Methods for treating a p53-associated cancer

Abstract

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, 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 A P53-ASSOCIATED CANCER

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 545,024, filed on October 20, 2023, which is incorporated by reference herein in its entirety.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “50006-0117WO1_ST26_SL.XML.” The XML file, created on October 17, 2024, is 2,257 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, 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, 1 4-160). 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 p53Y220Cmutation occurs in -1% 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 pharmaceutically acceptable salt thereof, wherein:

[0013] X1is O, S, or NR3; each of X2, X3, X4, and X3are CH, N, CR1or CR2, wherein two or more of X2, X3, X4, and X5are independently CH, CR1, or CR2;

[0014] R1is halogen, cyano, -OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, -C(=O)OR4, -C(=O)NR4R5, -SR4, -S(=O)R4, -S(O2)R4, -NR4C(=O)R5, -R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0015] RAis hydrogen, -OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, -C(=O)OR6, -NR6C(=O)OR7, -C(=O)NR6R7, -SR6, -S(=O)R6, -S(O2)R6, -S(O2)NR6, -NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0016] RBis halogen, cyano, hydroxyl, -NR8R9, -OR8, -C(=O)NR8R9, -C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, -OC(=O)R8, -OC(=O)NR8, -C(=O)NR8R9, -NR8C(=O)R9, -NR8C(=O)NR9, -SR8, -S(=O)R8, -S(O2)R8, -S(O2)NR8, -NR8S(O2)R9, -R8C(-O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0017] , each

[0018] Z1is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene;

[0019] Z2is CR2C, N, O, or a bond; wherein when Z2is O, R2Bis absent; when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1;

[0020] R2Aand R2Bare independently hydrogen, -C(=O)R10, -C(=O)OR10,

[0021] -C(=O)NR10Rn, -S(=O)R10, -S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2is O and R2Bis absent;

[0022] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[0023] L is an optionally substituted C2-C6 alkynylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2;

[0024] R3is hydrogen or C1-C6 alkyl; and each R4, R5, R6, R7, R8, R9, R10, and R11are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; with the proviso that when L is C2-C6 alkynylene, RBis -SR8.

[0025] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0026] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0027] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0028] 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0030] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0031] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0032] Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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.

[0033] 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 a pharmaceutically acceptable salt thereof.

[0034] Other embodiments include those described in the Detailed Description and / or in the claims.

[0035] Additional Definitions

[0036] 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. 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.

[0037] 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.

[0038] 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.

[0039] 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 eel, 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.

[0040] 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 dicyclohexylamine, 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.

[0041] 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.

[0042] 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.

[0043] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4) 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. 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, haloheterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido,

[0044] 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, and ureido.

[0045] The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0046] 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.

[0047] The term "hydroxyl" refers to an -OH radical.

[0048] The term “sulfhydryl” refers to a -SH radical.

[0049] The term "cyano" refers to a -CN radical.

[0050] The term “azido” refers to a -N3 radical.

[0051] The term “nitro” refers to a -NO2 radical.

[0052] The term “nitroso” refers to a -N=O radical.

[0053] 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. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, / .w-propyl, Zc / 7-butyl, / / -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.

[0054] The term “acyl” refers to a -C(=O)alkyl radical (e.g., acetyl), or a -C(=O)alkenyl radical

[0055] (e.g., -C(=O)-CH=CH2), or -C(=O)alkynyl radical (e.g., oO ). Acyl groups can be substituted with cyano or with 1-3 independently selected halogens.

[0056] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.

[0057] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

[0058] 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.

[0059] 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.E0]heptane, bicyclo[2.2.1]heptane, bicyclo[3 l.l]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.

[0060] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having

[0061] 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). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. 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, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-< / ]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| / Z][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[ / >][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 of pyridone pyrimidone (e.g., carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0062] 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

[0063] 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) and one or more N, P, or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an P-oxide, an S-oxide, or an S,S-dioxide), 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- azabicyclof 1.1.1 Jpentane, 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 azabi cy cl o [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[ 1.1.1 ]pentane, 3-oxabicyclo[3.1.0]hexane, 5 oxabicyclo[2. 1. l]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2. l]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.

[0064] The term “haloheterocyclyl” refers to a heterocyclyl, in which one or more hydrogen atoms are replaced with an independently selected halogen.

[0065] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

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

[0067] The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0068] The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

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

[0070] The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0071] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0072] The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy (e.g., methoxyethyl).

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

[0074] The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy.

[0075] The term “alkoxyamino” refers to an -O-amino radical (e.g., -OCH2CH2N(CH3)2).

[0076] The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3).

[0077] The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl).

[0078] The term “haloalkenoxy” refers to an -O-haloalkenyl radical.

[0079] The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl).

[0080] The term “haloalkynoxy” refers to an -O-haloalkynyl radical.

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

[0082] The term “heteroaryloxy” 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).

[0085] The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).

[0086] The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).

[0087] The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyl oxetanyl).

[0088] The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyloxy).

[0089] The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).

[0090] The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).

[0091] 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.

[0092] 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)).

[0093] A “sulfinyl” group refers to an “-S(=O)” group in which R can be the same as defined with respect to sulfenyl.

[0094] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.

[0095] 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.

[0096] 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, heterocyclylalkyl, or cycloalkylalkyl.

[0097] 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.

[0098] 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.

[0099] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy.

[0100] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.

[0101] 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.

[0102] 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.

[0103] An “N-sulfonamido” group refers to a “RS02N(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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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 cycloalkylalkyl.

[0109] 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.

[0110] 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.

[0111] The term “carboxaldehyde” refers to a -C(=O)H radical.

[0112] 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. 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.

[0114] 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.

[0115] 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

[0116] (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) ( a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

[0117] 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.

[0118] 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 the tautomeric 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.

[0119] 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.

[0120] 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.

[0121] DETAILED DESCRIPTION

[0122] This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, 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).

[0123] Formulae (I) Compounds

[0124] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0125] XHs O, S, or NR3; each of X2, X3, X4, and X are CH, N, CR1or CR2, wherein two or more of X2, X3, X4, and X5are independently CH, CR1, or CR2;

[0126] R1is halogen, cyano, -OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, -C(=O)OR4, -C(=O)NR4R5, -SR4, -S(=O)R4, -S(O2)R4, -NR4C(=O)R5, -R’C(=O)R\ optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0127] RAis hydrogen, -OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, -C(=O)OR6, -NR6C(=O)OR7, -C(=O)NR6R7, -SR6, -S(=O)R6, -S(O2)R6, -S(O2)NR6, -NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0128] , each Z1is a bond, -C=O-, -S(O2)-optionally substituted C 1 -C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene;

[0129] Z2is CR2C, N, O, or a bond; wherein when Z2is O, R2Bis absent; when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1;

[0130] R2Aand R2Bare independently hydrogen, -C(=O)R10, -C(=O)OR10,

[0131] -C(=O)NR10Rn, -S(=O)R10, -S(O2)R10, optionally substituted Cl -C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or

[0132] R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2is O and R2Bis absent;

[0133] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[0134] L is an optionally substituted C2-C6 alkynylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2;

[0135] R3is hydrogen or C1-C6 alkyl; and each R4, R5, R6, R7, R8, R9, R10, and R11are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; with the proviso that when L is C2-C6 alkynylene, RDis -SR8.

[0136] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting (I-A), or a pharmaceutically acceptable salt of any of the foregoing.

[0137] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of (I-B), or a pharmaceutically acceptable salt of any of the foregoing.

[0138] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of any of the foregoing.

[0139] In some embodiments, one of X2, X3, X4, and X5is N. In some embodiments, X2is N. In some embodiments, X3is N. In some embodiments, X4is N.

[0140] In some embodiments, two of X2, X3, X4, and X3are N.

[0141] In some embodiments, X5is CR1or CR2. In some embodiments, X5is CR1. In some embodiments, X3is CR2.

[0142] In some embodiments, X2, X3, and X4are CH.

[0143] In some embodiments, one of X2, X3, and X4is CR1and the others of X2, X3, and X4are

[0144] CH.

[0145] In some embodiments, one of X2, X3, and X4is N and the remaining of X2, X3, and X4are CH.

[0146] In some embodiments, X2, X3, and X4are CH and X3is CR2.

[0147] In some embodiments, R1is hydrogen.

[0148] In some embodiments, R1is halogen.

[0149] In some embodiments, R1is cyano. In some embodiments, R1is -OR4.

[0150] In some embodiments, R1is -NR4R5.

[0151] In some embodiments, R1is -C(=O)R4.

[0152] In some embodiments, R1is -OC(=O)R4.

[0153] In some embodiments, R1is -C(=O)OR4.

[0154] In some embodiments, R1is -C(=O)NR4R5.

[0155] In some embodiments, R1is -SR4.

[0156] In some embodiments,

[0157] In some embodiments,

[0158] In some embodiments,

[0159] In some embodiments,

[0160] In some embodiments, R4is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0161] In some embodiments, R4is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0162] In some embodiments, R4is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0163] In some embodiments, R4is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0164] In some embodiments, R4is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R4is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0165] In some embodiments, R5is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R3is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0166] In some embodiments, R5is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0167] In some embodiments, R5is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0168] In some embodiments, R5is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R5is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0169] In some embodiments, when R4and R are attached to the same nitrogen atom, R4and R5are the same. In some embodiments, when R4and R5are attached to the same nitrogen atom, R4and R5are different. In some embodiments, when R4and R3are attached to the same nitrogen atom, R4and R5are each hydrogen. In some embodiments, when R4and R5are attached to the same nitrogen atom, R4and R5are each an independently selected C1-C6 alkyl.

[0170] In some embodiments, when R4and R5are attached to the same nitrogen atom, one of R4and R5is hydrogen and the other of R4and R5is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0171] In some embodiments, when R4and R5are attached to the same nitrogen atom, one of R4and R3is hydrogen and the other of R4and R5is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0172] In some embodiments, R1is optionally substituted C1-C6 alkyl. In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is methyl or ethyl.

[0173] In some embodiments, R1is optionally substituted C2-C6 alkenyl. In some embodiments, R1is C2-C6 alkenyl. In some embodiments, RMs optionally substituted C2-C3 alkenyl. In some embodiments, R1is C2-C3 alkenyl. In some embodiments, R1is optionally substituted C2-C6 alkynyl. In some embodiments, R1is C2-C6 alkynyl. In some embodiments, R1is optionally substituted C2-C3 alkynyl. In some embodiments, R1is C2-C3 alkynyl.

[0174] In some embodiments, R1is optionally substituted C3-C6 cycloalkyl. In some embodiments, R1is C3-C6 cycloalkyl.

[0175] In some embodiments, R1is optionally substituted phenyl. In some embodiments, R1is phenyl.

[0176] In some embodiments, R1is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R1is 4-6 membered heterocyclyl.

[0177] In some embodiments, R1is optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is 5-6 membered heteroaryl.

[0178] In some embodiments, X1is O.

[0179] In some embodiments, X1is S.

[0180] In some embodiments, X1is NR3.

[0181] In some embodiments, R3is hydrogen.

[0182] In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is C1-C3 alkyl. In some embodiments, R1is methyl or ethyl. In some embodiments, R1is methyl.

[0183] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[0184] acceptable salt of any of the foregoing.

[0185] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group pharmaceutically acceptable salt of any of the foregoing.

[0186] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0187]

[0188] R) or a pharmaceutically acceptable salt of any of the foregoing.

[0189] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting pharmaceutically acceptable salt of any of the foregoing

[0190] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[0191] salt of any of the foregoing.

[0192] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I- A A). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

[0193] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting pharmaceutically acceptable salt of any of the foregoing

[0194] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0195] salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl.

[0196] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[0197] pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl

[0198] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl.

[0199] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted Cl-

[0200] C6 alkyl.

[0201] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0202] acceptable salt of any of the foregoing.

[0203] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0204] pharmaceutically acceptable salt of any of the foregoing.

[0205] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl.

[0206] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of a pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl.

[0207] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[0208] pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl.

[0209] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl.

[0210] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of a pharmaceutically acceptable salt of any of the foregoing, wherein R2Bis hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, RAis hydrogen.

[0211] In some embodiments, RAis -OR6.

[0212] In some embodiments, RAis -NR6R7.

[0213] In some embodiments, RAis -C(=O)R6.

[0214] In some embodiments, RAis -R6C(=O)R7.

[0215] In some embodiments, RAis -OC(=O)R6.

[0216] In some embodiments, RAis -OC(=O)NR6.

[0217] In some embodiments, RAis -C(=O)OR6.

[0218] In some embodiments, RAis -NR6C(=O)OR7.

[0219] In some embodiments, RAis -C(=O)NR6R7.

[0220] In some embodiments, RAis -SR6.

[0221] In some embodiments, RAis -S(=O)R6.

[0222] In some embodiments, RAis -S(O2)R6.

[0223] In some embodiments, RAis -S(O2)NR6.

[0224] In some embodiments, RAis -NR6S(O2)R7.

[0225] In some embodiments, RAis -NR6C(=O)R7.

[0226] In some embodiments, RAis -NR6C(=O)NR7.

[0227] In some embodiments, RAis -SiR6R7R8.

[0228] In some embodiments, R6is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0229] In some embodiments, R6is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0230] In some embodiments, R6is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0231] In some embodiments, R6is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R6is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R6is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0232] In some embodiments, R7is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0233] In some embodiments, R7is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0234] In some embodiments, R7is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0235] In some embodiments, R7is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0236] In some embodiments, R7is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R7is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0237] In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are the same. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are different. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are each hydrogen. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are each an independently selected C1-C6 alkyl.

[0238] In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0239] In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is substituted phenyl or optionally 5-10 membered heteroaryl.

[0240] In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0241] In some embodiments, R8is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0242] In some embodiments, R8is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0243] In some embodiments, R8is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0244] In some embodiments, R8is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0245] In some embodiments, R8is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0246] In some embodiments, RAis optionally substituted C1-C6 alkyl. In some embodiments, RAis C1-C6 alkyl. In some embodiments, RAis methyl, ethyl, or n-propyl.

[0247] In some embodiments, RAis C1-C6 haloalkyl. In some embodiments, RAis C1-C3 haloalkyl. In some embodiments, RAis trifluorom ethyl.

[0248] In some embodiments, RAis optionally substituted C2-C6 alkenyl. In some embodiments, RAis C2-C6 alkenyl. In some embodiments, RAis optionally substituted C2-C3 alkenyl. In some embodiments, RAis C2-C3 alkenyl.

[0249] In some embodiments, RAis optionally substituted C2-C6 alkynyl. In some embodiments, RAis C2-C6 alkynyl. In some embodiments, RAis optionally substituted C2-C3 alkynyl. In some embodiments, RAis C2-C3 alkynyl. In some embodiments, RAis optionally substituted C3-C10 cycloalkyl. In some embodiments, RAis optionally substituted C3-C6 cycloalkyl. In some embodiments, RAis C3- C10 cycloalkyl. In some embodiments, RAis C3-C6 cycloalkyl.

[0250] In some embodiments, RAis optionally substituted phenyl. In some embodiments, RAis phenyl.

[0251] In some embodiments, RAis optionally substituted 3-12 membered heterocyclyl. In some embodiments, RAis optionally substituted 4-8 membered heterocyclyl. In some embodiments, RAis 3-12 membered heterocyclyl. In some embodiments, RAis 4-8 membered heterocyclyl.

[0252] In some embodiments, RAis optionally substituted 5-10 membered heteroaryl. In some embodiments, RAis optionally substituted 5-6 membered heteroaryl. In some embodiments, RAis 5-10 membered heteroaryl. In some embodiments, RAis 5-6 membered heteroaryl. In some embodiments, RAis an optionally substituted 9-10 membered heteroaryl. In some embodiments, RAis a 9-10 membered heteroaryl.

[0253] In some embodiments, RAis phenyl optionally substituted with 1-3 independently selected RA1. In some embodiments, RAis pyridinyl, pyrimidinyl, pyridizinyl, orpyrazinyl, each optionally substituted with 1-3 independently selected RA2. In some embodiments, RAis a 9 membered heteroaryl optionally substituted with 1-3 independently selected RA3.

[0254] In some embodiments, each RA1is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy.

[0255] In some embodiments, each RA2is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.

[0256] In some embodiments, each RA3is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy. In some embodiments, each RA1, RA2and RA3is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, -C(=O)NRR’, -CO2H, -SO2(C1-C3 alkyl), -S(=O)C1-C3 alkyl, -SO2NRR’, - S(=O)(=NR)NRR’, or -P(=O)(C1-C3 alkyl)2, wherein each R and R’ are independently hydrogen or C1-C3 alkyl.

[0257] In some embodiments, each RA1is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclyloxy, -SO2(C1-C3 alkyl), -SO2NRR’, or -P(=O)(C1-C3 alkyl)2, wherein R and R’ are independently hydrogen or C1-C3 alkyl.

[0258] In some embodiments,

[0259] n some embodiments, RBis halogen. In some embodiments, RBis fluoro or chloro.

[0260] In some embodiments, RBis cyano.

[0261] In some embodiments, RBis hydroxyl.

[0262] In some embodiments, RBis -NR8R9.

[0263] In some embodiments, RBis -OR8.

[0264] In some embodiments, RBis -C(=O)NR8R9.

[0265] In some embodiments, RBis -C(=O)R8.

[0266] In some embodiments, RBis -C(=O)OR8.

[0267] In some embodiments, RBis -NR8C(=O)OR9

[0268] In some embodiments, RBis -OC(=O)R8.

[0269] In some embodiments, RBis -OC(=O)NR8.

[0270] In some embodiments, RBis -C(=O)NR8R9.

[0271] In some embodiments, RBis -NR8C(=O)R9.

[0272] In some embodiments, RBis -NR8C(=O)NR9.

[0273] In some embodiments, RBis -SR8. In some embodiments, RBis -SR8, wherein R8is optionally substituted Cl -C 6 alkyl. In some embodiments, RBis -SR8, wherein R8is -CHF2 or -CF3.

[0274] In some embodiments, RBis -S(=O)R8. In some embodiments,

[0275] In some embodiments,

[0276] In some embodiments,

[0277] In some embodiments,

[0278] In some embodiments, RBis -NR8C(=O)R9.

[0279] In some embodiments, RBis -NR8C(=O)NR9.

[0280] In some embodiments, R8is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0281] In some embodiments, R8is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0282] In some embodiments, R8is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0283] In some embodiments, R8is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0284] In some embodiments, R8is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0285] In some embodiments, R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0286] In some embodiments, R9is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0287] In some embodiments, R9is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R9is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0288] In some embodiments, R9is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R9is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0289] In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are the same. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are different. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are each hydrogen. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are each an independently selected C1-C6 alkyl.

[0290] In some embodiments, when R8and R9are attached to the same nitrogen atom, one of R8and R9is hydrogen and the other of R8and R9is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0291] In some embodiments, when R8and R9are attached to the same nitrogen atom, one of R8and R9is hydrogen and the other of R8and R9is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0292] In some embodiments, RBis optionally substituted C1-C6 alkyl. In some embodiments, RBis C1-C6 alkyl. In some embodiments, RBis methyl, ethyl, or n-propyl.

[0293] In some embodiments, RBis C1-C6 haloalkyl. In some embodiments, RBis C1-C3 haloalkyl. In some embodiments, RBis a C1-C3 fluoroalkyl. In some embodiments, RBis trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, RBis 2,2,2-trifluoroethyl.

[0294] In some embodiments, RBis optionally substituted C2-C6 alkenyl. In some embodiments, RBis C2-C6 alkenyl. In some embodiments, RBis optionally substituted C2-C3 alkenyl. In some embodiments, RBis C2-C3 alkenyl.

[0295] In some embodiments, RBis optionally substituted C2-C6 alkynyl. In some embodiments, RBis C2-C6 alkynyl. In some embodiments, RBis optionally substituted C2-C3 alkynyl. In some embodiments, RBis C2-C3 alkynyl. In some embodiments, RBis optionally substituted C3-C10 cycloalkyl. In some embodiments, RBis optionally substituted C3-C6 cycloalkyl. In some embodiments, RBis C3- C10 cycloalkyl. In some embodiments, RBis C3-C6 cycloalkyl.

[0296] In some embodiments, RBis optionally substituted phenyl. In some embodiments, RBis phenyl.

[0297] In some embodiments, RBis optionally substituted 3-12 membered heterocyclyl. In some embodiments, RBis optionally substituted 4-8 membered heterocyclyl. In some embodiments, RBis 3-12 membered heterocyclyl. In some embodiments, RBis 4-8 membered heterocyclyl.

[0298] In some embodiments, RBis optionally substituted 5-10 membered heteroaryl. In some embodiments, RBis optionally substituted 5-6 membered heteroaryl. In some embodiments, RBis 5-10 membered heteroaryl. In some embodiments, RBis 5-6 membered heteroaryl.

[0299] In some embodiments, RBis methyl, ethyl, or n-propyl.

[0300] F F

[0301] In some embodiments, RBis hydroxyl,F, orF.

[0302] In some embodiments, RBis . In some embodiments, RBis

[0303] In some embodiments, RBis orF. In some embodiments, RBisCFs

[0304] . In some embodiments,

[0305] In some embodiments, each

[0306] In some embodiments, one of X2, X3, X4, and X is CR2and the remaining X2, X3, X4, and X5are CH, N, or CR1.

[0307] In some embodiments, Z1is a bond.

[0308] In some embodiments, Z1is -C=O-.

[0309] In some embodiments, Z1is -S(O2)-.

[0310] In some embodiments, Z1is optionally substituted C1-C6 alkylene. In some embodiments, Z1is optionally substituted C1-C3 alkylene. In some embodiments, Z1is C1-C6 alkylene. In some embodiments, Z1is C1-C3 alkylene. In some embodiments, Z1is methylene or ethylene.

[0311] In some embodiments, Z1is optionally substituted C2-C6 alkenylene. In some embodiments, Z1is optionally substituted C2-C3 alkenylene. In some embodiments, Z1is C2-C6 alkenylene. In some embodiments, Z1is C2-C3 alkenylene.

[0312] In some embodiments, Z1is optionally substituted C2-C6 alkynylene. In some embodiments, Z1is optionally substituted C2-C3 alkynylene. In some embodiments, Z1is C2-C6 alkynylene. In some embodiments, Z1is C2-C3 alkynylene.

[0313] In some embodiments, Z1is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z1is C3-C4 cycloalkylene.

[0314] In some embodiments, Z2is N.

[0315] In some embodiments, Z2is O and R2Bis absent.

[0316] In some embodiments, Z2is a bond.

[0317] In some embodiments, Z2is CR2C.

[0318] In some embodiments, R2Cis hydrogen.

[0319] In some embodiments, R2Cis halogen. In some embodiments, R2Cis fluoro or chloro. In some embodiments, R2Cis Cl -C6 alkyl. In some embodiments, R2Cis Cl -C3 alkyl. In some embodiments, R2Cis methyl.

[0320] In some embodiments, when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1. In some embodiments, when Z2is a bond, R2Bis absent and R2Ais directly connected to Z1. In some embodiments, Z2is O and R2Bis absent.

[0321] In some embodiments, R2is -NR2AR2B, i.e., Z1is a bond and Z2is N. In some embodiments, R2is R2B, i.e., Z1and Z2are both a bond, R2Ais absent and R2Bis directly connected to Formula (I) via Z1.

[0322] In some embodiments, when Z1is a not a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Z1.

[0323] In some embodiments, R2Ais hydrogen.

[0324] In some embodiments, R2Ais -C(=O)R10.

[0325] In some embodiments, R2Ais -C(=O)OR10.

[0326] In some embodiments, R2Ais -C(=O)NR10R11.

[0327] In some embodiments, R2Ais -S(=O)R10.

[0328] In some embodiments, R2Ais -S(O2)R10.

[0329] In some embodiments, R10is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0330] In some embodiments, R10is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0331] In some embodiments, R10is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0332] In some embodiments, R10is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0333] In some embodiments, R10is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R10is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl. In some embodiments, R11is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0334] In some embodiments, R11is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0335] In some embodiments, R11is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0336] In some embodiments, R11is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0337] In some embodiments, R11is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R11is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0338] In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are the same. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are different. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are each hydrogen. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are each an independently selected C1-C6 alkyl.

[0339] In some embodiments, when R10and R11are attached to the same nitrogen atom, one of R10and R11is hydrogen and the other of R10and R11is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0340] In some embodiments, when R10and R11are attached to the same nitrogen atom, one of R10andR11is hydrogen and the other of R10andR11is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0341] In some embodiments, R2Ais optionally substituted C1-C6 alkyl. In some embodiments, R2Ais C1-C6 alkyl. In some embodiments, R2Ais methyl or ethyl. In some embodiments, R2Ais C1 -C6 haloalkyl. In some embodiments, R2Ais C1-C3 haloalkyl. In some embodiments, R2Ais trifluoromethyl.

[0342] In some embodiments, R2Ais optionally substituted C2-C6 alkenyl. In some embodiments, R2Ais C2-C6 alkenyl. In some embodiments, R2Ais optionally substituted C2-C3 alkenyl. In some embodiments, R2Ais C2-C3 alkenyl.

[0343] In some embodiments, R2Ais optionally substituted C2-C6 alkynyl. In some embodiments, R2Ais C2-C6 alkynyl. In some embodiments, R2Ais optionally substituted C2-C3 alkynyl. In some embodiments, R2Ais C2-C3 alkynyl.

[0344] In some embodiments, R2Ais optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Ais optionally substituted C3-C6 cycloalkyl. In some embodiments, R2Ais C3- C10 cycloalkyl. In some embodiments, R2Ais C3-C6 cycloalkyl.

[0345] In some embodiments, R2Ais optionally substituted phenyl. In some embodiments, R2Ais phenyl.

[0346] In some embodiments, R2Ais optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2Ais optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Ais 3-12 membered heterocyclyl. In some embodiments, R2Ais 4-8 membered heterocyclyl.

[0347] In some embodiments, R2Ais optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Ais optionally substituted 5-6 membered heteroaryl. In some embodiments, R2Ais 5-10 membered heteroaryl. In some embodiments, R2Ais 5-6 membered heteroaryl.

[0348] In some embodiments, R2Bis hydrogen.

[0349] In some embodiments, R2Bis -C(=O)R10.

[0350] In some embodiments, R2Bis -C(=O)OR10.

[0351] In some embodiments, R2Bis -C(=O)NR10R11.

[0352] In some embodiments, R2Bis -S(=O)R10.

[0353] In some embodiments, R2Bis -S(O2)R10.

[0354] In some embodiments, R2Bis optionally substituted C1-C6 alkyl. In some embodiments, R2Bis C1-C6 alkyl. In some embodiments, R2Bis methyl or ethyl.

[0355] In some embodiments, R2Bis C1-C6 haloalkyl. In some embodiments, R2Bis C1-C3 haloalkyl. In some embodiments, R2Bis trifluoromethyl. In some embodiments, R2Bis optionally substituted C2-C6 alkenyl. In some embodiments, R2Bis C2-C6 alkenyl. In some embodiments, R2Bis optionally substituted C2-C3 alkenyl. In some embodiments, R2Bis C2-C3 alkenyl.

[0356] In some embodiments, R2Bis optionally substituted C2-C6 alkynyl. In some embodiments, R2Bis C2-C6 alkynyl. In some embodiments, R2Bis optionally substituted C2-C3 alkynyl. In some embodiments, R2Bis C2-C3 alkynyl.

[0357] In some embodiments, R2Bis optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Bis optionally substituted C3-C6 cycloalkyl. In some embodiments, R2Bis C3- C10 cycloalkyl. In some embodiments, R2Bis C3-C6 cycloalkyl.

[0358] In some embodiments, R2Bis optionally substituted phenyl. In some embodiments, R2Bis phenyl.

[0359] In some embodiments, R2Bis optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2Bis optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Bis 3-12 membered heterocyclyl. In some embodiments, R2Bis 4-8 membered heterocyclyl.

[0360] In some embodiments, R2Bis optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Bis optionally substituted 5-6 membered heteroaryl. In some embodiments, R2Bis 5-10 membered heteroaryl. In some embodiments, R2Bis 5-6 membered heteroaryl.

[0361] In some embodiments, R2Bis -C(=O)R10, -C(=O)OR10, -C(=O)NR10Rn, -S(=O)R10, -S(C>2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; and R2Bis hydrogen.

[0362] In some embodiments, one of R2Aand R2Bis hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2Aand R2Bis hydrogen, -C(=O)R10, -C(=O)OR10, -C(=O)NR10Rn, -S(=O)R10, -S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl.

[0363] In some embodiments, one of R2Aand R2Bis hydrogen and the other of R2Aand R2Bis an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R2Aand R2Bis hydrogen and the other of R2Aand R2B is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R2Aand R2Bis hydrogen and the other of R2Aand R2Bis a substituted 4-12 membered heterocyclyl.

[0364] In some embodiments, R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.

[0365] In some embodiments, optionally substituted alkylene and Z2is N. In some embodiments,

[0366] R2A , i.e., Z1is optionally substituted alkylene, Z2is a bond, and R2Ais absent. In some embodiments,

[0367] In some embodiments, R2Ais hydrogen.

[0368] In some embodiments, embodiments,

[0369]

[0370] 10

[0371]

[0372]

[0373] In some embodiments, R2as defined herein, comprises an a, P-unsaturated system or an 10 electrophilic group. In some embodiments, R2is selected from the group consisting of:

[0374] In some embodiments, X3is CR2and R2as defined herein comprises an a, -unsaturated system or an electrophilic group, as described herein.

[0375] In some embodiments, one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR1, and the remaining X2, X3, X4, and X3are CH or N.

[0376] In some embodiments, one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR1, and the remaining X2, X3, X4, and X5are CH.

[0377] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0378] In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is an unsubstituted C2-C6 alkynylene. In some embodiments, L is a substituted C2-C6 alkynylene. In some embodiments, L is a C2 alkynylene. In some embodiments, L is a C3 alkynylene.

[0379] In some embodiments, L is an optionally substituted 5-6 membered heteroarylene. In some embodiments, L is a substituted 5-6 membered heteroarylene. In some embodiments, L is a substituted 6 membered heteroarylene. In some embodiments, L is a 5 membered heteroarylene. 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-

[0380] wherein each represents a bond to either the cabon of the 5-membered ring of Formula (I) or the CH2 or RAof Formula (I).

[0381] Non-Limiting Exemplary Compounds

[0382] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.

[0383] Table A

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390] Pharmaceutical Compositions

[0391] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0392] Methods of Treatment

[0393] 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).

[0394] 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.

[0395] 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 EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher ECso value.

[0396] Indications

[0397] Compounds of Formula (I), or pharmaceutically acceptable salts thereof, 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.

[0398] Some embodiments provide a method of treating cancer in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53 -associated cancer.

[0399] Some embodiments provide a method of treating cancer in a subj ect that has been identified or diagnosed as having a p53 -associated cancer, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the p53 -associated cancer harbors a Y220C mutation.

[0400] 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 compound of Examples 1-33, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation.

[0401] 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 a pharmaceutically acceptable salt thereof.

[0402] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0403] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0404] 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 a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome.

[0406] 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).

[0407] 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.

[0408] 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.

[0409] 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof. 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.

[0410] 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.

[0411] 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.

[0412] 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

[0413] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable thereof, 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 a pharmaceutically acceptable salt thereof.

[0414] Also provided herein are methods for treating a subject identified or diagnosed as having a p53 -associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 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 nonlimiting 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.

[0415] 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 a pharmaceutically acceptable salt thereof, 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 subj ect 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.

[0416] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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.

[0417] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, 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.

[0418] 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 a pharmaceutically acceptable salt thereof. 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 TP 53 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.

[0419] 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 a pharmaceutically acceptable salt thereof, 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.

[0420] Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. 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 a pharmaceutically acceptable salt thereof, 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.

[0421] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0422] 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. 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.

[0423] 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).

[0424] 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.

[0425] 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.

[0426] In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.

[0427] In some embodiments, the bladder cancer is bladder urothelial carcinoma.

[0428] In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.

[0429] In some embodiments, the skin cancer is cutaneous melanoma.

[0430] 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.

[0431] In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.

[0432] In some embodiments, the breast cancer is breast invasive ductal carcinoma.

[0433] In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma. In some embodiments, the ovarian cancer is serous ovarian cancer.

[0434] In some embodiments, the kidney cancer is chromophobe renal cell carcinoma.

[0435] In some embodiments, the colorectal cancer is colon adenocarcinoma.

[0436] In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

[0437] In some embodiments, the cancer is prostate cancer.

[0438] 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.

[0439] 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. Table 1. p53 Protein Amino Acid Substitutions / Insertions / DeletionsA

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451] Ill

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470] 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, pH (2013).

[0471] Combinations

[0472] 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), 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0473] 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.

[0474] In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) 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 a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.

[0475] 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.

[0476] 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.

[0477] 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), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SMI-71, TG 100801, FGFR1 inhibitor-6, or TG 100572.

[0478] In some embodiments, the ALK inhibitor is crizotinib (X.kl.KO I®. 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-01 L PF-06463922, ensartinib (X- 396), or CEP-37440.

[0479] In some embodiments, the NTRK / ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005),

[0480] 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).

[0481] 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).

[0482] 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, isobutyrylshikonin, acetyl shikonin, 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.

[0483] 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), IPI-504, PF299, pelitinib, S- 22261 1, and AEE-788.

[0484] 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.

[0485] 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, JDQ443, and adagrasib (MRTX-849).

[0486] 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.

[0487] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK 162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI 1040 (PD 184352), hypothemycin, or a combination thereof.

[0488] 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. 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.

[0489] 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, AT 13148, uprosertib, afuresertib, DC 120, 2-[4-(2- aminoprop-2-yl)phenyl]-3 -phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, 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.

[0490] 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.

[0491] 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.

[0492] In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.

[0493] In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide. 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.

[0494] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

[0495] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.

[0496] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.

[0497] 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.

[0498] 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.

[0499] 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®).

[0500] 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 INJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol. 11: 39 (2018).

[0501] 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.

[0502] 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.

[0503] EXAMPLES

[0504] Compound Preparation

[0505] 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.

[0506] 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.

[0507] 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.

[0508] The compounds described herein can be synthesized, for example, using the procedures below, using different coupling partners.

[0509] Example 1 - Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl) prop-2-yn-l-yl] amino}-3-methoxy-N- methylbenzamide (Compound 3)

[0510] Step 1

[0511] To a solution of 7-bromo-l-benzothiophene (2.00 g, 9.38 mmol, 1.00 equiv) in DCE (20.00 mL) were added 2-[(trifhioromethyl)sulfanyl]-llambda6,2-benzothiazole-l, 1,3-trione (2.92 g, 10.32 mmol, 1.10 equiv) and TfOH (802.89 mg, 5.35 mmol, 0.50 equiv) at 0°C. The resulting mixture was stirred for Ih at room temperature under air atmosphere. The reaction was quenched by the addition of sat. NaHCCh (aq.) (50.00 mL) at 0°C. The resulted mixture was extracted with DCM and the organic layer was washed with brine. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 7-bromo-3-[(trifluoromethyl)sulfanyl]-l -benzothiophene (1.20 g, 40.83%) as a light yellow oil. 'HNMR (400 MHz, DMSO-fifc) 8 8.73 (s, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.80 (dt, J= 1.1, 0.7 Hz, 1H), 7.57 (t, J= 7.9 Hz, 1H).19F NMR (377 MHz, DMSO-r / r,) 8 - 42.13.

[0512] Step 2

[0513] To a solution of 7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzothiophene (500.00 mg, 1.60 mmol, 1.00 equiv) in THF (6.00 mL) was added LDA (2M in THF, 1.60 mL, 3.20 mmol, 2.00 equiv) at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at - 78°C. To the above mixture was added h (486.30 mg, 1.92 mmol, 1.20 equiv, in 1.00 mL THF) dropwise at -78°C. The resulting mixture was stirred for 0.5 h at 78°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) and the resulted mixture was extracted with EA. The organic layer was washed with sat. Na S2O3 (aq.), brine and dried over Na2SO4. After removal of solvent, the residue was purified using Cl 8 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 7-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]-l-benzothiophene (230.00 mg, 32.81%) as a white solid. ' H NMR (400 MHz, DMSO-t / e) 87.94 (d, J = 8.1 Hz, 1H), 7.73 (dd, J = 1.1, 0.9 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H).19F NMR (377 MHz, DMSO-tL) 8 -40.99.

[0514] Step 3

[0515] To a solution of 7-bromo-2-iodo-3-[(trifluoromethyl) sulfanyl]-l-benzothiophene (200.00 mg, 0.46 mmol, 1.00 equiv) in DMSO (5.00 mL) were added 3-methoxy-N-methyl-4-(prop-2-yn- 1-ylamino) benzamide (109.36 mg, 0.50 mmol, 1.10 equiv), Pd(PPhs)4 (52.64 mg, 0.05 mmol, 0.10 equiv), i-PnNH (460.96 mg, 4.56 mmol, 10.00 equiv) and Cui (87.40 mg, 0.46 mmol, 1.00 equiv). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulted mixture was purified using Cl 8 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-2-yl} prop-2-yn-l-yl) amino]-3-methoxy-N-methylbenzamide (200.00 mg, 82.94%) as a white solid. LC-MS: (M+H)+found 528.98.

[0516] Step 4 To a solution of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl} prop-2-yn-l-yl) amino]-3-methoxy-N-methylbenzamide (160.00 mg, 0.30 mmol, 1.00 equiv) in dioxane (3.00 mL) were added (3S,4R)-3-fluoro-l-methylpiperidin-4-amine dihydrochloride (123.98 mg, 0.60 mmol, 2.00 equiv), CS2CO3 (590.84 mg, 1.81 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3 -chloropyridine (29.43 mg, 0.03 mmol, 0.10 equiv). The resulting mixture was stirred for 8 h at 100°C under N2 atmosphere. After removal of solvent, the residue was purified using C 18 flash chromatography with the following conditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). The crude was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 65% B in 8 min; Wave Length: 220 nm; RT: 7.35 min. This resulted in 4-{[3- (7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl] amino} -3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-2-yl) prop-2-yn-l-yl] amino}-3-methoxy-N-methylbenzamide (23.1 mg, 13.06%) as a light yellow solid. LC-MS: (M+H)+found 581.10. 'H NMR (400 MHz, DMSO-^) 8 8.13 (d, J= 4.7 Hz, 1H), 7.44-7.35 (m, 3H), 7.35 (d, J= 1.8 Hz, 1H), 6.84 (d, J= 7.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.07 (t, J = 6.3 Hz, 1H), 5.55 (d, J = 8.3 Hz, 1H), 4.80 (d, J = 49.3 Hz, 1H), 4.39 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 29.2 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (d, J= 4.4 Hz, 4H), 2.32-2.14 (m, 4H), 2.10-1.90 (m, 2H), 1.80-1.60 (m, 1H).

[0517] Example 2 - Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-N- methylbenzamide (Compound 27)

[0518] To a stirred solution of 4-amino-N-methylbenzamide (500.00 mg, 3.33 mmol, 1.00 equiv) in DMF (6.00 mL) were added DIEA (1290.91 mg, 9.99 mmol, 3.00 equiv) and propargyl bromide (475.27 mg, 4.00 mmol, 1.20 equiv) dropwise at room temperature. The resulting mixture was stirred for 8 h at 70°C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 0% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in N-methyl-4-(prop-

[0519] 2-yn-l-ylamino)benzamide (400 mg, 63.83%) as an off-white solid. LC-MS: (M+H)~ found: 189.10.

[0520] To a stirred mixture of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzothiophen-2- yl}prop-2-yn-l-yl)amino]-N-methylbenzamide (130.00 mg, 0.26 mmol, 1.00 equiv) and (3S,4R)-

[0521] 3-fluoro-l-methylpiperidin-4-amine dihydrochloride (69.41 mg, 0.34 mmol, 1.30 equiv) in 1,4- dioxane (2.00 m ) were added CS2CO3 (508.93 mg, 1.56 mmol, 6.00 equiv) and Pd-PEPPSI- IHeptCl 3 -chloropyridine (50.70 mg, 0.05 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. The crude was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 62% B in 10 min; Wave Length: 220nm; RT: 7.63 min. This resulted in 4-{[3- (7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-2-yl)prop-2-yn-l-yl]amino}-N-methylbenzamide (27.4 mg, 18.29%) as a yellow solid. LC-MS: (M+H)+found:551.10. 'HNMR (400 MHz, DMSO-rL) 8 8.04 (q, J= 4.5 Hz, 1H), 7.71-7.63 (m, 2H), 7.37 (t, J= 7.9 Hz, 1H), 7.23 (d, J= 7.9 Hz, 1H), 6.85 (d, J= 7.9 Hz, 1H), 6.77- 6.65 (m, 3H), 5.52 (d, .7= 8.2 Hz, 1H), 4.81 (d, J= 49.5 Hz, 1H), 4.37 (d, J= 6.1 Hz, 2H), 3.66 (d, J = 29.5 Hz, 1H), 3.04 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.73 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.09 (t, J= 11.5 Hz, 1H), 1.98 (qd, J= 12.0, 3.4 Hz, 1H), 1.71 (d, J= 11.9 Hz, 1H).

[0522] Example 3 - Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-4-methoxy-N- methylbenzamide (Compound 28)

[0523] To a stirred mixture of 3-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzothiophen-2- yl}prop-2-yn-l-yl)amino]-4-methoxy-N-methylbenzamide (90.00 mg, 0.17 mmol, 1.00 equiv) and 3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (52.30 mg, 0.26 mmol, 1.50 equiv) in 1,4-dioxane (3.00 mL) were added CS2CO3 (77.66 mg, 1.02 mmol, 6.00 equiv) and Pd-PEPPSI- IHeptCl 3 -chloropyridine (33.11 mg, 0.03 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100°C under nitrogen atmosphere. The resulting mixture was extracted with CH2CI2 (2 x lOmL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O+10mmol / L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 3-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-4-methoxy-N- methylbenzamide (6.9 mg, 6.35%) as a brown solid. LC-MS: (M+H)+found:581.10.JH NMR (400 MHz, DMSO-t / e) 58.14 (q, J= 4.5 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H), 7.28 (d, = 2.0 Hz, 1H), 7.25-7.15 (m, 2H), 6.86 (dd, J = 18.9, 8.1 Hz, 2H), 5.67 (t, J = 6.5 Hz, 1H), 5.51 (d, J= 8.3 Hz, 1H), 4.81 (d, J= 49.4 Hz, 1H), 4.38 (d, J= 6.5 Hz, 2H), 3.84 (s, 3H), 3.72-3.56 (m, 1H), 3.04 (t, J = 11.4 Hz, 1H), 2.85-2.69 (m, 4H), 2.20 (s, 3H), 2.10 (t, J = 11.5 Hz, 1H), 2.03-1.90 (m, 1H), 1.71 (d, J= 12.3 Hz, 1H), 1.40 (s, 1H).

[0524] Example 4 - Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-l-yn-l-yl}-3-[(trifluoromethyl)sulfanyl]-l-benzothiophen-7- yl)-l-methylpiperidin-4-amine (Compound 32)

[0525]

[0526] To a stirred solution of 4-methanesulfonyl-2-methoxyaniline (300.00 mg, 1.49 mmol, 1.00 equiv) in DMF (4.00 mL) were added D1EA (578.03 mg, 4.47 mmol, 3.00 equiv) and propargyl bromide (212.81 mg, 1.79 mmol, 1.20 equiv) dropwise at room temperature. The resulting mixture was stirred for 16 h at 70°C under nitrogen atmosphere. The residue was purified by reversed- phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water, 0% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 4- methanesulfonyl-2-methoxy-N-(prop-2-yn-l-yl)aniline (200 mg, 56.07%) as a yellow solid. LC- MS: (M+H)+found: 240.00.

[0527] Step 2

[0528] To a stirred mixture of N-(3-{7-bromo-3-[(trifhioromethyl)sulfanyl]-l-benzothiophen-2- yl}prop-2-yn-l-yl)-4-methanesulfonyl-2-methoxyaniline (130.00 mg, 0.24 mmol, 1.00 equiv) and (3 S,4R)-3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (62.97 mg, 0.31 mmol, 1.30 equiv) in 1,4-dioxane (2.00 mL) were added CS2CO3 (461.72 mg, 1.42 mmol, 6.00 equiv) andPd-PEPPSI- IHeptCl 3 -chloropyridine (23.00 mg, 0.02 mmol, 0.10 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 20 min; detector, UV 254nm. The crude was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 65% B in 30 min; Wave Length: 254nm / 220nm; RT: 6.37 min; Number Of Runs: 3. This resulted in (3S,4R)-3- fluoro-N-(2-{ 3 -[(4-methanesulfonyl-2-methoxyphenyl)amino]prop- 1 -yn- 1 -yl } -3- [(trifluoromethyl)sulfanyl]-l-benzothiophen-7-yl)-l-methylpiperidin-4-amine (31.9 mg, 21.77%) as a white solid. LC-MS: (M+H)+found:602.10. 'H NMR (400 MHz, DMSO- e) 8 7.43-7.33 (m, 2H), 7.28-7.19 (m, 2H), 6.87 (dd, J= 19.7, 8.1 Hz, 2H), 6.53 (t, J= 6.2 Hz, 1H), 5.52 (d, J= 8.3 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.44 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.66 (d, J = 29.3 Hz, 1H), 3.10 (s, 4H), 2.80 (d, J = 10.9 Hz, 1H), 2.35-2.14 (m, 4H), 2.09 (t, J = 11.4 Hz, 1H), 2.04- 1.91 (m, 1H), 1.71 (d, J= 12.3 Hz, 1H).

[0529] Example 5 - Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-

[0530] [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-4-methoxy-N- methylbenzamide (Compound 29)

[0531] To a stirred mixture of 3-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzothiophen-2- yl}prop-2-yn-l-yl)amino]-4-methoxy-N-methylbenzamide (130.00 mg, 0.25 mmol, 1.00 equiv) and CS2CO3 (480.06 mg, 1.48 mmol, 6.00 equiv) in 1,4-di oxane (3.00 mL) were added tert-butyl (3 S,4R)-4-amino-3 -fluoropiperidine- 1 -carboxylate (69.68 mg, 0.32 mmol, 1.30 equiv) and Pd- PEPPSI-IHeptCl 3 -chloropyridine (47.83 mg, 0.05 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-7-yl]amino}piperidine-l-carboxylate (60 mg, 36.65%) as an off-white solid. LC- MS: (M+H)+found:667.40.

[0532] Step 2

[0533] To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-7-yl]amino}piperidine-l -carboxylate (55.00 mg, 0.08 mmol, 1.00 equiv) in DCM (0.90 mL) was added TFA (0.30 mb, 4.04 mmol, 48.96 equiv) dropwise at 0°C. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 38% B to 57% B in 20 min; Wave Length: 254nm / 220nm; RT: 6.32 min; Number Of Runs: 2. This resulted in 3-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-

[0534] [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-4-methoxy-N- methylbenzamide (19.9 mg, 41.85%) as a white solid. LC-MS: (M+H)+found:567.15. 'H NMR (400 MHz, DMSO-tfc) 58.15 (q, J= 4.4 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H), 7.28 (d, J= 2.1 Hz, 1H), 7.25-7.14 (m, 2H), 6.87 (dd, J= 14.0, 8.1 Hz, 2H), 6.09 (s, 1H), 5.67 (t, J = 6.5 Hz, 1H), 5.63-5.41 (m, 1H), 4.70 (d, J= 50.2 Hz, 1H), 4.38 (d, J= 6.5 Hz, 2H), 3.84 (s, 4H), 3.13-3.03 (m, 1H), 2.96- 2.91 (m, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.58 (s, 1H), 2.10-1.57 (m, 2H).

[0535] Example 6 - Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-

[0536] [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-N- methylbenzamide (Compound 30)

[0537] Step 1

[0538] To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[4- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-7-yl]amino}piperidine-l-carboxylate (70.00 mg, 0.11 mmol, 1.00 equiv) in DCM (0.90 mL) was added TFA (0.30 mL, 4.04 mmol, 36.74 equiv) dropwise at 0°C. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 56% B in 10 min; Wave Length: 220nm; RT: 7.82 min. This resulted in 4-{[3- (7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]-l-benzothiophen-2- yl)prop-2-yn-l-yl]amino}-N-methylbenzamide (27.6 mg, 46.32%) as a light yellow solid. LC-MS: (M+H)+found:537.10. 'HNMR (400 MHz, DMSO ) 5 8.05 (q, J= 4.5 Hz, 1H), 7.67 (d, J= 8.5 Hz, 2H), 7.37 (t, .7= 7.9 Hz, 1H), 7.22 (d, J= 7.9 Hz, 1H), 6.86 (d, J= 7.9 Hz, 1H), 6.71 (dd, J = 17.7, 7.3 Hz, 3H), 5.51 (d, J = 8.2 Hz, 1H), 4.71 (d, J= 50.6 Hz, 1H), 4.37 (d, J= 6.2 Hz, 2H), 3.77 (d, J= 29.6 Hz, 1H), 3.12 (t, J= 12.5 Hz, 1H), 2.97 (d, J= 13.0 Hz, 1H), 2.87-2.69 (m, 4H), 2.60 (d, J= 12.5 Hz, 1H), 1.77 (qd, J= 12.3, 4.2 Hz, 1H), 1.65 (d, J= 11.7 Hz, 1H).

[0539] Example 7 - Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-

[0540] [(trifluoromethyl)sulfanyl]-l-benzothiophen-2-yl)prop-2-yn-l-yl]amino}-3-methoxy-N- methylbenzamide (Compound 31)

[0541] Step 1

[0542] To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-7-yl]amino}piperidine-l -carboxylate (50.00 mg, 0.08 mmol, 1.00 equiv) in DCM (0.90 mL) was added TFA (0.30 mb, 4.04 mmol, 53.86 equiv) dropwise at 0°C. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 59% B in 30 min; Wave Length: 254nm / 220nm; RT: 7.65 min. This resulted in 4-{[3-(7-{[(3S,4R)-3-fhjoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]-l- benzothiophen-2-yl)prop-2-yn-l-yl]amino} -3 -methoxy -N-methylbenzamide (12.6 mg, 27.84%) as a yellow solid. LC-MS: (M+H)+found:567.10. 'H NMR (400 MHz, DMSO- e) 8 8.11 (q, J = 4.5 Hz, 1H), 7.45-7.33 (m, 3H), 7.22 (d, J= 7.9 Hz, 1H), 6.81 (dd, J= 32.2, 8.1 Hz, 2H), 6.05 (t,

[0543] J= 6.3 Hz, 1H), 5.50 (d, J= 8.3 Hz, 1H), 4.71 (d, J= 50.6 Hz, 1H), 4.39 (d, J= 6.3 Hz, 2H), 3.84 (s, 4H), 3.14-2.93 (m, 3H), 2.86-2.66 (m, 4H), 2.59 (t, J= 12.2 Hz, 1H), 1.77 (qd, J= 12.3, 4.1 Hz, 1H), 1.70-1.62 (m, 1H).

[0544] Example 8 - Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]-l-benzofuran-2-yl)prop-2-yn-l-yl]amino}-3-methoxy-N- methylbenzamide (Compound 1) N-(benzenesulfonyl)-N-

[0545] [(trifluoromethyl)sulfanyl]benzenesulfonamido (1.21 g, 3.04 mmol, 2.00 equiv) in DMF (3.00 mb) were added 7-bromo-l -benzofuran (300.00 mg, 1.52 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80°C under nitrogen atmosphere. The resulting mixture was extracted with Et20 (3 x 3.00 mL). The combined organic layers were washed with brine (3 x 3.00 mL), dried over anhydrous Na2SCU and concentrated under vacuum. The residue was purified by Prep-TLC (n-hexane) to afford 7-bromo-3- [(trifhioromethyl)sulfanyl]-l -benzofuran (270.00 mg, 59.6%) as a colorless liquid. 'H NMR (400 MHz, DMSO-t / e) 5 8.80 (s, 1H), 7.75 (d, J= 7.8 Hz, 2H), 7.42 (t, J= 7.8 Hz, 1H).

[0546] 19F NMR (376 MHz, DMSO- e) 5 -42.48.

[0547] Step 2

[0548] To a stirred solution of 7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran (180.00 mg, 0.60 mmol, 1.00 equiv) in THF (3.00 mL) were added LDA (2M in THF, 1.21 mL, 2.42 mmol, 4.00 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added h (184.53 mg, 0.73 mmol, 1.20 equiv, 0.7 ml THF) dropwise at -78 °C. The resulting mixture was stirred for additional 30 min at -78 °C to room temperature. The reaction was quenched with sat. NH4CI (aq.) and sat. sodium sulfite (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 5.00 mL). The combined organic layers were washed with brine (3 x 5.00 mL), dried over anhydrous Na SO4 and concentrated under reduced pressure. The residue was purified by Prep- TLC (n-hexane) to afford 7-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran (110.00 mg, 42.9%) as a light yellow solid. 'H NMR (400 MHz, DMSO-t / e) 5 7.70-7.62 (m, 2H), 7.37 (t, J= 7.8 Hz, 1H).19F NMR (376 MHz, DMSO- fc) 8 -41.66.

[0549] Step 3

[0550] To a stirred solution of 7-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran (110.00 mg, 0.26 mmol, 1.00 equiv) in DMSO (2.00 mL) were added 3 -methoxy -N-methyL4- (prop-2-yn-l-ylamino)benzamide (73.79 mg, 0.33 mmol, 1.30 equiv), i-PnNH (263.16 mg, 2.60 mmol, 10.00 equiv), Cui (49.53 mg, 0.26 mmol, 1.00 equiv) and Pd(PPhs)4 (30.05 mg, 0.02 mmol, 0.10 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulted solution was purified using Cl 8 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 4-[(3- {7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-2-yl}prop-2-yn-l-yl)amino]-3-methoxy- N-methylbenzamide (67.00 mg, 50.1%) as a brown solid.

[0551] Step 4

[0552] To a stirred solution of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-2- yl}prop-2-yn-l-yl)amino]-3-methoxy-N-methylbenzamide (62.00 mg, 0.12 mmol, 1.00 equiv) and (3 S,4R)-3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (36.90 mg, 0.18 mmol, 1.50 equiv) in 1,4-dioxane (1.50 mL) were added CS2CO3 (196.76 mg, 0.60 mmol, 5.00 equiv) and Pd- PEPPSI-IHeptCl 3 -chloropyridine (11.76 mg, 0.01 mmol, 0.10 equiv) in portions at room temperature. The resulting mixture was stirred for 8 h at 100°C under nitrogen atmosphere. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). The crude was purified using prep-HPLC with following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 64% B in 7min; Wave Length: 254nm / 220nm; RT: 7.85 min. This resulted in 4-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]-l- benzofuran-2-yl)prop-2-yn-l-yl]amino}-3-methoxy-N-methylbenzamide (9.8 mg, 14.3%) as a light yellow solid. LC-MS: (M+H)+found 565.1. 'H NMR (400 MHz, DMSO-c / r,) 8 8.13 (q, J = 4.5 Hz, 1H), 7.42 (dd, J= 8.3, 1.9 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.19 (t, J= 7.9 Hz, 1H), 6.83 (dd, J= 17.8, 7.8 Hz, 2H), 6.75 (d, J= 8.3 Hz, 1H), 6.11 (t, J = 63 Hz, 1H), 5.67 (d, J= 8.7 Hz, 1H), 4.77 (d, J= 49.3 Hz, 1H), 4.42 (d, J= 6.3 Hz, 2H), 3.85 (s, 3H), 3.76-3.57 (m, 1H), 3.01 (t, J= 11.3 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.30-2.12 (m, 4H), 2.05 (t, J= 11.5 Hz, 1H), 1.98-1.84 (m, 1H), 1.69 (d, J= 11.9 Hz, 1H).

[0553] Example 9 - Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]-l-benzofuran-2-yl)prop-2-yn-l-yl]amino}-4-methoxy-N- methylbenzamide (Compound 19)

[0554] Step 1

[0555] To a stirred solution of 3-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-2- yl}prop-2-yn-l-yl)amino]-4-methoxy-N-methylbenzamide (40.00 mg, 0.08 mmol, 1.00 equiv) and (3 S,4R)-3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (20.78 mg, 0.10 mmol, 1.30 equiv) in 1,4-dioxane (0.50 mb) were added Pd-PEPPSI-IHeptCl 3 -chloropyridine (7.59 mg, 0.01 mmol, 0.1 equiv) and CS2CO3 (126.94 mg, 0.39 mmol, 5.00 equiv) at room temperature. The mixture was stirred at 100°C for 3 h under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 50% B in 30 min; 254 / 220 nm). The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HC03+0.05%NH.3'H20), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 38% B to 63% B in 7min; Wave Length: 254nm / 220nm nm; RTl(min): 6.33; Number Of Runs: 1) to afford 3-{[3-(7-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]-l-benzofuran-2-yl)prop-2-yn-l -yl]amino}-4-methoxy-N- methylbenzamide (12.70 mg, 28.81%) as a white solid. LC-MS: (M+H)+found 565.2. *H NMR (400 MHz, DMSO-c / r,) 8 8.16 (q, J = 4.3 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.22-7.14 (m, 2H), 6.93-6.77 (m, 3H), 5.73 (t, J= 6.5 Hz, 1H), 5.65 (d, J= 8.7 Hz, 1H), 4.76 (d, J= 49.3 Hz, 1H), 4.41 (d, J= 6.5 Hz, 2H), 3.84 (s, 3H), 3.65 (d, .7 = 29.1 Hz, 1H), 3.02 (t, J= 11.5 Hz, 1H), 2.75 (d, .7= 4.5 Hz, 4H), 2.18 (s, 4H), 2.06 (t, J = 11.6 Hz, 1H), 1.90 (qd, J= 12.2, 3.8 Hz, 1H), 1.69 (d, J = 12.3 Hz, 1H).

[0556] Example 10 - Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-l-yn-l-yl}-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-7-yl)-l- methylpiperidin-4-amine (Compound 33)

[0557] To a stirred solution of N-(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-2- yl}prop-2-yn-l-yl)-4-methanesulfonyl-2-methoxyaniline (40.00 mg, 0.08 mmol, 1.00 equiv) and (3 S,4R)-3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (19.96 mg, 0.10 mmol, 1.30 equiv) in 1,4-dioxane (0.50 mL) were added Pd-PEPPSI-IHeptCl 3 -chloropyridine (7.29 mg, 0.01 mmol, 0.10 equiv) and CS2CO3 (121.95 mg, 0.38 mmol, 5.00 equiv) at room temperature. The mixture was stirred at 100°C for 3 h under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 25% B to 39% B in 8min; Wave Length: 254nm / 220nm nm; RTl(min): 7.2) to afford (3S,4R)-3-fluoro-N-(2-{3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop- 1 -yn- 1 -yl } -3 -[(trifluoromethyl)sulfanyl]- 1 -benzofuran-7-yl)- 1 - methylpiperidin-4-amine; formic acid (3.10 mg, 6.49%) as an off-white solid. LC-MS: (M+H) found 586.1 . *HNMR (400 MHz, DMSO- e) 8 7.40 (dd, J= 8.3, 2.0 Hz, 1H), 7.26 (d, J= 2.0 Hz, 1H), 7.19 (t, J= 7.8 Hz, 1H), 6.87 (dd, J= 8.1, 4.7 Hz, 2H), 6.82 (d, J= 7.9 Hz, 1H), 6.57 (t, J = 6.3 Hz, 1H), 5.68 (d, J= 8.7 Hz, 1H), 4.79 (d, J= 49.3 Hz, 1H), 4.47 (d, J= 6.2 Hz, 2H), 3.90 (s, 3H), 3.67 (d, J= 30.2 Hz, 1H), 3.10 (s, 4H), 2.83 (d, J= 11.2 Hz, 1H), 2.34 (s, 1H), 2.22 (s, 3H), 2.15-2.05 (m, 1H), 1.89 (dd, J= 12.4, 3.9 Hz, 1H), 1.72 (dd, J= 13.5, 4.3 Hz, 1H).

[0558] Example 11 - Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-

[0559] [(trifluoromethyl)sulfanyl]-l-benzofuran-2-yl)prop-2-yn-l-yl]amino}-4-methoxy-N- methylbenzamide (Compound 24)

[0560] Step 1

[0561] To a stirred solution of 3-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-2- yl}prop-2-yn-l-yl)amino]-4-methoxy-N-methylbenzamide (80.00 mg, 0.16 mmol, 1.00 equiv) and tert-butyl (3 S,4R)-4-amino-3 -fluoropiperidine- 1 -carboxylate (44.22 mg, 0.20 mmol, 1.30 equiv) in 1,4-dioxane (1.00 mb) were added Pd-PEPPSI-IHeptCl 3 -chloropyridine (15.18 mg, 0.02 mmol, 0.10 equiv) and CS2CO3 (253.89 mg, 0.78 mmol, 5.00 equiv) at room temperature. The mixture was stirred at 100°C for 0.5 h under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 70% B in 30 min; 254 / 220 nm). This resulted in tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-7- yl]amino}piperidine-l-carboxylate (30.00 mg, 29.58%) as a yellow oil. LC-MS: (M+H)+found 651.2.

[0562] Step 2

[0563] A solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-7- yl]amino}piperidine-l-carboxylate (30.00 mg, 0.05 mmol, 1.00 equiv) in DCM (0.60 mL) and TFA (0.20 mL, 0.002 mmol) was stirred at room temperature for 0.5 h. The mixture was concentrated under vacuum. The mixture was washed with 3 x 5.00 mL of DCM. The resulting mixture was concentrated under vacuum. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XB Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCC>3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 33% B to 58% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.45) to afford 3-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-2- yl)prop-2-yn-l-yl]amino}-4-methoxy-N-methylbenzamide (2.30 mg, 8.87%) as an off-white solid. LC-MS: (M+H)+found 551.1. ’H NMR (400 MHz, DMSO- e) 5 8.16 (q, J= 4.5 Hz, 1H), 7.25 (d, J= 2.1 Hz, 1H), 7.22-7.14 (m, 2H), 6.89 (d, J= 8.3 Hz, 1H), 6.83 (dd, J= 12.1, 7.8 Hz, 2H), 5.73 (t, J= 6.5 Hz, 1H), 5.67 (d, J= 8.7 Hz, 1H), 4.68 (d, J = 50.4 Hz, 1H), 4.41 (d, J = 6.5 Hz, 2H), 3.84 (s, 4H), 3.12 (t, J= 12.2 Hz, 1H), 2.96 (d, J= 13.2 Hz, 1H), 2.84-2.66 (m, 4H), 2.63-2.55 (m, 1H), 1.67 (dt, J= 21.8, 7.1 Hz, 2H).

[0564] Example 12 - Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-

[0565] [(trifluoromethyl)sulfanyl]-l-benzofuran-2-yl)prop-2-yn-l-yl]amino}-3-methoxy-N- methylbenzamide (Compound 26)

[0566] Step 1

[0567] A solution of tert-butyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4- (methylcarbamoyl)phenyl]amino}prop-l-yn-l-yl)-3-[(trifluoromethyl)sulfanyl]-l-benzofuran-7- yl]amino}piperidine-l-carboxylate (35.00 mg, 0.05 mmol, 1.00 equiv) in DCM (1.50 mL) and TFA (0.50 mL) was stirred at room temperature for 0.5 h under air atmosphere. The mixture was concentrated under vacuum. The resulting mixture was washed with 3 x 5.00 mL of DCM. The resulting mixture was concentrated under vacuum. The crude product (mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30* 150mm 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 24% B to 35% B in8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.5) to afford 4- { [3 -(7- { [(3 S,4R)-3 -fluoropiperidin-4-yl]amino} -3 -[(trifluoromethyl)sulfanyl]- 1 -benzofuran-2- yl)prop-2-yn-l-yl]amino}-3-methoxy-N-methylbenzamide; formic acid (3.60 mg, 11.05%) as a yellow solid. LC-MS: (M+H)+found 551.1.XH NMR (400 MHz, DMSO-cL) 5 8.13 (q, J= 4.5 Hz, 1H), 7.41 (dd, .7= 8.2, 1.8 Hz, 1H), 7.35 (d, J= 1.8 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.84 (dd, J = 15.2, 7.8 Hz, 2H), 6.75 (d, J = 8.3 Hz, 1H), 6.08 (t, J= 6.3 Hz, 1H), 5.72 (d, J = 8.6 Hz, 1H), 4.73 (d, J = 49.9 Hz, 1H), 4.42 (d, J= 6.3 Hz, 2H), 3.85 (s, 4H), 3.17 (d, J = 12.3 Hz, 2H), 3.00 (d, J= 12.8 Hz, 1H), 2.88 (d, J= 14.4 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.62 (d, J= 12.7 Hz, 1H), 1.84-1.64 (m, 2H).

[0568] Assays

[0569] Surface Plasmon Resonance (SPR) Assay Protocol

[0570] 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, 100 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.

[0571] Thermal shift assay protocol

[0572] 5 pM recombinant p53 Y220C mutant protein (amino acid residues 94-293) is incubated with 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. Luciferase reporter assay protocol

[0573] 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) were stably expressed in NCIH1299 cells by lentiviral transduction. The cells were then used for p53 reporter assay. 5,000 cells were 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) was added to each well and the plate was incubated for 5 minutes with shaking at room temperature. The luciferase activity was immediately measured with PheraStar microplate reader. Luciferase activity was stimulated by 10 uM of a tool compound as positive control and ACso was calculated.

[0574] Cell proliferation assay

[0575] Inducible p53 Y220C and R273H constructs (Tet-One inducible expression system; Takara) were 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 were used for cell proliferation assay. 250-500 cells were seeded in each well of 384 plate and then compounds were dispensed into each well using Echo or Tecan. After 5 days of incubation, equal volume of CellTiter-Glo reagent (G7570; Promega) was added into each well and the plate was incubated at room temperature for 10 minutes with shaking. The luminescent signal was measured by PheraStar microplate reader and IC50 was calculated.

[0576] Table B shows results of the SPR p53 Y220C Kd_kinetic (nM), Luc p53 Y220C AC50 (nM), CTG H1299 p53 Y220C IC50 (nM), and CTG NUGC3 p53 Y220C IC50 (nM) assays. Activity categories are as follows:

[0577] • SPR p53 Y220C Kd_kinetic (nM): D > 1000 > C > 100 > B > 10 > A

[0578] • CTG NUGC3 p53 Y220C IC50 (nM): D > 3000 > C > 1500 > B > 750 > A

[0579] • CTG H1299 p53 Y220C IC50 (nM): D > 3000 > C > 1500 > B > 750 > A

[0580] • Luc p53 Y220C AC50 (nM): D > 3000 > C > 1500 > B > 750 > A Table B

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein:XHs O, S, or NR3; each of X2, X3, X4, and X5are CH, N, CR1or CR2, wherein two or more of X2, X3, X4, and X5are independently CH, CR1, or CR2;R1is halogen, cyano, -OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, -C(=O)OR4, -C(=O)NR4R5, -SR4, -S(=O)R4, -S(O2)R4, -NR4C(=O)R5, -R4C(===O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;RAis hydrogen, -OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, -C(=O)OR6, -NR6C(=O)OR7, -C(=O)NR6R7, -SR6, -S(=O)R6, -S(O2)R6, -S(O2)NR6, -NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;-NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;, eachZ1is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene;Z2is CR2C, N, O, or a bond; wherein when Z2is O, R2Bis absent; when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1;R2Aand R2Bare independently hydrogen, -C(=O)R10, -C(=O)OR10,-C(=O)NR10Rn, -S(=O)R10, -S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; orR2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2is O and R2Bis absent;R2Cis hydrogen, halogen, or C1-C6 alkyl;L is an optionally substituted C2-C6 alkynylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2;R3is hydrogen or C1-C6 alkyl; and each R4, R5, R6, R7, R8, R9, R10, and R11are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; with the proviso that when L is C2-C6 alkynylene, RBis -SR82. The compound of Claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting ofpharmaceutically acceptable salt of any of the foregoing.

3. The compound of Claim 1 or 2, wherein one of X2, X3, X4, and X5is N.

4. The compound of Claim 1 or 2, wherein two of X2, X3, X4, and X3are N.

5. The compound of Claim 1 or 2, wherein X2, X3, and X4are CH.

6. The compound of any one of Claims 1-4, wherein one of X2, X3, and X4is CR1.

7. The compound of any one of Claims 1-6, wherein X3is CR1.

8. The compound of any one of Claims 1-6, wherein X5is CR2.

9. The compound of any one of Claims 1-8, wherein R1is hydrogen.

10. The compound of any one of Claims 1-8, wherein R1is halogen.11 . The compound of any one of Claims 1 -8, wherein R1is cyano.

12. The compound of any one of Claims 1-8, wherein R1is -OR4.

13. The compound of any one of Claims 1-8, wherein R1is -NR4R5.

14. The compound of any one of Claims 1-8, wherein R1is -C(=O)R4.

15. The compound of any one of Claims 1-8, wherein R1is -OC(=O)R4.

16. The compound of any one of Claims 1-8, wherein R1is -C(=O)OR4.

17. The compound of any one of Claims 1-8, wherein R1is -C(=O)NR4R5.

18. The compound of any one of Claims 1-8, wherein R1is -SR4.

19. The compound of any one of Claims 1-8, wherein R1is -S(=O)R4.

20. The compound of any one of Claims 1-8, wherein R1is -S(O2)R4.

21. The compound of any one of Claims 1-8, wherein R1is -NR4C(=O)R:>.

22. The compound of any one of Claims 1-8, wherein R1is -R4C(:::O)R5.

23. The compound of any one of Claims 1-8, wherein R1is an optionally substituted C1-C6 alkyl.

24. The compound of any one of Claims 1-8, wherein R1is an optionally substituted C2-C6 alkenyl.

25. The compound of any one of Claims 1-8, wherein R1is an optionally substituted C2-C6 alkynyl.

26. The compound of any one of Claims 1-8, wherein R1is an optionally substituted C3-C10 cycloalkyl.

27. The compound of any one of Claims 1-8, wherein R1is an optionally substituted phenyl.

28. The compound of any one of Claims 1 -8, wherein R1is an optionally substituted 4- 12 membered heterocyclyl.

29. The compound of any one of Claims 1-8, wherein R1is an optionally substituted 5- 10 membered heteroaryl.

30. The compound of any one of Claims 1-29, wherein RAis hydrogen.

31. The compound of any one of Claims 1-29, wherein RAis -OR6.

32. The compound of any one of Claims 1-29, wherein RAis -NR6R7.

33. The compound of any one of Claims 1-29, wherein RAis -C(=O)R6.

34. The compound of any one of Claims 1-29, wherein RAis -R6C(=O)R7.

35. The compound of any one of Claims 1-29, wherein RAis -OC(=O)R6.

36. The compound of any one of Claims 1-29, wherein RAis -OC(=O)NR6.

37. The compound of any one of Claims 1-29, wherein RAis -C(=O)OR6.

38. The compound of any one of Claims 1-29, wherein RAis -NR6C(=O)OR7.

39. The compound of any one of Claims 1-29, wherein RAis -C(=O)NR6R7.

40. The compound of any one of Claims 1-29, wherein RAis -SR6.

41. The compound of any one of Claims 1-29, wherein RAis -S(=O)R6.

42. The compound of any one of Claims 1-29, wherein RAis -S(O2)R6.

43. The compound of any one of Claims 1-29, wherein RAis -S(C>2)NR6.

44. The compound of any one of Claims 1-29, wherein RAis -NR6S(C>2)R7.

45. The compound of any one of Claims 1-29, wherein RAis -NR6C(=O)R7.

46. The compound of any one of Claims 1-29, wherein RAis -NR6C(=O)NR7.

47. The compound of any one of Claims 1-29, wherein RAis -SiR6R7R8.

48. The compound of any one of Claims 1-29, wherein RAis an optionally substitutedC1-C6 alkyl.

49. The compound of any one of Claims 1-29, wherein RAis an optionally substituted C2-C6 alkenyl.

50. The compound of any one of Claims 1-29, wherein RAis an optionally substituted C2-C6 alkynyl.

51. The compound of any one of Claims 1-29, wherein RAis an optionally substituted C3-C10 cycloalkyl.

52. The compound of any one of Claims 1-29, wherein RAis an optionally substituted phenyl.

53. The compound of any one of Claims 1-29, wherein RAis an optionally substituted4-12 membered heterocyclyl.

54. The compound of any one of Claims 1-29, wherein RAis an optionally substituted5-10 membered heteroaryl.

55. The compound of any one of Claims 1-54, wherein RBis halogen.

56. The compound of any one of Claims 1-54, wherein RBis cyano.

57. The compound of any one of Claims 1-54, wherein RBis hydroxyl.

58. The compound of any one of Claims 1-54, wherein RBis -NR8R9.

59. The compound of any one of Claims 1-54, wherein RBis -OR8.

60. The compound of any one of Claims 1-54, wherein RBis -C(=O)NR8R9.

61. The compound of any one of Claims 1-54, wherein RBis -C(=O)R8.

62. The compound of any one of Claims 1-54, wherein RBis -C(=O)OR8.

63. The compound of any one of Claims 1-54, wherein RBis -NR8C(=O)OR964. The compound of any one of Claims 1-54, wherein RBis -OC(=O)R8.

65. The compound of any one of Claims 1-54, wherein RBis -OC(=O)NR8.

66. The compound of any one of Claims 1-54, wherein RBis -C(=O)NR8R9.

67. The compound of any one of Claims 1-54, wherein RBis -NR8C(=O)R9.

68. The compound of any one of Claims 1-54, wherein RBis -NR8C(=O)NR9.

69. The compound of any one of Claims 1-54, wherein RBis -SR8.

70. The compound of any one of Claims 1 -54, wherein RBis -SCF3.

71. The compound of any one of Claims 1-54, wherein RBis -S(=O)R8.

72. The compound of any one of Claims 1-54, wherein RBis -S(O2)R8.

73. The compound of any one of Claims 1-54, wherein RBis -S(O2)NR8.

74. The compound of any one of Claims 1-54, wherein RBis -NR8S(Ch)R9.

75. The compound of any one of Claims 1-54, wherein RBis -RSC(=O)R9.

76. The compound of any one of Claims 1-54, wherein RBis -NR8C(=O)R9.

77. The compound of any one of Claims 1-54, wherein RBis -NR8C(=O)NR9.

78. The compound of any one of Claims 1-54, wherein RBis an optionally substitutedC1-C6 alkyl.

79. The compound of any one of Claims 1-54, wherein RBis C1-C6 haloalkyl.

80. The compound of any one of Claims 1-54, wherein RBis an optionally substitutedC2-C6 alkenyl.

81. The compound of any one of Claims 1-54, wherein RBis an optionally substituted C2-C6 alkynyl.

82. The compound of any one of Claims 1-54, wherein RBis an optionally substituted C3-C10 cycloalkyl.

83. The compound of any one of Claims 1-54, wherein RBis an optionally substituted phenyl.

84. The compound of any one of Claims 1-54, wherein RBis an optionally substituted 3-12 membered heterocyclyl.

85. The compound of any one of Claims 1-54, wherein RBis an optionally substituted 5-10 membered heteroaryl.

86. The compound of any one of Claims 1-85, wherein each87. The compound of any one of Claims 1-86, wherein one of X2, X3, X4, and X5is CR2and the remaining X2, X3, X4, and X5are CH, N, or CR1.

88. The compound of any one of Claims 1-86, wherein Z1is a bond.

89. The compound of any one of Claims 1-86, wherein Z1is -C=O-.

90. The compound of any one of Claims 1-86, wherein Z1is -S(Ch)-.

91. The compound of any one of Claims 1-86, wherein Z1is an optionally substitutedC1-C6 alkylene.

92. The compound of any one of Claims 1 -86, wherein Z1is an optionally substituted C2-C6 alkenylene.

93. The compound of any one of Claims 1-86, wherein Z1is an optionally substituted C2-C6 alkynylene.

94. The compound of any one of Claims 1 -86, wherein Z1is an optionally substituted C3-C4 cycloalkylene.

95. The compound of any one of Claims 1-94, wherein Z2is N.

96. The compound of any one of Claims 1-94, wherein Z2is O and R2Bis absent.

97. The compound of any one of Claims 1-94, wherein Z2is a bond.

98. The compound of any one of Claims 1-94, wherein Z2is CR2C.

99. The compound of any one of Claims 1-94 or 98, wherein R2Cis hydrogen.

100. The compound of any one of Claims 1-94 or 98, wherein R2Cis halogen.

101. The compound of any one of Claims 1-94 or 98, wherein R2Cis C1-C6 alkyl.

102. The compound of any one of Claims 1-87, wherein Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1.

103. The compound of any one of Claims 1-102, wherein R2Ais hydrogen.

104. The compound of any one of Claims 1-102, wherein R2Ais -C(=O)R10.

105. The compound of any one of Claims 1-102, wherein R2Ais -C(=O)OR10.

106. The compound of any one of Claims 1-102, wherein R2 Ais -C(=O)NR10Rn.

107. The compound of any one of Claims 1-102, wherein R2Ais -S(=O)R10.

108. The compound of any one of Claims 1-102, wherein R2Ais -S(O2)R10.

109. The compound of any one of Claims 1-102, wherein R2Ais an optionally substituted C1-C6 alkyl.

110. The compound of any one of Claims 1-102, wherein R2Ais an optionally substituted C2-C6 alkenyl.

111. The compound of any one of Claims 1-102, wherein R2Ais an optionally substituted C2-C6 alkynyl.

112. The compound of any one of Claims 1-97, wherein R2Ais an optionally substituted C3-C10 cycloalkyl.

113. The compound of any one of Claims 1-102, wherein R2Ais an optionally substituted phenyl.

114. The compound of any one of Claims 1-102, wherein R2Ais an optionally substituted4-12 membered heterocyclyl.

115. The compound of any one of Claims 1-102, wherein R2Ais an optionally substituted5-10 membered heteroaryl.

116. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis hydrogen.

117. The compound of any one of Claims 1-101 and 103-115, wherein R2Dis -C(=O)R10.

118. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis -C(=O)OR10.

119. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis -C(=O)NR10Rn.

120. The compound of any one of Claims 1-101 and 103-115, whereinR2Bis -S(=O)R10.

121. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis -S(O2)R10.

122. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted C1-C6 alkyl.

123. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted C2-C6 alkenyl.

124. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted C2-C6 alkynyl.

125. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted C3-C10 cycloalkyl.

126. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted phenyl.

127. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted 4-12 membered heterocyclyl.

128. The compound of any one of Claims 1-101 and 103-115, wherein R2Bis an optionally substituted 5-10 membered heteroaryl.

129. The compound of any one of Claims 1-101, wherein one of R2Aand R2Bis hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2Aand R2Bis hydrogen, -C(=O)R10, -C(=O)OR10, -C(=O)NR10Rn, -S(=O)R10, -S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionallysubstituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl.

130. The compound of any one of Claims 1-101, wherein R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.

131. The compound of any one of Claims 1-130, wherein one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR1, and the remaining X2, X3, X4, and X5are CH or N.

132. The compound of any one of Claims 1-2 or 9-125, wherein one of X2, X3, X4, andX5is CR2, one of X2, X3, X4, and X5is CR1, and the remaining X2, X3, X4, and X5are CH.

133. The compound of any one of Claims 1 -132, wherein m is 0.

134. The compound of any one of Claims 1-132, wherein m is 1.

135. The compound of any one of Claims 1-132, wherein m is 2.

136. The compound of any one of Claims 1-135, wherein L is an optionally substitutedC2-C6 alkynylene.

137. The compound of any one of Claims 1-136, wherein L is a C2-C6 alkynylene.

138. The compound of any one of Claims 1-137, wherein L is a C2-C3 alkynylene.

139. The compound of any one of Claims 1-138, wherein L is a C2-C3 alkynylene and RBis -SCF3.

140. The compound of any one of Claims 1-135, wherein L is optionally substituted 5- 6 membered heteroarylene.

141. The compound of any one of Claims 1-135 or 140, L is 5-6 membered heteroarylene.

142. The compound of any one of Claims 1-135 or 140, L is 5-6 membered heteroarylene and RBis -SCF3.

143. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in Table A or the non-limiting exemplary compounds described herein, or a pharmaceutically acceptable salt of any of the foregoing.

144. A pharmaceutical composition comprising a compound of any one of Claims 1- 143, or a pharmaceutically acceptable salt thereof.

145. 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 1-143, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 144.

146. A method of treating cancer in a subject 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 1-143, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 144.

147. 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 1-143, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 144.

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