Methods for treating 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] Attorney Docket No. 59845-0148WO1

[0002] METHODS FOR TREATING P53-ASSOCIATED CANCER

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U. S. Provisional Appl. Nos. 63 / 748,262, filed on January 22, 2025, 63 / 774,528, filed on March 19, 2025 and 63 / 837,450 filed on July 2, 2025, which are hereby incorporated by reference in their entirety.

[0005] SEQUENCE LISTING

[0006] This application contains a Sequence Listing that has been submitted electronically as an XML file named “59845-0148_ST26_SL.” The XML file, created on January 21, 2026, is 2,254 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0007] TECHNICAL FIELD

[0008] 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).

[0009] BACKGROUND

[0010] 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 & DifferentiationAttorney Docket No. 59845-0148WO1

[0011] (2018) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both classes of mutations prevent p53-driven transcriptional activation, thus abrogating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).

[0012] 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).

[0013] SUMMARY

[0014] Some embodiments provide a compound of Formula (I):

[0015] R2

[0016] yi

[0017] X4 / Y1- ^ _

[0018]

[0019] SRF(I)

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] X1is CR1, N, NH, O, or S;

[0022] R1is hydrogen, 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,Attorney Docket No. 59845-0148WO1

[0023] optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0024] each of X2, X3, and X4is independently CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;

[0025] each of Y1and Y2is independently C or N,

[0026] wherein when X1is NH, O, or S, then each of X2, X3, and X4is independently CH or CR3, and each of Y1and Y2is C;

[0027] each — — represents a single bond or a double bond;

[0028] R2A

[0029] R

[0030]

[0031] 2is R2B;

[0032] Z is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;

[0033] R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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

[0034] R2Aand R2Btogether with the atom(s) 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;

[0035] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[0036] each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10Rn, -SR9, -S(=O)R9, -S(O2)R9, -

[0037]

[0038] S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

[0039] A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;

[0040] each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;Attorney Docket No. 59845-0148WO1

[0041] R’ is hydrogen or C1-C6 alkyl;

[0042] each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl, or

[0043] two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl;

[0044] RFis -CF3or -CHF2;

[0045] 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; and

[0046] m is 1 or 2.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.Attorney Docket No. 59845-0148WO1

[0052] 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.

[0053] 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.

[0054] 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 TP 53 gene, a p53 protein, or activity of any of the same.

[0055] 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.

[0056] Other embodiments include those described in the Detailed Description and / or in the claims.

[0057] Additional Definitions

[0058] 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.

[0059] 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.Attorney Docket No. 59845-0148WO1

[0060] 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.

[0061] 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.

[0062] The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe eta!., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rded.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0063] 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 notAttorney Docket No. 59845-0148WO1

[0064] specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form 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.

[0065] 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.

[0066] 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.

[0067] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. 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,Attorney Docket No. 59845-0148WO1

[0068] heteroaryl, heteroaryl oxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, alkoxy carbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O-carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, ureido, -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, and -S(O2)-(NR’)(C=O)R”, wherein R’ is hydrogen or alkyl, and R” is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl.

[0069] The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0070] 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.

[0071] The term "hydroxyl" refers to an -OH radical.

[0072] The term “sulfhydryl” refers to a -SH radical.

[0073] The term "cyano" refers to a -CN radical.

[0074] The term “azido” refers to a -N3 radical.

[0075] The term “nitro” refers to a -NO2 radical.

[0076] The term “nitroso” refers to a -N=O radical.

[0077] 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, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-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.Attorney Docket No. 59845-0148WO1

[0078] The term “acyl” refers to a -C(=O)alkyl radical (e.g., acetyl), or a -C(=O)alkenyl radical

[0079]

[0080] (eg., -C(=0)-CH=CH2), or -C(=O)alkynyl radical (eg., ° ). Acyl groups can be substituted with cyano or with 1-3 independently selected halogens. As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.

[0081] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.

[0082] 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.

[0083] 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[1.1.1]pentane, bicyclo[3 1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]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.

[0084] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the systemAttorney Docket No. 59845-0148WO1

[0085] contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazol yl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]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

[0086] 1 r n l| x JJ °

[0087]

[0088] nl\ -| or I ), and imidazolone (e.g., ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0089] 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, 1-6Attorney Docket No. 59845-0148WO1

[0090] heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam or phosphinane oxide) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S, S-di oxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1-2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[l.1. l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1 ]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2. l]heptane, 6-azabicyclo[3.1.1 ]heptane,

[0091]

[0092] 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[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5] octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.

[0093] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.Attorney Docket No. 59845-0148WO1

[0094] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0095] The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0096] The term “hydroxy lkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

[0097] The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0098] The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0099] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0100] The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy (e.g., methoxy ethyl).

[0101] The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with hydroxy.

[0102] The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy.

[0103] The term “alkoxyamino” refers to an -0-amino radical (e.g., -OCH2CH2N(CH3)2).

[0104] The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3).

[0105] The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl).

[0106] The term “haloalkenoxy” refers to an -O-haloalkenyl radical.

[0107] The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl).

[0108] The term “haloalkynoxy” refers to an -O-haloalkynyl radical.

[0109] The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).

[0110] The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy).

[0111] The term “heteroaryl oxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy).

[0112] The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or -O-oxetanyl).

[0113] The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl).Attorney Docket No. 59845-0148WO1

[0114] The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).

[0115] The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).

[0116] The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyl oxetanyl).

[0117] The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e g., benzyloxy).

[0118] The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).

[0119] The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).

[0120] 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.

[0121] 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)).

[0122] A “sulfinyl” group refers to an -S(=O)R group in which R can be the same as defined with respect to sulfenyl.

[0123] A “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl.

[0124] 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.

[0125] 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,Attorney Docket No. 59845-0148WO1

[0126] cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclyl alkyl, or cycloalkylalkyl.

[0127] 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.

[0128] 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.

[0129] A “thiocarbonyl” group refers to a -C(=S)R group in which R can be the same as defined with respect to O-carboxy.

[0130] A “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen. 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.

[0131] An “S-sulfonamido” group refers to a -SO2N(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.

[0132] An “N-sulfonamido” group refers to a RSC>2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0133] 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.

[0134] An “N-carbamyl” group refers to an R0C(=0)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.

[0135] 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,Attorney Docket No. 59845-0148WO1

[0136] cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] The terms “ureido” or “urea” refer to an -NR(C=0)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.

[0141] The term “carboxaldehyde” refers to a -C(=O)H radical.

[0142] 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.

[0143] 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).

[0144] The term “phosphine oxide” refers to a -P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree ofAttorney Docket No. 59845-0148WO1

[0145] 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.

[0146] 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

[0147] (e.g., [x.x. O] ring systems, in which 0 represents a zero atom bridge (e.g.,

[0148]

[0149] single ring atom (spiro-fused ring systems) (e

[0150]

[0151] .g.,, or

[0152] a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

[0153]

[0154]

[0155] , or

[0156] 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.

[0157] 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:

[0158]

[0159] encompasses the tautomeric form containing the moiety:

[0160]

[0161] H. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0162] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well asAttorney Docket No. 59845-0148WO1

[0163] 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.

[0164] 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.

[0165] DETAILED DESCRIPTION

[0166] 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).

[0167] Formulae

[0168]

[0169] Some embodiments provide a compound of Formula (I):

[0170] R2

[0171] NR6— A"^RA)m

[0172]

[0173] S" RF(I)

[0174] or a pharmaceutically acceptable salt thereof, wherein:

[0175] X1is CR1, N, NH, O, or S;

[0176] R1is hydrogen, 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,Attorney Docket No. 59845-0148WO1

[0177] optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0178] each of X2, X3, and X4is independently CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;

[0179] each of Y1and Y2is independently C or N,

[0180] wherein when X1is NH, O, or S, then each of X2, X3, and X4is independently CH or CR3, and each of Y1and Y2is C;

[0181] each — — represents a single bond or a double bond;

[0182] R2A

[0183] R

[0184]

[0185] 2is R2B;

[0186] Z is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;

[0187] R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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

[0188] R2Aand R2Btogether with the atom(s) 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;

[0189] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[0190] each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10Rn, -SR9, -S(=O)R9, -S(O2)R9, -

[0191]

[0192] S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

[0193] A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;

[0194] each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;Attorney Docket No. 59845-0148WO1

[0195] R’ is hydrogen or C1-C6 alkyl;

[0196] each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl, or

[0197] two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl;

[0198] RFis -CF3or -CHF2;

[0199] 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; and

[0200] m is 1 or 2.

[0201] Some embodiments provide a compound of Formula (la):

[0202] R2

[0203] / L vi

[0204] X4 /

[0205] \R6— A^(RA)m

[0206]

[0207] S~~RF(la)

[0208] or a pharmaceutically acceptable salt thereof, wherein:

[0209] X1is CR1, N, NH, O, or S;

[0210] R1is hydrogen, 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)R5optionally 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;

[0211] each of X2, X3, and X4are CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;

[0212] each of Y1and Y2are C or N,

[0213] wherein when X1is NH, O, or S, then each of X2, X3, and X4are CH or CR3, and each of Y1and Y2are C;

[0214] each represents a single bond or a double bond;Attorney Docket No. 59845-0148WO1

[0215] R2A

[0216] 7

[0217]

[0218] \2B;

[0219] Z is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;

[0220] R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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

[0221] 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 Z is O and R2Bis absent;

[0222] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[0223] each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10R11, -SR9, -S(=O)R9, -S(O2)R9, -

[0224]

[0225] S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

[0226] A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;

[0227] each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;

[0228] R’ is hydrogen or C1-C6 alkyl;

[0229] each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C3-C6 cycloalkyl;

[0230] RFis -CF3or -CHF2;

[0231] 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,Attorney Docket No. 59845-0148WO1

[0232] optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; and

[0233] m is 1 or 2.

[0234] Some embodiments provide a compound of Formula (lb):

[0235] R2

[0236] X4Y1

[0237] —NR«-A-<RA)™

[0238]

[0239] SRF(lb)

[0240] or a pharmaceutically acceptable salt thereof, wherein:

[0241] X1is CR1, N, NH, O, or S;

[0242] R1is hydrogen, 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)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;

[0243] each of X2, X3, and X4are CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;

[0244] each of Y1and Y2are C or N,

[0245] wherein when X1is NH, O, or S, then each of X2, X3, and X4are CH or CR3, and each of Y1and Y2are C;

[0246] each --represents a single bond or a double bond;

[0247] R2A

[0248] R2is R2B;

[0249] Z

[0250]

[0251] is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;

[0252] R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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; orAttorney Docket No. 59845-0148WO1

[0253] R2Aand R2Btogether with the atom(s) 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 Z is O and R2Bis absent;

[0254] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[0255] each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10R11, -SR9, -S(=O)R9, -S(O2)R9, -S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

[0256] A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;

[0257] each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;

[0258] R’ is hydrogen or C1-C6 alkyl;

[0259] each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl, or

[0260] two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl;

[0261] RFis -CF3or -CHF2;

[0262] 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; and

[0263] m is 1 or 2.

[0264] In some embodiments, one of X2, X3, and X4is N.

[0265] In some embodiments, two of X2, X3, and X4are N.

[0266] In some embodiments, X1is N.

[0267] In some embodiments, X1is NH.

[0268] In some embodiments, X1is O.Attorney Docket No. 59845-0148WO1

[0269] In some embodiments, X1is S.

[0270] In some embodiments, X1is CR1.

[0271] In some embodiments, R1is hydrogen.

[0272] In some embodiments, R1is halogen.

[0273] In some embodiments, R1is cyano.

[0274] In some embodiments, R1is -OR4.

[0275] In some embodiments, R1is -NR4R5.

[0276] In some embodiments, R1is -C(=O)R4.

[0277] In some embodiments, R1is -OC(=O)R4.

[0278] In some embodiments, R1is -C(=O)OR4.

[0279] In some embodiments, R1is -C(=O)NR4R5.

[0280] In some embodiments, R1is -SR4.

[0281] In some embodiments, R1is -S(=O)R4.

[0282] In some embodiments, R1is -S(O2)R4.

[0283] In some embodiments, R1is -NR4C(=O)R:>.

[0284] In some embodiments, R

[0285]

[0286] 1is -R4C(:=:O)R’.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.Attorney Docket No. 59845-0148WO1

[0292] In some embodiments, R3is 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.

[0293] In some embodiments, R5is 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.

[0294] In some embodiments, R3is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0295] In some embodiments, R3is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0296] 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.

[0297] In some embodiments, when R4and R5are 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 R5are 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.

[0298] In some embodiments, when R4and R5are attached to the same nitrogen atom, one of R4and R5is hydrogen and the other of R4and R5is an 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.

[0299] In some embodiments, when R4and R5are attached to the same nitrogen atom, one of R4and R5is 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.

[0300] In some embodiments, R1is an optionally substituted C1-C6 alkyl. In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is methyl or ethyl.Attorney Docket No. 59845-0148WO1

[0301] In some embodiments, R1is an optionally substituted C2-C6 alkenyl. Tn some embodiments, R1is C2-C6 alkenyl. In some embodiments, R1is an optionally substituted C2-C3 alkenyl. In some embodiments, R1is C2-C3 alkenyl.

[0302] In some embodiments, R1is an optionally substituted C2-C6 alkynyl. In some embodiments, R1is C2-C6 alkynyl. In some embodiments, R1is an optionally substituted C2-C3 alkynyl. In some embodiments, R1is C2-C3 alkynyl.

[0303] In some embodiments, R1is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R1is C3-C6 cycloalkyl.

[0304] In some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is phenyl.

[0305] In some embodiments, R1is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R1is 4-6 membered heterocyclyl.

[0306] In some embodiments, R1is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is 5-6 membered heteroaryl.

[0307] In some embodiments, Y1is C.

[0308] In some embodiments, Y1is N.

[0309] In some embodiments, Y2is C.

[0310] In some embodiments, Y2is N.

[0311] In some embodiments, when X1is NH, O, or S, then each of X2, X3, and X4are CH or CR3, and each of Y1and Y2are C.

[0312] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:Attorney Docket No. 59845-0148WO1

[0313]

[0314] J), or a pharmaceutically acceptable salt of any of the foregoing.

[0315] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:Attorney Docket No. 59845-0148WO1

[0316] (I-AA), (I-BB), (I-CC), (I-DD), (I-EE),

[0317]

[0318] (I-FF),Attorney Docket No. 59845-0148WO1

[0319] (I-GG),

[0320] (I-HH),

[0321] (I-II), and

[0322]

[0323] (I-JJ), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazine.

[0324] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting ofAttorney Docket No. 59845-0148WO1 R2

[0325] (I-K),

[0326] (I-L), R2

[0327] (I-M), R2

[0328] (I-N),

[0329] (1-0),

[0330] (I-P),

[0331]

[0332] Attorney Docket No. 59845-0148WO1

[0333] (I-Q),

[0334] (I-R),

[0335]

[0336] (I-S),

[0337]

[0338] (I-T), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazine.

[0339] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting ofAttorney Docket No. 59845-0148WO1

[0340]

[0341] Attorney Docket No. 59845-0148WO1

[0342]

[0343] (I-Jl) or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazine.

[0344] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[0345] (I-A2),

[0346] (I-B2),

[0347]

[0348] Attorney Docket No. 59845-0148WO1

[0349] (I-C2), (I-D2), (I-E2), (I-F2), (I-G2),

[0350]

[0351] Attorney Docket No. 59845-0148WO1

[0352] 0(I-H2),

[0353]

[0354] O (I-I2), and

[0355]

[0356] O (I-J2), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0357] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0358] thereof, is

[0359]

[0360] (I-A3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, isAttorney Docket No. 59845-0148WO1

[0361]

[0362] 0(I-A4). In some embodiments, the compound of Formula (I), or

[0363]

[0364] pharmaceutically acceptable salt thereof, is

[0365]

[0366] O (I-A5). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

[0367] O (I-A6). In some embodiments, the compound acceptable salt thereof, is

[0368] 0(I-A7). In some embodiments, the compound

[0369]

[0370] Attorney Docket No. 59845-0148WO1

[0371] of Formula (I), or a pharmaceutically acceptable salt thereof, is

[0372]

[0373] O (I-A8).

[0374] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0375]

[0376] (I-B3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0377] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0378] thereof, i

[0379]

[0380] s (I-C3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.Attorney Docket No. 59845-0148WO1

[0381] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0382] thereof, is

[0383]

[0384] O (I-D3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0385] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0386]

[0387] (I-E3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0388] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0389]

[0390] (I-F3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.Attorney Docket No. 59845-0148WO1

[0391] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0392]

[0393] (I-G3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0394] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0395]

[0396] (I-H3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0397] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0398] thereof,

[0399]

[0400] is (I-I3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.Attorney Docket No. 59845-0148WO1

[0401] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0402] thereof,

[0403]

[0404] is O (I-J3), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0405] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[0406] (I-A9),

[0407] (I-B4),

[0408] (I-C4),

[0409]

[0410] Attorney Docket No. 59845-0148WO1

[0411] (I-D4), (I-E4), (I-F4), (I-G4), (I-H4),

[0412]

[0413] Attorney Docket No. 59845-0148WO1

[0414] (I-I4),

[0415]

[0416] O (I-J4), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0417] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0418] thereof, i

[0419]

[0420] s (I-A10), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine. In some embodiments, the compound of thereof, is

[0421]

[0422] embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, isAttorney Docket No. 59845-0148WO1

[0423]

[0424] embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

[0425]

[0426] (I-A13). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

[0427]

[0428] O (I-A14). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

[0429]

[0430] Attorney Docket No. 59845-0148WO1

[0431] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0432] thereof, i

[0433]

[0434] s 0 (I-B5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0435] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0436] thereof, i

[0437]

[0438] s O (I-C5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0439] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0440] thereof, i

[0441]

[0442] s O (I-D5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.Attorney Docket No. 59845-0148WO1

[0443] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0444] thereof, i

[0445]

[0446] s O (I-E5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0447] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0448] thereof, i

[0449]

[0450] s (I-F5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0451] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0452]

[0453] (I-G5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.Attorney Docket No. 59845-0148WO1

[0454] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0455] thereof, i

[0456]

[0457] s O (I-H5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0458] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0459]

[0460] (I-I5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0461] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt

[0462] thereof, i

[0463]

[0464] s (I-J5), wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[0465] 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.Attorney Docket No. 59845-0148WO1

[0466] 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.

[0467] 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.

[0468] 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.

[0469] 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.

[0470] 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.

[0471] 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.

[0472] 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.

[0473] 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.

[0474] 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.

[0475] 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.Attorney Docket No. 59845-0148WO1

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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. In some embodiments, the optionally substituted C1-C6 alkyl of R8is a C1-C6 haloalkyl.

[0481] 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. In some embodiments, the optionally substituted C1-C3 alkyl of R8is a C1-C3 haloalkyl. In some embodiments, R8is substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen. In some embodiments, R8is substituted Cl alkyl, wherein the Cl alkyl is substituted with halogen. In some embodiments, R8is substituted Cl alkyl, wherein the Cl alkyl is substituted with 1, 2, or 3 halogen (e.g., fluoro or chloro). In some embodiments, R8is substituted Cl alkyl, wherein the Cl alkyl is substituted with 1 halogen. In some embodiments, R8is substituted Cl alkyl, wherein the Cl alkyl is substituted with 2 halogen. In some embodiments, R8is substituted Cl alkyl, wherein the Cl alkyl is substituted with 3 halogen.

[0482] In some embodiments, R8is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.Attorney Docket No. 59845-0148WO1

[0483] 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.

[0484] 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.

[0485] 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.

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] In some embodiments, A is optionally substituted C6-C10 aryl. In some embodiments, A is C6-C10 aryl. In some embodiments, A is substituted C6-C10 aryl. In some embodiments, A is C6-C10 aryl substituted with 1-3 optional substituents. In some embodiments, A is C6-C10 aryl substituted with 1-2 optional substituents. In some embodiments, A is C6-C10 aryl substituted with 1 optional substituent.

[0491] In some embodiments, A is optionally substituted phenyl. In some embodiments, A is optionally substituted 2,3-dihydro-lH-indenyl. In some embodiments, A is optionally substituted naphthyl. In some embodiments, A is optionally substituted tetrahydronaphthyl.

[0492] In some embodiments, A is optionally substituted 5-10 membered heteroaryl. In some embodiments, A is 5-10 membered heteroaryl. In some embodiments, A is substituted 5-10 membered heteroaryl. In some embodiments, A is 5-10 membered heteroaryl substituted with 1-3Attorney Docket No. 59845-0148WO1

[0493] optional substituents. In some embodiments, A is 5-10 membered heteroaryl substituted with 1-2 optional substituents. In some embodiments, A is 5-10 membered heteroaryl substituted with 1 optional substituent.

[0494] In some embodiments, A is optionally substituted 6 membered heteroaryl. In some embodiments, A is 6 membered heteroaryl. In some embodiments, A is substituted 6 membered heteroaryl. In some embodiments, A is 6 membered heteroaryl substituted with 1-3 optional substituents. In some embodiments, A is 6 membered heteroaryl substituted with 1-2 optional substituents. In some embodiments, A is 6 membered heteroaryl substituted with 1 optional substituent.

[0495] In some embodiments, A is optionally substituted 9 membered heteroaryl. In some embodiments, A is 9 membered heteroaryl. In some embodiments, A is substituted 9 membered heteroaryl. In some embodiments, A is 9 membered heteroaryl substituted with 1-3 optional substituents. In some embodiments, A is 9 membered heteroaryl substituted with 1-2 optional substituents. In some embodiments, A is 9 membered heteroaryl substituted with 1 optional substituent.

[0496] In some embodiments, A is optionally substituted 10 membered heteroaryl. In some embodiments, A is 10 membered heteroaryl. In some embodiments, A is substituted 10 membered heteroaryl. In some embodiments, A is 10 membered heteroaryl substituted with 1-3 optional substituents. In some embodiments, A is 10 membered heteroaryl substituted with 1-2 optional substituents. In some embodiments, A is 10 membered heteroaryl substituted with 1 optional substituent.

[0497] In some embodiments, the heteroaryl of A is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, 3,4-dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl, or isoquinolinyl. In some embodiments, the heteroaryl of A is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of A is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline.Attorney Docket No. 59845-0148WO1

[0498] In some embodiments, -A-(RA)mis

[0499]

[0500] ', wherein Ring A is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazine.

[0501] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is substituted phenyl. In some embodiments, Ring A is phenyl substituted with 1-3 optional substituents. In some embodiments, Ring A is phenyl substituted with 1-2 optional substituents. In some embodiments, Ring A is phenyl substituted with 1 optional substituent.

[0502] In some embodiments, Ring A is optionally substituted pyridinyl. In some embodiments, Ring A is substituted pyridinyl. In some embodiments, Ring A is pyridinyl substituted with 1-3 optional substituents. In some embodiments, Ring A is pyridinyl substituted with 1-2 optional substituents. In some embodiments, Ring A is pyridinyl substituted with 1 optional substituent.

[0503] In some embodiments, Ring A is optionally substituted pyrimidinyl. In some embodiments, Ring A is substituted pyrimidinyl. In some embodiments, Ring A is pyrimidinyl substituted with 1-3 optional substituents. In some embodiments, Ring A is pyrimidinyl substituted with 1-2 optional substituents. In some embodiments, Ring A is pyrimidinyl substituted with 1 optional substituent.

[0504] In some embodiments, Ring A is optionally substituted pyrazinyl. In some embodiments, Ring A is substituted pyrazinyl. In some embodiments, Ring A is pyrazinyl substituted with 1-3 optional substituents. In some embodiments, Ring A is pyrazinyl substituted with 1-2 optional substituents. In some embodiments, Ring A is pyrazinyl substituted with 1 optional substituent.

[0505] In some embodiments, Ring A is optionally substituted pyridazine. In some embodiments, Ring A is substituted pyridazine. In some embodiments, Ring A is pyridazine substituted with 1-3 optional substituents. In some embodiments, Ring A is pyridazine substituted with 1-2 optional substituents. In some embodiments, Ring A is pyridazine substituted with 1 optional substituent.Attorney Docket No. 59845-0148WO1

[0506] In some embodiments, -A-(RA)mis selected from the group of:

[0507]

[0508] In some embodiments, -A-(RA)mis

[0509]

[0510] Attorney Docket No. 59845-0148WO1

[0511]

[0512] In some embodiments, A is substituted with an acid bioisostere.

[0513] In some embodiments, A is substituted with alkoxy and -C(=O)(NR’)-SO2R”. In some embodiments, A is substituted with C1-C6 alkoxy and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with methoxy and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with deuterated methoxy (-OCD3) and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with ethoxy and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with -

[0514] OCH2CH2OCH3 and -C(=O)(NH)-SO2R”. In some embodiments, A is

[0515]

[0516] and -C(=O)(NH)-SO2R”.

[0517] In some embodiments, A is substituted with alkyl and -C(=O)(NR’)-SO2R”. In some embodiments, A is substituted with C1-C6 alkyl and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with methyl and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with deuterated methyl (-CD3) and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with ethyl and -C(=O)(NH)-SO2R”.Attorney Docket No. 59845-0148WO1

[0518] In some embodiments, A is substituted with haloalkyl and -C(=O)(NR’)-SO2R”. In some embodiments, A is substituted with C1-C6 haloalkyl and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with -CF3 or -CHF2, and -C(=O)(NH)-SO2R”.

[0519] In some embodiments, A is substituted with cycloalkyl and -C(=O)(NR’)-SC>2R”. In some embodiments, A is substituted with C3-C6 cycloalkyl and -C(=O)(NH)-SO2R”. In some embodiments, A is substituted with cyclopropyl and -C(=O)(NH)-SO2R”.

[0520] In some embodiments, A is substituted with C-amido and -C(=O)(NR’)-SO2R”. In some embodiments, A is substituted with -(C=O)NHCH3 and -C(=O)(NH)-SO2R”.

[0521] In some embodiments, m is 1.

[0522] In some embodiments, m is 2.

[0523] In some embodiments, RAis -C(=O)(NR’)-S(O2)R”.

[0524] In some embodiments, RAis -C(=O)(NR’)-S(O2)-NR”R”.

[0525] In some embodiments, RAis -C(=O)(NR’)-S(O2)-NR”R”, wherein each R” is independently optionally substituted C1-C6 alkyl.

[0526] In some embodiments, RAis -C(=O)(NR’)-S(O2)-NR”R”, wherein two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl. In some embodiments, RAis -S(O2)-(NR’)(C=O)R”.

[0527] In some embodiments, R’ is hydrogen.

[0528] In some embodiments, R’ is C1-C6 alkyl. In some embodiments, R’ is C1-C3 alkyl. In some embodiments, R’ is methyl.

[0529] In some embodiments, R” is optionally substituted Cl -C6 alkyl. In some embodiments, R” is unsubstituted C1-C6 alkyl. In some embodiments, R” is substituted C1-C6 alkyl. In some embodiments, R” is C1-C3 alkyl. In some embodiments, R” is methyl, ethyl, n-propyl, or isopropyl.

[0530] In some embodiments, R” is optionally substituted C1-C6 haloalkyl. In some embodiments, R” is unsubstituted C1-C6 haloalkyl. In some embodiments, R” is substituted Cl-C6 haloalkyl. In some embodiments, R” is C1-C3 haloalkyl. In some embodiments, R” is -CF3, -CH2CF3, or -CHF2.

[0531] In some embodiments, R” is optionally substituted C3-C6 cycloalkyl. In some embodiments, R” is unsubstituted C3-C6 cycloalkyl. In some embodiments, R” is substituted C3-Attorney Docket No. 59845-0148WO1

[0532] C6 cycloalkyl. In some embodiments, R” is C3-C4 cycloalkyl. In some embodiments, R” is cyclopropyl.

[0533] In some embodiments, two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form a substituted 3-12 membered heterocyclyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form an unsubstituted 3-12 membered heterocyclyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-8 membered heterocyclyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-6 membered heterocyclyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form an optionally substituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form a substituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, two R” taken together with the atom(s) to which they are attached together form an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0534]

[0535] Attorney Docket No. 59845-0148WO1

[0536]

[0537] Attorney Docket No. 59845-0148WO1

[0538] R2A

[0539] Iz(2B

[0540] In some embodiments,

[0541]

[0542] R2isR.

[0543] In some embodiments, Z is N.

[0544] In some embodiments, Z is O and R2Bis absent.

[0545] In some embodiments, Z is a bond.

[0546] In some embodiments, Z is CR2C.

[0547] In some embodiments, R2Cis hydrogen.

[0548] 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.

[0549] In some embodiments, R2is -NR2AR2B, i.e., Z is N.

[0550] In some embodiments, R2Ais hydrogen.

[0551] In some embodiments, R2Ais -C(=O)R7.

[0552] In some embodiments, R2Ais -C(=O)OR7.

[0553] In some embodiments, R2Ais -C(=O)NR7R8.

[0554] In some embodiments, R2Ais -S(=O)R7.

[0555] In some embodiments, R2Ais -S(O2)R8.

[0556] In some embodiments, R2Ais an optionally substituted Cl -C6 alkyl. In some embodiments, R2Ais C1-C6 alkyl. In some embodiments, R2Ais methyl or ethyl.

[0557] In some embodiments, R2Ais C1-C6 haloalkyl. In some embodiments, R2Ais C1-C3 haloalkyl. In some embodiments, R2Ais trifluoromethyl.

[0558] In some embodiments, R2Ais an optionally substituted C2-C6 alkenyl. In some embodiments, R2Ais C2-C6 alkenyl. In some embodiments, R2Ais an optionally substituted C2-C3 alkenyl. In some embodiments, R2Ais C2-C3 alkenyl.

[0559] In some embodiments, R2Ais an optionally substituted C2-C6 alkynyl. In some embodiments, R2Ais C2-C6 alkynyl. In some embodiments, R2Ais an optionally substituted C2-C3 alkynyl. In some embodiments, R2Ais C2-C3 alkynyl.Attorney Docket No. 59845-0148WO1

[0560] In some embodiments, R2Ais an optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Ais an optionally substituted C3-C6 cycloalkyl. In some embodiments, R2Ais C3-C10 cycloalkyl. In some embodiments, R2Ais C3-C6 cycloalkyl.

[0561] In some embodiments, R2Ais an optionally substituted phenyl. In some embodiments, R2Ais phenyl.

[0562] In some embodiments, R2Ais an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2Ais an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Ais 3-12 membered heterocyclyl. In some embodiments, R2Ais 4-8 membered heterocyclyl.

[0563] In some embodiments, R2Ais an optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Ais an optionally substituted 5-6 membered heteroaryl. In some embodiments, R2Ais 5-10 membered heteroaryl. In some embodiments, R2Ais 5-6 membered heteroaryl.

[0564] In some embodiments, R2Bis hydrogen.

[0565] In some embodiments, R2Bis -C(=O)R7.

[0566] In some embodiments, R2Bis -C(=O)OR7.

[0567] In some embodiments, R2Bis -C(=O)NR7R8.

[0568] In some embodiments, R2Bis -S(=O)R7.

[0569] In some embodiments, R2Bis -S(O2)R7.

[0570] In some embodiments, R2Bis an optionally substituted C1-C6 alkyl. In some embodiments, R2Bis C1-C6 alkyl. In some embodiments, R2Bis methyl or ethyl.

[0571] In some embodiments, R2Bis C1-C6 haloalkyl. In some embodiments, R2Bis C1-C3 haloalkyl. In some embodiments, R2Bis trifluoromethyl.

[0572] In some embodiments, R2Bis an optionally substituted C2-C6 alkenyl. In some embodiments, R2Bis C2-C6 alkenyl. In some embodiments, R2Bis an optionally substituted C2-C3 alkenyl. In some embodiments, R2Bis C2-C3 alkenyl.

[0573] In some embodiments, R2Bis an optionally substituted C2-C6 alkynyl. In some embodiments, R2Bis C2-C6 alkynyl. In some embodiments, R2Bis an optionally substituted C2-C3 alkynyl. In some embodiments, R2Bis C2-C3 alkynyl.

[0574] In some embodiments, R2Bis an optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Bis an optionally substituted C3-C6 cycloalkyl. In some embodiments, R2Bis C3-C10 cycloalkyl. In some embodiments, R2Bis C3-C6 cycloalkyl.Attorney Docket No. 59845-0148WO1

[0575] In some embodiments, R2Bis an optionally substituted phenyl. In some embodiments, R2Bis phenyl.

[0576] In some embodiments, R2Bis an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2Bis an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Bis 3-12 membered heterocyclyl. In some embodiments, R2Bis 4-8 membered heterocyclyl.

[0577] In some embodiments, R2Bis an optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Bis an optionally substituted 5-6 membered heteroaryl. In some embodiments, R2Bis 5-10 membered heteroaryl. In some embodiments, R2Bis 5-6 membered heteroaryl.

[0578] In some embodiments, R2Bis -C(=O)R7, -C(=O)OR7, C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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.

[0579] In some embodiments, one of R2Aand R2Bis hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2Aand R2Bis hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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.

[0580] 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 R2Bis 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.

[0581] 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.

[0582] In some embodiments, R2Ais hydrogen.Attorney Docket No. 59845-0148WO1

[0583] F.

[0584] In some embodiments, R

[0585]

[0586] 2Bis ''

[0587] OH

[0588] 6H embodiments, R

[0589]

[0590] 2Bis, or

[0591] In some embodiments, R2Bi

[0592]

[0593] Attorney Docket No. 59845-0148WO1

[0594]

[0595] Attorney Docket No. 59845-0148WO1 5

[0596]

[0597] Attorney Docket No. 59845-0148WO1

[0598]

[0599] 10

[0600]

[0601] Attorney Docket No. 59845-0148WO1

[0602] some embodiments, H

[0603]

[0604] Attorney Docket No. 59845-0148 WO 1

[0605]

[0606] Attorney Docket No. 59845-0148WO1

[0607]

[0608] Attorney Docket No. 59845-0148WO1

[0609]

[0610] Attorney Docket No. 59845-0148WO1

[0611] In some embodiments, R2Bis

[0612]

[0613] Attorney Docket No. 59845-0148WO1

[0614] 5

[0615]

[0616] Attorney Docket No. 59845-0148WO1

[0617] O

[0618]

[0619]

[0620] In some embodiments, R2is H. In some embodiments,

[0621]

[0622] R2is In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro.

[0623] In some embodiments, R3is cyano.

[0624] In some embodiments, R3is -NR9R10.

[0625] In some embodiments, R3is -OR9.

[0626] In some embodiments, R3is -C(=O)NR9R10.

[0627] In some embodiments, R3is -C(=O)R19.

[0628] In some embodiments, R3is -C(=O)OR9.

[0629] In some embodiments, R3is -OC(=O)R9.

[0630] In some embodiments, R3is -NR12(C=O)NR9R10.

[0631] In some embodiments, R3is -SR9.

[0632] In some embodiments, R3is -S(=O)R9.

[0633] In some embodiments, R3is -S(O2)R9.

[0634] In some embodiments, R3is -S(O2)NR9R10.

[0635] In some embodiments, R3is -NR9S(O2)NR10R11.

[0636] In some embodiments, R3is -R9C(=O)R10.

[0637] In some embodiments, R3is -NR9C(=O)R10.

[0638] 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.Attorney Docket No. 59845-0148WO1

[0639] 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.

[0640] 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.

[0641] 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.

[0642] 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.

[0643] 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.

[0644] 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 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

[0645] 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.

[0646] 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.

[0647] In some embodiments, R10is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R10is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0648] 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.Attorney Docket No. 59845-0148WO1

[0649] 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.

[0650] In some embodiments, R11is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0651] 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.

[0652] 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.

[0653] In some embodiments, R3is an optionally substituted C1-C6 alkyl. In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is methyl or ethyl.

[0654] In some embodiments, R3is an optionally substituted C2-C6 alkenyl. In some embodiments, R3is C2-C6 alkenyl. In some embodiments, R3is an optionally substituted C2-C3 alkenyl. In some embodiments, R3is C2-C3 alkenyl.

[0655] In some embodiments, R3is an optionally substituted C2-C6 alkynyl. In some embodiments, R3is C2-C6 alkynyl. In some embodiments, R3is an optionally substituted C2-C3 alkynyl. In some embodiments, R3is C2-C3 alkynyl.

[0656] In some embodiments, R3is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R3is C3-C6 cycloalkyl.

[0657] In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is phenyl.

[0658] In some embodiments, R3is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R3is 4-6 membered heterocyclyl.

[0659] In some embodiments, R3is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R3is 5-6 membered heteroaryl.

[0660] In some embodiments, RFis -CF3.

[0661] In some embodiments, RFis -CHF2.Attorney Docket No. 59845-0148WO1

[0662] Non-Limiting Exemplary Compounds

[0663] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.

[0664] Table A

[0665] Compound

[0666] Structure

[0667] Number

[0668] F

[0669] _

[0670] Lw “ o

[0671] 1 1DHN-S—

[0672] i T D-)-O d

[0673] VY

[0674] 2

[0675] S-^4 D b

[0676] FD_^...d

[0677] D

[0678]

[0679] Attorney Docket No. 59845-0148WO1

[0680]

[0681] Attorney Docket No. 59845-0148WO1

[0682]

[0683] Attorney Docket No. 59845-0148WO1

[0684]

[0685] Attorney Docket No. 59845-0148WO1

[0686]

[0687] Attorney Docket No. 59845-0148WO1

[0688]

[0689] Attorney Docket No. 59845-0148WO1

[0690]

[0691] Attorney Docket No. 59845-0148WO1

[0692]

[0693] Attorney Docket No. 59845-0148WO1

[0694]

[0695] Attorney Docket No. 59845-0148WO1

[0696]

[0697] Attorney Docket No. 59845-0148WO1

[0698]

[0699] Attorney Docket No. 59845-0148WO1

[0700]

[0701] Attorney Docket No. 59845-0148WO1

[0702]

[0703] Attorney Docket No. 59845-0148WO1

[0704]

[0705] Attorney Docket No. 59845-0148WO1

[0706]

[0707] Attorney Docket No. 59845-0148WO1

[0708]

[0709] Attorney Docket No. 59845-0148WO1

[0710]

[0711] Attorney Docket No. 59845-0148WO1

[0712]

[0713] Attorney Docket No. 59845-0148WO1

[0714]

[0715] Attorney Docket No. 59845-0148WO1

[0716]

[0717] Attorney Docket No. 59845-0148WO1

[0718] 2- s

[0719] OoZ)<-- - A X. X< '

[0720] y z m?■■■ j

[0721] / Z ' >-Z

[0722] CO \•,! 1

[0723] N i \' Tt- |; ±

[0724] j 4i x o r i o'

[0725] F

[0726] , ix 1.Q

[0727] e SJ-.

[0728] " f hi

[0729] Aj x

[0730] T T " _ o

[0731] • 'N-...........

[0732] 5. 6 A. \..n

[0733] >.

[0734] / x>™. N 0

[0735] V /

[0736] HN rt '.4. '>;. 0 /

[0737] \ x F"" A A ".yHN ' S-H

[0738] . / A %. A x o '

[0739] N,, XFO '

[0740] O C w

[0741]

[0742] Attorney Docket No. 59845-0148WO1

[0743] D V" N"

[0744] 0 ' D 1 J

[0745] o N— < b

[0746] >,?:» -A / . NH _

[0747] ' o - r-A

[0748] A""') F

[0749] 7 V -y

[0750] (zZH > -.

[0751] X

[0752] A / /

[0753] ' " top,.

[0754] Ek. z-'x X

[0755] h i VXN'

[0756] \0i « J. J

[0757] ’'N--S-NH J THN

[0758] Z i

[0759] zo X W

[0760] 0 N--<........................ J J

[0761] o—FA- F-VSi

[0762] F 4 x^,

[0763] O '

[0764] OQCO-- Z,

[0765]

[0766] Attorney Docket No. 59845-0148WO1

[0767] FNV"HN.^ / £ i 5

[0768] j j \

[0769] > H D 9-> W

[0770] f r* -O i

[0771] oow-- N_ X_ □' o ±,

[0772] X

[0773] rZ^'-'

[0774] U 1

[0775] 9 V

[0776] F <x a i a A'. Z-- ~

[0777] £-F

[0778] 1

[0779] rvQ

[0780] ^•'■x, J V I U.F0

[0781] r T 5.. x 4. \ HN 'S-N7'1

[0782] HN. ( / . < 6

[0783] / ! \, A L

[0784] f '"f \ X

[0785] / ) C tL — D-i 0

[0786] N. > (.

[0787] ■'■■'z.... L P

[0788] { } F

[0789] ■ '

[0790]

[0791] Attorney Docket No. 59845-0148WO1

[0792] \ /

[0793] < > \ / \ /

[0794] / / . V

[0795] ?) X - •n•

[0796] / /

[0797] "" CO'.

[0798] A F~~TJ: t

[0799] ""

[0800] o

[0801] 7FJ O O X; 0 H / ... F

[0802] 1 >... ' T r / .xHN-S-N' -X'

[0803] vv.7 oX,„

[0804] - 14. < > - '

[0805] D; NF

[0806] r "r □■••••}.0

[0807] T

[0808] ..... -> F X X

[0809] O

[0810] Ooco-- F

[0811] S-F

[0812] [f - =SS— A FN°

[0813] HN> F ° zvF

[0814] 1HHN-S-N X

[0815] f T0

[0816]

[0817] Attorney Docket No. 59845-0148WO1

[0818] / \

[0819] X!

[0820] OO&-- o. i

[0821] ~n

[0822] X y A z

[0823] ,, J 9

[0824] j o

[0825] F ^x"

[0826] / -1iF *n H ~ni

[0827] r >

[0828] $>- M'<s X u-u’ J Z£ 9

[0829] [ A.. s T;

[0830] x >^-N 0

[0831] J XH”-A >. <

[0832] / X. ■■' HN- °S -N r. '■

[0833] \ 0

[0834] <s 7 X U.

[0835] * \ / L. / . S >' I O '. "

[0836] A X.,

[0837] O '

[0838] OOW--

[0839] M / A

[0840] ^jC

[0841]

[0842] Attorney Docket No. 59845-0148WO1

[0843] In some embodiments, the compounds of Formula (I) have reduced lipophilicity (logD) compared to structurally related analogs outside the scope of Formula (I). A reduced lipophilicity (logD) can provide one or more of the following advantageous properties: (1) reduced CYP3A4 reversible and time dependent inhibition; (2) reduced hERG inhibition; (3) reduced in vitro microsomal and hepatocyte based intrinsic clearance of the unbound fraction (Clint, u) across mouse, rat, dog, cyno, and human; (4) reduced in vivo Clint, u across mouse, rat, dog, cyno, and human (5) Increased in vivo safety margin; and (6) lower overall dose. However, a reduced lipophilicity (logD) can often be accompanied by reduced oral bioavailability and reduced cell permeability. Advantageously, the compounds of Formula (I) can have a substantially lower lipophilicity (logD) (e.g., up to 2 units) and an increased topological polar surface area (TPSA) while maintaining an acceptable in vitro cell permeability and an acceptable in vivo oral bioavailability.

[0844] Pharmaceutical Compositions

[0845] 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.

[0846] Methods of Treatment

[0847] 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).

[0848] 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.

[0849] 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 providedAttorney Docket No. 59845-0148WO1

[0850] herein can be determined by ECso 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 EC50 value.

[0851] Indications

[0852] 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.

[0853] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53 -associated cancer.

[0854] Some embodiments provide a method of treating a p53 -associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation.

[0855] 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 1-510, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation.

[0856] Some embodiments provide a method of treating cancer in a subj ect that has been identified or diagnosed as having a p53-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0857] 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.Attorney Docket No. 59845-0148WO1

[0858] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0859] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0860] 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.

[0861] 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.

[0862] 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).

[0863] 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.

[0864] 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.

[0865] 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 aAttorney Docket No. 59845-0148WO1

[0866] 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.

[0867] 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.

[0868] 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.

[0869] Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPE AAPP VAPAP AAPTP AAP APAP S WPL S S S VP SQKTYQGS YGFRLGFLHSGT A KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERC SD SDGL APPQHLIRVEGNLRVEYLDDRNTFRHS VVVP YEPPEVGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAG KEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSDAttorney Docket No. 59845-0148WO1

[0870] 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.

[0871] 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.

[0872] 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 anti cancer 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.

[0873] 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 presenceAttorney Docket No. 59845-0148WO1

[0874] 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.

[0875] 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 subj ect. As provided herein, a p53-associated cancer includes those described herein and known in the art.

[0876] 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 TP 53 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,Attorney Docket No. 59845-0148WO1

[0877] e., FDA-approved, assay or kit.

[0878] 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.

[0879] 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.

[0880] 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.

[0881] 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.Attorney Docket No. 59845-0148WO1

[0882] 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.

[0883] 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).

[0884] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53-associated cancer) is a solid tumor.

[0885] 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.

[0886] 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.

[0887] In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.

[0888] In some embodiments, the bladder cancer is bladder urothelial carcinoma.

[0889] In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.

[0890] In some embodiments, the skin cancer is cutaneous melanoma.

[0891] 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.

[0892] In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.

[0893] In some embodiments, the breast cancer is breast invasive ductal carcinoma.Attorney Docket No. 59845-0148WO1

[0894] In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.

[0895] In some embodiments, the ovarian cancer is serous ovarian cancer.

[0896] In some embodiments, the kidney cancer is chromophobe renal cell carcinoma.

[0897] In some embodiments, the colorectal cancer is colon adenocarcinoma.

[0898] In some embodiments, the liver cancer is hepatocellular carcinoma.

[0899] In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

[0900] In some embodiments, the cancer is prostate cancer.

[0901] 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.

[0902] 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.

[0903] Table 1. p53 Protein Amino Acid Substitutions / Insertions / DeletionsA

[0904] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[0905] Position Exemplary Mutations Associated Cancer(s)

[0906] 1 Ml Head and Neck Squamous Cell Carcinoma

[0907] (translation start site)

[0908] 4 P4L Mucinous Stomach Adenocarcinoma

[0909] 10 XIO splice (splice site) Acute Myeloid Leukemia

[0910] 11 Ell* (nonsense mutation) Breast Invasive Ductal Carcinoma

[0911] E11K Renal Clear Cell Carcinoma

[0912] 20 S20* Bladder Urothelial Carcinoma

[0913] S20Qfs*24 Intestinal Type Stomach Adenocarcinoma

[0914] (frame shift, additional

[0915] amino acids)

[0916] 22 L22Yfs*22 Bladder Urothelial Carcinoma

[0917] 23 W23* Cervical Squamous Cell Carcinoma

[0918] 25 X25 splice Adrenocortical Carcinoma

[0919] Head and Neck Squamous Cell Carcinoma

[0920] Tubular Stomach Adenocarcinoma

[0921] 27 P27L Adrenocortical Carcinoma

[0922] P27Lfs*17 Astrocytoma

[0923] P27S Breast Invasive Ductal Carcinoma

[0924] Chromophobe Renal Cell Carcinoma

[0925]

[0926] Colon AdenocarcinomaAttorney Docket No. 59845-0148WO1

[0927] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[0928] Position Exemplary Mutations Associated Cancer(s)

[0929] Cutaneous Melanoma

[0930] Head and Neck Squamous Cell Carcinoma

[0931] Mucinous Carcinoma

[0932] Pancreatic Adenocarcinoma

[0933] Serous Ovarian Cancer

[0934] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[0935] 30 N30del Colon Adenocarcinoma

[0936] (in frame deletion)

[0937] 32 L32Cfs*12 Astrocytoma

[0938] X32_splice Chromophobe Renal Cell Carcinoma

[0939] Glioblastoma Multiforme

[0940] Head and Neck Squamous Cell Carcinoma

[0941] Head and Neck Squamous Cell Carcinoma

[0942] Lung Squamous Cell Carcinoma

[0943] Oligoastrocytoma

[0944] Renal Clear Cell Carcinoma

[0945] 33 S33Ffs*10 Astrocytoma

[0946] X33_splice Bladder Urothelial Carcinoma

[0947] Breast Invasive Ductal Carcinoma

[0948] Glioblastoma Multiforme

[0949] Head and Neck Squamous Cell Carcinoma

[0950] Hepatocellular Carcinoma

[0951] Lung Adenocarcinoma

[0952] Lung Squamous Cell Carcinoma

[0953] Oligoastrocytoma

[0954] Prostate Adenocarcinoma

[0955] Rectal Adenocarcinoma

[0956] Serous Ovarian Cancer

[0957] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[0958] 35 L35Cfs*9 Bladder Urothelial Carcinoma

[0959] L35Ffs*7 Colon Adenocarcinoma

[0960] L35Ffs*8 Lung Adenocarcinoma

[0961] L35Pfs*10 Lung Squamous Cell Carcinoma

[0962] Pancreatic Adenocarcinoma

[0963] Papillary Stomach Adenocarcinoma

[0964] Rectal Adenocarcinoma

[0965] Tubular Stomach Adenocarcinoma

[0966] Uterine Endometrioid Carcinoma

[0967] 36 P36Wfs*4 Serous Ovarian Cancer

[0968] 37 S37Vfs*6 Lung Squamous Cell Carcinoma

[0969] 38 Q38* Colon Adenocarcinoma

[0970] Q38Kfs*6 Head and Neck Squamous Cell Carcinoma

[0971] Lung Squamous Cell Carcinoma

[0972] Pancreatic Adenocarcinoma

[0973] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[0974] 40 M40Lfs*7 Acute Myeloid Leukemia

[0975]

[0976] 42 D42Tfs*2 Esophageal Squamous Cell CarcinomaAttorney Docket No. 59845-0148WO1

[0977] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[0978] Position Exemplary Mutations Associated Cancer(s)

[0979] 43 L43* Hepatocellular Carcinoma

[0980] L43Afs*7 Serous Ovarian Cancer

[0981] Uterine Endometrioid Carcinoma

[0982] 44 M44Ifs*79 Bladder Urothelial Carcinoma

[0983] M44Tfs*75 Lung Squamous Cell Carcinoma

[0984] 46 S46* Lung Squamous Cell Carcinoma

[0985] S46Tfs*5

[0986] 47 P47Rfs*76 Serous Ovarian Cancer

[0987] 48 D48Gfs*4 Cutaneous Melanoma

[0988] D48N Head and Neck Squamous Cell Carcinoma

[0989] D48Nfs*72 Lung Adenocarcinoma

[0990] D48Tfs*75 Lung Squamous Cell Carcinoma

[0991] 49 D49Sfs*69 Lung Squamous Cell Carcinoma

[0992] 51 E51* Breast Invasive Ductal Carcinoma

[0993] E51Gfs*6 Esophageal Adenocarcinoma

[0994] Serous Ovarian Cancer

[0995] 52 Q52* Breast Invasive Ductal Carcinoma

[0996] Head and Neck Squamous Cell Carcinoma

[0997] Lung Adenocarcinoma

[0998] 53 W53* Bladder Urothelial Carcinoma

[0999] W53Cfs*4 Diffuse Type Stomach Adenocarcinoma

[1000] W53Mfs*4 Glioblastoma Multiforme

[1001] Lung Adenocarcinoma

[1002] Lung Squamous Cell Carcinoma

[1003] Rectal Adenocarcinoma

[1004] Serous Ovarian Cancer

[1005] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 54 F54Sfs*69 Lung Adenocarcinoma

[1006] 56 E56* Adrenocortical Carcinoma

[1007] E56Kfs*67 Breast Invasive Ductal Carcinoma

[1008] Head and Neck Squamous Cell Carcinoma

[1009] Hepatocellular Carcinoma

[1010] Lung Squamous Cell Carcinoma

[1011] 57 D57Kfs*67 Lung Adenocarcinoma

[1012] D57N Pancreatic Adenocarcinoma

[1013] 58 P58Qfs*65 Head and Neck Squamous Cell Carcinoma

[1014] 61 D61* Uterine Endometrioid Carcinoma

[1015] D61G Uterine Mixed Endometrial Carcinoma

[1016] 62 E62* Cervical Squamous Cell Carcinoma

[1017] E62K Lung Squamous Cell Carcinoma

[1018] E62Kfs*61 Pancreatic Adenocarcinoma

[1019] Serous Ovarian Cancer

[1020] 64 P64Qfs*84 Esophageal Squamous Cell Carcinoma

[1021] P64Sfs*59 Lung Squamous Cell Carcinoma

[1022] P64T Uterine Endometrioid Carcinoma

[1023] 65 R65* Head and Neck Squamous Cell Carcinoma

[1024] R65Efs*58 Lung Adenocarcinoma

[1025]

[1026] R65Qfs*84 Lung Squamous Cell CarcinomaAttorney Docket No. 59845-0148WO1

[1027] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1028] Position Exemplary Mutations Associated Cancer(s)

[1029] 66 M66Tfs*60 Serous Ovarian Cancer

[1030] 67 P67S Uterine Endometrioid Carcinoma

[1031] 68 E68* Bladder Urothelial Carcinoma

[1032] Head and Neck Squamous Cell Carcinoma

[1033] Lung Adenocarcinoma

[1034] Lung Squamous Cell Carcinoma

[1035] 69 A69Gfs*80 Lung Adenocarcinoma

[1036] 72 P72Rfs*51 Cutaneous Melanoma

[1037] P72S Diffuse Type Stomach Adenocarcinoma

[1038] Lung Adenocarcinoma

[1039] 73 V73Rfs*76 Adrenocortical Carcinoma

[1040] V73Wfs*50 Colon Adenocarcinoma

[1041] Head and Neck Squamous Cell Carcinoma

[1042] Leiomyosarcoma

[1043] Lung Squamous Cell Carcinoma

[1044] Pancreatic Adenocarcinoma

[1045] Rectal Adenocarcinoma

[1046] Tubular Stomach Adenocarcinoma

[1047] 74 A74T Prostate Adenocarcinoma

[1048] 75 P75Lfs*48 Lung Squamous Cell Carcinoma

[1049] 76 A76Hfs*47 Serous Ovarian Cancer

[1050] 77 P77Cfs*73 Breast Invasive Ductal Carcinoma

[1051] P77Gfs*65 Lung Adenocarcinoma

[1052] P77L

[1053] 79 A79Pfs*70 Colon Adenocarcinoma

[1054] A79V Head and Neck Squamous Cell Carcinoma

[1055] 82 P82L Prostate Adenocarcinoma

[1056] P82Rfs*41 Stomach Adenocarcinoma

[1057] 83 A83Gfs*66 Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 84 A84Pfs*39 Head and Neck Squamous Cell Carcinoma

[1058] Lung Squamous Cell Carcinoma

[1059] 85 P85Lfs*38 Head and Neck Squamous Cell Carcinoma

[1060] 86 A86Cfs*63 Breast Invasive Ductal Carcinoma

[1061] A86Pfs*34 Prostate Adenocarcinoma

[1062] A86Vfs*55 Serous Ovarian Cancer

[1063] 90 S90Ffs*53 Astrocytoma

[1064] S90Pfs*33 Breast Invasive Ductal Carcinoma

[1065] S90Pfs*34 Head and Neck Squamous Cell Carcinoma S90Vfs*55 Hepatocellular Carcinoma

[1066] Lung Adenocarcinoma

[1067] Prostate Adenocarcinoma

[1068] Serous Ovarian Cancer

[1069] Uterine Endometrioid Carcinoma

[1070] 91 W91* Astrocytoma

[1071] Bladder Urothelial Carcinoma

[1072] Breast Invasive Ductal Carcinoma

[1073] Colon Adenocarcinoma

[1074]

[1075] Esophageal AdenocarcinomaAttorney Docket No. 59845-0148WO1

[1076] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1077] Position Exemplary Mutations Associated Cancer(s)

[1078] Glioblastoma Multiforme

[1079] Head and Neck Squamous Cell Carcinoma

[1080] Leiomyosarcoma

[1081] Lung Adenocarcinoma

[1082] Lung Squamous Cell Carcinoma

[1083] Papillary Renal Cell Carcinoma

[1084] Stomach Adenocarcinoma

[1085] 92 P92Afs*57 Bladder Urothelial Carcinoma

[1086] P92S Uterine Endometrioid Carcinoma

[1087] 93 L93Vfs*55 Breast Invasive Ductal Carcinoma

[1088] 94 S94* Bladder Urothelial Carcinoma

[1089] S94Cfs*30 Colon Adenocarcinoma

[1090] Esophageal Squamous Cell Carcinoma

[1091] Lung Squamous Cell Carcinoma

[1092] Oligoastrocytoma

[1093] Rectal Adenocarcinoma

[1094] Stomach Adenocarcinoma

[1095] 96 S96Ffs*25 Diffuse Type Stomach Adenocarcinoma

[1096] 97 V97D Cutaneous Melanoma

[1097] V97Efs*48 Hepatocellular Carcinoma

[1098] V97Sfs*26 Tubular Stomach Adenocarcinoma

[1099] Uterine Endometrioid Carcinoma

[1100] 98 P98Afs*51 Stomach Adenocarcinoma

[1101] 99 S99Rfs*23 Head and Neck Squamous Cell Carcinoma

[1102] Serous Ovarian Cancer

[1103] 100 Q100* Colon Adenocarcinoma

[1104] Q100Gfs*37 Lung Squamous Cell Carcinoma

[1105] Serous Ovarian Cancer

[1106] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1107] 101 K101* Head and Neck Squamous Cell Carcinoma

[1108] 102 T102Pfs*21 Glioblastoma Multiforme

[1109] Serous Ovarian Cancer

[1110] 103 Y103* Head and Neck Squamous Cell Carcinoma

[1111] Y103Lfs*46 Hepatocellular Carcinoma

[1112] Y103Tfs*20 Lung Squamous Cell Carcinoma

[1113] Stomach Adenocarcinoma

[1114] 104 Q104* Esophageal Adenocarcinoma

[1115] Q104H Head and Neck Squamous Cell Carcinoma Q104Tfs*20 Lung Adenocarcinoma

[1116] Lung Squamous Cell Carcinoma

[1117] Pancreatic Adenocarcinoma

[1118] Serous Ovarian Cancer

[1119] 105 G105C Bladder Urothelial Carcinoma

[1120] G105D Glioblastoma Multiforme

[1121] G105R Head and Neck Squamous Cell Carcinoma

[1122] G105S Lung Adenocarcinoma

[1123] G105V Lung Squamous Cell Carcinoma

[1124]

[1125] Serous Ovarian CancerAttorney Docket No. 59845-0148WO1

[1126] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1127] Position Exemplary Mutations Associated Cancer(s)

[1128] 106 S106R Esophageal Squamous Cell Carcinoma

[1129] Head and Neck Squamous Cell Carcinoma

[1130] Hepatocellular Carcinoma

[1131] Lung Squamous Cell Carcinoma

[1132] 107 Y107Cfs*16 Breast Invasive Ductal Carcinoma

[1133] Y107D Colon Adenocarcinoma

[1134] Stomach Adenocarcinoma

[1135] 108 G108Ffs*40 Breast Invasive Ductal Carcinoma

[1136] G108S Glioblastoma Multiforme

[1137] G108Vfs*15 Uterine Endometrioid Carcinoma

[1138] 109 F109C Colon Adenocarcinoma

[1139] F109Lfs*36 Esophageal Squamous Cell Carcinoma

[1140] F109S Lung Adenocarcinoma

[1141] F109V Lung Squamous Cell Carcinoma

[1142] Oligoastrocytoma

[1143] Oligodendroglioma

[1144] Rectal Adenocarcinoma

[1145] 110 R110_G112del Bladder Urothelial Carcinoma

[1146] R110C Breast Invasive Ductal Carcinoma

[1147] R110del Cutaneous Melanoma

[1148] R110L Esophageal Squamous Cell Carcinoma

[1149] R110P Head and Neck Squamous Cell Carcinoma

[1150] R110Sfs*14 Lung Adenocarcinoma

[1151] R110Vfs*13 Lung Squamous Cell Carcinoma

[1152] R110Wfs*12 Oligoastrocytoma

[1153] Pancreatic Adenocarcinoma

[1154] Serous Ovarian Cancer

[1155] 111 L111P Bladder Urothelial Carcinoma

[1156] L111Q Breast Invasive Ductal Carcinoma

[1157] L111R Diffuse Type Stomach Adenocarcinoma

[1158] Lung Squamous Cell Carcinoma

[1159] Papillary Renal Cell Carcinoma

[1160] 113 F113C Astrocytoma

[1161] F113del Breast Invasive Carcinoma (NOS)

[1162] F113L Breast Invasive Ductal Carcinoma

[1163] F113V Colon Adenocarcinoma

[1164] Esophageal Adenocarcinoma

[1165] Hepatocellular Carcinoma

[1166] Intestinal Type Stomach Adenocarcinoma

[1167] Leiomyosarcoma

[1168] Oligodendroglioma

[1169] 114 L114* Breast Invasive Carcinoma (NOS)

[1170] 115 H115Ifs*8 Breast Invasive Ductal Carcinoma

[1171] 118 T118Dfs*31 Breast Invasive Ductal Carcinoma

[1172] T118Qfs*5 Head and Neck Squamous Cell Carcinoma

[1173] Serous Ovarian Cancer

[1174] 120 K120E Cutaneous Melanoma

[1175] K120Sfs*3 Lung Adenocarcinoma

[1176] K120Tfs*2 Lung Squamous Cell Carcinoma

[1177]

[1178] OligoastrocytomaAttorney Docket No. 59845-0148WO1

[1179] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1180] Position Exemplary Mutations Associated Cancer(s)

[1181] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma

[1182] 121 S121Cfs*27 Bladder Urothelial Carcinoma

[1183] S121Y Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1184] 122 V122Cfs*27 V122Dfs*26 Astrocytoma

[1185] V122Lfs*25 Breast Invasive Ductal Carcinoma

[1186] Colon Adenocarcinoma

[1187] Esophageal Squamous Cell Carcinoma

[1188] Leiomyosarcoma

[1189] Oligoastrocytoma

[1190] Oligodendroglioma

[1191] Pancreatic Adenocarcinoma

[1192] Rectal Adenocarcinoma

[1193] Serous Ovarian Cancer

[1194] 123 T123Dfs*26 Glioblastoma Multiforme

[1195] T123Lfs*47 Pancreatic Adenocarcinoma

[1196] T123Rfs*48 Serous Ovarian Cancer

[1197] 124 C124* Breast Invasive Ductal Carcinoma

[1198] C124Afs*46 Colon Adenocarcinoma

[1199] C124G Esophageal Squamous Cell Carcinoma

[1200] C124Wfs*25 Prostate Adenocarcinoma

[1201] Serous Ovarian Cancer

[1202] 125 T125= Acute Myeloid Leukemia

[1203] (splice region) Adrenocortical Carcinoma

[1204] Astrocytoma

[1205] T125M Bladder Urothelial Carcinoma

[1206] T125P Breast Invasive Ductal Carcinoma

[1207] X125_splice Colon Adenocarcinoma

[1208] Cutaneous Melanoma

[1209] Glioblastoma Multiforme

[1210] Head and Neck Squamous Cell Carcinoma

[1211] Hepatocellular Carcinoma

[1212] Intestinal Type Stomach Adenocarcinoma

[1213] Lung Adenocarcinoma

[1214] Lung Squamous Cell Carcinoma

[1215] Mucinous Adenocarcinoma of the Colon and Rectum Mucinous Stomach Adenocarcinoma

[1216] Oligoastrocytoma

[1217] Oligodendroglioma

[1218] Pancreatic Adenocarcinoma

[1219] Rectal Adenocarcinoma

[1220] Serous Ovarian Cancer

[1221] Stomach Adenocarcinoma

[1222] Tubular Stomach Adenocarcinoma

[1223] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Endometrioid Carcinoma

[1224] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 126 Y126_M133del Acute Myeloid Leukemia

[1225]

[1226] Y126C Breast Invasive Ductal CarcinomaAttorney Docket No. 59845-0148WO1

[1227] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1228] Position Exemplary Mutations Associated Cancer(s)

[1229] Y126D Cutaneous Melanoma

[1230] Y126H Esophageal Squamous Cell Carcinoma

[1231] Y126N Glioblastoma Multiforme

[1232] Y126S Head and Neck Squamous Cell Carcinoma

[1233] X126_splice Hepatocellular Carcinoma

[1234] Intestinal Type Stomach Adenocarcinoma

[1235] Leiomyosarcoma

[1236] Lung Adenocarcinoma

[1237] Lung Squamous Cell Carcinoma

[1238] Mucinous Stomach Adenocarcinoma

[1239] Oligodendroglioma

[1240] Pancreatic Adenocarcinoma

[1241] Prostate Adenocarcinoma

[1242] Rectal Adenocarcinoma

[1243] Serous Ovarian Cancer

[1244] Signet Ring Cell Carcinoma of the Stomach

[1245] Stomach Adenocarcinoma

[1246] Tubular Stomach Adenocarcinoma

[1247] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1248] Uterine Endometrioid Carcinoma

[1249] 127 S127C Astrocytoma

[1250] S127F Breast Invasive Ductal Carcinoma

[1251] S127P Colon Adenocarcinoma

[1252] S127T Cutaneous Melanoma

[1253] S127Y Glioblastoma Multiforme

[1254] S127Yfs*43 Head and Neck Squamous Cell Carcinoma

[1255] Lung Adenocarcinoma

[1256] Pancreatic Adenocarcinoma

[1257] Serous Ovarian Cancer

[1258] Uterine Endometrioid Carcinoma

[1259] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 128 P128del Astrocytoma

[1260] P128Lfs*42 Breast Invasive Ductal Carcinoma

[1261] Esophageal Squamous Cell Carcinoma

[1262] Head and Neck Squamous Cell Carcinoma

[1263] Lung Squamous Cell Carcinoma

[1264] 129 A129Vfs*20 Lung Squamous Cell Carcinoma

[1265] 130 L130Cfs*20 Astrocytoma

[1266] L130F Breast Invasive Lobular Carcinoma

[1267] L130P Colon Adenocarcinoma

[1268] L130R Diffuse Type Stomach Adenocarcinoma

[1269] L130V Esophageal Squamous Cell Carcinoma

[1270] Glioblastoma Multiforme

[1271] Lung Adenocarcinoma

[1272] Serous Ovarian Cancer

[1273] Tubular Stomach Adenocarcinoma

[1274] Uterine Mixed Endometrial Carcinoma

[1275] 131 N131del Astrocytoma

[1276] N131I Breast Invasive Ductal Carcinoma

[1277] N131Kfs*39 Lung Adenocarcinoma

[1278]

[1279] N131Qfs*17 Lung Squamous Cell CarcinomaAttorney Docket No. 59845-0148WO1

[1280] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1281] Position Exemplary Mutations Associated Cancer(s)

[1282] N131S Pancreatic Adenocarcinoma

[1283] N131Tfs*39 Serous Ovarian Cancer

[1284] Stomach Adenocarcinoma

[1285] Uterine Mixed Endometrial Carcinoma

[1286] 132 K132E Adrenocortical Carcinoma

[1287] K132M Astrocytoma

[1288] K132N Bladder Urothelial Carcinoma

[1289] K132Q Breast Invasive Ductal Carcinoma

[1290] K132R Cervical Squamous Cell Carcinoma

[1291] K132T Colon Adenocarcinoma

[1292] K132Vfs*15 Glioblastoma Multiforme

[1293] Head and Neck Squamous Cell Carcinoma

[1294] Leiomyosarcoma

[1295] Lung Adenocarcinoma

[1296] Lung Squamous Cell Carcinoma

[1297] Oligoastrocytoma

[1298] Pleural Mesothelioma, Epithelioid Type

[1299] Serous Ovarian Cancer

[1300] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1301] 133 M133K Breast Invasive Carcinoma (NOS)

[1302] M133R Head and Neck Squamous Cell Carcinoma

[1303] Mucinous Adenocarcinoma of the Colon and Rectum

[1304] 134 F134L Cutaneous Melanoma

[1305] F134V Esophageal Squamous Cell Carcinoma

[1306] Head and Neck Squamous Cell Carcinoma

[1307] Serous Ovarian Cancer

[1308] Tubular Stomach Adenocarcinoma

[1309] Uterine Endometrioid Carcinoma

[1310] 135 C135* Adrenocortical Carcinoma

[1311] C135Afs*35 Bladder Urothelial Carcinoma

[1312] C135F Breast Invasive Ductal Carcinoma

[1313] C135Lfs*14 Colon Adenocarcinoma

[1314] C135R Diffuse Type Stomach Adenocarcinoma

[1315] C135W Esophageal Adenocarcinoma

[1316] C135Y Esophageal Squamous Cell Carcinoma

[1317] Head and Neck Squamous Cell Carcinoma

[1318] Hepatocellular Carcinoma

[1319] Lung Adenocarcinoma

[1320] Lung Squamous Cell Carcinoma

[1321] Pancreatic Adenocarcinoma

[1322] Papillary Stomach Adenocarcinoma

[1323] Prostate Adenocarcinoma

[1324] Serous Ovarian Cancer

[1325] Tubular Stomach Adenocarcinoma

[1326] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Endometrioid Carcinoma

[1327] 136 Q136* Astrocytoma

[1328]

[1329] Q136_C141del Breast Invasive Ductal CarcinomaAttorney Docket No. 59845-0148WO1

[1330] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1331] Position Exemplary Mutations Associated Cancer(s)

[1332] Q136del Glioblastoma Multiforme

[1333] Q136E Head and Neck Squamous Cell Carcinoma

[1334] Q136H Hepatocellular Carcinoma

[1335] Q136P Intestinal Type Stomach Adenocarcinoma

[1336] Leiomyosarcoma

[1337] Lung Adenocarcinoma

[1338] Lung Squamous Cell Carcinoma

[1339] Metaplastic Breast Cancer

[1340] Mucinous Stomach Adenocarcinoma

[1341] Oligodendroglioma

[1342] Rectal Adenocarcinoma

[1343] Serous Ovarian Cancer

[1344] Stomach Adenocarcinoma

[1345] 137 L137Pfs*32 Head and Neck Squamous Cell Carcinoma

[1346] L137Q

[1347] 138 A138_L145del Breast Invasive Ductal Carcinoma

[1348] A138_P142del Esophageal Adenocarcinoma

[1349] A138Cfs*27 Glioblastoma Multiforme

[1350] A138T Lung Adenocarcinoma

[1351] A138V Rectal Adenocarcinoma

[1352] Serous Ovarian Cancer

[1353] Uterine Endometrioid Carcinoma

[1354] 139 K139_P142del Bladder Urothelial Carcinoma

[1355] K139_P142delinsT Breast Invasive Carcinoma (NOS)

[1356] K139Afs*5 Esophageal Squamous Cell Carcinoma

[1357] K139Cfs*6 Glioblastoma Multiforme

[1358] K139N Head and Neck Squamous Cell Carcinoma K139Nfs*9 Hepatocellular Carcinoma

[1359] K139Rfs*31 Lung Adenocarcinoma

[1360] Uterine Endometrioid Carcinoma

[1361] 140 T140Mfs*28 Serous Ovarian Cancer

[1362] 141 C141* Acute Myeloid Leukemia

[1363] C141Afs*29 Astrocytoma

[1364] C141F Bladder Urothelial Carcinoma

[1365] C141G Breast Invasive Ductal Carcinoma

[1366] C141R Chromophobe Renal Cell Carcinoma

[1367] C141S Colon Adenocarcinoma

[1368] C141W Cutaneous Melanoma

[1369] C141Y Head and Neck Squamous Cell Carcinoma

[1370] Intrahepatic Cholangiocarcinoma

[1371] Lung Adenocarcinoma

[1372] Lung Squamous Cell Carcinoma

[1373] Oligoastrocytoma

[1374] Prostate Adenocarcinoma

[1375] Serous Ovarian Cancer

[1376] Stomach Adenocarcinoma

[1377] Uterine Endometrioid Carcinoma

[1378] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 142 P142del Lung Squamous Cell Carcinoma

[1379] P142L Oligoastrocytoma

[1380]

[1381] P142Lfs*28 Uterine Mixed Endometrial CarcinomaAttorney Docket No. 59845-0148WO1

[1382] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1383] Position Exemplary Mutations Associated Cancer(s)

[1384] 143 V143A Bladder Urothelial Carcinoma

[1385] V143Afs*29 Colon Adenocarcinoma

[1386] V143E Cutaneous Melanoma

[1387] V143G Esophageal Adenocarcinoma

[1388] V143M Head and Neck Squamous Cell Carcinoma V143Rfs*18 Hepatocellular Carcinoma

[1389] Oligoastrocytoma

[1390] Pancreatic Adenocarcinoma

[1391] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1392] 144 Q144* Bladder Urothelial Carcinoma

[1393] Q144_L145dup Breast Invasive Lobular Carcinoma

[1394] Q144Afs*16 Colon Adenocarcinoma

[1395] Q144Gfs*24 Head and Neck Squamous Cell Carcinoma Q144H Hepatocellular Carcinoma

[1396] Q144L Lung Adenocarcinoma

[1397] Q144Lfs*5 Lung Squamous Cell Carcinoma

[1398] Q144P Prostate Adenocarcinoma

[1399] Q144Tfs*5 Serous Ovarian Cancer

[1400] Stomach Adenocarcinoma

[1401] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 145 L145P Colon Adenocarcinoma

[1402] L145Q Oligoastrocytoma

[1403] L145R Serous Ovarian Cancer

[1404] Signet Ring Cell Carcinoma of the Stomach

[1405] 146 W146* Astrocytoma

[1406] W146S Bladder Urothelial Carcinoma

[1407] W146Vfs*3 Esophageal Squamous Cell Carcinoma

[1408] Head and Neck Squamous Cell Carcinoma

[1409] Intestinal Type Stomach Adenocarcinoma

[1410] Lung Adenocarcinoma

[1411] Lung Squamous Cell Carcinoma

[1412] Oligodendroglioma

[1413] Rectal Adenocarcinoma

[1414] Serous Ovarian Cancer

[1415] Uterine Endometrioid Carcinoma

[1416] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 147 V147_D148dup Breast Invasive Ductal Carcinoma

[1417] V147G Esophageal Adenocarcinoma

[1418] V147Lfs*23 Serous Ovarian Cancer

[1419] 148 D148Ifs*22 Bladder Urothelial Carcinoma

[1420] D148N Lung Adenocarcinoma

[1421] 149 S149Ffs*32 Pancreatic Adenocarcinoma

[1422] S149Pfs*21 Prostate Adenocarcinoma

[1423] Serous Ovarian Cancer

[1424]

[1425] 150 T150Afs*16 Stomach AdenocarcinomaAttorney Docket No. 59845-0148WO1

[1426] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1427] Position Exemplary Mutations Associated Cancer(s)

[1428] 151 P151A Astrocytoma

[1429] P151H Bladder Urothelial Carcinoma

[1430] P151L Breast Invasive Ductal Carcinoma

[1431] P151R Colon Adenocarcinoma

[1432] P151Rfs*27 Cutaneous Melanoma

[1433] P151S Esophageal Squamous Cell Carcinoma

[1434] P151T Head and Neck Squamous Cell Carcinoma

[1435] Hepatocellular Carcinoma

[1436] Leiomyosarcoma

[1437] Lung Adenocarcinoma

[1438] Lung Squamous Cell Carcinoma

[1439] Oligoastrocytoma

[1440] Pancreatic Adenocarcinoma

[1441] Rectal Adenocarcinoma

[1442] Serous Ovarian Cancer

[1443] Stomach Adenocarcinoma

[1444] Tubular Stomach Adenocarcinoma

[1445] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1446] Uterine Mixed Endometrial Carcinoma

[1447] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 152 P152Afs*14 Astrocytoma

[1448] P152L Bladder Urothelial Carcinoma

[1449] P152Lfs*18 Breast Invasive Ductal Carcinoma

[1450] P152Q Cutaneous Melanoma

[1451] P152Rfs*18 Diffuse Type Stomach Adenocarcinoma

[1452] P152S Glioblastoma Multiforme

[1453] P152Wfs*10 Head and Neck Squamous Cell Carcinoma

[1454] Intestinal Type Stomach Adenocarcinoma

[1455] Lung Adenocarcinoma

[1456] Lung Squamous Cell Carcinoma

[1457] Oligoastrocytoma

[1458] Pancreatic Adenocarcinoma

[1459] Serous Ovarian Cancer

[1460] Signet Ring Cell Carcinoma of the Stomach

[1461] Tubular Stomach Adenocarcinoma

[1462] 153 P153Afs*28 Bladder Urothelial Carcinoma

[1463] P153Rfs*18 Lung Squamous Cell Carcinoma

[1464] Oligoastrocytoma

[1465] Stomach Adenocarcinoma

[1466] 154 G154Afs*16 Bladder Urothelial Carcinoma

[1467] G154Rfs*27 Esophageal Squamous Cell Carcinoma

[1468] G154V Head and Neck Squamous Cell Carcinoma G154Wfs*10 Lung Adenocarcinoma

[1469] Lung Squamous Cell Carcinoma

[1470] Oligodendroglioma

[1471] Pancreatic Adenocarcinoma

[1472]

[1473] Serous Ovarian CancerAttorney Docket No. 59845-0148WO1

[1474] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1475] Position Exemplary Mutations Associated Cancer(s)

[1476] 155 T155_A161del Astrocytoma

[1477] T155_R156del Bladder Urothelial Carcinoma

[1478] T155_R156delinsN Breast Invasive Ductal Carcinoma

[1479] T155_R158del Colon Adenocarcinoma

[1480] T155_R158delinsC Glioblastoma Multiforme

[1481] T155I Head and Neck Squamous Cell Carcinoma

[1482] T155N Lung Adenocarcinoma

[1483] T155P Lung Squamous Cell Carcinoma

[1484] Oligoastrocytoma

[1485] Serous Ovarian Cancer

[1486] 156 R156Afs*12 Astrocytoma

[1487] R156C Bladder Urothelial Carcinoma

[1488] R156del Breast Invasive Ductal Carcinoma

[1489] R156G Glioblastoma Multiforme

[1490] R156H Head and Neck Squamous Cell Carcinoma R156Hfs*26 Hepatocellular Carcinoma

[1491] R156P Leiomyosarcoma

[1492] R156Pfs*13 Lung Adenocarcinoma

[1493] Serous Ovarian Cancer

[1494] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 157 V157_P177del Breast Invasive Ductal Carcinoma

[1495] V157_R158dup Colon Adenocarcinoma

[1496] V157Afs*24 Esophageal Squamous Cell Carcinoma

[1497] V157D Glioblastoma Multiforme

[1498] V157F Head and Neck Squamous Cell Carcinoma

[1499] V157G Hepatocellular Carcinoma

[1500] V157Hfs*21 Lung Adenocarcinoma

[1501] V157L Lung Squamous Cell Carcinoma

[1502] V157Pfs*23 Oligodendroglioma

[1503] V157Sfs*13 Prostate Adenocarcinoma

[1504] Serous Ovarian Cancer

[1505] Uterine Endometrioid Carcinoma

[1506] Uterine Mixed Endometrial Carcinoma

[1507] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 158 R158Afs*12 Astrocytoma

[1508] R158C Bladder Urothelial Carcinoma

[1509] R158G Breast Invasive Ductal Carcinoma

[1510] R158H Colon Adenocarcinoma

[1511] R158L Diffuse Type Stomach Adenocarcinoma

[1512] R158P Esophageal Squamous Cell Carcinoma

[1513] R158S Glioblastoma Multiforme

[1514] Head and Neck Squamous Cell Carcinoma

[1515] Hepatocellular Carcinoma

[1516] Intestinal Type Stomach Adenocarcinoma

[1517] Leiomyosarcoma

[1518] Lung Adenocarcinoma

[1519] Lung Squamous Cell Carcinoma

[1520] Oligoastrocytoma

[1521] Oligodendroglioma

[1522] Prostate Adenocarcinoma

[1523] Stomach Adenocarcinoma

[1524]

[1525] Uterine Endometrioid CarcinomaAttorney Docket No. 59845-0148WO1

[1526] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1527] Position Exemplary Mutations Associated Cancer(s)

[1528] 159 A159P Astrocytoma

[1529] A159V Bladder Urothelial Carcinoma

[1530] Cervical Squamous Cell Carcinoma

[1531] Chromophobe Renal Cell Carcinoma

[1532] Colon Adenocarcinoma

[1533] Cutaneous Melanoma

[1534] Head and Neck Squamous Cell Carcinoma

[1535] Lung Adenocarcinoma

[1536] Lung Squamous Cell Carcinoma

[1537] Rectal Adenocarcinoma

[1538] Serous Ovarian Cancer

[1539] Uterine Endometrioid Carcinoma

[1540] Uterine Serous Carcinoma / Uterine Papillaiy Serous Carcinoma 160 M160I Lung Squamous Cell Carcinoma

[1541] 161 A161_I162del Astrocytoma

[1542] A161D Bladder Urothelial Carcinoma

[1543] A161Gfs*3 Breast Invasive Ductal Carcinoma

[1544] A161P Colon Adenocarcinoma

[1545] A161S Cutaneous Melanoma

[1546] A161T Head and Neck Squamous Cell Carcinoma

[1547] A161V Hepatocellular Carcinoma

[1548] Lung Adenocarcinoma

[1549] Lung Squamous Cell Carcinoma

[1550] Oligoastrocytoma

[1551] Serous Ovarian Cancer

[1552] 162 I162_Y163delinsN Breast Invasive Ductal Carcinoma

[1553] I162dup Colon Adenocarcinoma

[1554] I162F Lung Squamous Cell Carcinoma

[1555] I162Hfs*12 Tubular Stomach Adenocarcinoma

[1556] I162N Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma I162Tfs*8

[1557] I162Wfs*10

[1558] 163 Y163* Astrocytoma

[1559] Y163D Breast Invasive Ductal Carcinoma

[1560] Y163H Colon Adenocarcinoma

[1561] Y163Lfs*18 Esophageal Squamous Cell Carcinoma

[1562] Y163N Head and Neck Squamous Cell Carcinoma

[1563] Lung Adenocarcinoma

[1564] Lung Squamous Cell Carcinoma

[1565] Malignant Peripheral Nerve Sheath Tumor Oligoastrocytoma

[1566] Prostate Adenocarcinoma

[1567] Serous Ovarian Cancer

[1568] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1569] 164 K164E Esophageal Squamous Cell Carcinoma

[1570] K164Sfs*5 Glioblastoma Multiforme

[1571] K164Sfs*6 Lung Squamous Cell Carcinoma

[1572] Mucinous Carcinoma

[1573] Rectal Adenocarcinoma

[1574]

[1575] Serous Ovarian CancerAttorney Docket No. 59845-0148WO1

[1576] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1577] Position Exemplary Mutations Associated Cancer(s)

[1578] 165 Q165* Breast Invasive Ductal Carcinoma

[1579] Q165Afs*6 Lung Adenocarcinoma

[1580] Q165Hfs*17 Prostate Adenocarcinoma

[1581] 166 S166* Head and Neck Squamous Cell Carcinoma

[1582] Lung Adenocarcinoma

[1583] Pancreatic Adenocarcinoma

[1584] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 167 Q167* Bladder Urothelial Carcinoma

[1585] Q167Hfs*3 Breast Invasive Ductal Carcinoma

[1586] Q167Tfs*14 Esophageal Adenocarcinoma

[1587] Head and Neck Squamous Cell Carcinoma

[1588] Lung Adenocarcinoma

[1589] Serous Ovarian Cancer

[1590] Stomach Adenocarcinoma

[1591] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Endometrioid Carcinoma

[1592] 168 H168Cfs*8 Adrenocortical Carcinoma

[1593] H168L Breast Invasive Ductal Carcinoma

[1594] H168P Esophageal Squamous Cell Carcinoma

[1595] H168R Head and Neck Squamous Cell Carcinoma

[1596] Lung Adenocarcinoma

[1597] Stomach Adenocarcinoma

[1598] 169 M169I Bladder Urothelial Carcinoma

[1599] M169T Breast Invasive Lobular Carcinoma

[1600] Stomach Adenocarcinoma

[1601] 171 E171* Bladder Urothelial Carcinoma

[1602] E171Gfs*3 Breast Invasive Ductal Carcinoma

[1603] E171Gfs*4 Cutaneous Melanoma

[1604] E171K Diffuse Large B-Cell Lymphoma, NOS

[1605] E171Lfs*2 Glioblastoma Multiforme

[1606] E171Rfs*3 Head and Neck Squamous Cell Carcinoma

[1607] Hepatocellular Carcinoma

[1608] Intestinal Type Stomach Adenocarcinoma

[1609] Lung Adenocarcinoma

[1610] Lung Squamous Cell Carcinoma

[1611] Oligoastrocytoma

[1612] Pleural Mesothelioma, Epithelioid Type

[1613] Rectal Adenocarcinoma

[1614] 172 V172D Esophageal Adenocarcinoma

[1615] V172F Glioblastoma Multiforme

[1616] V172G Head and Neck Squamous Cell Carcinoma V172Lfs*2 Lung Squamous Cell Carcinoma

[1617] Pleural Mesothelioma, Epithelioid Type

[1618] 173 V173* Acute Myeloid Leukemia

[1619] V173_R175del Adrenocortical Carcinoma

[1620] V173A Astrocytoma

[1621] V173Afs*69 Breast Invasive Ductal Carcinoma

[1622] V173dup Colon Adenocarcinoma

[1623] V173Efs*7 Esophageal Adenocarcinoma

[1624]

[1625] V173G Head and Neck Squamous Cell CarcinomaAttorney Docket No. 59845-0148WO1

[1626] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1627] Position Exemplary Mutations Associated Cancer(s)

[1628] V173L Lung Adenocarcinoma

[1629] V173M Lung Squamous Cell Carcinoma

[1630] Oligoastrocytoma

[1631] Oligodendroglioma

[1632] Pancreatic Adenocarcinoma

[1633] Serous Ovarian Cancer

[1634] Signet Ring Cell Carcinoma of the Stomach

[1635] Stomach Adenocarcinoma

[1636] Tubular Stomach Adenocarcinoma

[1637] Uterine Mixed Endometrial Carcinoma

[1638] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 174 R174Sfs*73 Breast Invasive Ductal Carcinoma

[1639] R174W Esophageal Squamous Cell Carcinoma

[1640] Hepatocellular Carcinoma

[1641] Uterine Endometrioid Carcinoma

[1642] 175 R175C Astrocytoma

[1643] R175G Bladder Urothelial Carcinoma

[1644] R175H Breast Invasive Ductal Carcinoma

[1645] R175L Colon Adenocarcinoma

[1646] Cutaneous Melanoma

[1647] Diffuse Type Stomach Adenocarcinoma

[1648] Esophageal Adenocarcinoma

[1649] Esophageal Squamous Cell Carcinoma

[1650] Glioblastoma Multiforme

[1651] Head and Neck Squamous Cell Carcinoma

[1652] Hepatocellular Carcinoma

[1653] Intestinal Type Stomach Adenocarcinoma

[1654] Leiomyosarcoma

[1655] Lung Adenocarcinoma

[1656] Lung Squamous Cell Carcinoma

[1657] Mucinous Adenocarcinoma of the Colon and Rectum Mucinous Stomach Adenocarcinoma

[1658] Oligoastrocytoma

[1659] Pancreatic Adenocarcinoma

[1660] Prostate Adenocarcinoma

[1661] Rectal Adenocarcinoma

[1662] Serous Ovarian Cancer

[1663] Stomach Adenocarcinoma

[1664] Tubular Stomach Adenocarcinoma

[1665] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1666] Uterine Endometrioid Carcinoma

[1667] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 176 C176* Acute Myeloid Leukemia

[1668] C176dup Bladder Urothelial Carcinoma

[1669] C176F Breast Invasive Carcinoma (NOS)

[1670] C176G Breast Invasive Ductal Carcinoma

[1671] C176R Chromophobe Renal Cell Carcinoma

[1672] C176S Colon Adenocarcinoma

[1673]

[1674] C176Sfs*71 Diffuse Type Stomach AdenocarcinomaAttorney Docket No. 59845-0148WO1

[1675] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1676] Position Exemplary Mutations Associated Cancer(s)

[1677] C176W Esophageal Adenocarcinoma

[1678] C176Y Esophageal Squamous Cell Carcinoma

[1679] Head and Neck Squamous Cell Carcinoma

[1680] Hepatocellular Carcinoma

[1681] Lung Adenocarcinoma

[1682] Lung Squamous Cell Carcinoma

[1683] Mucinous Stomach Adenocarcinoma

[1684] Oligoastrocytoma

[1685] Oligodendroglioma

[1686] Prostate Adenocarcinoma

[1687] Serous Ovarian Cancer

[1688] Stomach Adenocarcinoma

[1689] Tubular Stomach Adenocarcinoma

[1690] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1691] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 177 P177_C182del Astrocytoma

[1692] P177 H178del Colon Adenocarcinoma

[1693] P177H Cutaneous Melanoma

[1694] P177L Esophageal Adenocarcinoma

[1695] P177R Head and Neck Squamous Cell Carcinoma

[1696] P177S Lung Adenocarcinoma

[1697] P177T Prostate Adenocarcinoma

[1698] Serous Ovarian Cancer

[1699] 178 H178_S183del Bladder Urothelial Carcinoma

[1700] H178D Chromophobe Renal Cell Carcinoma

[1701] H178Pfs*3 Colon Adenocarcinoma

[1702] H178Pfs*70 Glioblastoma Multiforme

[1703] H178Q Head and Neck Squamous Cell Carcinoma H178Qfs*3 Lung Adenocarcinoma

[1704] H178Sfs*69 Lung Squamous Cell Carcinoma

[1705] H178Tfs*69 Pancreatic Adenocarcinoma

[1706] Renal Clear Cell Carcinoma

[1707] Stomach Adenocarcinoma

[1708] Uterine Endometrioid Carcinoma

[1709] 179 H179D Acute Myeloid Leukemia

[1710] H179L Astrocytoma

[1711] H179N Bladder Urothelial Carcinoma

[1712] H179P Breast Invasive Ductal Carcinoma

[1713] H179Q Colon Adenocarcinoma

[1714] H179R Cutaneous Melanoma

[1715] H179Y Diffuse Type Stomach Adenocarcinoma

[1716] Esophageal Adenocarcinoma

[1717] Esophageal Squamous Cell Carcinoma

[1718] Glioblastoma Multiforme

[1719] Head and Neck Squamous Cell Carcinoma

[1720] Leiomyosarcoma

[1721] Lung Adenocarcinoma

[1722] Lung Squamous Cell Carcinoma

[1723] Oligoastrocytoma

[1724] Oligodendroglioma

[1725]

[1726] Pancreatic AdenocarcinomaAttorney Docket No. 59845-0148WO1

[1727] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1728] Position Exemplary Mutations Associated Cancer(s)

[1729] Serous Ovarian Cancer

[1730] Stomach Adenocarcinoma

[1731] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1732] Uterine Endometrioid Carcinoma

[1733] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 180 E180* Adrenocortical Carcinoma

[1734] E180_D184del Bladder Urothelial Carcinoma

[1735] E180_S185del Head and Neck Squamous Cell Carcinoma

[1736] E180K Lung Adenocarcinoma

[1737] Lung Squamous Cell Carcinoma

[1738] Rectal Adenocarcinoma

[1739] 181 R181C Astrocytoma

[1740] R181H Bladder Urothelial Carcinoma

[1741] R181P Colon Adenocarcinoma

[1742] Lung Squamous Cell Carcinoma

[1743] Prostate Adenocarcinoma

[1744] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1745] Uterine Endometrioid Carcinoma

[1746] 183 S183* Bladder Urothelial Carcinoma

[1747] Breast Invasive Ductal Carcinoma

[1748] Cervical Squamous Cell Carcinoma

[1749] Lung Adenocarcinoma

[1750] Lung Squamous Cell Carcinoma

[1751] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1752] 184 D184Afs*62 Head and Neck Squamous Cell Carcinoma

[1753] 186 D186Vfs*61 Pancreatic Adenocarcinoma

[1754] 187 G187S Bladder Urothelial Carcinoma

[1755] X187_splice Breast Invasive Carcinoma (NOS)

[1756] Breast Invasive Ductal Carcinoma

[1757] Chromophobe Renal Cell Carcinoma

[1758] Colon Adenocarcinoma

[1759] Cutaneous Melanoma

[1760] Esophageal Squamous Cell Carcinoma

[1761] Glioblastoma Multiforme

[1762] Head and Neck Squamous Cell Carcinoma

[1763] Leiomyosarcoma

[1764] Lung Adenocarcinoma

[1765] Lung Squamous Cell Carcinoma

[1766] Oligoastrocytoma

[1767] Pancreatic Adenocarcinoma

[1768] Rectal Adenocarcinoma

[1769] Serous Ovarian Cancer

[1770] Stomach Adenocarcinoma

[1771] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous

[1772]

[1773] Histiocytoma / High-Grade Spindle Cell SarcomaAttorney Docket No. 59845-0148WO1

[1774] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1775] Position Exemplary Mutations Associated Cancer(s)

[1776] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1777] Uterine Endometrioid Carcinoma

[1778] 188 L188Gfs*20 Lung Squamous Cell Carcinoma

[1779] L188Tfs*21 Serous Ovarian Cancer

[1780] 189 A189Dfs*14 Bladder Urothelial Carcinoma

[1781] A189Pfs*58 Leiomyosarcoma

[1782] Lung Squamous Cell Carcinoma

[1783] 190 P190L Astrocytoma

[1784] P190R Chromophobe Renal Cell Carcinoma

[1785] Colon Adenocarcinoma

[1786] Glioblastoma Multiforme

[1787] Lung Squamous Cell Carcinoma

[1788] 191 P191del Astrocytoma

[1789] P191L Colon Adenocarcinoma

[1790] P191Qfs*51 Cutaneous Melanoma

[1791] Diffuse Type Stomach Adenocarcinoma

[1792] Head and Neck Squamous Cell Carcinoma

[1793] Hepatocellular Carcinoma

[1794] Lung Adenocarcinoma

[1795] Oligodendroglioma

[1796] Serous Ovarian Cancer

[1797] Stomach Adenocarcinoma

[1798] 192 Q192* Bladder Urothelial Carcinoma

[1799] Q192_H193del Breast Invasive Ductal Carcinoma

[1800] Q192del Cervical Squamous Cell Carcinoma

[1801] Q192R Glioblastoma Multiforme

[1802] Head and Neck Squamous Cell Carcinoma

[1803] Hepatocellular Carcinoma

[1804] Intestinal Type Stomach Adenocarcinoma

[1805] Leiomyosarcoma

[1806] Lung Adenocarcinoma

[1807] Lung Squamous Cell Carcinoma

[1808] Pancreatic Adenocarcinoma

[1809] Papillary Thyroid Cancer

[1810] Serous Ovarian Cancer

[1811]

[1812] Tubular Stomach AdenocarcinomaAttorney Docket No. 59845-0148WO1

[1813] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1814] Position Exemplary Mutations Associated Cancer(s)

[1815] 193 H193D Acute Myeloid Leukemia

[1816] H193L Astrocytoma

[1817] H193N Bladder Urothelial Carcinoma

[1818] H193P Breast Invasive Carcinoma (NOS)

[1819] H193R Breast Invasive Ductal Carcinoma

[1820] H193Y Esophageal Squamous Cell Carcinoma

[1821] Glioblastoma Multiforme

[1822] Head and Neck Squamous Cell Carcinoma

[1823] Hepatocellular Carcinoma

[1824] Intestinal Type Stomach Adenocarcinoma

[1825] Lung Adenocarcinoma

[1826] Lung Squamous Cell Carcinoma

[1827] Metaplastic Breast Cancer

[1828] Oligoastrocytoma

[1829] Papillary Renal Cell Carcinoma

[1830] Prostate Adenocarcinoma

[1831] Renal Clear Cell Carcinoma

[1832] Serous Ovarian Cancer

[1833] Stomach Adenocarcinoma

[1834] Tubular Stomach Adenocarcinoma

[1835] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1836] Uterine Endometrioid Carcinoma

[1837] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 194 L194Efs*51 Bladder Urothelial Carcinoma

[1838] L194F Breast Invasive Ductal Carcinoma

[1839] L194H Endometrioid Carcinoma

[1840] L194P Glioblastoma Multiforme

[1841] L194Pfs*13 Head and Neck Squamous Cell Carcinoma L194R Hepatocellular Carcinoma

[1842] Leiomyosarcoma

[1843] Lung Adenocarcinoma

[1844] Lung Squamous Cell Carcinoma

[1845] Oligoastrocytoma

[1846] Pancreatic Adenocarcinoma

[1847] Rectal Adenocarcinoma

[1848] Serous Ovarian Cancer

[1849] Thymoma

[1850] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 195 I195F Acute Myeloid Leukemia

[1851] I195Ffs*52 Astrocytoma

[1852] I195Lfs*53 Breast Invasive Ductal Carcinoma

[1853] I195M Colon Adenocarcinoma

[1854] I195N Cutaneous Melanoma

[1855] I195Nfs*14 Esophageal Squamous Cell Carcinoma

[1856] I195S Glioblastoma Multiforme

[1857] I195Sfs*52 Head and Neck Squamous Cell Carcinoma I195T Hepatocellular Carcinoma

[1858] I195Yfs*14 Leiomyosarcoma

[1859] Lung Adenocarcinoma

[1860] Lung Squamous Cell Carcinoma

[1861]

[1862] OligoastrocytomaAttorney Docket No. 59845-0148WO1

[1863] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1864] Position Exemplary Mutations Associated Cancer(s)

[1865] Oligodendroglioma

[1866] Rectal Adenocarcinoma

[1867] Serous Ovarian Cancer

[1868] Stomach Adenocarcinoma

[1869] Tubular Stomach Adenocarcinoma

[1870] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1871] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 196 R196* Astrocytoma

[1872] R196P Breast Invasive Carcinoma (NOS)

[1873] Breast Invasive Ductal Carcinoma

[1874] Cervical Squamous Cell Carcinoma

[1875] Chromophobe Renal Cell Carcinoma

[1876] Colon Adenocarcinoma

[1877] Cutaneous Melanoma

[1878] Esophageal Adenocarcinoma

[1879] Glioblastoma Multiforme

[1880] Head and Neck Squamous Cell Carcinoma

[1881] Intestinal Type Stomach Adenocarcinoma

[1882] Lung Adenocarcinoma

[1883] Lung Squamous Cell Carcinoma

[1884] Mucinous Adenocarcinoma of the Colon and Rectum Oligodendroglioma

[1885] Pancreatic Adenocarcinoma

[1886] Pleural Mesothelioma. Epithelioid Type

[1887] Rectal Adenocarcinoma

[1888] Serous Ovarian Cancer

[1889] Stomach Adenocarcinoma

[1890] Tubular Stomach Adenocarcinoma

[1891] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 197 V197G Breast Invasive Ductal Carcinoma

[1892] V197Ifs*42 Esophageal Squamous Cell Carcinoma

[1893] V197L Head and Neck Squamous Cell Carcinoma

[1894] V197M Hepatocellular Carcinoma

[1895] Lung Squamous Cell Carcinoma

[1896] Pancreatic Adenocarcinoma

[1897] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 198 E198* Breast Invasive Ductal Carcinoma

[1898] E198Gfs*11 Colon Adenocarcinoma

[1899] Cutaneous Melanoma

[1900] Esophageal Adenocarcinoma

[1901] Esophageal Squamous Cell Carcinoma

[1902] Lung Adenocarcinoma

[1903] Lung Squamous Cell Carcinoma

[1904] Serous Ovarian Cancer

[1905] Tubular Stomach Adenocarcinoma

[1906] 199 G199* Bladder Urothelial Carcinoma

[1907] G199Efs*48 Breast Invasive Ductal Carcinoma

[1908] G199Ifs*47 Colon Adenocarcinoma

[1909] G199V Head and Neck Squamous Cell Carcinoma

[1910] Pancreatic Adenocarcinoma

[1911]

[1912] Prostate AdenocarcinomaAttorney Docket No. 59845-0148WO1

[1913] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1914] Position Exemplary Mutations Associated Cancer(s)

[1915] Uterine Endometrioid Carcinoma

[1916] 200 N200Ifs*47 Head and Neck Squamous Cell Carcinoma Oligoastrocytoma

[1917] 201 L201* Breast Invasive Ductal Carcinoma

[1918] L201Ffs*8 Head and Neck Squamous Cell Carcinoma 202 R202 L206del Head and Neck Squamous Cell Carcinoma

[1919] 203 V203Gfs*44 Head and Neck Squamous Cell Carcinoma

[1920] V203Gfs*5 Leiomyosarcoma

[1921] V203L Mucinous Adenocarcinoma of the Colon and Rectum V203Wfs*44 Prostate Adenocarcinoma

[1922] 204 E204* Bladder Urothelial Carcinoma

[1923] E204D Breast Invasive Ductal Carcinoma

[1924] E204Q Esophageal Squamous Cell Carcinoma

[1925] E204Sfs*43 Head and Neck Squamous Cell Carcinoma E204Vfs*4 Hepatocellular Carcinoma

[1926] Lung Squamous Cell Carcinoma

[1927] Serous Ovarian Cancer

[1928] Uterine Endometrioid Carcinoma

[1929] Uterine Mixed Endometrial Carcinoma

[1930] 205 Y205* Astrocytoma

[1931] Y205C Breast Invasive Ductal Carcinoma

[1932] Y205D Chromophobe Renal Cell Carcinoma

[1933] Y205F Colon Adenocarcinoma

[1934] Y205H Esophageal Squamous Cell Carcinoma

[1935] Y205N Glioblastoma Multiforme

[1936] Y205S Head and Neck Squamous Cell Carcinoma

[1937] Hepatocellular Carcinoma

[1938] Intestinal Type Stomach Adenocarcinoma

[1939] Leiomyosarcoma

[1940] Lung Adenocarcinoma

[1941] Lung Squamous Cell Carcinoma

[1942] Pancreatic Adenocarcinoma

[1943] Rectal Adenocarcinoma

[1944] Serous Ovarian Cancer

[1945] Stomach Adenocarcinoma

[1946] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[1947] Uterine Endometrioid Carcinoma

[1948] Uterine Mixed Endometrial Carcinoma

[1949] Uterine Serous Carcinoma / Uterine Papillaiy Serous Carcinoma 206 L206Wfs*41 Head and Neck Squamous Cell Carcinoma

[1950] 207 D207Ffs*35 Lung Squamous Cell Carcinoma

[1951] D207Mfs*40

[1952] 208 D208G Bladder Urothelial Carcinoma

[1953] D208N Breast Invasive Ductal Carcinoma

[1954] D208V Oligoastrocytoma

[1955] Serous Ovarian Cancer

[1956] 209 R209* Bladder Urothelial Carcinoma

[1957] R209Hfs*5 Breast Invasive Carcinoma (NOS)

[1958]

[1959] R209I Breast Invasive Ductal CarcinomaAttorney Docket No. 59845-0148WO1

[1960] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[1961] Position Exemplary Mutations Associated Cancer(s)

[1962] R209K Esophageal Adenocarcinoma

[1963] R209Kfs*6 Esophageal Squamous Cell Carcinoma

[1964] Head and Neck Squamous Cell Carcinoma

[1965] Leiomyosarcoma

[1966] Lung Adenocarcinoma

[1967] Prostate Adenocarcinoma

[1968] Serous Ovarian Cancer

[1969] Signet Ring Cell Carcinoma of the Stomach

[1970] Uterine Endometrioid Carcinoma

[1971] 210 N210Tfs*37 Serous Ovarian Cancer

[1972] 211 T211_H214del Breast Invasive Carcinoma (NOS)

[1973] T211A Breast Invasive Ductal Carcinoma

[1974] T211Ffs*4 Colon Adenocarcinoma

[1975] T211I Glioblastoma Multiforme

[1976] T211Lfs*36 Head and Neck Squamous Cell Carcinoma

[1977] Lung Squamous Cell Carcinoma

[1978] Rectal Adenocarcinoma

[1979] Uterine Endometrioid Carcinoma

[1980] 212 F212Sfs*3 Astrocytoma

[1981] F212Yfs*34 Breast Invasive Ductal Carcinoma

[1982] Glioblastoma Multiforme

[1983] Lung Squamous Cell Carcinoma

[1984] 213 R213* Adrenocortical Carcinoma

[1985] R213Dfs*34 Astrocytoma

[1986] R213G Bladder Urothelial Carcinoma

[1987] R213L Breast Invasive Carcinoma (NOS)

[1988] R213P Breast Invasive Ductal Carcinoma

[1989] R213Q Chromophobe Renal Cell Carcinoma

[1990] Colon Adenocarcinoma

[1991] Cutaneous Melanoma

[1992] Dedifferentiated Liposarcoma

[1993] Diffuse Type Stomach Adenocarcinoma

[1994] Esophageal Adenocarcinoma

[1995] Esophageal Squamous Cell Carcinoma

[1996] Glioblastoma Multiforme

[1997] Head and Neck Squamous Cell Carcinoma

[1998] Hepatocellular Carcinoma

[1999] Intestinal Type Stomach Adenocarcinoma

[2000] Lung Adenocarcinoma

[2001] Lung Squamous Cell Carcinoma

[2002] Mucinous Adenocarcinoma of the Colon and Rectum Myxofibrosarcoma

[2003] Oligoastrocytoma

[2004] Oligodendroglioma

[2005] Pancreatic Adenocarcinoma

[2006] Rectal Adenocarcinoma

[2007] Renal Clear Cell Carcinoma

[2008] Serous Ovarian Cancer

[2009] Stomach Adenocarcinoma

[2010] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous

[2011]

[2012] Histiocytoma / High-Grade Spindle Cell SarcomaAttorney Docket No. 59845-0148WO1

[2013] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2014] Position Exemplary Mutations Associated Cancer(s)

[2015] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2016] Uterine Endometrioid Carcinoma

[2017] 214 H214L Astrocytoma

[2018] H214Qfs*33 Bladder Urothelial Carcinoma

[2019] H214R Chromophobe Renal Cell Carcinoma

[2020] Colon Adenocarcinoma

[2021] Glioblastoma Multiforme

[2022] Head and Neck Squamous Cell Carcinoma

[2023] Lung Adenocarcinoma

[2024] Lung Squamous Cell Carcinoma

[2025] Oligoastrocytoma

[2026] Pancreatic Adenocarcinoma

[2027] Serous Ovarian Cancer

[2028] Stomach Adenocarcinoma

[2029] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 215 S215G Acute Myeloid Leukemia

[2030] S215I Astrocytoma

[2031] S215Kfs*7 Breast Invasive Ductal Carcinoma

[2032] S215N Colon Adenocarcinoma

[2033] S215R Cutaneous Melanoma

[2034] Head and Neck Squamous Cell Carcinoma

[2035] Hepatocellular Carcinoma

[2036] Intestinal Type Stomach Adenocarcinoma

[2037] Leiomyosarcoma

[2038] Lung Adenocarcinoma

[2039] Lung Squamous Cell Carcinoma

[2040] Pancreatic Adenocarcinoma

[2041] Rectal Adenocarcinoma

[2042] Serous Ovarian Cancer

[2043] Uterine Endometrioid Carcinoma

[2044] 216 V216E Astrocytoma

[2045] V216G Breast Invasive Ductal Carcinoma

[2046] V216L Colon Adenocarcinoma

[2047] V216M Esophageal Adenocarcinoma

[2048] Glioblastoma Multiforme

[2049] Head and Neck Squamous Cell Carcinoma

[2050] Lung Adenocarcinoma

[2051] Lung Squamous Cell Carcinoma

[2052] Pleural Mesothelioma, Biphasic Type

[2053] Serous Ovarian Cancer

[2054] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2055] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 217 V217Gfs*31 Pancreatic Adenocarcinoma

[2056] 218 V218Cfs*29 Bladder Urothelial Carcinoma

[2057] V218del Cutaneous Melanoma

[2058] V218E Head and Neck Squamous Cell Carcinoma

[2059] V218G Lung Squamous Cell Carcinoma

[2060]

[2061] Serous Ovarian CancerAttorney Docket No. 59845-0148WO1

[2062] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2063] Position Exemplary Mutations Associated Cancer(s)

[2064] 219 P219Afs*3 Bladder Urothelial Carcinoma

[2065] P219Lfs*2 Head and Neck Squamous Cell Carcinoma P219T Rectal Adenocarcinoma

[2066] 220 Y220* Astrocytoma

[2067] Y220C Bladder Urothelial Carcinoma

[2068] Y220D Breast Invasive Carcinoma (NOS)

[2069] Y220H Breast Invasive Ductal Carcinoma

[2070] Y220Mfs*27 Cervical Squamous Cell Carcinoma

[2071] Y220S Chromophobe Renal Cell Carcinoma

[2072] Colon Adenocarcinoma

[2073] Cutaneous Melanoma

[2074] Dedifferentiated Liposarcoma

[2075] Esophageal Adenocarcinoma

[2076] Esophageal Squamous Cell Carcinoma

[2077] Glioblastoma Multiforme

[2078] Head and Neck Squamous Cell Carcinoma

[2079] Hepatocellular Carcinoma

[2080] Intestinal Type Stomach Adenocarcinoma

[2081] Leiomyosarcoma

[2082] Lung Adenocarcinoma

[2083] Lung Squamous Cell Carcinoma

[2084] Mucinous Stomach Adenocarcinoma

[2085] Oligoastrocytoma

[2086] Oligodendroglioma

[2087] Pancreatic Adenocarcinoma

[2088] Papillary Renal Cell Carcinoma

[2089] Serous Ovarian Cancer

[2090] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2091] Uterine Endometrioid Carcinoma

[2092] Uterine Mixed Endometrial Carcinoma

[2093] Uterine Serous Carcinoma / Uterine Papillary' Serous Carcinoma 221 E221* Bladder Urothelial Carcinoma

[2094] E221Afs*2 Breast Invasive Ductal Carcinoma

[2095] Hepatocellular Carcinoma

[2096] Intestinal Type Stomach Adenocarcinoma

[2097] Lung Squamous Cell Carcinoma

[2098] Serous Ovarian Cancer

[2099] 223 P223* Acute Myeloid Leukemia

[2100] P223Rfs*4 Serous Ovarian Cancer

[2101] X223_splice Tubular Stomach Adenocarcinoma

[2102] Uterine Serous Carcinoma / Uterine Papillary' Serous Carcinoma 224 E224* Astrocytoma

[2103] E224D Bladder Urothelial Carcinoma

[2104] E224Gfs*4 Breast Invasive Ductal Carcinoma

[2105] X224 splice Colon Adenocarcinoma

[2106] Cutaneous Melanoma

[2107] Diffuse Type Stomach Adenocarcinoma

[2108] Esophageal Squamous Cell Carcinoma

[2109] Head and Neck Squamous Cell Carcinoma

[2110] Hepatocellular Carcinoma

[2111]

[2112] LeiomyosarcomaAttorney Docket No. 59845-0148WO1

[2113] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2114] Position Exemplary Mutations Associated Cancer(s)

[2115] Lung Adenocarcinoma

[2116] Lung Squamous Cell Carcinoma

[2117] Myxofibrosarcoma

[2118] Oligoastrocytoma

[2119] Serous Ovarian Cancer

[2120] Tubular Stomach Adenocarcinoma

[2121] 225 V225Rfs*23 Acute Myeloid Leukemia

[2122] X225_splice Astrocytoma

[2123] Breast Invasive Ductal Carcinoma

[2124] Chromophobe Renal Cell Carcinoma

[2125] Esophageal Squamous Cell Carcinoma

[2126] Glioblastoma Multiforme

[2127] Head and Neck Squamous Cell Carcinoma

[2128] Hepatocellular Carcinoma

[2129] Lung Adenocarcinoma

[2130] Lung Squamous Cell Carcinoma

[2131] Pleural Mesothelioma, Epithelioid Type

[2132] Serous Ovarian Cancer

[2133] Uterine Endometrioid Carcinoma

[2134] Uterine Mixed Endometrial Carcinoma

[2135] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 226 G226Afs*21 Serous Ovarian Cancer

[2136] Tubular Stomach Adenocarcinoma

[2137] 227 S227* Oligoastrocytoma

[2138] 228 D228* Bladder Urothelial Carcinoma

[2139] D228E Hepatocellular Carcinoma

[2140] D228N Serous Ovarian Cancer

[2141] D228Vfs*18 Tubular Stomach Adenocarcinoma

[2142] 229 C229* Bladder Urothelial Carcinoma

[2143] C229_I232del Chromophobe Renal Cell Carcinoma

[2144] C229Lfs*18 Colon Adenocarcinoma

[2145] C229Yfs*10 Esophageal Squamous Cell Carcinoma

[2146] Head and Neck Squamous Cell Carcinoma

[2147] Lung Adenocarcinoma

[2148] Serous Ovarian Cancer

[2149] 230 T230_T231del Hepatocellular Carcinoma

[2150] T230Hfs*9 Lung Squamous Cell Carcinoma

[2151] T230P Oligoastrocytoma

[2152] 232 I232F Astrocytoma

[2153] I232N Breast Invasive Ductal Carcinoma

[2154] I232S Colon Adenocarcinoma

[2155] I232T Diffuse Large B-Cell Lymphoma, NOS

[2156] Lung Adenocarcinoma

[2157] Lung Squamous Cell Carcinoma

[2158] Rectal Adenocarcinoma

[2159] Serous Ovarian Cancer

[2160] Uterine Endometrioid Carcinoma

[2161] 234 Y234* Adrenocortical Carcinoma

[2162] Y234C Astrocytoma

[2163] Y234H Breast Invasive Ductal Carcinoma

[2164]

[2165] Y234N Colon AdenocarcinomaAttorney Docket No. 59845-0148WO1

[2166] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2167] Position Exemplary Mutations Associated Cancer(s)

[2168] Y234Pfs*7 Glioblastoma Multiforme

[2169] Y234S Head and Neck Squamous Cell Carcinoma

[2170] Y234Tfs*11 Intrahepatic Cholangiocarcinoma

[2171] Leiomyosarcoma

[2172] Lung Squamous Cell Carcinoma

[2173] Oligoastrocytoma

[2174] Pleural Mesothelioma. Biphasic Type

[2175] Rectal Adenocarcinoma

[2176] Renal Clear Cell Carcinoma

[2177] Serous Ovarian Cancer

[2178] 236 Y236* Astrocytoma

[2179] Y236C Bladder Urothelial Carcinoma

[2180] Y236D Colon Adenocarcinoma

[2181] Y236del Head and Neck Squamous Cell Carcinoma Y236H Lung Adenocarcinoma

[2182] Lung Squamous Cell Carcinoma

[2183] Oligoastrocytoma

[2184] Serous Ovarian Cancer

[2185] Uterine Mixed Endometrial Carcinoma

[2186] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 237 M237_N239del Astrocytoma

[2187] M237Cfs*10 Bladder Urothelial Carcinoma

[2188] M237Gfs*20 Breast Invasive Ductal Carcinoma

[2189] M237I Colon Adenocarcinoma

[2190] M237K Dedifferentiated Liposarcoma

[2191] M237L Esophageal Adenocarcinoma

[2192] M237V Head and Neck Squamous Cell Carcinoma

[2193] Hepatocellular Carcinoma

[2194] Intestinal Type Stomach Adenocarcinoma

[2195] Intrahepatic Cholangiocarcinoma

[2196] Lung Adenocarcinoma

[2197] Lung Squamous Cell Carcinoma

[2198] Myxofibrosarcoma

[2199] Oligoastrocytoma

[2200] Prostate Adenocarcinoma

[2201] Serous Ovarian Cancer

[2202] Tubular Stomach Adenocarcinoma

[2203] Uterine Endometrioid Carcinoma

[2204] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 238 C238* Astrocytoma

[2205] C238_M243del Bladder Urothelial Carcinoma

[2206] C238_N239delinsY Breast Invasive Ductal Carcinoma

[2207] C238F Endocervical Adenocarcinoma

[2208] C238G Esophageal Squamous Cell Carcinoma

[2209] C238Lfs*9 Glioblastoma Multiforme

[2210] C238R Head and Neck Squamous Cell Carcinoma

[2211] C238S Hepatocellular Carcinoma

[2212] C238W Intestinal Type Stomach Adenocarcinoma

[2213] C238Y Leiomyosarcoma

[2214] Lung Adenocarcinoma

[2215] Lung Squamous Cell Carcinoma

[2216]

[2217] OligodendrogliomaAttorney Docket No. 59845-0148WO1

[2218] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2219] Position Exemplary Mutations Associated Cancer(s)

[2220] Pancreatic Adenocarcinoma

[2221] Pleural Mesothelioma, Epithelioid Type

[2222] Rectal Adenocarcinoma

[2223] Serous Ovarian Cancer

[2224] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2225] Uterine Endometrioid Carcinoma

[2226] 239 N239* Astrocytoma

[2227] N239_S240del Breast Invasive Ductal Carcinoma

[2228] N239_S241del Chromophobe Renal Cell Carcinoma

[2229] N239D Colon Adenocarcinoma

[2230] N239Qfs*24 Esophageal Adenocarcinoma

[2231] N239S Glioblastoma Multiforme

[2232] Head and Neck Squamous Cell Carcinoma

[2233] Lung Adenocarcinoma

[2234] Pancreatic Adenocarcinoma

[2235] Prostate Adenocarcinoma

[2236] Serous Ovarian Cancer

[2237] Tubular Stomach Adenocarcinoma

[2238] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2239] Uterine Endometrioid Carcinoma

[2240] 240 S240 C242del Bladder Urothelial Carcinoma

[2241] S240G Colon Adenocarcinoma

[2242] S240Gfs*20 Head and Neck Squamous Cell Carcinoma S240Kfs*24 Stomach Adenocarcinoma

[2243] S240R Uterine Endometrioid Carcinoma

[2244] 241 S241A Bladder Urothelial Carcinoma

[2245] S241C Breast Invasive Ductal Carcinoma

[2246] S241dup Cervical Squamous Cell Carcinoma

[2247] S241F Cutaneous Melanoma

[2248] S241P Esophageal Adenocarcinoma

[2249] S241Pfs*6 Glioblastoma Multiforme

[2250] S241Y Head and Neck Squamous Cell Carcinoma

[2251] Invasive Breast Carcinoma

[2252] Lung Adenocarcinoma

[2253] Lung Squamous Cell Carcinoma

[2254] Oligoastrocytoma

[2255] Pancreatic Adenocarcinoma

[2256] Pancreatic Adenocarcinoma

[2257] Papillary Renal Cell Carcinoma

[2258] Papillary Stomach Adenocarcinoma

[2259] Perihilar Cholangiocarcinoma

[2260] Serous Ovarian Cancer

[2261] Serous Ovarian Cancer

[2262] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2263] Uterine Endometrioid Carcinoma

[2264] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma

[2265]

[2266] 242 C242* Bladder Urothelial CarcinomaAttorney Docket No. 59845-0148WO1

[2267] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2268] Position Exemplary Mutations Associated Cancer(s)

[2269] C242Afs*5 Breast Invasive Ductal Carcinoma

[2270] C242F Colon Adenocarcinoma

[2271] C242G Diffuse Type Stomach Adenocarcinoma

[2272] C242R Esophageal Adenocarcinoma

[2273] C242S Esophageal Squamous Cell Carcinoma

[2274] C242Y Glioblastoma Multiforme

[2275] Head and Neck Squamous Cell Carcinoma

[2276] Intestinal Type Stomach Adenocarcinoma

[2277] Lung Adenocarcinoma

[2278] Lung Squamous Cell Carcinoma

[2279] Pancreatic Adenocarcinoma

[2280] Pancreatic Adenocarcinoma

[2281] Serous Ovarian Cancer

[2282] Stomach Adenocarcinoma

[2283] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2284] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 243 M243I Bladder Urothelial Carcinoma

[2285] Lung Squamous Cell Carcinoma

[2286] Oligoastrocytoma

[2287] Serous Ovarian Cancer

[2288] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2289] 244 G244* Colon Adenocarcinoma

[2290] G244C Glioblastoma Multiforme

[2291] G244D Head and Neck Squamous Cell Carcinoma G244S Leiomyosarcoma

[2292] G244V Lung Adenocarcinoma

[2293] Lung Squamous Cell Carcinoma

[2294] Pleural Mesothelioma, Epithelioid Type

[2295] Serous Ovarian Cancer

[2296] Tubular Stomach Adenocarcinoma

[2297] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2298] Uterine Endometrioid Carcinoma

[2299] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 245 G245C Astrocytoma

[2300] G245D Bladder Urothelial Carcinoma

[2301] G245R Breast Invasive Ductal Carcinoma

[2302] G245S Colon Adenocarcinoma

[2303] G245V Esophageal Adenocarcinoma

[2304] Esophageal Squamous Cell Carcinoma

[2305] Glioblastoma Multiforme

[2306] Head and Neck Squamous Cell Carcinoma

[2307] Hepatocellular Carcinoma

[2308] Intestinal Type Stomach Adenocarcinoma

[2309] Lung Adenocarcinoma

[2310] Lung Squamous Cell Carcinoma

[2311] Oligoastrocytoma

[2312]

[2313] OligodendrogliomaAttorney Docket No. 59845-0148WO1

[2314] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2315] Position Exemplary Mutations Associated Cancer(s)

[2316] Pancreatic Adenocarcinoma

[2317] Pleural Mesothelioma, Epithelioid Type

[2318] Prostate Adenocarcinoma

[2319] Rectal Adenocarcinoma

[2320] Serous Ovarian Cancer

[2321] Signet Ring Cell Carcinoma of the Stomach

[2322] Stomach Adenocarcinoma

[2323] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2324] Uterine Endometrioid Carcinoma

[2325] 246 M246I Bladder Urothelial Carcinoma

[2326] M246R Breast Invasive Lobular Carcinoma

[2327] M246T Chromophobe Renal Cell Carcinoma

[2328] M246V Esophageal Adenocarcinoma

[2329] Glioblastoma Multiforme

[2330] Head and Neck Squamous Cell Carcinoma

[2331] Hepatocellular Carcinoma

[2332] Oligoastrocytoma

[2333] Pancreatic Adenocarcinoma

[2334] Tubular Stomach Adenocarcinoma

[2335] Uterine Mixed Endometrial Carcinoma

[2336] 247 N247I Breast Invasive Ductal Carcinoma

[2337] Lung Adenocarcinoma

[2338] 248 R248G Acute Myeloid Leukemia

[2339] R248Hfs*13 Astrocytoma

[2340] R248L Bladder Urothelial Carcinoma

[2341] R248P Breast Invasive Carcinoma (NOS)

[2342] R248Q Breast Invasive Ductal Carcinoma

[2343] R248W Cholangiocarcinoma

[2344] Colon Adenocarcinoma

[2345] Cutaneous Melanoma

[2346] Diffuse Large B-Cell Lymphoma, NOS

[2347] Diffuse Type Stomach Adenocarcinoma

[2348] Esophageal Adenocarcinoma

[2349] Esophageal Squamous Cell Carcinoma

[2350] Glioblastoma Multiforme

[2351] Head and Neck Squamous Cell Carcinoma

[2352] Hepatocellular Carcinoma

[2353] Intestinal Type Stomach Adenocarcinoma

[2354] Leiomyosarcoma

[2355] Lung Adenocarcinoma

[2356] Lung Squamous Cell Carcinoma

[2357] Mucinous Adenocarcinoma of the Colon and Rectum Oligoastrocytoma

[2358] Oligodendroglioma

[2359] Pancreatic Adenocarcinoma

[2360] Prostate Adenocarcinoma

[2361] Rectal Adenocarcinoma

[2362] Renal Clear Cell Carcinoma

[2363] Serous Ovarian Cancer

[2364] Stomach Adenocarcinoma

[2365]

[2366] ThymomaAttorney Docket No. 59845-0148WO1

[2367] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2368] Position Exemplary Mutations Associated Cancer(s)

[2369] Tubular Stomach Adenocarcinoma

[2370] Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[2371] Uterine Endometrioid Carcinoma

[2372] Uterine Mixed Endometrial Carcinoma

[2373] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 249 R249Ffs*96 Astrocytoma

[2374] R249G Bladder Urothelial Carcinoma

[2375] R249Gfs*96 Esophageal Squamous Cell Carcinoma

[2376] R249M Glioblastoma Multiforme

[2377] R249S Head and Neck Squamous Cell Carcinoma

[2378] R249T Hepatocellular Carcinoma

[2379] R249W Lung Adenocarcinoma

[2380] Lung Squamous Cell Carcinoma

[2381] Mucinous Adenocarcinoma of the Colon and Rectum Prostate Adenocarcinoma

[2382] Serous Ovarian Cancer

[2383] Stomach Adenocarcinoma

[2384] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2385] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 250 P250_I251delinsL Astrocytoma

[2386] P250Hfs*13 Breast Invasive Ductal Carcinoma

[2387] P250L Chromophobe Renal Cell Carcinoma

[2388] P250R Esophageal Squamous Cell Carcinoma

[2389] Glioblastoma Multiforme

[2390] Head and Neck Squamous Cell Carcinoma

[2391] Lung Adenocarcinoma

[2392] Lung Squamous Cell Carcinoma

[2393] Mucinous Stomach Adenocarcinoma

[2394] Oligoastrocytoma

[2395] Pancreatic Adenocarcinoma

[2396] Rectal Adenocarcinoma

[2397] Serous Ovarian Cancer

[2398] 251 I251F Breast Invasive Ductal Carcinoma

[2399] I251N Head and Neck Squamous Cell Carcinoma

[2400] I251S Hepatocellular Carcinoma

[2401] I251Sfs*94 Lung Squamous Cell Carcinoma

[2402] Serous Ovarian Cancer

[2403] 252 L252_I254del Breast Invasive Ductal Carcinoma

[2404] L252_T253delinsP Esophageal Squamous Cell Carcinoma

[2405] L252del Lung Squamous Cell Carcinoma

[2406] L252P Myxofibrosarcoma

[2407] L252Sfs*93 Uterine Mixed Endometrial Carcinoma

[2408] 253 T253A Breast Invasive Ductal Carcinoma

[2409] T253dup Esophageal Adenocarcinoma

[2410] T253Hfs*11 Hepatocellular Carcinoma

[2411] T253I Papillary Stomach Adenocarcinoma

[2412] T253N Serous Ovarian Cancer

[2413] 254 I254S Glioblastoma Multiforme

[2414]

[2415] Intestinal Type Stomach AdenocarcinomaAttorney Docket No. 59845-0148WO1

[2416] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2417] Position Exemplary Mutations Associated Cancer(s)

[2418] Pancreatic Adenocarcinoma

[2419] 255 1255del Breast Invasive Lobular Carcinoma

[2420] I255F Esophageal Adenocarcinoma

[2421] I255N Esophageal Squamous Cell Carcinoma

[2422] I255S Glioblastoma Multiforme

[2423] I255T Glioblastoma Multiforme

[2424] Lung Adenocarcinoma

[2425] Oligodendroglioma

[2426] Pancreatic Adenocarcinoma

[2427] Papillary Renal Cell Carcinoma

[2428] 256 T256del Breast Invasive Ductal Carcinoma

[2429] T256Hfs*8 Head and Neck Squamous Cell Carcinoma T256I Prostate Adenocarcinoma

[2430] T256Ifs*90 Serous Ovarian Cancer

[2431] T256Nfs*8 Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Endometrioid Carcinoma

[2432] 257 L257P Bladder Urothelial Carcinoma

[2433] L257Pfs*7 Breast Invasive Ductal Carcinoma

[2434] L257Q Esophageal Adenocarcinoma

[2435] L257R Hepatocellular Carcinoma

[2436] Serous Ovarian Cancer

[2437] 258 E258* Bladder Urothelial Carcinoma

[2438] E258A Breast Invasive Ductal Carcinoma

[2439] E258D Esophageal Adenocarcinoma

[2440] E258G Head and Neck Squamous Cell Carcinoma E258K Hepatocellular Carcinoma

[2441] E258Q Lung Adenocarcinoma

[2442] E258Qfs*3 Lung Squamous Cell Carcinoma

[2443] X258_splice Prostate Adenocarcinoma

[2444] Rectal Adenocarcinoma

[2445] Serous Ovarian Cancer

[2446] 259 D259Efs*86 Bladder Urothelial Carcinoma

[2447] D259N Colon Adenocarcinoma

[2448] D259V Head and Neck Squamous Cell Carcinoma D259Y Leiomyosarcoma

[2449] Lung Adenocarcinoma

[2450] Lung Squamous Cell Carcinoma

[2451] Pancreatic Adenocarcinoma

[2452] Tubular Stomach Adenocarcinoma

[2453] 260 S260_L264dup Serous Ovarian Cancer

[2454] S260Lfs*4

[2455] 261 S261Vfs*84 Breast Invasive Ductal Carcinoma

[2456] X261_splice Esophageal Adenocarcinoma

[2457] Esophageal Squamous Cell Carcinoma

[2458] Head and Neck Squamous Cell Carcinoma

[2459] Intestinal Type Stomach Adenocarcinoma

[2460] Leiomyosarcoma

[2461] Lung Adenocarcinoma

[2462] Lung Squamous Cell Carcinoma

[2463]

[2464] OligoastrocytomaAttorney Docket No. 59845-0148WO1

[2465] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2466] Position Exemplary Mutations Associated Cancer(s)

[2467] Renal Clear Cell Carcinoma

[2468] Serous Ovarian Cancer

[2469] Signet Ring Cell Carcinoma of the Stomach

[2470] Stomach Adenocarcinoma

[2471] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2472] 262 G262del Head and Neck Squamous Cell Carcinoma

[2473] G262V Hepatocellular Carcinoma

[2474] G262Vfs*83 Leiomyosarcoma

[2475] Lung Adenocarcinoma

[2476] Lung Squamous Cell Carcinoma

[2477] Rectal Adenocarcinoma

[2478] Serous Ovarian Cancer

[2479] Uterine Endometrioid Carcinoma

[2480] 263 N263Ifs*82 Hepatocellular Carcinoma

[2481] N263Kfs*9 Oligoastrocytoma

[2482] N263Sfs*8

[2483] 264 L264Yfs*81 Glioblastoma Multiforme

[2484] 265 L265P Astrocytoma

[2485] L265R Bladder Urothelial Carcinoma

[2486] L265Tfs*7 Breast Invasive Ductal Carcinoma

[2487] Head and Neck Squamous Cell Carcinoma

[2488] Lung Squamous Cell Carcinoma

[2489] Oligoastrocytoma

[2490] Serous Ovarian Cancer

[2491] Tubular Stomach Adenocarcinoma

[2492] 266 G266* Breast Invasive Ductal Carcinoma

[2493] G266Dfs*79 Colon Adenocarcinoma

[2494] G266E Cutaneous Melanoma

[2495] G266R Glioblastoma Multiforme

[2496] G266V Head and Neck Squamous Cell Carcinoma

[2497] Hepatocellular Carcinoma

[2498] Intestinal Type Stomach Adenocarcinoma

[2499] Leiomyosarcoma

[2500] Lung Adenocarcinoma

[2501] Lung Squamous Cell Carcinoma

[2502] Oligodendroglioma

[2503] Pancreatic Adenocarcinoma

[2504] Prostate Adenocarcinoma

[2505] Rectal Adenocarcinoma

[2506] Serous Ovarian Cancer

[2507] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2508] Uterine Mixed Endometrial Carcinoma

[2509] Uterine Serous Carcinoma / Uterine Papillaiy Serous Carcinoma 267 R267G Astrocytoma

[2510] R267L Chromophobe Renal Cell Carcinoma

[2511] R267P Colon Adenocarcinoma

[2512] R267Q Glioblastoma Multiforme

[2513] R267W Head and Neck Squamous Cell Carcinoma

[2514]

[2515] Lung AdenocarcinomaAttorney Docket No. 59845-0148WO1

[2516] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2517] Position Exemplary Mutations Associated Cancer(s)

[2518] Lung Squamous Cell Carcinoma

[2519] Mucinous Adenocarcinoma of the Colon and Rectum Oligoastrocytoma

[2520] Tubular Stomach Adenocarcinoma

[2521] Uterine Endometrioid Carcinoma

[2522] 268 N268* Head and Neck Squamous Cell Carcinoma

[2523] N268_R273del Lung Squamous Cell Carcinoma

[2524] N268Kfs*77 Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous N268Tfs*77 Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Carcinosarcoma / U terine Malignant Mixed Mullerian Tumor

[2525] 269 S269_E271delinsK Oligodendroglioma

[2526] S269Ifs*2 Pancreatic Adenocarcinoma

[2527] 270 F270C Astrocytoma

[2528] F270I Breast Invasive Ductal Carcinoma

[2529] F270L Head and Neck Squamous Cell Carcinoma

[2530] F270Lfs*2 Intestinal Type Stomach Adenocarcinoma

[2531] F270S Leiomyosarcoma

[2532] F270V Lung Adenocarcinoma

[2533] Oligodendroglioma

[2534] Serous Ovarian Cancer

[2535] Stomach Adenocarcinoma

[2536] Tubular Stomach Adenocarcinoma

[2537] 271 E271* Bladder Urothelial Carcinoma

[2538] E271K Breast Invasive Ductal Carcinoma

[2539] E271Q Colon Adenocarcinoma

[2540] E271V Endometrioid Carcinoma

[2541] Glioblastoma Multiforme

[2542] Head and Neck Squamous Cell Carcinoma

[2543] Hepatocellular Carcinoma

[2544] Lung Adenocarcinoma

[2545] Lung Squamous Cell Carcinoma

[2546] Prostate Adenocarcinoma

[2547] Serous Ovarian Cancer

[2548] Tubular Stomach Adenocarcinoma

[2549] 272 V272A Astrocytoma

[2550] V272Cfs*73 Breast Invasive Carcinoma (NOS)

[2551] V272G Breast Invasive Ductal Carcinoma

[2552] V272L Cervical Squamous Cell Carcinoma

[2553] V272M Colon Adenocarcinoma

[2554] Esophageal Squamous Cell Carcinoma

[2555] Head and Neck Squamous Cell Carcinoma

[2556] Intestinal Type Stomach Adenocarcinoma

[2557] Leiomyosarcoma

[2558] Lung Adenocarcinoma

[2559] Lung Squamous Cell Carcinoma

[2560] Pancreatic Adenocarcinoma

[2561] Rectal Adenocarcinoma

[2562] Renal Clear Cell Carcinoma

[2563] Serous Ovarian Cancer

[2564] Stomach Adenocarcinoma

[2565]

[2566] Uterine Serous Carcinoma / Uterine Papillary Serous CarcinomaAttorney Docket No. 59845-0148WO1

[2567] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2568] Position Exemplary Mutations Associated Cancer(s)

[2569] 273 R273C Acute Myeloid Leukemia

[2570] R273G Adrenocortical Carcinoma

[2571] R273H Astrocytoma

[2572] R273L Bladder Urothelial Carcinoma

[2573] R273Lfs*72 Breast Invasive Carcinoma (NOS)

[2574] R273P Breast Invasive Ductal Carcinoma

[2575] R273S Colon Adenocarcinoma

[2576] Diffuse Large B-Cell Lymphoma, NOS

[2577] Esophageal Adenocarcinoma

[2578] Esophageal Squamous Cell Carcinoma

[2579] Glioblastoma Multiforme

[2580] Head and Neck Squamous Cell Carcinoma

[2581] Hepatocellular Carcinoma

[2582] Intestinal Type Stomach Adenocarcinoma

[2583] Leiomyosarcoma

[2584] Lung Adenocarcinoma

[2585] Lung Squamous Cell Carcinoma

[2586] Mucinous Adenocarcinoma of the Colon and Rectum Oligoastrocytoma

[2587] Oligodendroglioma

[2588] Pancreatic Adenocarcinoma

[2589] Pleural Mesothelioma, Biphasic Type

[2590] Prostate Adenocarcinoma

[2591] Rectal Adenocarcinoma

[2592] Serous Ovarian Cancer

[2593] Stomach Adenocarcinoma

[2594] Thymoma

[2595] Tubular Stomach Adenocarcinoma

[2596] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2597] Uterine Endometrioid Carcinoma

[2598] Uterine Mixed Endometrial Carcinoma

[2599] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 274 V274_C275dup Astrocytoma

[2600] V274_G279del Breast Invasive Ductal Carcinoma

[2601] V274D Colon Adenocarcinoma

[2602] V274dup Esophageal Adenocarcinoma

[2603] V274F Esophageal Squamous Cell Carcinoma

[2604] V274G Head and Neck Squamous Cell Carcinoma V274L Intestinal Type Stomach Adenocarcinoma

[2605] Lung Adenocarcinoma

[2606] Lung Squamous Cell Carcinoma

[2607] Oligoastrocytoma

[2608] Pancreatic Adenocarcinoma

[2609] Serous Ovarian Cancer

[2610] 275 C275* Adrenocortical Carcinoma

[2611] C275_R282delinsW Astrocytoma

[2612] C275F Bladder Urothelial Carcinoma

[2613] C275G Breast Invasive Ductal Carcinoma

[2614] C275Lfs*67 Chromophobe Renal Cell Carcinoma

[2615] C275Lfs*70 Colon Adenocarcinoma

[2616]

[2617] C275R Cutaneous MelanomaAttorney Docket No. 59845-0148WO1

[2618] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2619] Position Exemplary Mutations Associated Cancer(s)

[2620] C275S Esophageal Squamous Cell Carcinoma

[2621] C275Vfs*70 Glioblastoma Multiforme

[2622] C275W Head and Neck Squamous Cell Carcinoma C275Y Hepatocellular Carcinoma

[2623] Leiomyosarcoma

[2624] Low-Grade Glioma (NOS)

[2625] Lung Adenocarcinoma

[2626] Lung Squamous Cell Carcinoma

[2627] Pancreatic Adenocarcinoma

[2628] Rectal Adenocarcinoma

[2629] Serous Ovarian Cancer

[2630] Uterine Serous Carcinoma / U terine Papillary Serous Carcinoma 276 A276D Breast Invasive Ductal Carcinoma

[2631] A276G Cutaneous Melanoma

[2632] A276Lfs*29 Head and Neck Squamous Cell Carcinoma A276Lfs*31 Hepatocellular Carcinoma

[2633] A276P Lung Squamous Cell Carcinoma

[2634] Pleural Mesothelioma, Biphasic Type

[2635] Serous Ovarian Cancer

[2636] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 277 C277* Astrocytoma

[2637] C277dup Bladder Urothelial Carcinoma

[2638] C277F Head and Neck Squamous Cell Carcinoma

[2639] C277G Lung Adenocarcinoma

[2640] C277Vfs*68 Oligoastrocytoma

[2641] C277W Oligodendroglioma

[2642] C277Y Serous Ovarian Cancer

[2643] Serous Ovarian Cancer

[2644] 278 P278A Astrocytoma

[2645] P278H Bladder Urothelial Carcinoma

[2646] P278L Breast Invasive Ductal Carcinoma

[2647] P278Lfs*67 Colon Adenocarcinoma

[2648] P278Lfs*68 Cutaneous Melanoma

[2649] P278R Esophageal Squamous Cell Carcinoma

[2650] P278S Head and Neck Squamous Cell Carcinoma

[2651] P278T Lung Adenocarcinoma

[2652] Lung Squamous Cell Carcinoma

[2653] Metaplastic Breast Cancer

[2654] Mucinous Adenocarcinoma of the Colon and Rectum Mucinous Carcinoma

[2655] Myxofibrosarcoma

[2656] Pancreatic Adenocarcinoma

[2657] Rectal Adenocarcinoma

[2658] Serous Ovarian Cancer

[2659] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 279 G279E Bladder Urothelial Carcinoma

[2660] G279Pfs*69 Breast Invasive Ductal Carcinoma

[2661] G279R Lung Squamous Cell Carcinoma

[2662] Oligoastrocytoma

[2663] Prostate Adenocarcinoma

[2664] Serous Ovarian Cancer

[2665]

[2666] Uterine Endometrioid CarcinomaAttorney Docket No. 59845-0148WO1

[2667] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2668] Position Exemplary Mutations Associated Cancer(s)

[2669] 280 R280* Acute Myeloid Leukemia

[2670] R280Efs*65 Astrocytoma

[2671] R280G Bladder Urothelial Carcinoma

[2672] R280I Breast Invasive Carcinoma (NOS)

[2673] R280K Breast Invasive Ductal Carcinoma

[2674] R280Kfs*59 Cervical Squamous Cell Carcinoma

[2675] R280S Cutaneous Melanoma

[2676] R280T Esophageal Adenocarcinoma

[2677] Head and Neck Squamous Cell Carcinoma

[2678] Hepatocellular Carcinoma

[2679] Lung Adenocarcinoma

[2680] Lung Squamous Cell Carcinoma

[2681] Metaplastic Breast Cancer

[2682] Oligoastrocytoma

[2683] Oligodendroglioma

[2684] Serous Ovarian Cancer

[2685] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2686] 281 D281A Astrocytoma

[2687] D281Afs*62 Bladder Urothelial Carcinoma

[2688] D281Afs*64 Breast Invasive Ductal Carcinoma

[2689] D281Afs*66 Diffuse Type Stomach Adenocarcinoma

[2690] D281E Glioblastoma Multiforme

[2691] D281Efs*26 Head and Neck Squamous Cell Carcinoma D281Gfs*63 Hepatocellular Carcinoma

[2692] D281H Leiomyosarcoma

[2693] D281N Lung Adenocarcinoma

[2694] D281V Lung Squamous Cell Carcinoma

[2695] D281Y Metaplastic Breast Cancer

[2696] Renal Clear Cell Carcinoma

[2697] Serous Ovarian Cancer

[2698] Stomach Adenocarcinoma

[2699] Thymoma

[2700] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[2701] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 282 R282_R283del Astrocytoma

[2702] R282G Bladder Urothelial Carcinoma

[2703] R282Gfs*63 Breast Invasive Carcinoma (NOS)

[2704] R282Q Breast Invasive Ductal Carcinoma

[2705] R282W Cervical Squamous Cell Carcinoma

[2706] Chromophobe Renal Cell Carcinoma

[2707] Colon Adenocarcinoma

[2708] Diffuse Type Stomach Adenocarcinoma

[2709] Esophageal Adenocarcinoma

[2710] Esophageal Squamous Cell Carcinoma

[2711] Glioblastoma Multiforme

[2712] Head and Neck Squamous Cell Carcinoma

[2713] Intestinal Type Stomach Adenocarcinoma

[2714] Lung Adenocarcinoma

[2715] Lung Squamous Cell Carcinoma

[2716]

[2717] Mucinous Adenocarcinoma of the Colon and RectumAttorney Docket No. 59845-0148WO1

[2718] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2719] Position Exemplary Mutations Associated Cancer(s)

[2720] Mucinous Stomach Adenocarcinoma

[2721] Oligoastrocytoma

[2722] Oligodendroglioma

[2723] Pancreatic Adenocarcinoma

[2724] Prostate Adenocarcinoma

[2725] Rectal Adenocarcinoma

[2726] Serous Ovarian Cancer

[2727] Signet Ring Cell Carcinoma of the Stomach

[2728] Stomach Adenocarcinoma

[2729] Uterine Endometrioid Carcinoma

[2730] Uterine Mixed Endometrial Carcinoma

[2731] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 283 R283Afs*62 Bladder Urothelial Carcinoma

[2732] R283H Head and Neck Squamous Cell Carcinoma R283P Lung Adenocarcinoma

[2733] Lung Squamous Cell Carcinoma

[2734] Pancreatic Adenocarcinoma

[2735] 284 T284Hfs*22 Serous Ovarian Cancer

[2736] T284Kfs*61 Tubular Stomach Adenocarcinoma

[2737] T284Qfs*61

[2738] 285 E285* Bladder Urothelial Carcinoma

[2739] E285K Breast Invasive Ductal Carcinoma

[2740] E285Q Breast Invasive Lobular Carcinoma

[2741] E285Rfs*54 Cervical Squamous Cell Carcinoma

[2742] E285V Colon Adenocarcinoma

[2743] Diffuse Type Stomach Adenocarcinoma

[2744] Esophageal Squamous Cell Carcinoma

[2745] Head and Neck Squamous Cell Carcinoma

[2746] Lung Adenocarcinoma

[2747] Lung Squamous Cell Carcinoma

[2748] Mucinous Carcinoma

[2749] Pheochromocytoma

[2750] Prostate Adenocarcinoma

[2751] Rectal Adenocarcinoma

[2752] Stomach Adenocarcinoma

[2753] 286 E286* Acute Myeloid Leukemia

[2754] E286_E287del Bladder Urothelial Carcinoma

[2755] E286A Breast Invasive Carcinoma (NOS)

[2756] E286G Breast Invasive Ductal Carcinoma

[2757] E286K Colon Adenocarcinoma

[2758] E286Q Cutaneous Melanoma

[2759] E286V Diffuse Type Stomach Adenocarcinoma

[2760] Head and Neck Squamous Cell Carcinoma

[2761] Hepatocellular Carcinoma

[2762] Lung Adenocarcinoma

[2763] Lung Squamous Cell Carcinoma

[2764] Oligoastrocytoma

[2765] Pancreatic Adenocarcinoma

[2766] Rectal Adenocarcinoma

[2767] Serous Ovarian Cancer

[2768]

[2769] Stomach AdenocarcinomaAttorney Docket No. 59845-0148WO1

[2770] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2771] Position Exemplary Mutations Associated Cancer(s)

[2772] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Endometrioid Carcinoma

[2773] 287 E287* Bladder Urothelial Carcinoma

[2774] E287D Breast Invasive Ductal Carcinoma

[2775] E287Pfs*9 Cervical Squamous Cell Carcinoma

[2776] E287Q Lung Squamous Cell Carcinoma

[2777] Rectal Adenocarcinoma

[2778] 288 N288Efs*18 Astrocytoma

[2779] N288Kfs*59 Myxofibrosarcoma

[2780] 289 L289F Breast Invasive Ductal Carcinoma

[2781] 290 R290C Colon Adenocarcinoma

[2782] R290Kfs*53 Cutaneous Melanoma

[2783] R290Sfs*56 Head and Neck Squamous Cell Carcinoma 291 K291Sfs*51 Lung Squamous Cell Carcinoma

[2784] 292 K292* Breast Invasive Ductal Carcinoma

[2785] K292Gfs*52 Chromophobe Renal Cell Carcinoma

[2786] Hepatocellular Carcinoma

[2787] 294 E294* Astrocytoma

[2788] E294Sfs*51 Bladder Urothelial Carcinoma

[2789] Breast Invasive Ductal Carcinoma

[2790] Esophageal Squamous Cell Carcinoma

[2791] Head and Neck Squamous Cell Carcinoma

[2792] Lung Adenocarcinoma

[2793] Lung Squamous Cell Carcinoma

[2794] Pancreatic Adenocarcinoma

[2795] Serous Ovarian Cancer

[2796] Tubular Stomach Adenocarcinoma

[2797] Uterine Endometrioid Carcinoma

[2798] 296 H296Tfs*49 Lung Adenocarcinoma

[2799] 297 H297Pfs*48 Astrocytoma

[2800] Head and Neck Squamous Cell Carcinoma

[2801] 298 E298* Bladder Urothelial Carcinoma

[2802] Head and Neck Squamous Cell Carcinoma

[2803] Lung Adenocarcinoma

[2804] Lung Squamous Cell Carcinoma

[2805] Pancreatic Adenocarcinoma

[2806] Prostate Adenocarcinoma

[2807] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma

[2808] 299 L299Afs*7 Breast Invasive Ductal Carcinoma

[2809] 301 P301Qfs*44 Bladder Urothelial Carcinoma

[2810] P301T Colon Adenocarcinoma

[2811] Cutaneous Melanoma

[2812] Lung Squamous Cell Carcinoma

[2813] Stomach Adenocarcinoma

[2814] 302 G302Afs*31 Colon Adenocarcinoma

[2815] G302Efs*3 Glioblastoma Multiforme

[2816]

[2817] G302Rfs*4 Head and Neck Squamous Cell CarcinomaAttorney Docket No. 59845-0148WO1

[2818] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2819] Position Exemplary Mutations Associated Cancer(s)

[2820] Hepatocellular Carcinoma

[2821] Pancreatic Adenocarcinoma

[2822] 303 S303Afs*42 Breast Invasive Ductal Carcinoma

[2823] 304 T304Ifs*41 Breast Invasive Ductal Carcinoma

[2824] 305 K305* Head and Neck Squamous Cell Carcinoma

[2825] K305Efs*39 Lung Adenocarcinoma

[2826] X305_splice Lung Squamous Cell Carcinoma

[2827] Serous Ovarian Cancer

[2828] 306 R306* Astrocytoma

[2829] R306Afs*31 Bladder Urothelial Carcinoma

[2830] Breast Invasive Lobular Carcinoma

[2831] Colon Adenocarcinoma

[2832] Esophageal Adenocarcinoma

[2833] Esophageal Squamous Cell Carcinoma

[2834] Glioblastoma Multiforme

[2835] Head and Neck Squamous Cell Carcinoma

[2836] Hepatocellular Carcinoma

[2837] Lung Squamous Cell Carcinoma

[2838] Mucinous Adenocarcinoma of the Colon and Rectum Mucinous Stomach Adenocarcinoma

[2839] Oligoastrocytoma

[2840] Pancreatic Adenocarcinoma

[2841] Rectal Adenocarcinoma

[2842] Serous Ovarian Cancer

[2843] Stomach Adenocarcinoma

[2844] Uterine Endometrioid Carcinoma

[2845] 307 X307_splice Adrenocortical Carcinoma

[2846] Astrocytoma

[2847] Breast Invasive Carcinoma (NOS)

[2848] Chromophobe Renal Cell Carcinoma

[2849] Colon Adenocarcinoma

[2850] Diffuse Type Stomach Adenocarcinoma

[2851] Esophageal Adenocarcinoma

[2852] Esophageal Squamous Cell Carcinoma

[2853] Glioblastoma Multiforme

[2854] Head and Neck Squamous Cell Carcinoma

[2855] Hepatocellular Carcinoma

[2856] Lung Adenocarcinoma

[2857] Lung Squamous Cell Carcinoma

[2858] Prostate Adenocarcinoma

[2859] Serous Ovarian Cancer

[2860] 308 L308Afs*28 Breast Invasive Ductal Carcinoma

[2861] L308Qfs*27 Esophageal Adenocarcinoma

[2862] 310 N310Tfs*35 Diffuse Type Stomach Adenocarcinoma

[2863] 313 S313Afs*32 Glioblastoma Multiforme

[2864] Lung Adenocarcinoma

[2865] Uterine Endometrioid Carcinoma

[2866] 315 S315C Lung Squamous Cell Carcinoma

[2867] S315Lfs*30 Uterine Endometrioid Carcinoma

[2868]

[2869] 316 P316Sfs*21 Serous Ovarian CancerAttorney Docket No. 59845-0148WO1

[2870] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2871] Position Exemplary Mutations Associated Cancer(s)

[2872] 317 Q317* Acute Myeloid Leukemia

[2873] Q317Afs*19 Astrocytoma

[2874] Q317Pfs*20 Bladder Urothelial Carcinoma

[2875] Cutaneous Melanoma

[2876] Esophageal Squamous Cell Carcinoma

[2877] Head and Neck Squamous Cell Carcinoma

[2878] Intestinal Type Stomach Adenocarcinoma

[2879] Leiomyosarcoma

[2880] Lung Adenocarcinoma

[2881] Lung Squamous Cell Carcinoma

[2882] Serous Ovarian Cancer

[2883] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 318 P318Tfs*15 Breast Invasive Ductal Carcinoma

[2884] 319 K319* Bladder Urothelial Carcinoma

[2885] K319Afs*19 Cervical Squamous Cell Carcinoma

[2886] K319N Prostate Adenocarcinoma

[2887] K319Rfs*26 Rectal Adenocarcinoma

[2888] 320 K320E Head and Neck Squamous Cell Carcinoma

[2889] K320Gfs*22 Lung Squamous Cell Carcinoma

[2890] K320Nfs*19 Serous Ovarian Cancer

[2891] K320Rfs*25

[2892] 321 K321* Astrocytoma

[2893] K321Efs*16 Serous Ovarian Cancer

[2894] 322 P322Hfs*23 Colon Adenocarcinoma

[2895] 325 G325* Esophageal Adenocarcinoma

[2896] 327 Y327* Cutaneous Melanoma

[2897] Glioblastoma Multiforme

[2898] Serous Ovarian Cancer

[2899] 328 F328Sfs*17 Breast Invasive Ductal Carcinoma

[2900] Hepatocellular Carcinoma

[2901] 329 T329Hfs*8 Head and Neck Squamous Cell Carcinoma

[2902] T329Rfs*14 Hepatocellular Carcinoma

[2903] 330 L330Ffs*15 Cutaneous Melanoma

[2904] L330I Head and Neck Squamous Cell Carcinoma

[2905] L330R Serous Ovarian Cancer

[2906] 331 Q331* Astrocytoma

[2907] Q331H Bladder Urothelial Carcinoma

[2908] Q331Sfs*6 Breast Invasive Ductal Carcinoma

[2909] X331_splice Colon Adenocarcinoma

[2910] Cutaneous Melanoma

[2911] Head and Neck Squamous Cell Carcinoma

[2912] Intestinal Type Stomach Adenocarcinoma

[2913] Leiomyosarcoma

[2914] Lung Adenocarcinoma

[2915] Lung Squamous Cell Carcinoma

[2916] Mucinous Adenocarcinoma of the Colon and Rectum Mucinous Carcinoma

[2917] Pancreatic Adenocarcinoma

[2918] Pleural Mesothelioma, Epithelioid Type

[2919]

[2920] Prostate AdenocarcinomaAttorney Docket No. 59845-0148WO1

[2921] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2922] Position Exemplary Mutations Associated Cancer(s)

[2923] Rectal Adenocarcinoma

[2924] Serous Ovarian Cancer

[2925] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 332 I332F Astrocytoma

[2926] X332_splice Diffuse Large B-Cell Lymphoma, NOS

[2927] Esophageal Squamous Cell Carcinoma

[2928] Head and Neck Squamous Cell Carcinoma

[2929] Hepatocellular Carcinoma

[2930] Lung Adenocarcinoma

[2931] Lung Squamous Cell Carcinoma

[2932] Mucinous Adenocarcinoma of the Colon and Rectum Oligoastrocytoma

[2933] Serous Ovarian Cancer

[2934] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 333 R333C Breast Invasive Ductal Carcinoma

[2935] R333Vfs*12 Cervical Squamous Cell Carcinoma

[2936] Mucinous Adenocarcinoma of the Colon and Rectum

[2937] Serous Ovarian Cancer

[2938] 334 G334V Lung Adenocarcinoma

[2939] G334W Lung Squamous Cell Carcinoma

[2940] Seminoma

[2941] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 335 R335Lfs*10 Adrenocortical Carcinoma

[2942] R335Qfs*2 Colon Adenocarcinoma

[2943] R335Vfs*10 Oligoastrocytoma

[2944] Rectal Adenocarcinoma

[2945] Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma

[2946] 336 E336* Bladder Urothelial Carcinoma

[2947] E336 R337del Colon Adenocarcinoma

[2948] E336Afs*10 Head and Neck Squamous Cell Carcinoma E336Sfs*9 Leiomyosarcoma

[2949] Lung Adenocarcinoma

[2950] 337 R337C Acute Myeloid Leukemia

[2951] R337H Adrenocortical Carcinoma

[2952] R337L Bladder Urothelial Carcinoma

[2953] R337P Cervical Squamous Cell Carcinoma

[2954] R337S Chromophobe Renal Cell Carcinoma

[2955] Colon Adenocarcinoma

[2956] Glioblastoma Multiforme

[2957] Head and Neck Squamous Cell Carcinoma

[2958] Intestinal Type Stomach Adenocarcinoma

[2959] Leiomyosarcoma

[2960] Lung Adenocarcinoma

[2961] Lung Squamous Cell Carcinoma

[2962] Oligodendroglioma

[2963] Pancreatic Adenocarcinoma

[2964] Prostate Adenocarcinoma

[2965]

[2966] Rectal AdenocarcinomaAttorney Docket No. 59845-0148WO1

[2967] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[2968] Position Exemplary Mutations Associated Cancer(s)

[2969] Stomach Adenocarcinoma

[2970] 338 F338I Chromophobe Renal Cell Carcinoma

[2971] F338Lfs*7 Serous Ovarian Cancer

[2972] 339 E339* Adrenocortical Carcinoma

[2973] E339Afs*8 Breast Invasive Ductal Carcinoma

[2974] E339Rfs*6 Head and Neck Squamous Cell Carcinoma

[2975] Lung Adenocarcinoma

[2976] Oligodendroglioma

[2977] Stomach Adenocarcinoma

[2978] 340 M340Sfs*8 Serous Ovarian Cancer

[2979] 341 F341Efs*7 Head and Neck Squamous Cell Carcinoma

[2980] F341L Hepatocellular Carcinoma

[2981] F341V Lung Adenocarcinoma

[2982] 342 R342* Acute Myeloid Leukemia

[2983] R342Efs*2 Astrocytoma

[2984] R342Efs*3 Breast Invasive Ductal Carcinoma

[2985] R342P Colon Adenocarcinoma

[2986] Cutaneous Melanoma

[2987] Esophageal Adenocarcinoma

[2988] Esophageal Squamous Cell Carcinoma

[2989] Glioblastoma Multiforme

[2990] Head and Neck Squamous Cell Carcinoma

[2991] Intestinal Type Stomach Adenocarcinoma

[2992] Lung Adenocarcinoma

[2993] Lung Squamous Cell Carcinoma

[2994] Myxofibrosarcoma

[2995] Oligoastrocytoma

[2996] Pancreatic Adenocarcinoma

[2997] Prostate Adenocarcinoma

[2998] Rectal Adenocarcinoma

[2999] Serous Ovarian Cancer

[3000] Stomach Adenocarcinoma

[3001] Uterine Endometrioid Carcinoma

[3002] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma 343 E343* Esophageal Squamous Cell Carcinoma

[3003] E343Gfs*2 Head and Neck Squamous Cell Carcinoma

[3004] Lung Adenocarcinoma

[3005] Serous Ovarian Cancer

[3006] 345 N345D Mucinous Stomach Adenocarcinoma

[3007] N345Mfs*25 Serous Ovarian Cancer

[3008] N345Sfs*2 Tubular Stomach Adenocarcinoma

[3009] 346 E346* Lung Adenocarcinoma

[3010] Oligoastrocytoma

[3011] 347 A347V Uterine Mixed Endometrial Carcinoma

[3012] 348 L348* Head and Neck Squamous Cell Carcinoma

[3013] L348F Lung Squamous Cell Carcinoma

[3014] L348S Serous Ovarian Cancer

[3015] L348Wfs*22

[3016] 351 K351* Leiomyosarcoma

[3017]

[3018] K351E Lung AdenocarcinomaAttorney Docket No. 59845-0148WO1

[3019] Amino Acid Non-Limiting Non-Limiting Exemplary p53

[3020] Position Exemplary Mutations Associated Cancer(s)

[3021] Lung Squamous Cell Carcinoma

[3022] 354 Q354* Lung Adenocarcinoma

[3023] 355 A355T Lung Adenocarcinoma

[3024] 367 X367_splice Bladder Urothelial Carcinoma

[3025] Head and Neck Squamous Cell Carcinoma

[3026] Uterine Mixed Endometrial Carcinoma

[3027] 375 Q375* Bladder Urothelial Carcinoma

[3028] Q375K Glioblastoma Multiforme

[3029] Papillary Thyroid Cancer

[3030] 376 S376C Cervical Squamous Cell Carcinoma

[3031] 379 R379C Uterine Serous Carcinoma / U terine Papillary Serous Carcinoma 382 K382Nfs*40 Bladder Urothelial Carcinoma

[3032] Oligoastrocytoma

[3033] Uterine Endometrioid Carcinoma

[3034] Uterine Mixed Endometrial Carcinoma

[3035] 383 L383Cfs*38 Head and Neck Squamous Cell Carcinoma

[3036] 385 F385L Bladder Urothelial Carcinoma

[3037] 390 P390Qfs*32 Esophageal Squamous Cell Carcinoma

[3038]

[3039] 392 S392Tfs*76 Intestinal Type Stomach Adenocarcinoma

[3040] AUnless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pll (2013).

[3041] Combinations

[3042] 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.Attorney Docket No. 59845-0148WO1

[3043] 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.

[3044] 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.

[3045] 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.

[3046] 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,Attorney Docket No. 59845-0148WO1

[3047] 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.

[3048] 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), orBPI-16350.

[3049] 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, tyrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD 173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB 1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SM1-71, TG 100801, FGFR1 inhibitor-6, or TG 100572.

[3050] In some embodiments, the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X-396), or CEP-37440

[3051] In some embodiments, the NTRK / ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005),

[3052] 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).

[3053] 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).Attorney Docket No. 59845-0148WO1

[3054] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyryl shikonin, acetylshikonin, p,p-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[3055] 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.

[3056] 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 orAttorney Docket No. 59845-0148WO1

[3057] 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.

[3058] 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).

[3059] 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.

[3060] 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, CI1040 (PD184352), hypothemycin, or a combination thereof.

[3061] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 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),Attorney Docket No. 59845-0148WO1

[3062] SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-Oxozeaenol, 5 -iodotuberci din, GDC0994, ONC201, or a combination thereof.

[3063] 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.

[3064] 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.

[3065] 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.

[3066] 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.

[3067] In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.Attorney Docket No. 59845-0148WO1

[3068] In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.

[3069] In some embodiments, the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5-fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capeci tabine (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.

[3070] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.

[3071] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.

[3072] 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.

[3073] 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.

[3074] 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®).

[3075] 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®), dostarlimabAttorney Docket No. 59845-0148WO1

[3076] (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IB 1308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo, et al., J Hematol Oncol. 11: 39 (2018).

[3077] 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.

[3078] 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.

[3079] EXAMPLES

[3080] Compound Preparation

[3081] 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.

[3082] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientificAttorney Docket No. 59845-0148WO1

[3083] 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.

[3084] 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.Attorney Docket No. 59845-0148WO1

[3085] The compounds described herein can be synthesized, for example, using the following procedurein the scheme below.

[3086] Pd / C, H AcOH, MeOH / THF

[3087] 01. AcOH, MeOH 2. NaBH3CN step 3

[3088]

[3089] 2AAttorney Docket No. 59845-0148WO1

[3090] The compounds described herein can also be synthesized, for example, using the following procedure in the scheme below.

[3091] dioxane / H2O DABCO, rt, 1h Br step 1 1

[3092] N’ 1)TMEDA, Zn(OTf) IBX K2CO3, MeOH2

[3093] Et, N, PhMe, rt, 2h 80°C, 2h 0°C, 2h H - - step 5 step 6 2)alkyne 4, 60°C, 1h 3)POM(2.2eq), 60°C, 1h 7 step 7

[3094] PPh3Br2, PCM OH rt, 1h K2CO3, DMF step 8 step 9 9

[3095]

[3096] The compounds described herein can also be synthesized according to the methods as described in PCT Appl. Pub. Nos. WO 2024 / 086809 Al and WO 2024 / 086804 Al, hereby incorporated by reference in their entirety.

[3097] Example 1. Synthesis of 5-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-methoxy-N- (methylsulfonyl)picolinamide (Compound 41)Attorney Docket No. 59845-0148WO1

[3098]

[3099] Step 1. A solution of 6-methoxy-5-nitropicolinic acid (4.5 g, 22.71 mmol, 1 eq.) and di(imidazol-l-yl) methanone (4.05 g, 24.98 mmol, 1.1 eq.) in THF (100 mL), the reaction mixture was stirred at 80 °C for 2 hrs. Then methanesulfonamide (2.58 g, 27.08 mmol, 1.2 eq.) and DBU (4.12 g, 27.08 mmol, 4.08 mL, 1.2 eq.) was added at 25 °C, the reaction mixture was stirred at 25 °C for 12 hr. The reaction mixture was adjusted to pH = 3 with 1 M HC1, and concentrated under reduced pressure until a lot of solid was precipitated, filtered to give 6-methoxy-N-(methylsulfonyl)-5-nitropicolinamide (4 g, 14.53 mmol, 64.41% yield, 100% purity) was obtained as an off-white solid. LCMS: MS (ESI): 298.0 (M+23) +. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 8.43 (d, J= 8.0 Hz, 1H), 8.00 (d, J= 8.0 Hz, 1H), 4.20 (s, 3H), 3.45 (s, 3H).

[3100] Step 2. To a solution of 6-methoxy-N-(methylsulfonyl)-5-nitropicolinamide (4 g, 14.53 mmol, 1 eq.} in EtOH (40 mL) and H₂O (8 mL) was added Fe (4.06 g, 72.66 mmol, 5 *eq.*) and NH₄Cl (3.89 g, 72.66 mmol, 5 eq.}, the reaction mixture was stirred at 80 °C for 1 hr. The reaction mixture was filtered, then the filtrate was extracted with EA (100 mL * 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The reaction mixture was used for the next without other purification. 5-amino-6-methoxy-N-(methylsulfonyl)picolinamide (2.8 g, crude) was obtained as a yellow solid, which was confirmed by HNMR.XH NMR (400 MHz, DMSO-de) 8 = 10.80 (br s, 1H), 7.55 (d, J= 7.6 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 6.06 (s, 2H), 4.01 (s, 3H), 3.34 (s, 3H).

[3101] Step 3. To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-ol (6 g, 17.14 mmol, 1 eq.} in DCM (200 mL) was added Dess-Martin (9.45 g, 22.28 mmol, 6.90 mL, 1.3 eq.}, the reaction mixture was stirred at 25 °C for 1 hr. TLC (PE: EA = 20: 1) showed that the reactant (Rf = 0.1) was consumed and a new spot (Rf = 0.4) formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE EA = 1 / 0 to 10 / 1). 3-(8-bromo-3-Attorney Docket No. 59845-0148WO1

[3102] ((trifluoromethyl)thio)indolizin-2-yl)propiolaldehyde (4.8 g, 13.79 mmol, 80.46% yield) was obtained as a yellow solid. ’H NMR (400 MHz, CHLOROFORM-d) 8 = 9.72 (s, 1H), 8.64 (d, J = 7.2 Hz, 1H), 7.51 - 7.47 (m, 2H), 6.98 (t, J= 7.2 Hz, 1H).

[3103] Step 4. To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)propiolaldehyde (1.00 g, 2.87 mmol, 1 eq.) and 5-amino-6-methoxy-N-(methylsulfonyl)picolinamide (845.37 mg, 3.45 mmol, 1.2 eq.) in MeOH (30 mb) was added AcOH (258.73 mg, 4.31 mmol, 246.64 pL, 1.5 eq.), the mixture was stirred at 60 °C for 2 hrs. The NaBH3CN (722.01 mg, 11.49 mmol, 4 eq.) was added, the mixture was stirred at 60 °C for 2 hrs. The reaction mixture became clear from suspension. After 30 mins later, lots of precipitates were observed. The mixture was filtered and the cake was washed with MeOH (10 mL) to get the product. 5-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-methoxy-N-(methylsulfonyl)picolinamide (1.08 g, 1.71 mmol, 59.46% yield, 91.31% purity) was obtained as a gray solid, which was checked by LCMS, HNMR and FNMR. LCMS: MS (ESI): 577, 579 (M+l) +. ’HNMR (400 MHz, DMSO-d6) 8 = 10.93 (br s, 1H), 8.55 (d, J= 7.2 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.88 (t, J= 7.2 Hz, 1H), 6.81 (br t, J= 5.6 Hz, 1H), 6.78 (s, 1H), 4.35 (br d, J= 6.0 Hz, 2H), 4.06 (s, 3H), 3.34 (s, 3H).

[3104] Step 5. A mixture of 5-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-methoxy-N-(methylsulfonyl)picolinamide (100 mg, 173.19 pmol, 1 eq.), (3S, 4R) -3-fluoro-l-methyl-piperidin-4-amine (39.07 mg, 190.51 pmol, 1.1 eq., 2HC1), di cyclohexyl -[3, 6-dimethoxy-2-(2, 4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate;[2-[2- (methylamino)phenyl] phenyl]palladium (1+) (15.94 mg, 17.32 pmol, 0.1 eq.), CS2CO3 (282.15 mg, 865.96 pmol, 5 eq.) in DMF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The mixture was fdtered through celite and washed with EA (10 mL) and DCM (10 mL). The filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [H2O (0.225% FA) -ACN]; gradient: 18%-48% B over 10.0 min). 5-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-methoxy-N-(methylsulfonyl)picolinamide (14.68 mg, 23.16 pmol, 13.37% yield, 99.19% purity) was obtained as a gray solid, which was checked by LCMS, HPLC, HNMR and FNMR. LCMS: MS (ESI): 629.1 (M+l) +. ’H NMR (400 MHz, DMSO-d6 ) 8 = 7.85 (d, J =Attorney Docket No. 59845-0148WO1

[3105] 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.85 - 6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.86 (br d, J = 8.4 Hz, 1H), 4.96 - 4.75 (m, 1H), 4.33 (d, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.67 - 3.58 (m, 1H), 3.32 (br s, 3H), 3.09 (brt, J= 10.4 Hz, 1H), 2.90 - 2.83 (m, 1H), 2.46 - 2.26 (m, 2H), 2.24 (s, 3H), 2.21 - 2.12 (m, 1H), 2.07 - 1.95 (m, 1H), 1.71 (br d, J = 10.4 Hz, 1H).

[3106] Example 2. Synthesis of 5-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (Compound 20)

[3107]

[3108] Step 1. To a solution of 6-chloro-5-nitro-pyridine-2-carboxylic acid (14 g, 69.12 mmol, 1 eq.) in THF (280 mL) was added NaH (5.53 g, 138.24 mmol, 60% purity, 2 eq.) at 0 °C. 30 min later, CD3OD (12.46 g, 345.59 mmol, 14.04 mL, 5 eq..) was added at 0 °C. The mixture was stirred at 20 °C for 1.5 hr. LCMS (EW62608-5-P1 A) showed reactant was consumed and product was detected. The reaction was quenched with aq. NH4CI (300 mL) and adjusted to pH = 4 with aq. HC1 (2N), then extracted with EA (300 mL). The organic layers were concentrated give 6-(methoxy-d3)-5-nitropicolinic acid (12 g, 59.66 mmol, 86.31% yield) as a yellow solid. LCMS: MS (ESI): 201.9 (M+l) +. ’H NMR (400 MHz, DMSO-d6) 5 = 8.55 (d, J= 8.0 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H).

[3109] Step 2. The mixture of 6-(methoxy-d3)-5-nitropicolinic acid (7 g, 34.80 mmol, 1 eq.) in THF (70 mL) was added CDI (8.46 g, 52.20 mmol, 1.5 eq.). The mixture was stirred at 20 °C for 1 hr. Then DBU (7.95 g, 52.20 mmol, 7.87 mL, 1.5 eq.) and methanesulfonamide (4.97 g, 52.20 mmol, 1.5 eq.) were added. The resulting mixture was stirred at 20 °C for 15 hrs. The mixture was adjusted to pH = 4 with aq. HC1 (2N) and filtered. The filter cake was washed with THF (10 mL) to give 6-(methoxy-d3)-N-(methylsulfonyl)-5-nitropicolinamide (8 g, 27.31 mmol, 78.49% yield, 95% purity) as a yellow solid.Attorney Docket No. 59845-0148WO1

[3110] Step 3. To a solution of 6-(methoxy-d3)-N-(methylsulfonyl)-5-nitropicolinamide (8 g, 28.75 mmol, 1 eq.) in EtOH (80 mL) and H2O (15 mL) was added NH4CI (7.69 g, 143.75 mmol, 5 eq.) and Fe (8.03 g, 143.75 mmol, 5 eq.). The mixture was stirred at 80 °C for 1 hr. The mixture was fdtered and the fdter cake was washed with EA (80 mL) and water (50 mL). The organic layer was concentrated to give 5-amino-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (6 g, 22.96 mmol, 79.85% yield, 95% purity) as a gray solid. 'HNMR (400 MHz, DMSO-d6) 8 = 10.81 (br s, 1H), 7.55 (d, J= 8.0 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 6.05 (s, 2H), 3.34 (s, 3H).

[3111] Step 4. To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)propiolaldehyde (1 g, 2.87 mmol, 1 eq.) and 5-amino-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (855.78 mg, 3.45 mmol, 1.2 eq.) in MeOH (30 mL) was added AcOH (258.73 mg, 4.31 mmol, 246.65 pL, 1.5 eq.). The mixture was stirred at 60 °C for 2 hrs. The NaBH₃CN (722.01 mg, 11.49 mmol, 4 eq.) was added, the mixture was stirred at 60 °C for 2 hrs. The reaction mixture became clear from suspension. After 30 mins later, lots of precipitates were observed. The mixture was filtered and the cake was washed with MeOH (10 mL) to give 5-((3-(8-bromo-3-((tri fluoromethyl )thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (1.2 g, 1.93 mmol, 67.03% yield, 93.12% purity) was obtained as an off-white solid, which was checked by LCMS, HNMR and FNMR. LCMS: MS (ESI): 580.0, 582.0 (M+l) +. ’H NMR (400 MHz, DMSO-d6) 6 = 10.95 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.44 (d, J= 7.2 Hz, 1H), 7.09 (d, J= 8.0 Hz, 1H), 6.93 - 6.80 (m, 2H), 6.78 (s, 1H), 4.34 (br d, J= 6.0 Hz, 2H), 3.34 (s, 3H)

[3112] Step 5. A mixture of 5-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (100 mg, 172.29 pmol, 1 eq.), (3S, 4R) -3 -fluoro- l-methyl-piperidin-4-amine (38.87 mg, 189.52 pmol, 1.1 eq., 2HC1), dicyclohexyl-[3, 6-dimethoxy-2-(2, 4, 6-triisopropylphenyl) phenyl]phosphane; methanesulfonate; [2-[2-(methylamino) phenyl]phenyl]palladium (1+) (15.86 mg, 17.23 pmol, 0.1 eq.), CS2CO3 (280.68 mg, 861.46 pmol, 5 eq.) in DMF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The mixture was filtered through celite and washed with EA (10 mL) and DCM (10 mL). The filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna Cl 8 150*25 mm* lOum; mobile phase: [H2O (0.225% FA) -ACN]; gradient: 18%-48% B over 10.0 min). 5-((3-(8-Attorney Docket No. 59845-0148WO1

[3113] (((3 S,4R)-3-fluoro- 1 -methylpiperi din-4-yl)amino)-3-((tri fluoromethyl )thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (16.02 mg, 25.02 pmol, 14.52% yield, 98.65% purity) was obtained as a gray solid, which was checked by LCMS, HPLC, HNMR and FNMR. LCMS: MS (ESI): 580.0, 582.0 (M+l) +. ‘HNMR (400 MHz, DMSO-de) 8 = 7.85 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.0Hz, 1H), 6.84 - 6.72 (m, 2H), 6.14 (d, J= 8.0 Hz, 1H), 5.86 (br d, J= 8.4 Hz, 1H), 4.97 - 4.74 (m, 1H), 4.32 (d, J= 6.0 Hz, 2H), 3.66 - 3.56 (m, 1H), 3.33 (br s, 3H), 3.14 (br d, J= 11.6 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.54 (s, 1H), 2.43 (br d, J= 12.4 Hz, 1H), 2.36 - 2.29 (m, 1H), 2.26 (s, 3H), 2.24 - 2.17 (m, 1H), 2.06 -1.95 (m, 1H), 1.72 (brd, J= 10.4 Hz, 1H).

[3114] Example 3. Synthesis of 5-((3-(l-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)ainino)- 6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-7-yl)prop-2-yn-l-yl)amino)-6-methoxy-N- (methylsulfonyl)picolinamide (Compound 44)

[3115]

[3116] Step 1. To a solution of 7-bromopyrrolo[l,2-a]pyrazin-l(2H)-one (6 g, 28.16 mmol, 1 eq) in MeOH (200 mL) was added NH4SCN (9.99 g, 131.25 mmol, 9.99 mL, 4.66 eq and NCS (17.90 g, 134.06 mmol, 4.76 eq. The mixture was stirred at 25 C for 2 hr. LCMS (EW62611-7-P1B) showed Reactanti wasn't consumed and 79% desired mass signal was detected. The reaction mixture was filtered. The crude compound without further purification was used into next step.

[3117] 7-bromo-6-thiocyanatopyrrolo[l,2-a]pyrazin-l-ol (10 g, crude) was obtained as a yellow solid. LCMS: MS (ESI) Retention time: 0. 436 min, (M+l) ’ =269.9. ‘H NMR (400 MHz, DMSO-de) 5 = 7.47 - 7.39 (m, 1H), 7.37 - 7.27 (m, 1H), 7.20 (d, J= 10.1 Hz, 1H).

[3118] Step 2. To a solution of 7-bromo-6-thiocyanatopyrrolo[l,2-a]pyrazin-l-ol (8.9 g, 32.95 mmol, 1 eq) in MeCN (100 mL) and DMF (50 mL) were added TMSCF3 (18.74 g, 131.80 mmol, 4 eq) and CsF (15.02 g, 98.85 mmol, 3 eq), the mixture was stirred at 20 C for 2 hr. LCMS (EW63318-1-P1A) showed reactant consumed and one main peak with desired mass. TLCAttorney Docket No. 59845-0148WO1

[3119] (PE: EA = 1:1) showed two main spots. The mixture was concentrated under vacuo to remove MeCN and diluted with water (150 mL), extracted with EA(100 mL X 3) and organic layer was washed with brine (100 mL X 3), dried over Na2SC>4 and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Eluent of 0~50% EtOAc / PE gradient @ 65 mL / min). 7-bromo-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-ol (2.8 g, 8.94 mmol, 27.14% yield, 100% purity) was obtained as a brown solid. LCMS: MS (ESI) Retention time: 0.518 min, (M+1)+=315.1. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 10.48 (br s, 1H), 7.47 (br d, J= 5.6 Hz, 1H), 7.31 (s, 1H), 6.73 (br s, 1H).

[3120] Step 3. To POCh (12 mL) was added 7-bromo-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-ol (2.8 g, 8.94 mmol, 1 eq), the mixture was stirred at 1000C for 1 hr. TLC (PE: EA = 3:1) showed reactant (Rf = 0.5) consumed and a new main spot (Rf = 0.95) was observed. The mixture was quenched by adding slowly into a stirring water (150 mL) and basified by adding 3N NaOH slowly under ice-bath to adjust pH = 9-10, then extracted with EtOAc (100 mL X 3) and organic layer was washed with brine (100 mL X 3), dried over Na2SO4 and concentrated under vacuum. The reaction mixture was used for the next without any purification. 7-bromo-l-chloro-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazine (3 g, 8.80 mmol, 98.35% yield, 97.2% purity) was obtained as a dark brown solid. LCMS: MS (ESI) Retention time: 0. 691 min, (M+1)+=332.9. ’H NMR (400 MHz, CHLOROFORM-d) 5 = 8.21 (d, J=4.8Hz, 1H), 7.62 (d, J= 4.8 Hz, 1H), 7.15 (s, 1H).

[3121] Step 4. To a solution of 7-bromo-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-ol (3 g, 9.05 mmol, 1 eq) and tert-butyl (3 S,4R)-4-amino-3-fluoropiperi dine- 1 -carboxylate (3.56 g, 16.29 mmol, 1.8 eq) inDMSO (30 mL) was added KF (1.05 g, 18.10 mmol, 2 eq), the mixture was stirred at 140 ° C for 2 hr. TLC (PE: EA = 5:1) showed reactant (Rf = 0.6) consumed and one main spot (Rf = 0.15) The mixture was cooled to ambient temperature, diluted with water (150 mL) and extracted with EtOAc (100 mL X 3), organic layer was washed with brine (100 mL X 3) and dried over Na2SO4, concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-35% EtOAc / PE gradient @ 60 mL / min). Tert-butyl (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)-3-fluoropiperidine-l-carboxylate (2.6 g, 4.59 mmol, 50.77% yield, 90.7%Attorney Docket No. 59845-0148WO1

[3122] purity) was obtained as a brown solid. LCMS: MS (EST) Retention time: 0. 620 min, (M+1)+=515.1. 'H NMR (400 MHz, DMSO-de) 5 = 7.80 (d, J= 4.9 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.32 (d, J= 4.9 Hz, 1H), 5.02 - 4.75 (m, 1H), 4.50 - 4.32 (m, 1H), 4.32 - 4.15 (m, 1H), 4.14 - 4.05 (m, 1H), 3.29 - 2.80 (m, 2H), 1.94 - 1.80 (m, 1H), 1.75 - 1.64 (m, 1H), 1.40 (s, 9H).

[3123] Step 5. To a solution of tert-butyl (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)-3-fluoropiperidine-l -carboxylate (500 mg, 974.00 u mol, 1 eq) and tert-butyldimethyl(prop-2-yn-l-yloxy)silane (1.16 g, 6.82 mmol, 1.38 mL, 7 eq) in acetonitrile (10 mL) was added [2-(2-aminophenyl) phenyl]palladium (1+);dicyclohexyl-[2-(2, 4, 6-triisopropylphenyl) phenyl]phosphane;methanesulfonate (82.44 mg, 97.40 u mol, 0.1 eq) and N-cyclohexyl-N-methyl-cyclohexanamine (570.78 mg, 2.92 mmol, 619.74 u L, 3 eq). The mixture was stirred at 120 C under microwave for 3 hr. LCMS (EW62818-61-P1A) showed the reactant 1 was remained and desired mass was founded. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE: EA = 100 / 1 TO 3 / 1). (Pl Rf = 0.5). tert-butyl (3S,4R)-4-((7-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)-6-((trifhjoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)-3-fluoropiperidine-l -carboxylate (620 mg, 730.31 u mol, 37.49% yield, 71% purity) was obtained as a white solid. LCMS: MS (ESI) Retention time: 0. 677 min, (M+1)+=603.4.

[3124] Step 6. To a solution of tert-butyl (3S,4R)-4-((7-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn- 1 -yl)-6-((trifluorom ethyl )thio)pyrrolo[ 1,2-a]pyrazin- 1 -yl)amino)-3 -fluoropiperidine- 1 -carboxylate (150 mg, 248.86 u mol, 1 eq) in THF (2 mL) was added TBAF (1 M, 995.42 L, 4 eq). The mixture was stirred at 25 ° C for 2 hr. LCMS (EW62818-72-P1 A) showed the reactant 1 was consumed and desired mass was founded. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was purified by column chromatography (SiCh, PE: EA = 100 / 1 TO 2 / 1). (TLC PE: EA = 2 / 1 Pl Rf = 0.5). tert-butyl (3S,4R)-3-fluoro-4-((7-(3-hydroxyprop-l-yn-l-yl)-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)piperidine-l-carboxylate (132 mg, 191.85 n mol, 77.09% yield, 71% purity) was obtained as a white solid. LCMS: MS (ESI) Retention time: 0. 496 min, (M+1)+=489.2.Attorney Docket No. 59845-0148WO1

[3125] Step 7. To a solution of tert-butyl (3S,4R)-3-fluoro-4-((7-(3-hydroxyprop-l-yn-l-yl)-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)piperidine-l-carboxylate (130 mg, 266.12 mol, 1 eq) in DCM (3 mL) was added DMP (225.75 mg, 532.24 p mol, 164.90 p L, 2 eq). The mixture was stirred at 25 ° C for 1 hr. LCMS (EW62818-74-P1A) showed the reactant 1 was consumed and desired mass was founded. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue.. The residue was purified by column chromatography (SiO2, PE: EA = 100 / 1 TO 3 / 1) (TLC PE: EA = 3 / 1, Rf = 0.4). tert-butyl (3S,4R)-3 -fluoro-4-((7-(3 -oxoprop- 1 -yn- 1 -yl)-6-((trifluoromethyl)thio)pyrrolo[ 1,2-a]pyrazin- 1 -yl)amino)piperidine-l -carboxylate (160 mg, 194.05 p mol, 72.92% yield, 59% purity) was obtained as awhite solid. LCMS: MS (ESI) Retention time: 0. 570 min, (M+1)+=487.3. 'H NMR (400 MHz, CHLOROFORM-d) 6 = 9.49 (s, 1H), 7.76 (d, J = 4.9 Hz, 1H), 7.40 (d, J= 4.9 Hz, 1H), 7.00 (s, 1H), 5.23 - 5.10 (m, 1H), 4.94 - 4.75 (m, 1H), 4.63 - 4.37 (m, 2H), 3.26 - 2.72 (m, 2H), 1.98 - 1.86 (m, 2H), 1.51 (s, 9H).

[3126] Step 8. To a solution of tert-butyl (3S,4R)-3-fluoro-4-((7-(3-oxoprop-l-yn-l-yl)-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)piperi dine- 1 -carboxylate (100 mg, 205.56 pmol, 1 eq) and 5-amino-6-methoxy-N-(methylsulfonyl)picolinamide (55.46 mg, 226.11 pmol, 1.1 eq) in MeOH (3 mL) was added AcOH (1.23 mg, 20.56 pmol, 1.18 pL, 0.1 eq), the reaction mixture was stirred at 25 °C for 12 hr, then NaBI I3CN (25.84 mg, 411.11 pmol, 2 eq) was added, the reaction mixture was stirred at 25 °C for 2 hr. LCMS (EW62609-22-P1A) showed that the reactant was consumed and desired mass observed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10um;mobile phase: [H2O (0.225% FA) -ACN];gradient:45%-75% B over 10.0 min), tert-butyl (3S,4R)-3-fluoro-4-((7-(3-((2-methoxy-6-((methylsulfonyl)carbamoyl)pyri din-3 -yl)amino)prop- 1 -yn- 1 -yl)-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)piperidine-l-carboxylate (70 mg, 97.80 pmol, 47.58% yield, 100% purity) was obtained as yellow solid. LCMS: MS (ESI) Retention time: 0. 548 min, (M+1)+=716.2.

[3127] Step 9. A solution of tert-butyl (3S,4R)-3-fluoro-4-((7-(3-((2-methoxy-6-((methylsulfonyl)carbamoyl)pyri din-3 -yl)amino)prop- 1 -yn- 1 -yl)-6-((trifhioromethyl)thio)pyrrolo[l,2-a]pyrazin-l-yl)amino)piperidine-l-carboxylate (65 mg, 90.82Attorney Docket No. 59845-0148WO1

[3128] pmol, 1 eq) in HCl / dioxane (2 M, 1 mL, 22.02 eq), the reaction mixture was stirred at 25 °C for 1 hr. LCMS (EW62609-28-P1A) showed that the reactant was consumed and desired mass observed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10um;mobile phase: [H2O (0.225% FA) -ACN];gradient:12%-42% B over 14.0 min). 5-((3-(l-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[ 1,2-a]pyrazin-7-yl)prop-2-yn- 1 -yl)amino)-6-methoxy-N-(methylsulfonyl)picolinamide (25 mg, 40.52 pmol, 44.62% yield, 99.79% purity) was obtained as off-white solid. LCMS: MS (ESI) Retention time: 0.459 min, (M+l)+=616.1.1HNMR (400 MHz, DMSO-d6) 8 = 8.19 (s, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.45 (br d, J = 7.2 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 5.03 - 4.87 (m, 1H), 4.45 (br dd, J = 5.8, 13.2 Hz, 1H), 4.31 (br d, J = 6.0 Hz, 2H), 4.01 (s, 3H), 3.40 - 3.34 (m, 1H), 3.19 - 3.14 (m, 4H), 3.04 (br s, 1H), 2.90 - 2.82 (m, 1H), 2.06 - 1.87 (m, 1H), 1.79 - 1.70 (m, 1H).

[3129] Step 10. To a solution of 5-((3-(l-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-7-yl)prop-2-yn-l-yl)amino)-6-methoxy-N-(methylsulfonyl)picolinamide (20 mg, 32.49 pmol, 1 eq) and HCHO (2.90 mg, 35.74 pmol, 2.66 pL, 1.1 eq) in MeOH (1 mL) was added AcOH (19.51 pg, 3.25e-l pmol, 1.86e-2 pL, 0.01 eq), then NaBHiCN (4.08 mg, 64.97 pmol, 2 eq) was added, the reaction mixture was stirred at 25 °C for 1 hr. LCMS (EW62609-35-P1A3) showed that the reactant was consumed and desired mass observed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10um;mobile phase:

[3130] [H2O (lOmM NH4HCO3) -ACN];gradient:20%-50% B over 10.0 min). 5-((3-(l-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[l,2-a]pyrazin-7-yl)prop-2-yn-l-yl)amino)-6-methoxy-N-(methylsulfonyl)picolinamide (17.05 mg, 25.17 pmol, 77.48% yield, 92.96% purity) was obtained as white solid. LCMS: MS (ESI) Retention time: 1.060 min, (M+l)+=630.2. ‘HNMR (400 MHz, DMSO-de) 8 = 11.19 - 10.40 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.30 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.78 (br t, J = 6.0 Hz, 1H), 4.97 - 4.78 (m, 1H), 4.33 (br d, J = 6.0 Hz, 2H), 4.27 - 4.11 (m, 1H), 4.05 (s, 3H), 3.31 (br s, 3H), 3.14 - 3.06 (m, 1H), 2.87 (br d, J = 10.4 Hz, 1H), 2.33 - 2.18 (m, 4H), 2.17 - 2.08 (m, 1H), 2.07 - 1.94 (m, 1H), 1.68 (br d, J = 9.2 Hz, 1H).Attorney Docket No. 59845-0148WO1

[3131] Example 4. Synthesis of N-(cyclopropylsulfonyl)-5-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)picolinamide (Compound 3)

[3132]

[3133] Step 1. The mixture of 6-(methoxy-d3)-5-nitropicolinic acid (300 mg, 1.49 mmol, 1 eq.) in THF (3 mL) was added CDI (362.75 mg, 2.24 mmol, 1.5 eq.). The mixture was stirred at 80 °C for 1 hr. Then DBU (340.58 mg, 2.24 mmol, 337.21 pL, 1.5 eq.) and cyclopropanesulfonamide (271.05 mg, 2.24 mmol, 1.5 eq.) was added. The resulting mixture was stirred at 20 °C for 15 hrs. LCMS showed reactant was consumed and desired mass was detected. The mixture was adjusted to pH = 4 with aq. HCl (2N) and filtered. The filter cake was washed with THF (2 mL) to give N-(cyclopropylsulfonyl)-6-(methoxy-d3)-5-nitropicolinamide (320 mg, 999.03 pmol, 66.99%yield, 95% purity) as a yellow solid. LCMS: MS (ESI): 304.9 (M+H) +. 'H NMR (400 MHz, DMSO-de) 6 8.60 (d, <7= 8.0 Hz, 1H), 7.83 (d,. / - 8.0 Hz, 1H), 3.20 - 3.08 (m, 1H), 1.34 - 1.06 (m, 4H).

[3134] Step 2. To a solution of N-(cyclopropylsulfonyl)-6-(methoxy-d3)-5-nitropicolinamide (320 mg, 1.05 mmol, 1 eq.) in EtOH (4 mL) and H2O (0.8 mL) was added Fe (293.64 mg, 5.26 mmol, 5 eq.) and NH4Q (281.26 mg, 5.26 mmol, 5 eq.), the reaction mixture was stirred at 80 °C for 1 hr. LCMS showed reactant was consumed and desired mass observed. The reaction mixture was filtered, then the filtrate was extracted with EA (30 mL * 3). The combined organic layers were dried over NazSO-i, filtered and concentrated under reduced pressure to give a 5-amino-N-(cyclopropylsulfonyl)-6-(methoxy-d3)picolinamide (280 mg, crude) as a yellow solid. 'H NMR (400 MHz, CHLOROFORM-d) 8 = 9.68 (br s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.39 (br s, 2H), 3.07 (tt, J = 4.8, 8.0 Hz, 1H), 1.53 - 1.45 (m, 2H), 1.18 - 1.10 (m, 2H).

[3135] Step 3. To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)propiolaldehyde (200 mg, 574.48 pmol, 1 eq.) and 5-amino-N-(cyclopropylsulfonyl)-6-(methoxy-dsjpicolinamide (189.10 mg, 689.38 pmol, 1.2 eq.) in MeOH (6 mL) was added AcOH (51.75 mg, 861.73 pmol, 49.33 pL, 1.5 eq.). The mixture was stirred at 60 °C for 2 hrs. TheAttorney Docket No. 59845-0148WO1

[3136] NaBH₃CN (108.30 mg, 1.72 mmol, 3 eq.) was added at 25 °C, the mixture was stirred at 60 °C for 1 hr. The reaction mixture became clear from suspension. After 1 hr later, lots of precipitates were observed. LCMS (EW63059-20-P1A) showed reactant was consumed and 48% of desired mass was detected. The mixture was filtered and the cake was washed with MeOH (10 mL) to give 5-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-N- (cyclopropylsulfonyl)-6-(methoxy-d3)picolinamide (196 mg, 284.22 pmol, 49.47% yield, 87.94% purity) as an off-white solid. LCMS: MS (ESI): 606.1, 608.1 (M+H) +. 'H NMR (400 MHz, DMSO-de) 5 = 10.95 (s, 1H), 8.55 (d, J= 6.8 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 7.2 Hz, 1H), 7.09 (d, J= 8.0 Hz, 1H), 6.88 (t, J= 7.2 Hz, 1H), 6.78 (s, 2H), 4.35 (br d, J= 6.0 Hz, 2H), 3.14 - 3.06 (m, 1H), 1.17 (br d, J= 3.6 Hz, 2H), 1.08 (br d, J= 5.6Hz, 2H).

[3137] Step 4. A mixture of 5-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-N-(cyclopropylsulfonyl)-6-(methoxy-d3)picolinamide (186 mg, 306.70 pmol, 1 eq.), (3S, 4R) -3 -fluoro- l-methyl-piperidin-4-amine (69.20 mg, 337.37 pmol, 1.1 eq., 2HC1), Pd2 (dba)3 (28.09 mg, 30.67 pmol, 0.1 eq.), Xantphos (35.49 mg, 61.34 pmol, 0.2 eq.) and CS2CO3 (499.65 mg, 1.53 mmol, 5 eq.) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 4 hrs under N2 atmosphere. The mixture was filtered through celite and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [H2O (0.225% FA) -ACN]; gradient: 20%-50% B over 10.0 min) to give a crude. It was further purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [H2O (0.225% FA) -ACN]; gradient: 23%-53% B over 15.0 min). N-(cyclopropylsulfonyl)-5-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)picolinamide (15.07 mg, 22.77 pmol, 7.43% yield, 99.39% purity) was obtained as an off-white solid. LCMS: EW63059-25-P1H, MS (ESI): 658.4 (M+H) +. 'HNMR (400 MHz, METHANOL-d4) 8 = 7.95 - 7.85 (m, 1H), 7.83 - 7.72 (m, 1H), 7.22 - 7.11 (m, 1H), 6.93 - 6.87 (m, 1H), 6.78 -6.66 (m, 1H), 6.17 - 6.09 (m, 1H), 4.42 - 4.28 (m, 2H), 3.79 - 3.59 (m, 1H), 3.30 - 3.21 (m, 1H), 3.17 - 2.99 (m, 2H), 2.59 - 2.43 (m, 1H), 2.43 - 2.34 (m, 4H), 2.15 - 2.00 (m, 1H), 2.00 - 1.88 (m, 1H), 1.42 - 1.22 (m, 3H), 1.20 - 1.08 (m, 2H).

[3138] Example 5. Synthesis of 5-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (Compound 21)Attorney Docket No. 59845-0148WO1

[3139]

[3140] Step 1. A mixture of 8-bromo-2-iodo-3-(trifluoromethylsulfanyl) imidazo[l, 2-a]pyridine (2 g, 4.73 mmol, 1 eq.), tert-butyl-dimethyl-prop-2-ynoxy-silane (1.21 g, 7.09 mmol, 1.44 mL, 1.5 eq.), Pd(PPh3)2C12 (331.87 mg, 472.82 pmol, 0.1 eq.), Cui (180.10 mg, 945.65 pmol, 0.2 eq.) and TEA (2.39 g, 23.64 mmol, 3.29 mL, 5 eq.) in THF (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 3 hrs under N2 atmosphere. The mixture was fdtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 60 g SepaFlash® Silica Flash Column, Eluent of 0~10 % Ethyl acetate / Commercial hexanes gradient @ 80 mL / min). 8-bromo-2-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridine (2.4 g, 3.88 mmol, 81.99% yield, 75.18% purity) was obtained as an orange solid. LCMS: MS (ESI): 465.0, 467.0 (M+H) +.

[3141] Step 2. To a solution of 8-bromo-2-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)-3-((trifhioromethyl)thio)imidazo[l,2-a]pyridine (2.3 g, 4.94 mmol, 1 eq.) in THF (20 mL) was added TBAF (1 M, 5.44 mL, 1.1 eq.). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). 3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-ol (1.3 g, 3.70 mmol, 74.91% yield) was obtained as an orange solid.1H NMR (400 MHz, DMSO-de) 8 = 8.68 (d, J= 6.8 Hz, 1H), 7.95 (d, J= 7.2 Hz, 1H), 7.16 (t, J= 7.2 Hz, 1H), 5.54 (t, J= 6.0 Hz, 1H), 4.40 (d, J= 6.0 Hz, 2H).

[3142] Step 3. To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-ol (1.2 g, 3.42 mmol, 1 eq.) in DCM (25 mL) was added Dess-Martin (1.88 g, 4.44 mmol, 1.38 mL, 1.3 eq.). The mixture was stirred at 25 °C for 1 h. TLC (PE / EA = 1: 1) showed a little of reactant remained and new spots formed. The mixture was washed with saturated NaHCCh solution (20 mL), lots of solid were observed. The suspension was fdtered and organicAttorney Docket No. 59845-0148WO1

[3143] phase was separated from filtrate. The aqueous phase was extracted with EA (30 mL * 2). The organic phase washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~40 %Ethyl acetate / Petroleum ether gradient @ 80 mL / min). 3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)propiolaldehyde (1 g, 2.86 mmol, 83.81% yield) was obtained as a yellow solid.JH NMR (400 MHz, DMSO-de) 8 = 9.52 (s, 1H), 8.76 (d, J= 6.8 Hz, 1H), 8.03 (d, J= 7.6 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H).

[3144] Step 4. To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)propiolaldehyde (900 mg, 2.58 mmol, 1 eq.) and 5-amino-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (768.02 mg, 3.09 mmol, 1.2 eq.) in MeOH (16 m ) was added AcOH (232.21 mg, 3.87 mmol, 221.36 μL, 1.5 eq.). The mixture was stirred at 60 °C for 2.5 hrs. The NaBH₃CN (485.99 mg, 7.73 mmol, 3 eq.) was added, the mixture was stirred at 60 °C for 1 hr. After completion, lots of precipitates were observed. The mixture was filtered and the cake was washed with MeOH (10 mL) to get the product. 5-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (869 mg, 1.36 mmol, 52.74% yield, 90.96% purity) was obtained as a yellow solid. LCMS: MS (ESI): 582.9 (M+H) +. 'H NMR (400 MHz, DMSO-de) 8 = 10.98 (br s, 1H), 8.64 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.90 (t, J = 6.0 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3.35 (br s, 3H).

[3145] Step 5. A mixture of 5-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (449 mg, 772.27 μmol, 1 eq.), (3S, 4R) -3 -fluoro- l-methyl-piperidin-4-amine (190.07 mg, 926.73 μmol, 1.2 eq., 2 HCl), CS2CO3 (1.26 g, 3.86 mmol, 5 eq.), BINAP (192.35 mg, 308.91 μmol, 0.4 eq.) and [[1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphanyl]-(2-phenylanilino) palladium (2+); methanesulfonate (153.28 mg, 154.45 μmol, 0.2 eq.) in dioxane (12 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The mixture was filtered through celite and washed with DMF (5 mL) and EA (50 mL). The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether-0~15% DCM / MeOH gradient@ 80 mL / min) to give a residue. It wasAttorney Docket No. 59845-0148WO1

[3146] further purified by Prep-HPLC (column: Phenomenex Luna Cl 8 150*40 mm* 15um; mobile phase: [H2O (0.225% FA) -ACN]; gradient: 18%-48% B over 15.0 min). 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-(methoxy-d3)-N-(methylsulfonyl)picolinamide (71.88 mg, 109.34 μmol, 14.16% yield, 96.24% purity) was obtained as a yellow solid. LCMS: MS (ESI): 633.2 (M+H) +.

[3147] 1HNMR(400 MHz, DMSO-de) 8 = 11.53 - 10.49 (m, 1H), 8.15 (s, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.78 (br t, J = 6.0 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.59 (d, J = 8.8 Hz, 1H), 4.94 - 4.74 (m, 1H), 4.38 (d, J = 6.0 Hz, 2H), 3.84 - 3.68 (m, 1H), 3.32 (s, 3H), 3.07 (br t, J = 10.4 Hz, 1H), 2.80 (br d, J = 11.2 Hz, 1H), 2.36 (br d, J = 14.0 Hz, 1H), 2.32 - 2.24 (m, 1H), 2.23 (s, 3H), 2.16 (br t, J = 10.4 Hz, 1H), 1.93 -1.77 (m, 2H).

[3148] Assays

[3149] Surface Plasmon Resonance (SPR) Assay Protocol

[3150] 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 varied 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 were fit into the 1: 1 binding model using the Biacore Insight Evaluation software.

[3151] Thermal shift assay (TSA) protocol

[3152] 5 pM recombinant p53 Y220C mutant protein (amino acid residues 94-293) is incubated with 10 pM or 100 pM compound for 3 hours at 20°C in buffer containing 20 mM HEPES, pH7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific catalog number 4461146), on a 384-well PCR plate (Applied Biosystems catalog number 4483285). The volume is 5 pL / well. The sealed plate is then loaded onto a QuantStudio 7 Flex instrument for melting temperature (TM) measurement. The temperatureAttorney Docket No. 59845-0148WO1

[3153] 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.

[3154] Luciferase reporter assay protocol

[3155] 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.

[3156] Cell proliferation assay

[3157] Inducible p53 Y220C construct (Tet-One inducible expression system; Takara) was stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, a p53 Y220C esophagogastric cancer cell line, was used for cell proliferation assay. 250-650 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.

[3158] Table B shows results of the Luc p53 Y220C ACso (nM), CTGNUGC3 p53 Y220C ICso (nM), and CTG H1299 p53 Y220C ICso (nM) assays. Activity categories are as follows:

[3159] • CTGNUGC3 p53 Y220C IC50 (nM): D > 3000 > C > 1500 > B > 750 > A;

[3160] • CTG H1299 p53 Y220C IC50 (nM): D > 3000 > C > 1500 > B > 750 > A; • Luc p53 Y220C AC50 (nM): D > 3000 > C > 1500 > B > 750 > A.

[3161] • TSA P53 Y220C dTM (deg C)D > 6 > C > 8 > B > 10 > AAttorney Docket No. 59845-0148WO1

[3162] Table B.

[3163] Compound Luc p53 Y220C CTG NUGC3 CTG H1299 TSA P53

[3164] No. ACso (nM) p53 Y220C IC50p53 Y220C Y220C dTM

[3165] (nM) IC50 (nM) (deg C)

[3166] 3 A A A A

[3167] 20 A A A A

[3168] 21 A A A A

[3169] 22 A A A A

[3170] 35 B B A A

[3171] 41 A A A A

[3172] 44 A A

[3173]

[3174] Attorney Docket No. 59845-0148WO1

[3175] EMBODIMENTS 1:

[3176] 1. A compound of Formula (la)

[3177] R2

[3178] vi

[3179] X4 / \

[3180] — \R»— A-<RA)m

[3181]

[3182] S~rF(la)

[3183] or a pharmaceutically acceptable salt thereof, wherein:

[3184] X1is CR1, N, NH, O, or S;

[3185] R1is hydrogen, 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;

[3186] each of X2, X3, and X4are CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;

[3187] each of Y1and Y2are C or N,

[3188] wherein when X1is NH, O, or S, then each of X2, X3, and X4are CH or CR3, and each of Y1and Y2are C;

[3189] each - - represents a single bond or a double bond;

[3190] R2A

[3191] 71

[3192] R

[3193]

[3194] 2is R2B;

[3195] Z is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;

[3196] R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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

[3197] 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 substitutedAttorney Docket No. 59845-0148WO1

[3198] 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z is O and R2Bis absent;

[3199] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[3200] each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10R11, -SR9, -S(=O)R9, -S(O2)R9, -

[3201]

[3202] S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

[3203] A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;

[3204] each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;

[3205] R’ is hydrogen or C1-C6 alkyl;

[3206] each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and optionally substituted C3-C6 cycloalkyl;

[3207] RFis -CF3or -CHF2;

[3208] 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; and

[3209] m is 1 or 2.

[3210] 2. The compound of Embodiment 1, wherein A is optionally substituted pyridinyl.

[3211] 3. The compound of Embodiment 1, wherein A is optionally substituted phenyl. 4. The compound of any one of Embodiments 1-3, wherein RFis -CF3.

[3212] 5. The compound of any one of Embodiments 1-3, wherein RFis -CHF2.

[3213] The compound of any one of Embodiments 1-5, wherein R2is

[3214]

[3215] Attorney Docket No. 59845-0148WO1

[3216] 7. The compound of any one of Embodiments 1-6, wherein -A-(RA)mis

[3217]

[3218] 8. The compound of Embodiment 1, wherein the compound of Formula (la), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[3219] (I-A2),

[3220] (I-B2),

[3221] (I-C2),

[3222] (I-D2),

[3223]

[3224] Attorney Docket No. 59845-0148WO1

[3225] (LE2),

[3226] (I-F2),

[3227] (I-G2),

[3228] (I-H2),

[3229]

[3230] (I-I2), andAttorney Docket No. 59845-0148WO1

[3231]

[3232] 0 (I-J2), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[3233] 9. A compound of Formula (la), or a pharmaceutically acceptable salt thereof, selected from the compounds described Table A, or a pharmaceutically acceptable salt of any of the foregoing.

[3234] 10. A pharmaceutical composition comprising a compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof.

[3235] 11. 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 Embodiments 1-9, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 10.

[3236] 12. 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 Embodiments 1-9, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 10.

[3237] 13. A method of treating cancer in a subject in need thereof, comprising:

[3238] (a) determining that the subject has one or more p53 mutations, and

[3239] (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 10.Attorney Docket No. 59845-0148WO1

[3240] EMBODIMENTS 2:

[3241] 1. A compound of Formula (lb)

[3242] R2

[3243] vl

[3244] — NR«- A-<RA>™

[3245]

[3246] s~”f(lb)

[3247] or a pharmaceutically acceptable salt thereof, wherein:

[3248] X1is CR1, N, NH, O, or S;

[3249] R1is hydrogen, 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;

[3250] each of X2, X3, and X4are CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;

[3251] each of Y1and Y2are C or N,

[3252] wherein when X1is NH, O, or S, then each of X2, X3, and X4are CH or CR3, and each of Y1and Y2are C;

[3253] each - - represents a single bond or a double bond;

[3254] R2A

[3255] 71

[3256] R

[3257]

[3258] 2is R2B;

[3259] Z is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;

[3260] R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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

[3261] 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 substitutedAttorney Docket No. 59845-0148WO1

[3262] 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z is O and R2Bis absent;

[3263] R2Cis hydrogen, halogen, or C1-C6 alkyl;

[3264] each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10R11, -SR9, -S(=O)R9, -S(O2)R9, -

[3265]

[3266] S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

[3267] A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;

[3268] each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;

[3269] R’ is hydrogen or C1-C6 alkyl;

[3270] each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl, or

[3271] two R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl;

[3272] RFis -CF3or -CHF2;

[3273] 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; and

[3274] m is 1 or 2.

[3275] 2. The compound of Embodiment 1, wherein A is optionally substituted pyridinyl.

[3276] 3. The compound of Embodiment 1, wherein A is optionally substituted phenyl. 4. The compound of any one of Embodiments 1-3, wherein RFis -CF3.

[3277] 5. The compound of any one of Embodiments 1-3, wherein RFis -CHF2.

[3278] The compound of any one of Embodiments 1-5, wherein R2is

[3279]

[3280] Attorney Docket No. 59845-0148WO1

[3281] 7. The compound of any one of Embodiments 1-6, wherein -A-(RA)mis

[3282]

[3283] 8. The compound of any one of embodiments 1-6, wherein at least one RAis -C(=O)(NR’)-S(O2)-NR”R”.

[3284] 9. The compound of Embodiment 1, wherein the compound of Formula (lb), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[3285] (I-A2),

[3286] (I-B2),

[3287] (I-C2),

[3288] (I-D2),

[3289]

[3290] Attorney Docket No. 59845-0148WO1

[3291] (LE2),

[3292] (I-F2),

[3293] (I-G2),

[3294] (I-H2),

[3295]

[3296] (I-I2), andAttorney Docket No. 59845-0148WO1

[3297]

[3298] 0 (I-J2), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[3299] 10. The compound of Embodiment 1, wherein the compound of Formula (lb), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

[3300] (I-A9),

[3301] (I-B4),

[3302] (I-C4),

[3303]

[3304] Attorney Docket No. 59845-0148WO1

[3305] (I-D4), (I-E4), (I-F4), (I-G4), (I-H4),

[3306]

[3307] Attorney Docket No. 59845-0148WO1

[3308] (I-I4), and

[3309]

[3310] (I-J4), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

[3311] 11. A compound of Formula (lb), or a pharmaceutically acceptable salt thereof, selected from the compounds described Table A, or a pharmaceutically acceptable salt of any of the foregoing.

[3312] 12. A pharmaceutical composition comprising a compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof.

[3313] 13. 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 Embodiments 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 12.

[3314] 14. 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 Embodiments 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 12.

[3315] 15. A method of treating cancer in a subject in need thereof, comprising:

[3316] (a) determining that the subject has one or more p53 mutations, and

[3317] (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 12.

Claims

Attorney Docket No. 59845-0148WO1WHAT IS CLAIMED IS:

1. A compound of Formula (I)R2vlX4 xY1— W— A-<RA)»S~RF(I)or a pharmaceutically acceptable salt thereof, wherein:X1is CR1, N, NH, O, or S;R1is hydrogen, 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;each of X2, X3, and X4is independently CH, N, or CR3, wherein two or more of X2, X3, and X4are independently CH or CR3;each of Y1and Y2is independently C or N,wherein when X1is NH, O, or S, then each of X2, X3, and X4is independently CH or CR3, and each of Y1and Y2is C;each - - represents a single bond or a double bond;R2AZR2is R2B;Z is CR2C, N, O, or a bond; wherein when Z is O, R2Bis absent;R2Aand R2Bare independently hydrogen, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R7, -S(O2)R7, 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; orAttorney Docket No. 59845-0148WO1R2Aand R2Btogether with the atom(s) 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;R2Cis hydrogen, halogen, or C1-C6 alkyl;each R3is independently halogen, cyano, -NR9R10, -OR9, -C(=O)NR9R10, -C(=O)R9, -C(=O)OR9, -OC(=O)R9, -NR9(C=O)NR10R11, -SR9, -S(=O)R9, -S(O2)R9, -S(O2)NR9R10, -NR9S(O2)NR10R11, -R9C(=O)R10, -NR9C(=O)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;A is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl;each RAis independently -C(=O)(NR’)-S(O2)R”, -C(=O)(NR’)-S(O2)-NR”R”, or -S(O2)-(NR’)(C=O)R”;R’ is hydrogen or C1-C6 alkyl;each R” is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl, ortwo R” taken together with the atom(s) to which they are attached together form an optionally substituted 3-12 membered heterocyclyl;RFis -CF3 or -CHF2;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; andm is 1 or 2.

2. The compound of Claim 1, wherein A is optionally substituted pyridinyl.

3. The compound of Claim 1, wherein A is optionally substituted phenyl.

4. The compound of any one of Claims 1-3, wherein RFis -CF3.

5. The compound of any one of Claims 1-3, wherein RFis -CHF2.Attorney Docket No. 59845-0148WO16. The compound of any one of Claims 1-5, wherein R2isH7. The compound of any one of Claims 1-6, wherein -A-(RA)mis8. The compound of any one of claims 1-6, wherein at least one RAis -C(=O)(NR’)-S(O2)-NR”R”.

9. The compound of Claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting ofO (I-A2),(I-B2),(I-C2),Attorney Docket No. 59845-0148WO1(I-D2),(I-E2),(I-F2),(I-G2),(I-H2),Attorney Docket No. 59845-0148WO1(I-J2), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

10. The compound of Claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of(I-A9),(I-B4),(I-C4),Attorney Docket No. 59845-0148WO1(I-D4),(I-E4),(I-F4),(I-G4),(I-H4),Attorney Docket No. 59845-0148WO1(I-I4), and(I-J4), or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazine.

11. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described Table A, or a pharmaceutically acceptable salt of any of the foregoing.

12. A pharmaceutical composition comprising a compound of any one of Claims 1-11, or a pharmaceutically acceptable salt thereof.

13. 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 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 12.

14. 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 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 12.

15. 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 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 12.

Images