried EtOAc extracts, yielding N-(3-chloropropyl)benzo[d]thiazol-2-amines (Compound 3) in up to 83% yields. [0207] Step 3: 3-chloropropyl intermediates (Compound 3), triethylamine (3.3 eq), and cyclic secondary amines were refluxed in THF at 80ºC overnight. The reaction mixture was then concentrated on silica gel and purified by flash chromatography to give the desired benzo[d]thiazol-2-amines (Compound 4) in moderate yields. [0208] Step 4: Substituted phenylacetic acid (1.2 eq) and hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) (1.5 eq) were stirred in DMF at 0ºC for a few minutes then treating it with N,N-diisopropylethylamine (DIPEA) (2.0 eq). Addition of the required benzo[d]thiazol-2-amines 4 (0.505 mmol) followed, and the stirring continued overnight while the reaction mixture warmed up to room temperature. The reaction mixture was subsequently partitioned between water and EtOAc. The organic layer was collected, dried over anhydrous Na2SO4 and concentrated on silica gel for flash chromatography purification. This resulted in the production of the target OTI-900 analogs in moderate yields.
Figure imgf000088_0001
[0209] Step 1: 2-bromothiazole (Compound 1) (1.0 mmol), tryptamine 2 (1.2 eq), and K2CO3 (1.5 eq) were heated in DMF at 85ºC overnight. After the reaction was complete, the mixture was poured into cold water, basified using NaHCO3 and subsequently extracted with EtOAc. The resultant solution then underwent flash chromatographic purification post drying of the EtOAc extracts over Na2SO4. This process yielded N-(2-(1H-indol-3-yl)ethyl)thiazol-2-amines (Compound 3) in quantities up to a 65% yield. [0210] Step 2: The thiazol-2-amines (Compound 3) were transformed into the desired OTI- 1100 analogs by following the method previously described in Step 4. [0211] Hit-to-lead validation experiments Promising hits were examined for their ability to inhibit CSC stemness, using the clonogenic colony formation assay. The mesenchymal phenotype of SW620 cells was selected for the cell- based assays in this validation scheme since it displays enhanced tumorigenic properties, including multidrug resistance and CSC stemness. Therefore, this phenotype has the highest potential for colony formation, metastasis, and represents an aggressive CRC tumor cell model. Finally, top hits from these experiments were evaluated for their metabolic stability in mouse liver microsomes. [0212] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. NUMBERED EMBODIMENTS Embodiment 1. A compound having the structure:
Figure imgf000089_0001
,
Figure imgf000089_0002
, , or
Figure imgf000089_0003
. Embodiment 2. A pharmaceutical composition for treating a cancer comprising: a chromodomain helicase/ATPase DNA binding protein 1-like gene (CDH1L) inhibitor. Embodiment 3. The pharmaceutical composition of embodiment 2, wherein the chemotherapy is effective against colorectal cancer. Embodiment 4. The pharmaceutical composition of embodiment 2, wherein the CHD1L inhibitor has the structure:
Figure imgf000089_0004
, o
Figure imgf000089_0006
Figure imgf000089_0005
r . Embodiment 5. A method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising: a CHD1L inhibitor. Embodiment 6. The method of embodiment 5, wherein the CHD1L inhibitor has the structure:
Figure imgf000089_0007
, or
Figure imgf000089_0008
Embodiment 7. A compound for treating a cancer, wherein the compound binds to an allosteric binding site of CHD1L. Embodiment 8. The compound of embodiment 7, wherein the allosteric binding site comprises a lysine and a glutamate. Embodiment 9.The compound of embodiment 7, wherein the CHD1L comprises a sequence having at least 70% sequence identity to SEQ ID NO: 1. Embodiment 10. The compound of embodiment 7, wherein the CHD1L comprises a sequence of Table 3. Embodiment 11. A method for treating a cancer, comprising administering a compound selected from Table 1, wherein the cancer is a colorectal cancer (CRC).

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I):
Figure imgf000091_0003
Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), - OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, and - (C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Ra; R2 is H or C1-C6 alkyl; L1 is absent or -CH2-*, -O-*, -C(=O)-*, -NH-*, -NHC(=O)-*,
Figure imgf000091_0001
, or
Figure imgf000091_0002
, wherein * indicates a bond to R3; R3 is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -(C1-C6 haloalkyl), - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, C3-C9 carbocycle, C3-C9 heterocycle, wherein the 3- to 9- membered carbocycle or 3- to 9-membered heterocycle are optionally substituted with one or more Rb; X is =O, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or halogen; each Ra and Rb is independently -(C2-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, - O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -(C1-C6 haloalkyl), -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle; wherein: when R1 is phenyl and Ra is -F, Rb is other than -F or -Br, when R1 is -H or phenyl, R3 is other than fluorophenyl, or when R1 is -C(CH3)3, R3 is other than chloro, phenyl, or phenyl substituted with methyl, fluoro, or chloro.
2. The compound of claim 1, wherein the compound is not 5-(tert-butyl)-3-(4- fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.
3. The compound of claim 1 or 2, wherein R3 is substituted with at least one Rb.
4. The compound of any one of claims 1-3, wherein L1 is absent.
5. The compound of claim 4, wherein the compound has the structure of Formula (II):
Figure imgf000092_0001
Formula (II), wherein Ring A is phenyl, pyridinyl, pyrimidyl, furanyl, thiophenyl, and Ring A is optionally substituted with one or more Rb.
6. The compound of claim 5, wherein Ring A is substituted with at least one Rb, wherein each Rb is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1- C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1- C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9- membered heterocycle.
7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein L1 is -NH-*, -NHC(=O)-*,
Figure imgf000092_0003
, or
Figure imgf000092_0002
, wherein * indicates a bond to R3 .
8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R3 is
Figure imgf000093_0001
, wherein Y is S or N, and W is N or C.
9. The compound of claim 8, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Y is S, W is N, and Rb is halogen.
10. The compound of any one of claims 7 to 9, wherein L1-R3 is
Figure imgf000093_0002
, , , ,
Figure imgf000093_0003
, or
Figure imgf000093_0004
11. The compound of any one of claims 1 to 10, wherein R1 is -CH2CH3, -CH(CH3)2, - C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl.
12. The compound of any one of claims claim 8 to 11, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the compound of Formula (I) is
Figure imgf000093_0005
, , ,
Figure imgf000093_0006
, or
Figure imgf000093_0007
.
13. The compound of any one of claims 1-3, wherein the compound is of Formula (III-A):
Figure imgf000094_0001
Formula (III-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, and Ring A is optionally substituted with one or more Rb.
14. The compound of claim 13, wherein Ring A is phenyl.
15. The compound of claim 13 or 14, wherein L1 is -NH-*, -NHC(=O)-*,
Figure imgf000094_0002
,
Figure imgf000094_0003
or , wherein * indicates a bond to R5.
16. The compound of any one of claims 13-15, wherein R1 is -CH2CH3, -CH(CH3)2, - C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl.
17. The compound of claim 16, wherein R1 is phenyl substituted with one or more halogen.
18. The compound of claim 17, wherein the halogen is chloro.
19. The compound of any one of claims 13-18, wherein the compound of Formula (III-A) is:
Figure imgf000094_0004
or
Figure imgf000094_0005
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
20. The compound of any one of claims 1-4, wherein the compound is of Formula (III-B):
Figure imgf000095_0001
Formula (III-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
21. The compound of claim 20, wherein R1 is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), - NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle, or a 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Ra.
22. The compound of claim 21, wherein R1 is -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl, wherein R1 is optionally substituted with one or more Ra.
23. The compound of claim 22, wherein each Ra is independently -OH, -O(C1-C6 alkyl), - (C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1- C6 alkyl)2, or -(C1-C6 alkyl)-NHC(=O)NH2.
24. The compound of claim 23, wherein the compound of Formula (III-B) is: ,
Figure imgf000095_0002
,
Figure imgf000096_0002
, , or
Figure imgf000096_0003
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
25. The compound of claim 1, wherein the compound is:
Figure imgf000096_0001
Figure imgf000097_0002
, , ,
Figure imgf000097_0003
, or
Figure imgf000097_0004
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
26. A compound of Formula (IV):
Figure imgf000097_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Ring B is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle optionally substituted with one or more Rb; each Ra and Rb is independently selected from -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle; Rx is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, - C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, or two Rx are taken together with the C atom to which they are bound to form a 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, wherein each 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Rn, wherein Rn is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2- C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2; m is an integer from 0 to 4; and n is an integer from 0 to 5.
27. The compound of claim 26, wherein when Ring B is
Figure imgf000098_0001
, then Rx is other than pyridinyl.
28. The compound of claim 26 or 27, wherein when Ring B is
Figure imgf000098_0002
and Rx is pyridinyl, then Rx is substituted with one or more Rn.
29. The compound of claim 26 or 27, wherein when Ring B is
Figure imgf000098_0003
and Rx is phenyl, then Rn is other than methoxy.
30. The compound of claim 26 or 27, wherein when Ring B is
Figure imgf000098_0004
and Rx is phenyl, then Rn is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -(C1-C6 alkylene)-OH, - NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, - NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, - C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, - (C1-C6 alkyl)-NHC(=O)NH2.
31. The compound of any one of claims 26-30, wherein when two or more Rx are taken together with the C atom to which they are bound to form
Figure imgf000099_0002
, n is an integer from 1 to 5.
32. The compound of claim 26, wherein the compound is:
Figure imgf000099_0001
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
33. A method of treating a proliferative disease comprising administering a compound, wherein the compound binds to a CHD1L.
34. The method of claim 33, wherein the compound is of any one of claims 26-32.
35. The method of claim 33, wherein the compound has a structure of Formula (V):
Figure imgf000099_0003
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), - OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, -(C1- C6 alkylene)-NH2, 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more Ra; R2 is H or C1-C6 alkyl; L1 is absent or -CH2-*, -O-*, -C(=O)-*, -NH-*, -NHC(=O)-*,
Figure imgf000100_0002
, or
Figure imgf000100_0003
, wherein * indicates a bond to R3; R3 is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, - C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, C3-C9 carbocycle, C3-C9 heterocycle, wherein the 3- to 9-membered carbocycle, 3- to 9-membered heterocycle are optionally substituted with one or more Rb; X is -H, =O, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or halogen; each Ra and Rb is independently -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, - O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1- C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle.
36. The method of claim 33 or 35, wherein the compound is not 5-(tert-butyl)-3-(4- fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.
37. The method of claim 33 or 36, wherein R3 is substituted with at least one Rb.
38. The method of any one of claims 33 to 37, wherein L1 is absent.
39. The method of claim 38, wherein the compound has the structure of Formula (VI):
Figure imgf000100_0001
Formula (VI), wherein Ring A is phenyl, pyridinyl, pyrimidyl, furanyl, thiophenyl, and Ring A is optionally substituted with one or more Rb.
40. The method of claim 39, wherein Ring A is substituted with at least one Rb, wherein each Rb is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1- C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, - NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), -halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1- C6 alkyl)2, -(C1-C6 alkyl)-NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9- membered heterocycle.
41. The method of claim 33 or 36, wherein R1 is H.
42. The method of claim 41, wherein the compound i
Figure imgf000101_0001
.
43. The method of any one of claims 33 to 37, wherein L1 is -NH-*, -NHC(=O)-*, , or , wherei 3
Figure imgf000101_0002
Figure imgf000101_0003
n * indicates a bond to R .
44. The method of any one of claims 33 to 38, wherein R3 is
Figure imgf000101_0004
, wherein Y is S or N, and W is N or C.
45. The method of claim 44, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Y is S, W is N, and Rb is halogen.
46. The method of any one of claims 43 to 45, wherein L1-R3 is
Figure imgf000101_0005
, , , ,
Figure imgf000101_0006
, or
Figure imgf000101_0007
47. The method of any one of claims 33 to 46, wherein R1 is -CH2CH3, -CH(CH3)2, - C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl.
48. The method of any one of claims claim 26 to 47, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the compound of Formula (V) is
Figure imgf000102_0002
, ,
Figure imgf000102_0003
, or
Figure imgf000102_0004
.
49. The method of claim 33, wherein the compound is of Formula (VII):
Figure imgf000102_0001
Formula (VII), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, and Ring A is optionally substituted with one or more Rb, and wherein X is =O or -OH.
50. The method of claim 49, wherein Ring A is phenyl.
51. The method of claim 49 or 50, wherein L1 is -NH-*, -NHC(=O)-*,
Figure imgf000103_0001
, or
Figure imgf000103_0002
, wherein * indicates a bond to R5.
52. The method of any one of claims 49 to 51, wherein R1 is -CH2CH3, -CH(CH3)2, - C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl.
53. The method of claim 52, wherein R1 is H.
54. The method of claim 52, wherein R1 is phenyl or pyridinyl.
55. The method of claim 52, wherein R1 is phenyl or pyridinyl substituted with one or more halogen.
56. The method of claim 55, wherein the halogen is chloro.
57. The method of any one of claims 40-43 and 46-54, wherein Rb is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, -NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -(C1-C6 alkyl)- NHC(=O)NH2, 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle.
58. The method of any one of claims 49 to 57, wherein Rb is -(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(=O)H, - NHC(=O)(C1-C6 alkyl), -NO2, halogen, -C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, phenyl, thiazolyl, pyrazolyl, or furanyl.
59. The method of any one of claims 49 to 58, wherein the compound of Formula (VII) is:
Figure imgf000103_0003
, , ,
Figure imgf000104_0001
Figure imgf000105_0002
, , ,
Figure imgf000105_0003
, or
Figure imgf000105_0004
or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
60. The method of any one of claims 33 to 39, wherein the compound is of Formula (IX):
Figure imgf000105_0001
Formula (IX), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
61. The method of claim 60, wherein R1 is -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, 3- to 9-membered carbocycle, or a 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9- membered heterocycle is optionally substituted with one or more Ra.
62. The method of claim 61, wherein R1 is -CH2CH3, -CH(CH3)2, -C(CH3)3, -phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, tetrahydropyrrolyl, thiophenyl, wherein R1 is optionally substituted with one or more Ra.
63. The method of claim 62, wherein Ra is -OH, -O(C1-C6 alkyl), -(C1-C6 alkylene)-OH, - NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NHC(=O)H, - NHC(=O)(C1-C6 alkyl), -NO2, -CN, -SCN, -SH, -S(C1-C6 alkyl), halogen, -C(=O)OH, - C(=O)O(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, or - (C1-C6 alkyl)-NHC(=O)NH2.
64. The method of claim 60, wherein the compound of Formula (IX) is:
Figure imgf000106_0001
, , ,
Figure imgf000106_0002
, , or
Figure imgf000106_0003
, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
65. A method of treating a proliferative disease or disorder comprising administering a compound of any one of Formulas (I)-(IV) to a subject in need thereof.
66. A method of decreasing tumor cell viability comprising administering to the tumor cell a compound of any one of Formulas (I)-(IX).
67. The method of claim 65 or 66, the method comprising measuring an average tumor cell size.
68. The method of any one of claims 65 to 67, wherein administering the compound of any one of Formulas (I)-(IX) reduces an average tumor cell size by about 10% to about 100%.
69. The method of any one of claims 65 to 68, wherein the proliferative disease comprises a T cell factor (TCF)-driven cancer.
70. The method of claim 69, wherein the method comprises inhibiting chromatin helicase DNA-binding protein 1-like (CHD1L).
71. The method of claim 70, wherein the inhibiting of CHD1L comprises determining a loss of ATPase activity.
72. The method of claim 71, wherein the determining comprises performing an ATPase activity assay.
73. The method of any one of claims 65 to 72, wherein the method comprises trapping CHD1L onto chromatin.
74. The method of claim 73, wherein the trapping comprises increasing an amount of CHD1L by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6- fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold.
75. The method of any one of claims 69 to 74, wherein the TCF-driven cancer comprises colorectal cancer or metastatic colorectal cancer.
76. A method of reducing catalytic activity of a CHD1L comprising contacting the CHD1L with a compound of any one of Formulas (I)-(IX).
77. The method of claim 76, wherein the catalytic activity of the CHD1L is an ATPase activity.
78. The method of claim 76 or 77, wherein the catalytic activity of the CHD1L is reduced by about 10% to about 90%.
79. The method of any one of claims 76 to 78, wherein the catalytic activity is measured by an ATPase assay.
80. The method of any one of claims 76 to 79, wherein the compound is: ,
Figure imgf000107_0001
, , ,
Figure imgf000108_0001
,
Figure imgf000109_0001
, , ,
Figure imgf000109_0003
Figure imgf000109_0002
, or , or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
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Publication number Priority date Publication date Assignee Title
WO2021195279A2 (en) * 2020-03-24 2021-09-30 The Regents Of The University Of Colorado, A Body Corporate Small molecule inhibitors of oncogenic chd1l with preclinical activity against colorectal cancer
WO2023055763A2 (en) * 2021-09-30 2023-04-06 The Regents Of The University Of Colorado, A Body Corporate Small molecule inhibitors of oncogenic chd1l with preclinical activity against colorectral cancer
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WO2021195279A2 (en) * 2020-03-24 2021-09-30 The Regents Of The University Of Colorado, A Body Corporate Small molecule inhibitors of oncogenic chd1l with preclinical activity against colorectal cancer
US20230103444A1 (en) * 2020-03-24 2023-04-06 The Regents Of The University Of Colorado, A Body Corporate Small molecule inhibitors of oncogenic chd1l with preclinical activity against colorectal cancer
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