Methods for treating cancer

Abstract

This disclosure provides compounds of Formula (I) or Formula (II), and pharmaceutically acceptable salts of either of the foregoing, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and / or symptoms and / or progression of the disease (e.g., cancer) in a subject (e.g., a human).

Description

[0001] METHODS FOR TREATING CANCER

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 667,463, filed on July 3, 2024, which is hereby incorporated by reference in its entirety.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named 50006-0139W01_ST26_SL.XML.” The XML file, created on July 2, 2025, is 2,257 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] FIELD

[0007] This disclosure provides compounds of Formula (I), Formula (II), and pharmaceutically acceptable salts of either of the foregoing, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and / or symptoms and / or progression of the disease (e.g., cancer) in a subject (e.g., a human).

[0008] BACKGROUND

[0009] The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242). The great majority of TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation (2018) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both classes of mutations prevent p53-driven transcriptional activation, thus abrogating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).

[0010] Reactivation of the mutant p53 protein emerges as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). Theoretically, mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53'1220Cmutation occurs in~l% of human cancers; -100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and / or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74). In some instances, such as the Y200C mutation, there is a small molecule binding pocket far away from the binding interface between p53 and DNA, such that small molecule engagement at this pocket will not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504).

[0011] SUMMARY

[0012] Some embodiments provide a compound of Formula (I) or a compound of Formula (II): or a pharmaceutically acceptable salt of either of the foregoing, wherein:

[0013] X1is N or CR1;

[0014] X2is N or CH;

[0015] X3is N or CR3; X4is N or CR4;

[0016] Ring A is optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0017] Ring B is an optionally substituted 5-6 membered heteroaryl or optionally substituted C6- C10 aryl;

[0018] R1, R3, and R4are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0019] R2and R6are independently hydrogen or C1-C6 alkyl;

[0020] L is an optionally substituted C2-C6 alkynylene, optionally substituted 4-6 membered heterocylylene, or optionally substituted 5-6 membered heteroarylene;

[0021] L1is an optionally substituted C2-C12 alkylene or an optionally substituted 2-12 membered heteroalkylene, wherein 0-2 methylene units of the alkylene or heteroalkylene are independently replaced by RL1; each RL1is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclylene, an optionally substituted C6-C10 arylene, or an optionally substituted 5-10 membered heteroarylene; m is 0, 1, or 2; and

[0022] R5is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C4 cycloalkyl optionally substituted with 1-2 independently selected halogen.

[0023] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, and one or more pharmaceutically acceptable excipients.

[0024] Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein.

[0025] Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein.

[0026] Provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein.

[0027] This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein.

[0028] Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein.

[0029] This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein.

[0030] Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.

[0031] This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing.

[0032] Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions

[0033] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0034] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0035] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0036] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein.

[0037] The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe etal., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. ; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed:, Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0038] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as di cyclohexyl amine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0039] As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the cancer to be treated.

[0040] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0041] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. A group can also be denoted as having particular number of such substituents, for example, monosubstituted, di substituted, tri substituted, and the like. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O-carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, ureido, -C(=0)(NR’)-S(02)R”, -C(=0)(NR’)-S(02)-NR”R”, and -S(02)-(NR’)(C=0)R”, wherein R’ is hydrogen or alkyl, and R” is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (T).

[0042] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0043] The term "hydroxyl" refers to an -OH radical.

[0044] The term “sulfhydryl” refers to a -SH radical.

[0045] The term "cyano" refers to a -CN radical.

[0046] The term “azido” refers to a -N3 radical.

[0047] The term “nitro” refers to a -NO2 radical.

[0048] The term “nitroso” refers to a -N=O radical.

[0049] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Cl -CIO indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, zso-propyl, tert-butyl, zz-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0050] The term “acyl” refers to a -C(=O)alkyl radical (e.g., acetyl), or a -C(=O)alkenyl radical

[0051] (e g., -C(=O)-CH=CH2), or -C(=O)alkynyl radical (e g., ). Acyl groups can be substituted with cyano or with 1-3 independently selected halogens. As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.

[0052] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.

[0053] The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0054] The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l. l. l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0055] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotri azolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-t7]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4- / >]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3- / >]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[ ][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[Z>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more

[0056] N_| imidazolone (e.g., ’ ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0057] The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam or phosphinane oxide) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S- di oxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1- 2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[l. l.l]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1 ,0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[l. l.l]pentane, 3- oxabicyclo[3.1 ,0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3- oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7- oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5] octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like.

[0058] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0059] The term “alkylene” refers to a divalent radical derived from an alkyl group, as described herein.

[0060] The term “heteroalkylene” refers to a divalent radical derived from an alkyl group, as described herein, wherein at least one carbon atom in the alkyl chain is replaced with a heteroatom. Heteroalkylene groups include, but are not limited to glycols such as ethylene and propylene glycols, aminoglycols, and the like.

[0061] The term “cycloalkylene” refers to a divalent radical derived from a cycloalkyl group, as described herein.

[0062] The term “alkynylene” refers to a divalent radical derived from an alkynyl group, as described herein.

[0063] The term “arylene” refers to a divalent radical derived from an aryl group, as described herein.

[0064] The term “heteroarylene” refers to a divalent radical derived from a heteroaryl group, as described herein.

[0065] The term “heterocyclylene” refers to a divalent radical derived from a heterocyclyl group, as described herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0066] The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0067] The term “hydroxy lkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

[0068] The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0069] The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0070] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0071] The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy (e.g., methoxy ethyl).

[0072] The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with hydroxy.

[0073] The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy.

[0074] The term “alkoxyamino” refers to an -O-amino radical (e.g., -OCH2CH2N(CH3)2).

[0075] The term “haloalkoxy” refers to an -O-haloalkyl radical (e g., -OCF3).

[0076] The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl).

[0077] The term “haloalkenoxy” refers to an -O-haloalkenyl radical.

[0078] The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl).

[0079] The term “haloalkynoxy” refers to an -O-haloalkynyl radical.

[0080] The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).

[0081] The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy).

[0082] The term “heteroaryl oxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy).

[0083] The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or -O-oxetanyl).

[0084] The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl). The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).

[0085] The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).

[0086] The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyl oxetanyl).

[0087] The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e g., benzyloxy).

[0088] The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).

[0089] The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).

[0090] A “sulfenyl” group refers to an -SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0091] A “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen (e.g., -S(CF3) or -S(CHF2)).

[0092] A “sulfinyl” group refers to an -S(=O)R group in which R can be the same as defined with respect to sulfenyl.

[0093] A “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl.

[0094] A “sulfoximine” group refers to an -S(=O)(=NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0095] A “sulfonimidamido” group refers to an -S(=O)(=NR)NR’R” where R, R’, and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclyl alkyl, or cycloalkylalkyl.

[0096] An “O-carboxy” group refers to a RC(=O)O- group in which R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0097] The terms “ester” and “C-carboxy” refer to a -C(=O)OR group in which R can be the same as defined with respect to O-carboxy.

[0098] A “thiocarbonyl” group refers to a -C(=S)R group in which R can be the same as defined with respect to O-carboxy.

[0099] A “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen.

[0100] A “trihalomethanesulfonamido” group refers to an X3CS(O)2N(R’)- group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0101] An “S-sulfonamido” group refers to a -S02N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0102] An “N-sulfonamido” group refers to a RSC>2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0103] An “O-carbamyl” group refers to a -OC(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0104] An “N-carbamyl” group refers to an ROC(=O)N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0105] An “O-thiocarbamyl” group refers to a -OC(=S)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0106] An “N-thiocarbamyl” group refers to an ROC(=S)N(R’) — group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0107] A “C-amido” group refers to a -C(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkyl alkyl.

[0108] An “N-amido” group refers to a RC(=O)N(R’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0109] The terms “ureido” or “urea” refer to an -NR(C=O)NR’R” group, in which R, R’, and R” are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0110] The term “carboxaldehyde” refers to a -C(=O)H radical.

[0111] The term “imine” or “imino” refers to a -N=R radical, in which R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0112] The term “amino” refers to a -NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some instances, an amino group is -NH2, a mono-alkyl amine (R is hydrogen and R’ is alkyl) or a dialkylamine (R and R’ are independently selected alkyl).

[0113] The term “phosphine oxide” refers to a -P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0114] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms

[0115] (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., (ii) a a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

[0116] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0117] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses thetautomeric form containing the moiety: Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0118] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0119] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0120] DETAILED DESCRIPTION

[0121] This disclosure provides compounds of Formula (I), Formula (II), and pharmaceutically acceptable salts of either of the foregoing, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and / or symptoms and / or progression of the disease (e.g., cancer) in a subject (e.g., a human).

[0122] Formulae (I) and (IT) Compounds

[0123] Some embodiments provide a compound of Formula (I) or a compound of Formula (II): or a pharmaceutically acceptable salt of either of the foregoing, wherein:

[0124] X1is N or CR1;

[0125] X2is N or CH;

[0126] X3is N or CR3; X4is N or CR4;

[0127] Ring A is optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0128] Ring B is an optionally substituted 5-6 membered heteroaryl or optionally substituted C6- C10 aryl;

[0129] R1, R3, and R4are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0130] R2and R6are independently hydrogen or C1-C6 alkyl;

[0131] L is an optionally substituted C2-C6 alkynylene, optionally substituted 4-6 membered heterocylylene, or optionally substituted 5-6 membered heteroarylene;

[0132] L1is an optionally substituted C2-C12 alkylene or an optionally substituted 2-12 membered heteroalkylene, wherein 0-2 methylene units of the alkylene or heteroalkylene are independently replaced by RL1; each RL1is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclylene, an optionally substituted C6-C10 arylene, or an optionally substituted 5-10 membered heteroarylene; m is 0, 1, or 2; and

[0133] R5is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C4 cycloalkyl optionally substituted with 1-2 independently selected halogen.

[0134] In some embodiments, X1is N.

[0135] In some embodiments, X1is CR1.

[0136] In some embodiments, R1is hydrogen.

[0137] In some embodiments, R1is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0138] In some embodiments, R1is halogen. In some embodiments, R1is fluoro or chloro.

[0139] In some embodiments, R1is cyano.

[0140] In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is C1-C3 alkyl. In some embodiments, R1is methyl. In some embodiments, R1is C1 -C6 haloalkyl. In some embodiments, R1is C1-C3 haloalkyl. In some embodiments, R1is C1-C6 trifluoroalkyl. In some embodiments, R1is difluoromethyl or trifluoromethyl.

[0141] In some embodiments, R1is C1-C6 alkoxy. In some embodiments, R1is C1-C3 alkoxy. In some embodiments, R1is methoxy.

[0142] In some embodiments, R1is C1-C6 haloalkoxy. In some embodiments, R1is C1-C3 haloalkoxy. In some embodiments, R1is C1-C6 trifluoroalkoxy. In some embodiments, R1is trifluoromethoxy.

[0143] In some embodiments, X2is N.

[0144] In some embodiments, X2is CH.

[0145] In some embodiments, X3is N.

[0146] In some embodiments, X3is CR3.

[0147] In some embodiments, R3is hydrogen.

[0148] In some embodiments, the R3is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0149] In some embodiments, R3is halogen. In some embodiments, R3is fluoro or chloro.

[0150] In some embodiments, R3is cyano.

[0151] In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is C1-C3 alkyl. In some embodiments, R3is methyl.

[0152] In some embodiments, R3is C1-C6 haloalkyl. In some embodiments, R3is C1-C3 haloalkyl. In some embodiments, R3is C1-C6 trifluoroalkyl. In some embodiments, R3is difluoromethyl or trifluoromethyl.

[0153] In some embodiments, R3is C1-C6 alkoxy. In some embodiments, R3is C1-C3 alkoxy. In some embodiments, R3is methoxy.

[0154] In some embodiments, R3is C1-C6 haloalkoxy. In some embodiments, R3is C1-C3 haloalkoxy. In some embodiments, R3is C1-C6 trifluoroalkoxy. In some embodiments, R3is trifluoromethoxy.

[0155] In some embodiments, the X4is N.

[0156] In some embodiments, the X4is CR4.

[0157] In some embodiments, the R4is hydrogen. In some embodiments, the R4is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0158] In some embodiments, R4is halogen. In some embodiments, R4is fluoro or chloro.

[0159] In some embodiments, R4is cyano.

[0160] In some embodiments, R4is C1-C6 alkyl. In some embodiments, R4is C1-C3 alkyl. In some embodiments, R4is methyl.

[0161] In some embodiments, R4is C1-C6 haloalkyl. In some embodiments, R4is C1-C3 haloalkyl. In some embodiments, R4is C1-C6 trifluoroalkyl. In some embodiments, R4is difluoromethyl or trifluoromethyl.

[0162] In some embodiments, R4is C1-C6 alkoxy. In some embodiments, R4is C1-C3 alkoxy. In some embodiments, R4is methoxy.

[0163] In some embodiments, R4is C1-C6 haloalkoxy. In some embodiments, R4is C1-C3 haloalkoxy. In some embodiments, R4is C1-C6 trifluoroalkoxy. In some embodiments, R4is tri fluoromethoxy .

[0164] In some embodiments, each of R1, R3, and R4are hydrogen.

[0165] In some embodiments, Ring A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, Ring A is an optionally substituted C4-C8 cycloalkyl. In some embodiments, Ring A is an optionally substituted cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring A is an optionally substituted cyclohexyl.

[0166] In some embodiments, Ring A is a C3-C10 cycloalkyl. In some embodiments, Ring A is a C4-C8 cycloalkyl. In some embodiments, Ring A is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring A is cyclohexyl.

[0167] In some embodiments, Ring A is an optionally substituted C6-C10 aryl. In some embodiments, Ring A is phenyl.

[0168] In some embodiments, Ring A is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, Ring A is an optionally substituted 4-10 membered heterocyclyl. In some embodiments, Ring A is an optionally substituted 5-6 membered heterocyclyl. In some embodiments, Ring A is an optionally substituted piperidinyl.

[0169] In some embodiments, Ring A is a 3-12 membered heterocyclyl. In some embodiments, Ring A is a 4-10 membered heterocyclyl. In some embodiments, Ring A a 5-6 membered heterocyclyl. In some embodiments, Ring A is piperidinyl. In some embodiments, Ring A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, Ring A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, Ring A is an optionally substituted ring selected from: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatri azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0170] In some embodiments, Ring A is a 5-10 membered heteroaryl. In some embodiments, Ring A is a 5-6 membered heteroaryl. In some embodiments, Ring A is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatri azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0171] In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, Ring B is an optionally substituted ring selected from the group consisting of optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, Ring B is an optionally substituted pyridinyl. In some embodiments, Ring B is an optionally substituted pyrimidinyl.

[0172] In some embodiments, Ring B is a 5-6 membered heteroaryl. In some embodiments, Ring B is selected from the group consisting of optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, Ring B is pyridinyl. In some embodiments, Ring B is pyrimidinyl.

[0173] In some embodiments, Ring B is an optionally substituted C6-C10 aryl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is an optionally substituted phenyl.

[0174] In some embodiments, R2is hydrogen.

[0175] In some embodiments, R2is C1-C6 alkyl. In some embodiments, R2is C1-C3 alkyl. In some embodiments, R2is methyl.

[0176] In some embodiments, R6is hydrogen. In some embodiments, R6is C1 -C6 alkyl. In some embodiments, R6is C1-C3 alkyl. In some embodiments, R6is methyl.

[0177] In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is an optionally substituted C2-C4 alkynylene. In some embodiments, L is an optionally substituted C3 alkynylene.

[0178] In some embodiments, L is a C2-C6 alkynylene. In some embodiments, L is aC2-C4 alkynylene. In some embodiments, L is a C3 alkynylene.

[0179] In some embodiments, L is an optionally substituted 4-6 membered heterocylylene. In some embodiments, the L is a 4-6 membered heterocylylene. In some embodiments, the L is a 4 membered heterocylylene.

[0180] In some embodiments, L is an optionally substituted 5-6 membered heteroarylene. In some embodiments, L is an optionally substituted ring selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatri azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0181] In some embodiments, L is a 5-6 membered heteroarylene. In some embodiments, L is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatri azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. represents a bond to either the carbon of the 5-membered ring of

[0182] Formula (I) or Formula (II) or the CH2 or N of Formula (I) or Formula (II). In some embodiments, L is a 2,5-(l,3,4-oxadiazolyl)ene, a 2,5-(l,3,4-thiadiazolyl)ene, or a 3,5-(l,2,4-oxadiazolyl)ene.

[0183] In some embodiments, L1is an optionally substituted C2-C12 alkylene, wherein 0-2 methylene units of the alkylene are independently replaced by RL1. In some embodiments, L1is an optionally substituted C2-C12 alkylene, wherein 1-2 methylene units of the alkylene are independently replaced by RL1. In some embodiments, L1is an optionally substituted C2-C12 alkylene.

[0184] In some embodiments, L1is a C2-C12 alkylene, wherein 0-2 methylene units of the alkylene are independently replaced by RL1. In some embodiments, L1is a C2-C12 alkylene, wherein 1-2 methylene units of the alkylene are independently replaced by RL1. In some embodiments, L1is a C2-C12 alkylene.

[0185] In some embodiments, L1is an optionally substituted 2-12 membered heteroalkylene, wherein 0-2 methylene units of the heteroalkylene are independently replaced by RL1. In some embodiments, L1is an optionally substituted 4-10 membered heteroalkylene, wherein 0-2 methylene units of the heteroalkylene are independently replaced by RL1. In some embodiments, L1is an optionally substituted 2-12 membered heteroalkylene, wherein 1-2 methylene units of the heteroalkylene are independently replaced by RL1. In some embodiments, L1is an optionally substituted 2-12 membered heteroalkylene.

[0186] In some embodiments, L1is a 2-12 membered heteroalkylene, wherein 0-2 methylene units of the heteroalkylene are independently replaced by RL1. In some embodiments, L1is a 4-10 membered heteroalkylene, wherein 0-2 methylene units of the heteroalkylene are independently replaced by RL1. In some embodiments, L1is a 2-12 membered heteroalkylene, wherein 1-2 methylene units of the heteroalkylene are independently replaced by RL1. In some embodiments, L1is a 2-12 membered heteroalkylene.

[0187] In some embodiments, L1comprises 1-3 PEG units. In some embodiments, L1consists of 1-3 PEG units. In some embodiments, L1comprises 1-3 PEG units wherein 1 or 2 methylene units are independently replaced by RL1.

[0188] In some embodiments, RL1is indpendently an optionally substituted C3-C10 cycloalkylene. In some embodiments, RL1is indpendently an optionally substituted C3-C6 cycloalkylene. In some embodiments, RL1is indpendently a C3-C10 cycloalkylene. In some embodiments, RL1is indpendently a C3-C6 cycloalkylene. In some embodiments, RL1is an optionally substituted 4-12 membered heterocyclylene. In some embodiments, RL1is an optionally substituted 4-6 membered heterocyclylene. In some embodiments, RL1is a 4-12 membered heterocyclylene. In some embodiments, RL1a 4-6 membered heterocyclylene.

[0189] In some embodiments, RL1is an optionally substituted C6-C10 arylene. In some embodiments, RL1is a C6-C10 arylene. In some embodiments, RL1is an optionally substituted phenylene. In some embodiments, RL1is phenylene.

[0190] In some embodiments, the RL1is an optionally substituted 5-10 membered heteroarylene. In some embodiments, the RL1is an optionally substituted 5-6 membered heteroarylene. In some embodiments, the RL1is a 5-10 membered heteroarylene. In some embodiments, the RL1is a5-6 membered heteroarylene.

[0191] In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is C1-C3 alkyl. In some embodiments, R5is methyl.

[0192] In some embodiments, R5is C1-C6 haloalkyl. In some embodiments, R5is C1-C3 haloalkyl. In some embodiments, R3is C1-C3 fluoroalkyl. In some embodiments, R5is -CHF2, -CH2F, or -CF3. In some embodiments, R3is -CHF2. In some embodiments, R3is - CH2F. In some embodiments, R3is -CF3.

[0193] In some embodiments, R5is C3-C4 cycloalkyl optionally substituted with 1-2 independently selected halogen. In some embodiments, R3is C3-C4 cycloalkyl substituted with 1-2 independently selected halogen. In some embodiments, R5is C3-C4 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R5is C3-C4 cycloalkyl.

[0194] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0195] In some embodiments, R2is hydrogen, R6is hydrogen, R5is -CF3, Ring A is an optionally substituted cyclohexyl, and Ring B is an optionally substituted phenyl. In some embodiments, R2is hydrogen, R6is hydrogen, R5is -CF3, Ring A is a monosubstituted cyclohexyl, and Ring B is a monosubstituted phenyl. In some embodiments, R2is hydrogen, R6is hydrogen, R?is -CF3, Ring A is an optionally substituted piperidinyl, and Ring B is an optionally substituted phenyl. In some embodiments, R2is hydrogen, R6is hydrogen, R5is -CF3, Ring A is a monosubstituted piperidinyl, and Ring B is a monosubstituted phenyl. In some embodiments, each of X1, X2, X3, and X4are independently N or CH. In some embodiments, one of X1, X2, X3, and X4is N and the other of X1, X2, X3, and X4are CH. In some embodiments, two of X1, X2, X3, and X4are N and the other of X1, X2, X3, and X4are CH. In some embodiments, three of of X1, X2, X3, and X4are N and the other of X1, X2, X3, and X4is CH. In some embodiments, each of X1, X2, X3, and X4are CH. In some embodiments, each of X1, X2, X3, and X4are CH, R2is hydrogen, R6is hydrogen,

[0196] R5is -CF3, Ring A is an optionally substituted cyclohexyl, and Ring B is an optionally substituted phenyl. In some embodiments, each of X1, X2, X3, and X4are CH, R2is hydrogen, R6is hydrogen, R5is -CF3, Ring A is a monosubstituted cyclohexyl, and Ring B is a monosubstituted phenyl.

[0197] In some embodiments, each of X1, X2, X3, and X4are CH, R2is hydrogen, R6is hydrogen, R5is -CF3, Ring A is an optionally substituted piperidinyl, and Ring B is an optionally substituted phenyl. In some embodiments, each of X1, X2, X3, and X4are CH, R2is hydrogen, R6is hydrogen, R is -CF3, Ring A is a monosubstituted piperidinyl, and Ring B is a monosubstituted phenyl.

[0198] In some embodiments, the compound is a compound of Formula (I):

[0199] In some embodiments, the compound is a compound of Formula (I-A):

[0200] In some embodiments, the compound is a compound of Formula (I-B):

[0201] In some embodiments, the compound is a compound of Formula (I-C):

[0202] In some embodiments, the compound is a compound of Formula (I-D): In some embodiments, the compound is a compound of Formula (I-E):

[0203] In some embodiments, the compound is a compound of Formula (II):

[0204] In some embodiments, the compound is a compound of Formula (II-A):

[0205] In some embodiments, the compound is a compound of Formula (II-B): In some embodiments, the compound is a compound of Formula (II-C) :

[0206] In some embodiments, the the compound is a compound of Formula (II-D):

[0207] In some embodiments, the compound is a compound of Formula (II-E):

[0208] Non-Limiting Exemplary Compounds

[0209] In some embodiments, the compound is selected from the group consisting of the compounds described in Table A, or a pharmaceutically acceptable salt thereof. Table A

[0210]

[0211]

[0212]

[0213]

[0214] Pharmaceutical Compositions

[0215] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I) or a compound of Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, and one or more pharmaceutically acceptable excipients.

[0216] Methods of Treatment

[0217] Provided herein are methods for restoring p53 function, encoded by TP53 gene. For example, provided herein are compounds that restore p53 function that are useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53-associated disease), such as cancer (e.g., p53-associated cancer).

[0218] The terms “restore” or “restoration of’ means to increase the activity and / or function of the specified target by a measurable amount. For example, restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound.

[0219] The ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and / or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by ECso value. A compound with a lower ECso value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher ECso value. Indications

[0220] Compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salt of either of the foregoing, are useful for treating diseases which can be treated with a p53 restorer, such as p53 -associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53 -associated disease or disorder is Li-Fraumeni syndrome.

[0221] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the cancer is a p53-associated cancer.

[0222] Some embodiments provide a method of treating a p53 -associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the p53-associated cancer harbors a Y220C mutation.

[0223] Some embodiments provide a method of treating a p53 -associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds of Table A, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation.

[0224] Some embodiments provide a method of treating cancer in a subj ect that has been identified or diagnosed as having a p53-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing.

[0225] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53 -associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing,.

[0226] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing.

[0227] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing.

[0228] In some embodiments, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, is administered prophylactically to a subject with Li- Fraumeni syndrome. In some embodiments, a therapeutically effective amount of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, is administered prophylactically to a subject with Li-Fraumeni syndrome.

[0229] The term “p53 -associated disease” as used herein refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein). Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer).

[0230] The term “p53 -associated cancer” as used herein refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein.

[0231] The term “wild type” or “wild-type” describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein.

[0232] Provided herein is a method of treating cancer (e.g., a p53-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I) or Formula (IT), or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions / point mutations / insertions. Non-limiting examples of p53 protein substitutions / insertions / deletions are described in Table 1.

[0233] In some embodiments, the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y. In some embodiments, the p53 protein substitution / insertion / deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof. In some embodiments, the p53 protein substitution / insertion / deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution / insertion / deletion is Y220C. In some embodiments, the p53 protein substitution / insertion / deletion is Y220S.

[0234] In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation. In some embodiments, the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation.

[0235] Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPE AAPP VAPAPAAPTP AAPAPAP S WPL S S S VP SQKTYQGS YGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAG KEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

[0236] In some embodiments, compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salt of either of the foregoing, are useful for treating a cancer that has been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing.

[0237] Also provided herein are methods for treating a subject identified or diagnosed as having a p53 -associated cancerthat include administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer.

[0238] Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a p53-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer.

[0239] Also provided is a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition thereof, for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53 -associated cancer.

[0240] Also provided is a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53-associated cancer. In some embodiments, a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a p53 -associated cancer includes those described herein and known in the art.

[0241] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a p53-associated cancer. In some embodiments, provided herein are methods for treating a p53 -associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations / insertions / deletions, as described herein. In some embodiments, the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency -approved, e.g., FDA-approved, assay or kit.

[0242] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.

[0243] Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, to a subject having a cell having aberrant p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53- associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein.

[0244] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition thereof as defined herein.

[0245] Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, in an amount effective to increase tumor cell death.

[0246] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from a hematological cancer and a solid tumor.

[0247] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a hematological cancer. In some embodiments, the hematological cancer is a leukemia. In some embodiments, the hematological cancer is a lymphoma. In some embodiments, the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the hematological cancer is acute myeloid leukemia (AML).

[0248] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a solid tumor.

[0249] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.

[0250] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer.

[0251] In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.

[0252] In some embodiments, the bladder cancer is bladder urothelial carcinoma.

[0253] In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.

[0254] In some embodiments, the skin cancer is cutaneous melanoma.

[0255] In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma. In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.

[0256] In some embodiments, the breast cancer is breast invasive ductal carcinoma.

[0257] In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.

[0258] In some embodiments, the ovarian cancer is serous ovarian cancer.

[0259] In some embodiments, the kidney cancer is chromophobe renal cell carcinoma.

[0260] In some embodiments, the colorectal cancer is colon adenocarcinoma.

[0261] In some embodiments, the liver cancer is hepatocellular carcinoma.

[0262] In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

[0263] In some embodiments, the cancer is prostate cancer.

[0264] In some embodiments of any of the methods or uses described herein, the p53-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53 -associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is lung cancer.

[0265] In some embodiments of any of the methods or uses described herein, the p53-associated cancer is selected from the cancers described in Table 1.

[0266] Table 1. p53 Protein Amino Acid Substitutions / Insertions / DeletionsA

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298] AUnless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pll (2013).

[0299] Combinations

[0300] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies, or combinations of any of the foregoing. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), Formula (II), or pharmaceutically acceptable salts thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action. In some embodiments, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0301] In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject has undergone prior therapy. In some embodiments, a subject is naive to p53 restoration therapy. In some embodiments, a subject is not naive to p53 restoration therapy. In some embodiments, a subject is kinase inhibitor naive. In some embodiments, a subject is not kinase inhibitor naive.

[0302] In some embodiments of any the methods described herein, the compound of Formula (I) or Formula (II) (or a pharmaceutically acceptable salt of either of the foregoing) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein. For example, in some embodiments, the compound of Formula (I) or Formula (II) (or a pharmaceutically acceptable salt of either of the foregoing) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein. Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4 / 6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK / ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), antiandrogens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.

[0303] In some embodiments, the CDK4 / 6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELA™, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.

[0304] In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BAL VERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD 173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB 1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SMI -71, TG 100801, FGFR1 inhibitor-6, or TG 100572.

[0305] In some embodiments, the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440.

[0306] In some embodiments, the NTRK / ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005),

[0307] In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride). In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS- 172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).

[0308] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyryl shikonin, acetylshikonin, P,P-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM- 151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0309] Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPL504, PF299, pelitinib, S- 22261 1, and AEE-788. A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway such as RAS (e.g, KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g, the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g, kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K / AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g, the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.

[0310] Non-limiting examples of a KRAS-targeted therapeutic agents (e.g, KRAS inhibitors) include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, IDQ443, and adagrasib (MRTX-849).

[0311] Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

[0312] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof. In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-1 le, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5 -iodotuberci din, GDC0994, ONC201, or a combination thereof.

[0313] In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI- 103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

[0314] In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3 -phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SRI 3668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3 -fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0315] In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.

[0316] In some embodiments, a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVEN™), or combinations thereof. In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.

[0317] In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.

[0318] In some embodiments, the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing. In some embodiments, the antimetabolite is methotrexate, pemetrexed, or 5-FU.

[0319] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

[0320] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.

[0321] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.

[0322] Non-limiting examples of P ARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289.

[0323] Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[0324] Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).

[0325] Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®) In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IB 1308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol. 11: 39 (2018).

[0326] In some embodiments, the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing.

[0327] In some embodiments, additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and / or as palliative therapy, for example, opioids and corticosteroids.

[0328] EXAMPLES

[0329] Compound Preparation

[0330] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0331] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0332] The compounds described herein can be synthesized, for example, using the following procedures, using different coupling partners from diversifiable Intermediate 1, Intermediate 2, and Intermediate 3 or the like in the schemes below.

[0333] Synthesis of Compound 30 Synthesis of Compound 25

[0334] Synthesis of Compound 28

[0335] Synthesis of Compound 26

[0336] Synthesis of Compound 12

[0337] Assays Surface Plasmon Resonance (SPR) Assay Protocol

[0338] SPR experiments are performed on a Biacore 8K instrument. Biotinylated recombinant p53 Y220C mutant protein (amino acid residues 94-293) is immobilized onto a streptavidin sensor chip (Sensor Chip SA), by flowing the protein solution through the sensor chip at typically 10 pg / mL concentration, 5 pL / min flow rate for 70 seconds. Compounds are 2-fold, 7-point serial diluted; the top concentration varies depending on the potency. Compound binding affinities are measured in the multi-cycle kinetics mode, at 30 pL / min flow rate with 60 seconds association time and 120 seconds dissociation time. The running buffer contains 50 mM Tris, pH 7.5, lOO mM NaCl, 1 mM DTT, 0.01% Brij35, 0.05% Tween-20 and 1% DMSO. The assay temperature is maintained at 16 or 20°C and data are fit into the 1 :1 binding model using the Biacore Insight Evaluation software.

[0339] Thermal shift assay (TSA) protocol

[0340] 5 pM recombinant p53 Y220C mutant protein (amino acid residues 94-293) is incubated with 10 pM or 100 pM compound for 3 hours at 20°C in buffer containing 20 mM HEPES, pH7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific catalog number 4461146), on a 384-well PCR plate (Applied Biosystems catalog number 4483285). The volume is 5 pL / well. The sealed plate is then loaded onto a QuantStudio 7 Flex instrument for melting temperature (TM) measurement. The temperature is increased from 30 °C to 50°C, at a rate of 0.03°C / second. Data are fit into a Boltzmann two-state model to determine the TM.

[0341] Luciferase reporter assay protocol

[0342] Luciferase reporter (Luc) driven by p53 response element (LTV-p53-Luc (SKU#: LTLR007); G&P Biosciences) and inducible p53 Y220C construct (Tet-One inducible expression system; Takara) are stably expressed in NCIH1299 cells by lentiviral transduction. The cells are then used for p53 reporter assay. 5,000 cells are seeded in each well of 384 plate and cultured in 0.5 ug / mL doxycycline (D3072; Sigma) containing medium for 24 hours before compound treatment. After 6 hour of compound treatment, equal volume of One-Gio reagent (E6110; Promega) is added to each well and the plate is incubated for 5 minutes with shaking at room temperature. The luciferase activity is immediately measured with PheraStar microplate reader. Luciferase activity is stimulated by 10 uM of a tool compound as positive control and ACso is calculated.

[0343] Cell proliferation assay

[0344] Inducible p53 Y220C and R273H constructs (Tet-One inducible expression system; Takara) are stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, A549, BxPC3, T3M4, HuH7, HCC2935, MFE296, NCIH1299, NCIH1299-inducible p53 Y220C, and NCIH1299-inducible p53 R273H cell lines are used for the cell proliferation assay. 250-500 cells are seeded in each well of 384 plate and then compounds are dispensed into each well using Echo or Tecan. After 5 days of incubation, an equal volume of CellTiter-Glo reagent (G7570; Promega) is added into each well and the plate is incubated at room temperature for 10 minutes with shaking. The luminescent signal is measured by PheraStar microplate reader and ICso is calculated.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I) or a compound of Formula (II):or a pharmaceutically acceptable salt of either of the foregoing, wherein:X1is N or CR1;X2is N or CH;X3is N or CR3;X4is N or CR4;Ring A is optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;Ring B is an optionally substituted 5-6 membered heteroaryl or optionally substituted C6- C10 aryl;R1, R3, and R4are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;R2and R6are independently hydrogen or C1-C6 alkyl;L is an optionally substituted C2-C6 alkynylene, optionally substituted 4-6 membered heterocylylene, or optionally substituted 5-6 membered heteroarylene;L1is an optionally substituted C2-C12 alkylene or an optionally substituted 2-12 membered heteroalkylene, wherein 0-2 methylene units of the alkylene or heteroalkylene are independently replaced by RL1; each RL1is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclyl ene, an optionally substituted C6-C10 arylene, or an optionally substituted 5-10 membered heteroarylene; m is 0, 1, or 2; andR5is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C4 cycloalkyl optionally substituted with 1-2 independently selected halogen.

2. The compound of claim 1, wherein X1is N.

3. The compound of claim 1 or 2, wherein X1is CR1.

4. The compound of claim 3, wherein R1is hydrogen.

5. The compound of claim 3, wherein R1is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

6. The compound of any one of claims 1-5, wherein X2is N.

7. The compound of any one of claims 1-5, wherein X2is CH.

8. The compound of any one of claims 1-7, wherein X3is N.

9. The compound of any one of claims 1-7, wherein X3is CR3.

10. The compound of any one of claims 1-7 or 9, wherein R3is hydrogen.

11. The compound of any one of claims 1-7 or 9, wherein R3is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

12. The compound of any one of claims 1-11, wherein X4is N.

13. The compound of any one of claims 1-11, wherein X4is CR4.

14. The compound of any one of claims 1-11 or 13, wherein R4is hydrogen.

15. The compound of any one of claims 1 -1 1 or 13, wherein R4is halogen, cyano, Cl - C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

16. The compound of any one of claims 1, 3-4, 7, 9-10, or 13-14, wherein each of R1, R3, and R4are hydrogen.

17. The compound of any one of claims 1-16, wherein Ring A is optionally substituted C3-C10 cycloalkyl.

18. The compound of any one of claims 1-17, wherein Ring A is optionally substituted C4-C8 cycloalkyl.

19. The compound of any one of claims 1-18, wherein Ring A is optionally substituted cyclobutyl, cyclopentyl, or cyclohexyl.

20. The compound of any one of claims 1-19, wherein Ring A is optionally substituted cyclohexyl.

21. The compound of any one of claims 1-16, wherein Ring A is optionally substituted C6-C10 aryl.

22. The compound of any one of claims 1-16, wherein Ring A is optionally substituted 3-12 membered heterocyclyl.

23. The compound of any one of claims 1-16 or 22, wherein Ring A is optionally substituted 4-10 membered heterocyclyl.

24. The compound of any one of claims 1-16 or 22-23, wherein Ring A is optionally substituted 5-6 membered heterocyclyl.

25. The compound of any one of claims 1 -16 or 22-24, wherein Ring A is optionally substituted piperidinyl.

26. The compound of any one of claims 1-16, wherein Ring A is optionally substituted 5-10 membered heteroaryl.

27. The compound of any one of claims 1-16 or 26, wherein Ring A is optionally substituted 5-6 membered heteroaryl.

28. The compound of any one of claims 1-16 or 26-27, wherein Ring A is selected from the group consisting of optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

29. The compound of any one of claims 1-28, wherein Ring B is an optionally substituted 5-6 membered heteroaryl.

30. The compound of any one of claims 1-29, wherein Ring B is selected from the group consisting of optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

31. The compound of any one of claims 1-30, wherein Ring B is pyridinyl.

32. The compound of any one of claims 1-30, wherein Ring B is pyrimidinyl.

33. The compound of any one of claims 1-28, wherein Ring B optionally substituted phenyl.

34. The compound of any one of claims 1 -33, wherein R2is hydrogen.

35. The compound of any one of claims 1-33, wherein R2is C1-C6 alkyl.

36. The compound of any one of claims 1-35, wherein R6is hydrogen.

37. The compound of any one of claims 1-35, wherein R6is C1-C6 alkyl.

38. The compound of any one of claims 1-37, wherein L is an optionally substituted C2-C6 alkynylene.

39. The compound of any one of claims 1-37, wherein L is an optionally substituted C2-C4 alkynylene.

40. The compound of any one of claims 1-37, wherein L is an optionally substituted C3 alkynylene.

41. The compound of any one of claims 1-37, wherein L is an optionally substituted 4- 6 membered heterocylylene.

42. The compound of any one of claims 1-37 or 41, wherein L is a 4-6 membered heterocylylene.

43. The compound of any one of claims 1-37 or 41-42, wherein L is a 4 membered heterocylylene.

44. The compound of any one of claims 1-37, wherein L is an or optionally substituted 5-6 membered heteroarylene.

45. The compound of any one of claims 1-37 or 44, wherein L is selected from the group consisting of optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.carbon of the 5-membered ring of Formula (I) or Formula (II) or the CH2 or N of Formula (I) or Formula (II).

47. The compound of any one of claims 1-46, wherein L is a 2,5-(l,3,4- oxadiazolyl)ene, a 2,5-(l,3,4-thiadiazolyl)ene, or a 3,5-(l,2,4-oxadiazolyl)ene.

48. The compound of claims 1-47, wherein L1is an optionally substituted C2-C12 alkylene, wherein 0-2 methylene units of the alkylene are independently replaced by RL1.

49. The compound of claims 1-47, wherein L1is an optionally substituted C2-C12 alkylene, wherein 1-2 methylene units of the alkylene are independently replaced by RL1.

50. The compound of claims 1-47, wherein L1is an optionally substituted C2-C12 alkylene.

51. The compound of claims 1-47, wherein L1is an optionally substituted 2-12 membered heteroalkylene, wherein 0-2 methylene units of the heteroalkylene are independently replaced by RL1.

52. The compound of claims 1-47 or 51, wherein L1is an optionally substituted 4-10 membered heteroalkylene, wherein 0-2 methylene units of the heteroalkylene are independently replaced by RL1.

53. The compound of claims 1-47, wherein L1is an optionally substituted 2-12 membered heteroalkylene, wherein 1-2 methylene units of the heteroalkylene are independently replaced by RL1.

54. The compound of claims 1-47, wherein L1is an optionally substituted 2-12 membered heteroalkylene.

55. The compound of claims 1-54, wherein R1 1is independently an optionally substituted C3-C10 cycloalkylene.

56. The compound of claims 1-54, wherein RL1is an optionally substituted 4-12 membered heterocyclylene.

57. The compound of claims 1-54, wherein RL1is an optionally substituted phenylene.

58. The compound of claims 1-54, wherein RL1is an optionally substituted 5-10 membered heteroarylene.

60. The compound of claims 1-59, wherein R2is hydrogen.

61. The compound of claims 1-59, wherein R2is C1-C6 alkyl.

62. The compound of claims 1-59 or 61, wherein R2is methyl.

63. The compound of claims 1-62, wherein R6is hydrogen.

64. The compound of claims 1-62, wherein R6is C1-C6 alkyl.

65. The compound of claims 1-62 or 64, wherein R6is methyl.

66. The compound of claims 1-65, wherein R5is C1-C6 alkyl.

67. The compound of claims 1-66, wherein R5is C1-C3 alkyl.

68. The compound of claims 1-67, wherein R3is methyl.

69. The compound of claims 1-65, wherein R3is C1-C6 haloalkyl.

70. The compound of claims 1-65 or 69, wherein R5is C1-C3 haloalkyl.

71. The compound of claims 1-65 or 69-70, wherein R5is -CHF2, -CH2F, or -CF3.

72. The compound of claims 1-65 or 69-71, wherein R? is -CF3.

73. The compound of claims 1-65, wherein R5is C3-C4 cycloalkyl optionally substituted with 1-2 independently selected halogen.

74. The compound of claims 1-65, wherein R5is C3-C4 cycloalkyl substituted with 1- 2 independently selected halogen.

75. The compound of claims 1-65 or 74, wherein R5is C3-C4 cycloalkyl.

76. The compound of any one of claims 1-75, wherein the compound is a compound of Formula (I):

77. The compound of any one of claims 1-76, wherein the compound is a compound ofFormula (78. The compound of any one of claims 1-76, wherein the compound is a compound of Formula (I-B):

79. The compound of any one of claims 1-76, wherein the compound is a compound ofFormula (I-C):

80. The compound of any one of claims 1-76, wherein the compound is a compound of Formula (I-D) :

81. The compound of any one of claims 1-76, wherein the compound is a compound of Formula (I-E):

82. The compound of any one of claims 1-75, wherein the compound is a compound ofFormula (II):

83. The compound of any one of claims 1-75 and 82, wherein the compound is a compound of Formula (II-A):

84. The compound of any one of claims 1-75 and 82, wherein the compound is a compound of Formula (II-B):e of claims 1-75 and 82, wherein the compound is a compound of Formula (II-C):

86. The compound of any one of claims 1-75 and 82, wherein the compound is a compound of Formula (II-D):

87. The compound of any one of claims 1-75 and 82, wherein the compound is a compound of Formula (II-E):

88. A compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt of either of the foregoing, selected from the compounds described in Table A, or a pharmaceutically acceptable salt thereof.

89. A pharmaceutical composition comprising a compound of any one of Claims 1-88, or a pharmaceutically acceptable salt thereof.

90. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-88, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 89.

91. A method of treating cancer in a subj ect previously identified as having one or more p53 mutations, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-88, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 89.

92. A method of treating cancer in a subject in need thereof, comprising:(a) determining that the subject has one or more p53 mutations, and(b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-88, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 89.

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