Compounds and composition for targeting TP53-y220c mutants

Abstract

Provided are compounds of Formula (I) and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with the activation of p53.

Description

132266-01220 COMPOUNDS AND COMPOSITION FOR TARGETING TP53-Y220C MUTANTS RELATEDAPPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 619,000 filed January 9, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] The transcription factor TP53 functions as a tumor suppressor and is inactivated via mutation in about 50% of all tumors. TP53 regulates a host of intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence. The Y220C mutation is a frequent TP53 missense mutant and is associated with over 100,000 new cancer cases per year worldwide, predominantly breast and ovarian cancer. The Y220C mutation causes major structural changes in the TP53 protein and is known to form a new protein cavity reckoned to accommodate small molecule drug candidates. Critically, the mutation-induced crevice is distant from the TP53 surfaces involved in DNA recognition or protein-protein interactions, allowing for the development of targeted chemical agents that stabilize the DNA-binding domain without interfering with binding of its natural substrates. Stabilization allows for restoration of TP53 function, thereby reactivating TP53 tumor suppressor pathways and shrinking or killing the tumor. SUMMARY

[0003] Provided herein are compounds having the Formula I:and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, R3, A, X, Y and Z are as described herein. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof act as covalent modifiers of TP53 Y220C. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof stabilize TP53 Y220C. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof restore wild-type tumor suppressor protein TP53 (WT TP53) function. In one aspect, it is believed that the described compounds are covalent modifiers of TP53 Y220C which lead to stabilization of the mutant protein and may restore 1ME151606857v.1132266-01220 wild-type function to the dysfunctional mutant protein. See e.g., the exemplification section below.

[0004] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the disclosed compounds of Formula I, as well as methods for their preparation are also included. DETAILEDDESCRIPTION1. General Description of Compounds

[0005] In a first embodiment, provided herein is a compound of Formula I:R1is selected from optionally substituted alkyl; R2is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRaRb, -ORc, -NHC(O)Rc, -C(O)NRdRe, -C(O)Rf, and -SRg; R3is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRa1Rb1, -ORc1, -NHC(O)Rc1, - C(O)NRd1Re1, -C(O)Rf1, and -SRg1; X is selected from halo, -S(O)2alkyl, and –S(O)alkyl; one of A, Y, or Z is N and the two remaining variables that are not N are -CH-; Ra, Ra1, Rb, Rb1, Rc, and Rc1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted heterocyclyl; Rdand Reare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’, -C(O)OR’, -C(O)NR’R’’, -S(O)R’, and -S(O)2R’; or Rdand Retogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; Rd1and Re1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, - 2ME151606857v.1132266-01220 S(O)R’1, and -S(O)2R’1; or Rd1and Re1together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; Rfand Rf1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and R’ R’1, R’’, and R’’1are each independently selected from hydrogen and optionally substituted (C1-C4)alkyl. 2. Definitions

[0006] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NRaRbmeans that the point of attachment for this group occurs on the nitrogen atom.

[0007] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0008] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical.

[0009] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0010] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0011] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., –OCHF2 or –OCF3.

[0012] The term oxo means the group =O.

[0013] The term “heteroaryl” used alone or as part of a larger moiety refers to a 5- to 12- membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, 3ME151606857v.1132266-01220 pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.

[0014] The term “heterocyclyl” means a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (e.g., in the case of an optionally substituted heterocyclyl or heterocyclyl which is optionally substituted).

[0015] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0016] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0017] The term “bridged” refers to two rings that share three ring atoms with one another.

[0018] The term “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl or cycloaliphatic group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached. 4ME151606857v.1132266-01220

[0019] The term “optionally substituted” means that one or more hydrogens of the designated moiety may be replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group as valency permits. Optional substituents include, but are not limited to, one or more groups selected from cyano (–CN), halo, imino (=NH), nitro (–NO2), oxo (=O), – C(O)Ri, –C(O)ORi, –C(O)NRiiRiii, –C(O)SRi, –C(NRi)NRiiRiii, –C(S)Ri, –C(S)ORi, – C(S)NRiiRiii, –ORi, –OC(O)Ri, –OC(O)ORi, –OC(O)NRiiRiii, –OC(O)SRi, –OC(NRi)NRiiRiii, –OC(S)Ri, –OC(S)ORi, –OC(S)NRiiRiii, –OP(O)(ORii)ORiii, –OS(O)Ri, –OS(O)2Ri, – OS(O)NRiiRiii, –OS(O)2NRiiRiii, –NRiiRiii, –NRiC(O)Riv, –NRiC(O)ORiv, –NRiC(O)NRiiRiii, – NRaC(O)SRiv, –NRiC(NRiv)NRiiRiii, –NRiC(S)Riv, –NRiC(S)ORiv, –NRiC(S)NRiiRiii, – NRiS(O)Riv, –NRiS(O)2Riv, –NRiS(O)NRiiRiii, –NRiS(O)2NRiiRiv, –SRi, –S(O)Ri, –S(O)2Ri, – S(O)NRiiRiv, –S(O)2NRiiRiv, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each Ri, Rii, Riii, and Rivis independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qaor Riiand Riiitogether with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each Qais independently selected from cyano, halo, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, –C(O)Rv, –C(O)ORv, –C(O)NRviRvii, –C(O)SRv, –C(NRv)NRviRvii, – C(S)Rv, –C(S)ORv, –C(S)NRviRvii, –ORv, –OC(O)Rv, –OC(O)ORv, –OC(O)NRviRvii, – OC(O)SRv, –OC(NRv)NRviRvii, –OC(S)Rv, –OC(S)ORv, –OC(S)NRviRvii, –OP(O)(ORv)ORvi, –OS(O)Rv, –OS(O)2Rv, –OS(O)NRviRvii, –OS(O)2NRvRvii, –NRviRvii, –NRvC(O)Rviii, – NReC(O)ORvi, –NRvC(O)NRviRvii, –NRvC(O)SRvi, –NRvC(NRviii)NRviRvii, –NRvC(S)Rviii, – NRvC(S)ORvi, –NRvC(S)NRviRvii, –NRvS(O)Rviii, –NRvS(O)2Rviii, –NRvS(O)NRviRvii, – NRvS(O)2NRviRvii, –SRv, –S(O)Rv, –S(O)2Rv, –S(O)NRviRvii, and –S(O)2NRviRvii; wherein each Rv, Rvi, Rvii, and Rviiiis independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; or (iii) Rviand Rviiitogether with the N atom to which they are attached form heterocyclyl.

[0020] In certain aspects, where specified, one or more hydrogen atoms on a disclosed compound may be replaced with deuterium. Such deuterated compounds may have one or 5ME151606857v.1132266-01220 more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent “un-deuterated” compound.

[0021] One or more of the compounds described herein may exist in various tautomeric forms and are part of the present disclosure. The terms “tautomers” or “tautomeric” refer to two or more interconvertible compounds / substituents resulting from at least one formal migration of a hydrogen atom and at least one change in valency. All such isomeric forms of such compounds are expressly included. Thus, when a compound herein is represented by a structural formula or designated by a chemical name herein, all tautomeric forms which may exist for the compound are encompassed by the structural formula.

[0022] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. A “geometric isomer” refers to isomers that differ in the orientation of substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers to substituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0023] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0024] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicated geometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture. 6ME151606857v.1132266-01220

[0025] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0026] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0027] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0028] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0029] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0030] For use in medicines, the salts of the compounds described herein refer to non- toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of 7ME151606857v.1132266-01220 inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0031] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg / kg body weight / day. 3. Compounds

[0032] In a second embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is halo, wherein the remaining variables are as described above for Formula I

[0033] In a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from chloro, bromo, fluoro, -SO2CH3, and -SOCH, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, as part of a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from chloro, bromo, fluoro, and - SO2CH3, wherein the remaining variables are as described above for Formula I or the second embodiment. In another alternative, as part of a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is chloro, wherein the remaining variables are as described above for Formula I or the second embodiment.

[0034] In a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyano(C1-C4)alkyl, and -(C1-C4)alkyl(C3-C6)cycloalkyl), wherein the remaining variables are as described above for Formula I or the second or third embodiment. Alternatively, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or the second or third embodiment. In another alternative, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically 8ME151606857v.1132266-01220 acceptable salt thereof, is selected from -CH2CH3, -CH2CF3, -CH2CF2CH3, and -CH2CF2CF3, wherein the remaining variables are as described above for Formula I or the second or third embodiment. In yet another alternative, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -CH2CF3, wherein the remaining variables are as described above for Formula I or the second or third embodiment.

[0035] In a fifth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, - (C1-C4)alkyl[4- to 6-membered heterocyclyl], -NRaRb, -ORc, -(C1-C4)alkylORc, -C(O)Rf, - C(O)NRdRe, -(C1-C4)alkylNRdRe, -(C1-C4)alkylC(O)Rf, -(C1-C4)alkylC(O)NRdRe, and -SRg, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5; Ra, Rb, and Rcare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, - (C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6; Rdand Reare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -(C1-C4)alkylOR’, -(C1-C4)alkylNR’R’’, -(C1-C4)alkylC(O)NR’R’’, -(C1- C4)alkylC(O)R’, -(C1-C4)alkylC(O)OR’, -(C1-C4)alkylS(O)R’, -(C1-C4)alkylS(O)2R’, (C1- C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], -C(O)R’, -C(O)OR’, -C(O)NR’R’’, -S(O)R’, and -S(O)2R’, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7; or Rdand Retogether with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7; Rfis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, 9ME151606857v.1132266-01220 wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8; Ra, R6, R7, and R8are each independently selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -NR’R’’, -(C1- C4)alkylNR’R’’ -(C1-C4)alkylC(O)NR’R’’, oxo, -(C1-C4)alkylOR’, -C(O)R’, -S(O)R’, and - S(O)2R’; and R’ and R’’ are each independently selected from hydrogen, (C1-C4)alkyl, and (C3- C6)cycloalkyl, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments.

[0036] In a sixth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NRaRb, -ORc, -C(O)NRdRe, -(C1-C4)alkylNRdRe, and -(C1-C4)alkylC(O)NRdRe, wherein for each occurrence of 5- to 7- membered heteroaryl, phenyl, (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. Alternatively, as part of a sixth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NRaRb, -ORc, - C(O)NRdRe, -(C1-C4)alkylNRdRe, and -(C1-C4)alkylC(O)NRdRe, wherein said cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R5, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments.

[0037] In a seventh embodiment, Ra, Rb, and Rcin the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, and -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl, said groups are each optionally substituted with 1 to 3 groups selected from R6, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments.

[0038] In an eighth embodiment, R5and R6in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from (C1-C4)alkyl 10ME151606857v.1132266-01220 and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments.

[0039] In a ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3,variables are as described above for Formula I or any one of the second to eighth embodiments. Alternatively, as part of ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, chloro, and - OCH2CF3, wherein the remaining variables are as described above for Formula I or any one of the second to eighth embodiments. In another alternative, as part of a ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second to eighth embodiments.

[0040] In a tenth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylORc1, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -NRa1Rb1, - NHC(O)Rc1, -ORc1, -(C1-C4)alkylORc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1- C4)alkylC(O)Rf1, -(C1-C4)alkylC(O)NRd1Re1, and -SRg1, wherein for each occurrence of (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5a; 11ME151606857v.1132266-01220 Ra1, Rb1, and Rc1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a; Rd1, Re1, Rg1, and Rh1, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, -(C1-C4)alkylC(O)OR’1, -(C1-C4)alkylS(O)R’1, -(C1-C4)alkylS(O)2R’1, (C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6- membered heterocyclyl], -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, -S(O)R’1, and -S(O)2R’1, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7a; or Rd1and Re1together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7a; Rf1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8a; R5a, R6a, R7a, and R8aare each independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, cyano, -- (C1-C4)alkylNR’1R’’1, -(C1-C4)alkylC(O)NR’1R’’1, oxo, -(C1-C4)alkylOR’1, -C(O)R’1, - S(O)R’1, and -S(O)2R’1; and R’1and R’’1are each independently selected from hydrogen, (C1-C4)alkyl, (C3- C6)cycloalkyl, and 4- to 7-membered heterocyclyl, wherein the remaining variables are as described above for Formula I or any one of the second to ninth embodiments.

[0041] In an eleventh embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -(C1-C4)alkyl[5- to 7-membered heteroaryl], 4- to 6-membered heterocyclyl, - (C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, and -(C1- C4)alkylNRg1Rh1, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 6- membered heterocyclyl, and 4- to 9-membered heterocyclyl are each optionally substituted 12ME151606857v.1132266-01220 with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. Alternatively, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -(C1- C4)alkylORc1, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, wherein said 4- to 6-membered heterocyclyl and 4- to 9-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. In another embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from - (C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, - (C1-C4)alkyl[piperazinyl], -(C1-C4)alkyl[piperidinyl], -(C1-C4)alkyl[morpholinyl], -(C1- C4)alkyl[pyrrolindyl], -(C1-C4)alkyl[diazepanyl], -(C1-C4)alkyl[azetindinyl], piperazinyl, and tetrahydropyridinyl, wherein said piperidinyl, morpholinyl, pyrrolindyl, diazepanyl, tetrahydropyridinyl, azetindinyl, and each occurrence of piperazinyl are optionally substituted with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments.

[0042] In a twelfth embodiment, R5ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl,wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments. Alternatively, as part of a twelfth embodiment, R5ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, -N[(C1-C4)alkyl]2, -(C1-C4)alkylN[(C1-C4)alkyl]2, -(C1- C4)alkylOH, -(C1-C4)alkylO(C1-C4)alkyl, and -C(O)(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments.

[0043] In a thirteenth embodiment, Rc1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, Rc1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is piperidinyl or pyridinyl, each 13ME151606857v.1132266-01220 optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments.

[0044] In a fourteenth embodiment, R6ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to thirteenth embodiments.

[0045] In a fifteenth embodiment, Ra1and Rb1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, - (C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein for each occurrence of 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to fourteenth embodiments. Alternatively, as part of a fifteenth embodiment, Ra1and Rb1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and -(C1-C4)alkyl[5- to 7-membered heteroaryl], wherein said 5- to 7-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to fourteenth embodiments. In another alternative, as part of a fifteenth embodiment, Ra1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen and Rb1is -(C1-C4)alkyl[pyridinyl], wherein said pyridinyl is optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to fourteenth embodiments.

[0046] In a sixteenth embodiment, Rf1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R8a, wherein the remaining variables are as described above for Formula I or any one of the second to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, Rf1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is piperazinyl optionally substituted with 1 to 3 groups selected from R8a, wherein the remaining variables are as described above for Formula I or any one of the second to fifteenth embodiments.

[0047] In a seventeenth embodiment, R8ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to sixteenth embodiments.

[0048] In an eighteenth embodiment, Rd1and Re1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, - 14ME151606857v.1132266-01220 (C1-C4)alkylNR’1R’’1, (C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein said 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, Rd1and Re1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkylN[(C1-C4)alkyl]2, (C1- C4)alkyl[pyridinyl], and piperidinyl, wherein said pyridinyl and piperidinyl, are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to seventeenth embodiments.

[0049] In a nineteenth embodiment, Rg1and Rh1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -C4)alkylC(O)NR’1R’’1, -(C1-C4)alkylC(O)R’1, (C1-C4)alkylphenyl, -(C1-C4)alkyl[5- to 7- membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein said phenyl, 5- to 7- membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments. Alternatively, as part of a nineteenth embodiment, Rg1and Rh1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkyl[pyridinyl], -(C1-C4)alkylO(C1-C4)alkyl, (C1-C4)alkylphenyl, - (C1-C4)alkylN[(C1-C4)alkyl]2, piperidinyl, pyrrolidinyl, -(C1-C4)alkylC(O)N[(C1-C4)alkyl]2, halo(C1-C4)alkyl, -(C1-C4)alkylC(O)(morpholinyl), wherein said phenyl, pyridinyl, piperidinyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments. In another alternative, as part of a nineteenth embodiment, R7ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, (C1-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments.

[0050] In a twentieth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from –CH2NHCH3, –CH2N(CH3)2, 15ME151606857v.1132266-01220Formula I or any one of the second to nineteenth embodiments. 16ME151606857v.1132266-01220

[0051] In a twenty-first embodiment, A in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a twenty-first embodiment, Y in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a twenty- first embodiment, Z in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula I.

[0052] In a twenty-second embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or the twenty-first embodiment.

[0053] In a twenty-third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is halo, wherein the remaining variables are as described above for Formula I or the twenty-first or twenty-second embodiment. Alternatively, as part of a twenty-third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is bromo or chloro, wherein the remaining variables are as described above for Formula I or the twenty-first or twenty-second embodiment.

[0054] In a twenty-fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is halo(C1-C4)alkyl or cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the twenty-first to twenty-third embodiments. Alternatively, as part of a twenty-fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is –CH2CH3 or – CH2CN, wherein the remaining variables are as described above for Formula I or any one of the twenty-first to twenty-third embodiments.

[0055] In a twenty-fifth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is optionally substituted alkyl, wherein the remaining variables are as described above for Formula I or any one of the twenty-first to twenty-fourth embodiments. Alternatively, as part of a twenty-fifth embodiment, R3is -(C1- C4)alkylheterocyclyl or -(C1-C4)alkylNRg1Rh1, where Rg1and Rh1are each independently selected from hydrogen and (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the twenty-first to twenty-fourth embodiments. Alternatively, as part of a twenty-fifth embodiment, R3is -(C1-C4)bicyclicheterocylyl or -(C1- C4)alkylNRg1Rh1, wherein Rg1and Rh1are each independently selected from hydrogen and (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any 17ME151606857v.1132266-01220 one of the twenty-first to twenty-fourth embodiments. Alternatively, as part of a twenty-fifth embodiment, R3is selected fromdescribed above for Formula I or any one of the twenty-first to twenty-fourth embodiments.

[0056] Compounds having the Formula I are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. 4. Uses, Formulation and Administration

[0057] The compounds and compositions described herein are generally useful for modulating the activity of TP53. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein are covalent modifiers of Y220C. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein stabilize TP53. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein restore wild-type tumor suppressor protein p53 (WT TP53) function.

[0058] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition associated with TP53 function. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition responsive to the activation of TP53 function. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition responsive to the restoration of TP53 function, e.g., where protein function has been lost due to mutation such as a Y220C mutation.

[0059] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a cancer. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a cancer expressing a TP53 mutant (e.g., a cancer harboring a Y220C mutation)

[0060] Specific cancers treatable by the present compounds, salts, and compositions include, but are not limited to, solid tumors, heme malignancy, ovarian, esophageal, 18ME151606857v.1132266-01220 colorectal, head and neck, larynx, lung, leukemia (e.g., acute myeloid leukemia (AML)), sarcoma, testicular, melanoma, cervical, breast, pancreatic, glioma, glioblastoma, endometrial, esophageal, gastric cancer, prostate, bladder, myelodysplastic syndromes (MDS), sarcoma, and melanoma.

[0061] Use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a described condition is also provided. Further provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a described condition.

[0062] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0063] In some aspects, the pharmaceutical compositions are administered orally.

[0064] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition. EXEMPLIFICATION Chemical Synthesis 19ME151606857v.1132266-01220

[0065] The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention.

[0066] Scheme 1.

[0067] 4-Chloropyridopyrollopyrimidines like S10 may be prepared via a nine-step process beginning with the appropriate fluorocyanopyridine S1. Alkylation of S1 with ethyl bromoacetate provides intermediate S2 which can be cyclized with Boc2O and DMAP to provide the indole intermediate S3. Condensation of S3 with DMF-DMA followed by treatment with ammonia provides the pyridopyrrolopyrimidine intermediate S5. Chlorination with POCl3, followed by alkylation with trifluoroethyl triflate provides intermediate S7. Treatment of S7 with sodium methoxide affords intermediate S8, which can be converted to the target compounds like S10 via a two-step sequence consisting of Suzuki coupling with potassium ((dimethylamino)methyl)trifluoroborate and treatment with POCl3.

[0068] Scheme 2. 20ME151606857v.1132266-01220

[0069] 4-Chloropyridopyrollopyrimidines like S15 may also be prepared via a four-step process beginning with intermediate S11. Alkykation of S11 with trifluoroethyl triflate provides intermediate S12. Suzuki coupling with 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane, followed by ozonolysis provides the aldehyde intermediate S14. Reductive amination with an amine provides target compounds like S15.

[0070] Scheme 3.

[0071] 4-Chloropyridopyrollopyrimidines like S23 may be prepared via a seven-step process beginning with the appropriate fluorocyanopyridine S16. Alkylation of S16 with ethyl bromoacetate provides intermediate S17 which can be cyclized with Boc2O and DMAP to provide the indole intermediate S18. Condensation of S18 with DMF-DMA followed by treatment with ammonia provides the pyridopyrrolopyrimidine intermediate S20. Chlorination with POCl3, followed by alkylation with trifluoroethyl triflate provides intermediate S22. Suzuki coupling of S22 with potassium ((dimethylamino)methyl)- trifluoroborate provides target compounds like S23. 21ME151606857v.1132266-01220

[0072] Abbreviations: ACN = acetonitrile AcOH = acetic acid Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DCE = 1,2-dichloroethane DIEA = N,N-diisopropylethylamine DMAP = 4-dimethylaminopyridine DPPA = Diphenylphosphoryl azide DMF = dimethylformamide DMF-DMA = N,N-dimethylformamide dimethyl acetal DPPA = diphenylphosphoryl azide EtOAc = ethyl acetate EtOH = ethanol IPA = isopropanol MeOH = methanol TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TMSCl = trimethylsilyl chloride TMSBr = trimethylsilylbromide Example 1. 1-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin- 8-yl)-N,N-dimethylmethanamine

[0073] Scheme 1, step 1. Ethyl 2-[(6-bromo-4-cyano-3-pyridyl)amino]acetate:

[0074] To a solution of 2-bromo-5-fluoro-pyridine-4-carbonitrile (2.0 g, 9.95 mmol, 1 equiv.) in ACN (25 mL) was added ethyl 2-aminoacetate hydrochloride (2.78 g, 19.90 mmol, 2 equiv.) and DIEA (3.86 g, 29.85 mmol, 5.20 mL, 3 equiv.). The mixture was stirred at 22ME151606857v.1132266-01220 60°C for 12 hours. The reaction was cooled to RT and diluted with EtOAc (30.0 mL). The mixture was washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether) to afford the title compound (1.95 g, 69% yield) as a yellow solid.

[0075] LCMS [M+1, M+3] = 284.0, 286.0.

[0076] Scheme 1, step 2. 1-(tert-Butyl) 2-ethyl 3-amino-5-bromo-1H-pyrrolo[2,3- c]pyridine-1,2-dicarboxylate:

[0077] To a solution of ethyl 2-[(6-bromo-4-cyano-3-pyridyl)amino]acetate (1.45 g, 5.10 mmol, 1 equiv.) in DCM (15 mL) was added Boc2O (1.34 g, 6.12 mmol, 1.20 equiv.), TEA (710 μL, 5.10 mmol, 1 equiv.) and DMAP (62 mg, 510 μmol, 0.1 equiv.). Then the mixture was stirred at RT for 2 hours. The reaction was diluted with DCM (30.0 mL). The mixture was washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether) to afford the title compound (2.58 g, crude) as a yellow solid.

[0078] LCMS [M+1, M+3] = 384.1, 386.0.

[0079] Scheme 1, step 3. ethyl 5-bromo-3-[(E)-dimethylaminomethyleneamino]- pyrrolo[2,3-c]pyridine-1,2-dicarboxylate:

[0080] To a solution of 1-(tert-butyl) 2-ethyl 3-amino-5-bromo-1H-pyrrolo[2,3- c]pyridine-1,2-dicarboxylate (2.3 g, 5.99 mmol, 1 equiv.) in DMF (25 mL) was added 1,1- dimethoxy-N,N-dimethyl-methanamine (1.03 mL, 7.78 mmol, 1.3 equiv.). Then the mixture was stirred at 100°C for 4 hours. The reaction was cooled to RT and the reaction was diluted with EtOAc (30.0 mL). The mixture was washed with H2O, brine, dried over Na2SO4, filtered and concentrated to afford the title compound (2.68 g, crude) as a green solid.

[0081] LCMS [M+1, M+3] = 439.0, 441.0.

[0082] Scheme 1, step 4. 8-Bromo-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-4-ol:

[0083] To a solution of ethyl 5-bromo-3-[(E)-dimethylaminomethyleneamino]- pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (2.2 g, 5.01 mmol, 1 equiv..) in MeOH (20 mL) was added NH3·H2O (20 mL). Then the mixture was stirred at 70°C for 16 hours. The reaction was cooled to RT and the mixture was concentrated under reduced pressure to afford the title compound (1.45 g, crude) as a brown solid.

[0084] LCMS [M+1, M+3] = 265.1, 267.1.

[0085] Scheme 1, step 5. 8-Bromo-4-chloro-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine: 23ME151606857v.1132266-01220

[0086] A solution of 8-bromo-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-4-ol (1.45 g, 5.47 mmol, 1 equiv.) in POCl3 (15 mL) was stirred at 110°C for 16 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. Then the crude product was triturated with ACN (5 mL) at RT to afford the title compound (1.12 g, 61% yield, 84% purity) as a brown solid.

[0087] LCMS [M+1, M+3] = 282.9, 284.9.

[0088] Scheme 1, step 6. 8-Bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]- pyrrolo[3,2-d]pyrimidine:

[0089] To a solution of 8-bromo-4-chloro-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine (1.12 g, 3.95 mmol, 1 equiv.) in DMF (12 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.83 g, 7.90 mmol, 2 equiv.) and K2CO3 (1.09 g, 7.90 mmol, 2 equiv.). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with EtOAc (30.0 mL), washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether) to afford the title compound (850 mg, 56% yield) as a white solid.

[0090] LCMS [M+1, M+3] = 364.8, 366.9.

[0091] Scheme 1, step 7. 8-Bromo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0092] To a solution of 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]- pyrrolo[3,2-d]pyrimidine (100 mg, 273.57 μmol, 1 equiv.) in MeOH (1.5 mL) was added sodium methoxide (39.4 mg, 219 μmol, 0.8 equiv.; 30% solution in methanol). Then the mixture was stirred at 40°C for 1 hour. The reaction was cooled to RT and diluted with ethyl acetate (30.0 mL). The mixture was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (95 mg, 96% yield) as a white solid.

[0093] LCMS [M+1, M+3] = 360.9, 362.9.

[0094] Scheme 1, step 8. 1-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]- pyrrolo[3,2-d]pyrimidin-8-yl)-N,N-dimethylmethanamine:

[0095] To a solution of 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine (95 mg, 263 μmol, 1 equiv.) in 2-methylbutan-2-ol (1 mL) and H2O (0.25 mL) was added potassium ((dimethylamino)methyl)trifluoroborate (86.8 mg, 526 μmol, 2 equiv.), Cs2CO3 (171 mg, 526 μmol, 2 equiv.), and [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (17.1 mg, 26.3 μmol, 0.1 equiv.). The suspension was degassed with nitrogen and then stirred at 80°C for 8 hours. The reaction 24ME151606857v.1132266-01220 was cooled to RT and diluted with EtOAc (30.0 mL). The organic layer was washed with H2O, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 DCM: MeOH) to afford the title compound (65 mg, 73% yield) as a brown solid.

[0096] LCMS [M+1] = 340.1.

[0097] Scheme 1, step 9. 1-(4-chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-8-yl)-N,N-dimethylmethanamine:

[0098] A mixture of 1-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]- pyrrolo[3,2-d]pyrimidin-8-yl)-N,N-dimethylmethanamine (15 mg, 44.21 μmol, 1 equiv.) and POCl3(0.5 mL) was degassed with nitrogen and then stirred at 110°C for 20 hours. The reaction mixture was cooled to RT and then added dropwise to a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (2 x 10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 DCM : MeOH) to afford the title compound (8.2 mg, 53.48% yield) as a brown solid.

[0099] LCMS [M+1, M+3] = 343.9, 345.9.

[0100] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.12 (s, 1H), 9.04 (s, 1H), 8.40 (s, 1H), 5.45 (q, J = 8.0 Hz, 2H), 3.97 (br s, 2H), 2.49 (br s, 6H). Example 2. 1-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin- 8-yl)-N-methylmethanamine

[0101] Scheme 2, step 1. 8-Bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]- pyrrolo[3,2-d]pyrimidine:

[0102] To a solution of 8-bromo-4-chloro-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine (1.12 g, 3.95 mmol, 1 equiv.) in DMF (12 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.83 g, 7.90 mmol, 2 equiv.) and K2CO3 (1.09 g, 7.90 mmol, 2 equiv.). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with EtOAc (30.0 mL), washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column 25ME151606857v.1132266-01220 chromatography (10-25% ethyl acetate in petroleum ether) to afford the title compound (850 mg, 56% yield) as a white solid.

[0103] LCMS [M+1, M+3] = 364.8, 366.9.

[0104] Scheme 2, step 2. 4-Chloro-5-(2,2,2-trifluoroethyl)-8-vinyl-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0105] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (195 μL, 1.15 mmol, 1.2 equiv.), 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine (350 mg, 958 μmol, 1 equiv.), Cs2CO3 (343 mg, 1.05 mmol, 1.1 equiv.), [1,1′- bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (62.4 mg, 95.8 μmol, 0.1 equiv.) in H2O (4 mL) and 2-methylbutan-2-ol (16 mL) was degassed with nitrogen and then stirred at 80°C for 2 hours under an atmosphere of nitrogen. The reaction mixture was cooled to RT, poured into H2O (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 3:1 petroleum ether: ethyl acetate) to afford the title compound (150 mg, 50% yield) as a white solid.

[0106] LCMS: [M+1, M+3] = 313.1, 315.2.

[0107] Scheme 2, step 3. 4-chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine-8-carbaldehyde:

[0108] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-8-vinyl-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine (150 mg, 480 μmol, 1 equiv.) in dioxane (6 mL) and H2O (3 mL) was added K2OsO4·H2O (4.4 mg, 11.9 μmol, 0.025 equiv.) and NaIO4 (410 mg, 1.92 mmol, 4 equiv.) and 2,6-dimethylpyridine (112 μL, 959 μmol, 2 equiv.). The mixture was stirred at RT for 2 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-50% ethyl acetate in petroleum ether) to afford the title compound (140 mg, 93% yield) as a white solid.

[0109] LCMS: [M+1, M+3] = 315.1, 317.1.

[0110] Scheme 2, step 4. 1-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]- pyrrolo[3,2-d]pyrimidin-8-yl)-N-methylmethanamine:

[0111] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine-8-carbaldehyde (90 mg, 286 μmol, 1 equiv.) and methylamine (286.0 μL, 592 μmol, 2 equiv.; 2M in THF) in DCE (0.1 mL) was added NaBH(OAc)3(152 mg, 715 μmol, 2.5 equiv.) and AcOH (33 μL, 572 μmol, 2 equiv.) and the mixture was stirred at RT for 30 26ME151606857v.1132266-01220 minutes. At this time additional NaBH(OAc)3 (151.5 mg, 715.1 μmol, 2.5 equiv.) was added and the mixture was stirred at RT for 2 hrs. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875mm x 30 mm x 3µm; mobile phase: 5-35% acetonitrile in water (+0.04% HCl)) to afford the title compound (36.7 mg, 35% yield; HCl salt) as a white solid.

[0112] LCMS: [M+1, M+3] = 330.1, 332.1.

[0113] 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.45 (m, 1H), 9.11 (s, 1H), 8.52 (s, 1H), 5.93 (q, J = 8.8 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 5.6 Hz, 3H). Example 3. 2-(4-Chloro-8-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-5-yl)acetonitrile

[0114] Scheme 2, step 1. 2-(8-Bromo-4-chloro-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidin-5-yl)acetonitrile:

[0115] To a solution of 8-bromo-4-chloro-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine (100.0 mg, 352.7 μmol, 1 equiv.) in DMF (3.0 mL) cooled to 0°C was added Cs2CO3 (459.6 mg, 1.4 mmol, 4.0 equiv.) and 2-chloroacetonitrile (45 μL, 705 μmol, 2.0 equiv.). The solution was allowed to warm to RT and then stirred fo 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in petroleum ether) to afford the title compound (100.0 mg, 88% yield) as a yellow solid.

[0116] LCMS [M +1, M+3] = 322.0, 324.0.

[0117] Scheme 2, step 2. 2-(4-chloro-8-vinyl-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidin-5-yl)acetonitrile:

[0118] To a solution of 2-(8-bromo-4-chloro-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidin-5-yl)acetonitrile (50.0 mg, 155.0 μmol, 1.0 equiv.) in H2O (1.0 mL) and 2- methylbutan-2-ol (4.0 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (19.1 27ME151606857v.1132266-01220 mg, 124.0 μmol, 0.8 equiv.), Cs2CO3 (56 mg, 171 μmol, 1.1 equiv.), and [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (10.1 mg, 15.5 μmol, 0.1 equiv.). The reaction mixture was stirred at 80°C for 1 hour under an atmosphere of nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (40.0 mg, 96% yield) as a yellow solid.

[0119] LCMS [M +1, M+3] = 270.1, 272.1.

[0120] Scheme 2, step 3. 2-(4-chloro-8-formyl-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidin-5-yl)acetonitrile:

[0121] To a solution of 2-(4-chloro-8-vinyl-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin- 5-yl)acetonitrile (100.0 mg, 370.8 μmol, 1.0 equiv.) in 1,4-dioxane (10.0 mL) and H2O (5.0 mL) was added 2,6-dimethylpyridine (86 μL, 742 μmol, 2 equiv.) and NaIO4 (317 mg, 1.4 mmol, 4.0 equiv.) and K2OsO4·H2O (3.4 mg, 9.2 μmol, 0.025 equiv.). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (60.0 mg, 60% yield) as a yellow solid.

[0122] LCMS [M +1, M+3] = 272.1, 274.1.

[0123] Scheme 2, step 4. 2-(4-Chloro-8-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3- yl)methyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-5-yl)acetonitrile:

[0124] To a solution of 8-methyl-3,8-diazabicyclo[3.2.1]octane (10.9 mg, 55.2 μmol, 1.5 equiv.; bis-HCl salt) in THF (0.5 mL) was added 2-(4-chloro-8-formyl-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-5-yl)acetonitrile (10.0 mg, 36.8 μmol, 1.0 equiv.) and titanium (IV) isopropoxide (65.1 μL, 220.8 μmol, 6.0 equiv.). The mixture was stirred at RT for 30 minutes and then NaBH(OAc)3 (23.4 mg, 110.4 μmol, 3 equiv.) was added. The reaction mixture was stirred at RT for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100mm x 40 mm x 5 µm; mobile phase:1-25% acetonitrile in water (+0.04% HCl)) to afford the title compound (15.3 mg, 54% yield; HCl salt) as a white solid. 28ME151606857v.1132266-01220

[0125] LCMS [M +1, M+3] = 382.2, 384.1.

[0126] 1H NMR (400 MHz, METHANOL-d4) δ 9.84 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 6.17 (s, 2H), 4.30 (s, 2H), 4.00 (s, 2H), 3.19 - 3.07 (m, 4H), 2.84 (s, 3H), 2.39 - 2.29 (m, 4H). Example 4. 4-Chloro-8-(((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine

[0127] Scheme 2, step 3. 4-Chloro-8-(((8-methyl-3,8-diazabicyclo[3.2.1]octan-3- yl)methyl)-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0128] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine-8-carbaldehyde (300.0 mg, 953.4 μmol, 1.0 equiv.) in DCE (3.0 mL) was added 8-methyl-3,8-diazabicyclo[3.2.1]octane (232.6 mg, 1.4 mmol, 1.5 equiv; HCl salt) and AcOH (109 μL, 1.9 mmol, 2.0 equiv.) at RT. The mixture was stirred at RT for 30 minutes, then NaBH(OAc)3 (606 mg, 2.8 mmol, 3.0 equiv.) was added and the solution was stirred at RT for 12 hours. The reaction mixture was diluted with water (10.0 mL) and extracted with dichloromethane (3 x 10.0 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-15% methanol in ethyl acetate) to afford the title compound (180.0 mg, 44% yield) as a yellow solid.

[0129] LCMS [M +1, M+3] = 425.0, 427.0.

[0130] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.06 (s, 1H), 8.25 (s, 1H), 5.85 (q, J = 8.8 Hz, 2H), 3.80 (s, 2H), 3.13 - 3.04 (m, 2H), 2.59 (d, J = 10.0 Hz, 2H), 2.38 (d, J = 10.0 Hz, 2H), 2.23 - 2.15 (m, 3H), 1.96 - 1.87 (m, 2H), 1.87 - 1.78 (m, 2H). Example 5. 4-Chloro-8-((2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine29ME151606857v.1132266-01220

[0131] Scheme 2, step 3. 4-Chloro-8-((2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl)- 5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0132] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine-8-carbaldehyde (50 mg, 159 μmol, 1 equiv.) and 2-methyl-2,7- diazaspiro[3.5]nonane;dihydrochloride (33.9 mg, 158.9 μmol, 1 equiv.) in DCE (0.5 mL) was added TEA (44 μL, 318 μmol, 2 equiv.) and the mixture was stirred at RT for 30 minutes. Then NaBH(OAc)3(84.2 mg, 397.3 μmol, 2.5 equiv.) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100mm x 30mm x 10µm; mobile phase: 15-60% acetonitrile in water (+10 mM NH4HCO3)) to afford the title compound (9.7 mg, 6.68% yield) as a white solid.

[0133] LCMS: [M+1, M+3] = 439.2, 441.1.

[0134] 1H NMR (400 MHz, METHANOL-d4) δ = 9.27 (s, 1H), 8.99 (s, 1H), 8.39 (s, 1H), 5.76 (q, J = 8.4 Hz, 2H), 3.85 (s, 2H), 3.14 (s, 4H), 2.50 (br s, 4H), 2.38 (s, 3H), 1.81 (br t, J = 5.2 Hz, 4H). Example 6. 4-Chloro-8-((7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine

[0135] Scheme 2, step 3. 4-Chloro-8-((7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)methyl)- 5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0136] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine-8-carbaldehyde (155 mg, 493 μmol, 1.0 equiv.) and 2-methyl-2,7- diazaspiro[4.4]nonane (104 mg, 739 μmol, 1.5 equiv.) in DCE (2.0 mL) was added AcOH (200 µL 3.4 mmol, 7.0 equiv.) and the mixture was stirred at RT for 30 minutes. Then NaBH(OAc)3(313.2 mg, 1.4 mmol, 3.0 equiv.) was added to the reaction and the mixture was stirred at RT for 1 hour. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by 30ME151606857v.1132266-01220 preparative HPLC (Phenomenex Luna C1875mm x 30 mm x 3 µm; mobile phase: 1-43% acetonitrile in water (+0.04%HCl)). A second purification by preparatie HPLC (Agela DuraShell NH2150mm x 30mm x 5µm; mobile phase: 50-95% ethanol in heptane) to afforded the title compound (9.6 mg, 4.3% yield) as a brown solid.

[0137] LCMS [M+1, M+3] = 439.2, 441.1.

[0138] 1H NMR (400 MHz, MeOD) δ 9.27 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 5.77 (q, J = 8.4 Hz, 2H), 4.03 (s, 2H), 2.84 - 2.71 (m, 5H), 2.69 - 2.62 (m, 3H), 2.43 (s, 3H), 2.05 - 1.87 (m, 4H). Example 7. 4-Chloro-8-((8-methyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine

[0139] Scheme 2, step 3. 4-Chloro-8-((8-methyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)- 5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0140] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine-8-carbaldehyde (100.0 mg, 317.8 μmol, 1.0 equiv.) in DCE (1.0 mL) was added 8-methyl-2,8-diazaspiro[4.5]decane (73.5 mg, 476.7 μmol, 1.5 equiv.) and AcOH (0.1 mL) and the mixture was stirred at RT for 30 minutes. Then NaBH(OAc)3 (202.0 mg, 953.4 μmol, 3.0 equiv.) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by preparative HPLC (Agela DuraShell NH2150mm x 30mm x 5µm; mobile phase: [Heptane - EtOH]; gradient: 50% - 95% B over 10.0 min) to afford the title compound (16.8 mg, 10.9% yield) as a brown solid.

[0141] LCMS [M+1, M+3] = 453.2, 455.1.

[0142] 1H NMR (400 MHz, MeOD) δ 9.27 (s, 1H), 9.00 (s, 1H), 8.40 (s, 1H), 5.76 (q, J = 8.4 Hz, 2H), 3.99 (s, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.57 (s, 2H), 2.44 (s, 3H), 2.27 (s, 3H), 1.73 - 1.67 (m, 7H). Example 8.8-((3,8-Diazabicyclo[3.2.1]octan-3-yl)methyl)-4-chloro-5-(2,2,2-trifluoroethyl)- 5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine 31ME151606857v.1132266-01220

[0143] Scheme 2, step 3. tert-Butyl 3-((4-chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-8-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate:

[0144] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2- d]pyrimidine-8-carbaldehyde (50 mg, 159 μmol, 1 equiv.) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (67 mg, 318 μmol, 2 equiv.) in DCE (0.5 mL) was added NaBH(OAc)3 (84.20 mg, 397.27 μmol, 2.5 equiv.) and AcOH (19.09 mg, 317.81 μmol, 18.19 μL, 2 equiv.), the mixture was stirred at RT for 30 minutes. Additional NaBH(OAc)3 (84.2 mg, 397 μmol, 2.5 equiv.) was added and the mixture was stirred for an additional 2 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 1:1 petroleum ether:Ethyl acetate) to afford the title compound (80 mg, 99% yield) as a white solid.

[0145] LCMS: [M+1, M+3] = 511.3, 513.3.

[0146] Scheme 2, step 3a. 8-((3,8-Diazabicyclo[3.2.1]octan-3-yl)methyl)-4-chloro-5- (2,2,2-trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0147] To a flask containing tert-butyl 3-((4-chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidin-8-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (80 mg, 156.57 μmol, 1 equiv.) was added HCl (8.00 mL, 204 equiv.; 4M in dioxane). The mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875mm x 30mm x 3µm; mobile phase: 5-35% acetonitrile in water (+0.04% HCl)) to afford the title compound (38.1 mg, 54% yield; HCl salt) as a white solid.

[0148] LCMS: [M+1, M+3] = 411.1, 413.1.

[0149] 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.51 - 9.26 (m, 1H), 9.11 (s, 1H), 8.58 (br s, 1H), 5.91 (q, J = 8.4 Hz, 2H), 4.28 (br s, 2H), 4.09 (br s, 2H), 3.19 (br s, 4H), 2.22 (br d, J = 6.8 Hz, 2H), 2.09 - 1.90 (m, 2H). 32ME151606857v.1132266-01220 Example 9. 4-Fluoro-8-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine

[0150] 4-Fluoro-8-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0151] To a solution of cesium fluoride (21.4 mg, 141.2 μmol, 5.2 μL, 3.0 equiv.) was added 1,4,7,10,13,16-hexaoxacyclooctadecane (1.2 mg, 4.7 μmol, 0.1 equiv.) and tetramethylammonium chloride (515.9 μg, 4.7 μmol, 0.1 equiv.) at RT. Then 4-chloro-8-((8- methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-(2,2,2-trifluoroethyl)-5H- pyrido[4',3':4,5]pyrrolo[3,2-d]pyrimidine (20.0 mg, 47.0 μmol, 1.0 equiv.) was added as a solution in acetonitrile (0.3 mL) and the reaction mixture was stirred at 45°C for 25 minutes. The reaction mixture was cooled to RT, diluted with water (10 mL), and extracted with dichloromethane (3 x 10.0 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C 18150mm x 40mm x 10 um; mobile phase: 20-50% acetonitrile in water (+10 mM NH4HCO3)) to afford the title compound (5.0 mg, 5.1% yield) as a white solid.

[0152] LCMS [M+1] = 409.1.

[0153] 1H NMR (400 MHz, ACETONITRILE-d3) δ 9.14 (s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 5.28 (q, J = 8.8 Hz, 2H), 3.81 (s, 2H), 3.04 (s, 2H), 2.62 (dd, J = 2.4, 10.4 Hz, 2H), 2.41 (d, J = 10.0 Hz, 2H), 2.20 (s, 3H), 1.92 - 1.80 (m, 4H). Example 10. 1-(4-Chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[2',3':4,5]pyrrolo[3,2- d]pyrimidin-8-yl)-N,N-dimethylmethanamine

[0154] Scheme 3, step 1. Ethyl 2-[(6-bromo-2-cyano-3-pyridyl)amino]acetate: 33ME151606857v.1132266-01220

[0155] To a solution of 6-bromo-3-fluoro-pyridine-2-carbonitrile (500 mg, 2.49 mmol, 1 equiv.) and ethyl 2-aminoacetate hydrochloride (694 mg, 4.98 mmol, 2 equiv.) in acetonitrile (5 mL) was added DIEA (1.30 mL, 7.46 mmol, 3 equiv.). The mixture was stirred at 65°C for 12 hours. Three reactions of this scale were carried out and were combined for workup. The reaction mixtures were poured into H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-10% ethyl acetate in petroleum ether) to afford the title compound (2.7 g, crude) as a white solid.

[0156] LCMS: [M+1, M+3] = 284.5, 286.4.

[0157] Scheme 3, step 2. 1-(tert-Butyl) 2-ethyl 3-amino-5-bromo-1H-pyrrolo[3,2- b]pyridine-1,2-dicarboxylate:

[0158] To a solution of ethyl 2-[(6-bromo-2-cyano-3-pyridyl)amino]acetate (900 mg, 3.17 mmol, 1 equiv.) in DCM (10 mL) was added DMAP (39 mg, 317 μmol, 0.1 equiv.) and Boc2O (830 mg, 3.80 mmol, 1.2 equiv.) and DIEA (441 μL, 3.17 mmol, 1 equiv.). The mixture was stirred at RT for 2 hours. Three reactions of this scale were carried out and were combined for workup. The reaction mixtures were poured into H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-10% ethyl acetate in petroleum ether) to afford the title compound (2.6 g, 71% yield) as a white solid.

[0159] LCMS: [M+1, M+3] = 384.2, 386.3.

[0160] Scheme 3, step 3. 1-(tert-Butyl) 2-ethyl (E)-5-bromo-3- (((dimethylamino)methylene)amino)-1H-pyrrolo[3,2-b]pyridine-1,2-dicarboxylate:

[0161] To a solution of 1-(tert-butyl) 2-ethyl 3-amino-5-bromo-1H-pyrrolo[3,2- b]pyridine-1,2-dicarboxylate (2.1 g, 5.47 mmol, 1 equiv.) in DMF (20 mL) was added DMF- DMA (944 μL, 7.11 mmol, 1.3 equiv.). The mixture was stirred at 100°C for 4 hours. The reaction mixture was cooled to RT, poured into H2O (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (2.2 g, 92% yield) as a white solid.

[0162] Scheme 3, step 4. 8-Bromo-5H-pyrido[2',3':4,5]pyrrolo[3,2-d]pyrimidin-4-ol:

[0163] To a solution of 1-(tert-butyl) 2-ethyl (E)-5-bromo-3- (((dimethylamino)methylene)amino)-1H-pyrrolo[3,2-b]pyridine-1,2-dicarboxylate (1.8 g, 34ME151606857v.1132266-01220 4.10 mmol, 1 equiv.) in MeOH (18 mL) was added NH3·H2O (18.00 mL, 140.22 mmol, 34.2 equiv.; 30% in water). The mixture was stirred at 70°C for 72 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure to afford the titlc compound (1.1 g, crude) as a white solid.

[0164] Scheme 3, step 5. 8-Bromo-4-chloro-5H-pyrido[2',3':4,5]pyrrolo[3,2- d]pyrimidine:

[0165] To a solution of 8-bromo-5H-pyrido[2',3':4,5]pyrrolo[3,2-d]pyrimidin-4-ol (100 mg, 377 μmol, 1 equiv.) was added POCl3 (1.20 mL, 12.9 mmol, 34 equiv.). The mixture was stirred at 110°C for 12 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure to afford the title compound (100 mg, crude) as a white solid.

[0166] LCMS: [M+1, M+3] = 284.9, 286.9.

[0167] Scheme 3, step 6. 8-Bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[2',3':4,5]pyrrolo[3,2-d]pyrimidine:

[0168] To a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (327 mg, 1.41 mmol, 2 equiv.) and 8-bromo-4-chloro-5H-pyrido[2',3':4,5]pyrrolo[3,2-d]pyrimidine (200 mg, 705 μmol, 1 equiv.) in DMF (3 mL) was added K2CO3(293 mg, 2.12 mmol, 3 equiv.). The mixture was stirred at RT for 2 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-10% ethyl acetate in petroleum ether) to afford the title compound (300 mg, crude) as a white solid.

[0169] LCMS: [M+1, M+3] = 321.0, 322.9.

[0170] Scheme 3, step 7. 1-(4-Chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[2',3':4,5]pyrrolo[3,2-d]pyrimidin-8-yl)-N,N-dimethylmethanamine:

[0171] A mixture of 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H- pyrido[2',3':4,5]pyrrolo[3,2-d]pyrimidine (270 mg, 739 μmol, 1 equiv.), potassium ((dimethylamino)methyl)trifluoroborate (244 mg, 1.48 mmol, 2 equiv.), Cs2CO3(481.33 mg, 1.4 mmol, 2 equiv.), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (48.14 mg, 73.86 μmol, 0.1 equiv.) in 2-methylbutan-2-ol (3 mL) and H2O (0.8 mL) was degassed with nitrogen and then the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to RT, diluted with H2O, and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna 35ME151606857v.1132266-01220 C1880mm x 30mm x 3µm; mobile phase: 1-30% acetonitrile in water (+0.04% HCl)) to afford the title compound (14.4 mg, 5.1% yield; HCl salt) as a white solid.

[0172] LCMS: [M+1, M+3] = 344.1, 346.1.

[0173] 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 5.85 (q, J = 8.8 Hz, 2H), 4.70 (br s, 2H), 2.87 (s, 6H). Example 11. 1-(4-Chloro-5-(2,2,2-trifluoroethyl)-5H-pyrido[3',2':4,5]pyrrolo[3,2- d]pyrimidin-8-yl)-N,N-dimethylmethanamine

[0174] Example 11 was prepared using the same sequence following scheme 3 that was described for Example 10 but starting with 5-bromo-2-fluoro-pyridine-3-carbonitrile instead of 6-bromo-3-fluoro-pyridine-2-carbonitrile in step 1.

[0175] LCMS [M+1, M+3] = 344.1, 346.1.

[0176] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.98 (s, 1H), 8.76 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 1.8 Hz, 1H), 5.57 (d, J = 8.0 Hz, 2H), 3.71 (s, 2H), 2.34 (s, 6H). Preparation of Y220C TP53 TR-FRET binding probe, BP1, 5-[(3aS,4S,6aR)-2-oxo- 1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4- (tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]pentanamide 36ME151606857v.1132266-01220

[0177] BP1 synthesis, step 1a, 2-iodo-4-nitro-1-(2,2,2-trifluoroethyl)indole: To a solution of 2-iodo-4-nitro-1H-indole (3.0 g, 10.4 mmol, 1.0 equiv.) in THF (20 mL) was added NaH (2.0 g, 52.0 mmol, 5.0 equiv.; 60.0% dispersion in oil) at 0°C by portions, and stirred at 0°C for 30 minutes. 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.6 g, 41.0 mmol, 4.0 equiv.) was added to the reaction mixture at 0°C in portions. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (20 mL) and the resulting mixture was partitioned between EtOAc (200 mL) and H2O (200 mL) and the aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (15:1 to 12:1 petroleum ether:EtOAc) to afford the title compound (5.0 g, crude) as yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (d, J = 8.2 Hz, 1H), 7.80 - 7.63 (m, 2H), 7.33 (t, J = 8.2 Hz, 1H), 4.85 (q, J = 8.2 Hz, 2H). 37ME151606857v.1132266-01220

[0178] BP1 synthesis, step 2a, 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine: To a solution of 2-iodo-4-nitro-1-(2,2,2-trifluoroethyl)indole (1.9 g, 5.1 mmol, 1.0 equiv.) in EtOH (20.0 mL) and H2O (5.0 mL) was added Fe (717 mg, 12.8 mmol, 2.5 equiv.) and NH4Cl (687 mg, 12.8 mmol, 2.5 equiv.). The mixture was stirred at 80 °C for 2 hours. The reaction solution was filtered through a pad of diatomite and the filtrate was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.7 g, 97% yield) as yellow solid. LCMS [M+1] = 341.1.

[0179] BP1 synthesis, step 3a, 2-iodo-N-tetrahydropyran-4-yl-1-(2,2,2- trifluoroethyl)indol-4-amine: To a solution of 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine (600 mg, 1.7 mmol, 1.0 equiv.) in DMF (10 mL) was added chloro(trimethyl)silane (559.8 μL, 4.4 mmol, 2.5 equiv.) and tetrahydropyran-4-one (648.1 μL, 7.0 mmol, 4.0 equiv.). The mixture was stirred at 0°C for 2 hours. Borane-tetrahydrofuran complex (1 M, 8.8 mL, 5.0 equiv.) was added to the mixture under N2and the resulting mixture was stirred at 0-20°C for 12 hours. The reaction was poured into a saturated aqueous solution of NH4Cl (1.5 ml) and extracted with EtOAc (3 × 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (600 mg, 80% yield) as white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.03 (s, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.90 - 6.70 (m, 2H), 6.34 (d, J = 7.8 Hz, 1H), 4.69 (q, J = 8.4 Hz, 2H), 4.11 - 4.00 (m, 2H), 3.92 - 3.71 (m, 1H), 3.73 - 3.63 (m, 1H), 3.56 (t, J = 10.6 Hz, 2H), 2.97 (s, 2H), 2.89 (s, 1H), 2.68 (d, J = 9.4 Hz, 1H), 2.24 - 2.01 (m, 2H). LCMS [M+1] = 425.1.

[0180] BP1 synthesis, step 1b, tert-Butyl N-[2-[2-[2-[2-[(3-methoxy-4-nitro- phenyl)sulfonylamino]ethoxy]ethoxy]-ethoxy]ethyl]carbamate: To a solution of tert-butyl N- [2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-ethyl]carbamate (906 mg, 3.1 mmol, 1.3 equiv.) in DCM (15 mL) was added TEA (1.6 mL, 11.9 mmol, 5.0 equiv.) and 3-methoxy-4-nitro- benzenesulfonyl chloride (600 mg, 2.4 mmol, 1.0 equiv.). The mixture was stirred at 15°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (50 mL) and H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.1 g, 91% yield) as a brown oil. 38ME151606857v.1132266-012201H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 4.00 (s, 3H), 3.53 - 3.41 (m, 10H), 3.15 - 2.90 (m, 6H), 2.65 (t, J = 5.7 Hz, 1H), 1.36 (s, 9H).

[0181] LCMS [M+1] = 408.2.

[0182] BP1 synthesis, step 2b, tert-Butyl N-[2-[2-[2-[2-[(4-amino-3-methoxy- phenyl)sulfonylamino]ethoxy]ethoxy]-ethoxy]ethyl]carbamate: To a solution of tert-butyl N- [2-[2-[2-[2-[(3-methoxy-4-nitro-phenyl)sulfonylamino]ethoxy]ethoxy]ethoxy]- ethyl]carbamate (2.0 g, 3.9 mmol, 1.0 equiv.) in EtOH (12.0 mL) and H2O (3.0 mL) was added Fe (1.1 g, 19.7 mmol, 5.0 equiv.) and NH4Cl (1.1 g, 19.7 mmol, 5.0 equiv.). The mixture was stirred at 80°C for 1 hour. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (3 × 20 mL). The filtrate was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (50 mL) and H2O (30 mL). Then the aqueous layer was extracted again with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.5 g, 80% yield) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 7.20 (t, J = 6.0 Hz, 1H), 7.16 - 7.13 (m, 1H), 7.12 (s, 1H), 6.76 (br t, J = 5.6 Hz, 1H), 6.69 - 6.63 (m, 1H), 6.73 - 6.60 (m, 1H), 5.56 (s, 2H), 3.80 (s, 3H), 3.50 - 3.42 (m, 7H), 3.40 - 3.35 (m, 3H), 3.05 (q, J = 6.0 Hz, 2H), 2.80 (q, J = 6.0 Hz, 2H), 1.36 (s, 9H).

[0183] LCMS [M+1] = 378.3.

[0184] BP1 synthesis, step 3b, tert-Butyl N-[2-[2-[2-[2-[[3-methoxy-4-(3- trimethylsilylprop-2-ynylamino)phenyl]- sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl N-[2-[2-[2- [2-[(4-amino-3-methoxy-phenyl)sulfonylamino]ethoxy]ethoxy]ethoxy]-ethyl]carbamate (1.5 g, 3.1 mmol, 1.0 equiv.) in DCM (15 mL) and acetic acid (3 mL) was added 3- trimethylsilylprop-2-ynal (396 mg, 3.1 mmol, 1.0 equiv.). The mixture was stirred at 35°C for 17 hours and then sodium triacetoxyborohydride (2.6 g, 12.5 mmol, 4.0 equiv.) was added to the mixture. The mixture was stirred at 35°C for 17 hours. The reaction mixture was diluted with EtOAc (50 mL) and H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 50 ml). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 (250mm × 70mm 39ME151606857v.1132266-01220 × 15 um); mobile phase: 40-75% ACN in water (+NH4HCO3 modifier)) to afford the title compound (480 mg, 26% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.23 (m, 2H), 7.16 (d, J = 1.8 Hz, 1H), 6.73 (br t, J = 5.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.11 (t, J = 6.0 Hz, 1H), 4.01 (d, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.54 - 3.40 (m, 8H), 3.36 (br t, J = 5.8 Hz, 4H), 3.31 (s, 2H), 3.05 (q, J = 6.0 Hz, 2H), 2.82 (q, J = 6.0 Hz, 2H), 2.07 (s, 1H), 1.36 (s, 9H).

[0185] LCMS [M+1] = 488.4.

[0186] BP1 synthesis, step 4b, tert-Butyl N-[2-[2-[2-[2-[[3-methoxy-4-(prop-2- ynylamino)phenyl]sulfonylamino]-ethoxy]ethoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-(3-trimethylsilylprop-2- ynylamino)phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]-carbamate (580.0 mg, 986.7 μmol, 1.0 equiv.) in MeOH (6.0 mL) was added K2CO3 (272.7 mg, 1.9 mmol, 2.0 equiv.). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (400 mg, 79% yield) as an off-white oil.

[0187] 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.24 (m, 2H), 7.15 (d, J = 1.8 Hz, 1H), 6.74 (t, J = 5.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.13 (t, J = 6.0 Hz, 1H), 3.97 (dd, J = 2.0, 6.2 Hz, 2H), 3.83 (s, 3H), 3.50 - 3.41 (m, 8H), 3.39 - 3.33 (m, 4H), 3.11 - 3.00 (m, 3H), 2.81 (q, J = 6.0 Hz, 2H), 2.07 (s, 3H), 1.36 (s, 9H). LCMS [M+1] = 416.3.

[0188] BP1 synthesis, step 5b, tert-Butyl N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4- (tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]-ethyl]carbamate: To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-(prop-2-ynylamino)phenyl]sulfonylamino]ethoxy]- ethoxy]ethoxy]ethyl]carbamate (200 mg, 388 μmol, 1.0 equiv.) in ACN (2.0 mL) was added dichloropalladium-triphenylphosphane (27.2 mg, 38.7 μmol, 0.1 equiv.) and copper(I)iodide (7.4 mg, 38.8 μmol, 0.1 equiv.), 2-iodo-N-tetrahydropyran-4-yl-1-(2,2,2-trifluoroethyl)indol- 4-amine (165 mg, 388 μmol, 1.0 equiv.) and triethylamine (162 µL, 1.1 mmol, 3.0 equiv.) under an atmosphere of nitrogen gas. The mixture was stirred at 70°C for 2 hours. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL) and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed 40ME151606857v.1132266-01220 with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (200 mg, 64% yield) as a white solid.

[0189] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.32 - 7.24 (m, 1H), 7.19 (d, J = 1.6 Hz, 2H), 7.08 (s, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.80 - 6.63 (m, 2H), 6.32 (t, J = 6.4 Hz, 1H), 6.21 (d, J = 7.8 Hz, 1H), 5.96 - 5.96 (m, 1H), 5.54 (d, J = 8.4 Hz, 1H), 5.01 - 4.84 (m, 2H), 4.33 (d, J = 6.2 Hz, 1H), 3.93 - 3.83 (m, 4H), 3.51 - 3.39 (m, 9H), 3.38 - 3.34 (m, 1H), 3.38 - 3.29 (m, 7H), 3.04 (q, J = 5.8 Hz, 2H), 2.81 (q, J = 5.8 Hz, 2H), 2.50 (d, J = 1.6 Hz, 72H), 2.04 - 1.97 (m, 1H), 1.91 (br d, J = 13.4 Hz, 1H), 1.95 - 1.85 (m, 1H), , 1.36 (s, 9H).

[0190] LCMS [M+1] = 812.3.

[0191] BP1 synthesis, step 6b, N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]-3- methoxy-4-[3-[4-(tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]benzenesulfonamide: To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-[3- [4-(tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]-ethyl]carbamate (200 mg, 246 μmol, 1.0 equiv.) in DCM (0.6 mL) was added TFA (0.8 mL). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (150 mg, 86% yield) as a brown oil. The crude product was used directly in the next step.

[0192] LCMS [M+1] = 712.4.

[0193] BP1 synthesis, step 7b, TR-FRET binding probe, BP1, 5-[(3aS,4S,6aR)-2-oxo- 1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4- (tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]phenyl]- sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]pentanamide: To a solution of N-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethyl]-3-methoxy-4-[3-[4-(tetrahydropyran-4-ylamino)-1-(2,2,2- trifluoroethyl)indol-2-yl]prop-2-ynylamino]benzenesulfonamide (40.0 mg, 56.2 μmol, 1.0 equiv.) in DCM (1 mL) was added TEA (28.4 mg, 281 μmol, 39.1 μL, 5.0 equiv.) and (2,5- dioxopyrrolidin-1-yl) 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol- 4-yl]pentanoate (19.1 mg, 56.2 μmol, 1.0 equiv.). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford a residue that was purified by preparative HPLC (column: Phenomenex Luna C18200mm × 40mm × 10um; mobile phase: 35-70% ACN in water (+formic acid modifier)) to afford the title compound (11.2 mg, 21% yield) as a white solid. 41ME151606857v.1132266-01220

[0194] 1H NMR (400 MHz, DMSO-d6) δ 7.80 (t, J = 5.6 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.19 (d, J = 1.8 Hz, 1H), 7.08 (s, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.40 (s, 1H), 6.36 - 6.28 (m, 2H), 6.22 (d, J = 7.8 Hz, 1H), 5.55 (d, J = 2.2 Hz, 1H), 4.93 (q, J = 9.2 Hz, 2H), 4.41 - 4.22 (m, 3H), 4.18 - 4.07 (m, 1H), 3.95 - 3.79 (m, 5H), 3.52 - 3.36 (m, 14H), 3.23 - 3.13 (m, 2H), 3.11 - 3.02 (m, 1H), 2.90 - 2.74 (m, 3H), 2.57 (d, J = 12.6 Hz, 1H), 2.05 (t, J = 7.4 Hz, 2H), 1.91 (d, J = 12.4 Hz, 2H), 1.57 - 1.39 (m, 5H), 1.70 - 1.38 (m, 2H), 1.36 - 1.20 (m, 2H). LCMS [M+1] = 938.3. Biological Assays

[0001] Compound potency (IC50) was assessed in a TR-FRET binding assay measuring the association of the biotinylated-small molecule probe BP1 to the Y220C TP53 mutant DBD. Specifically, a 5 microliter mixture consisting of 32 nM BP1 and 48 nM streptavidin- d2 (Cisbio) in 10 mM KH2PO4pH 7.2, 150 mM NaCl, 0.01% BSA, 0.01% Tween-20 and 0.1 mM TCEP was added to 384-well plates containing duplicate 10-point dose response titrations of test compounds in 60 nL DMSO (0.6% f.c. DMSO (v / v)). An additional 5 microliter mixture consisting of 10 nM Y220C TP53 DBD (e. coli expressed, His-TEV-P89- T312-FLAG; Uniprot ID P04637-1) and 0.3 nM MAb Anti FLAG M2-Tb cryptate (Perkin Elmer) in 10 mM KH2PO4 pH 7.2, 150 mM NaCl, 0.01% BSA, 0.01% Tween-20 and 0.1 mM TCEP was added to the 384-well plates. Mixtures were incubated at 20°C. The TR- FRET response was monitored after 4 hours and 24 hours of incubation of the BP1 mixture and compound mixture. Plates were read in an EnVision plate reader (Perkin Elmer) with Ex / Em 615 / 665. To determine the potency (IC50) of the test compounds (competitive binding to TP53 Y220C protein in the presence of the biotinylated probe, BP1), TR-FRET ratios were normalized to the average ratio of DMSO control wells (0% inhibition) and to the average minimum ratio (100% inhibition) obtained with 5 micromolar BP1 positive control compound. Test compound dose-responses were fitted using a non-linear regression with 4- parameters fitting, providing IC50and nHill slope. Results are show in Table 1 below and are expressed as the ranges described here: A: IC50< 0.100 μM; % inhibition > 90%; B: IC50= 0.100-1.00 µM; % inhibition = 70-90%; C: IC50 = 1.00-10.0 µM; % inhibition = 50-70%; D: IC50= 10.0-60.0 µM; % inhibition = 10-50%; E: IC50> 60.0 µM; % inhibition < 10%.

[0002] The TR-FRET assay described above may be used to assess the binding affinity of both reversible and covalent TP53 Y220C ligands, stabilizers, and correctors and can also discrimate between reversible and covalent TP53 Y220C ligands, stabilizers, and correctors. 42ME151606857v.1132266-01220 To validate the TR-FRET assay described above we characterized a selection of TP53 Y220C ligands, stabilizers, and correctors previously described in the scientific literature. PK9301 and PK9323, compounds described by Joerger, et. al. (ACS Chem. Biology 2020, 15, 657- 668) that have been shown to bind to TP53 Y220C via X-ray crysallography and stabilize the mutant protein as judged by differential scanning fluorimetry (DSF), have an IC50 = 1.5 µM and 4.1 µM, respectively, in the TR-FRET binding assay described above. PK5196, a compound described by Jeorger, Boeckler, et.al. (J. Am. Chem. Soc. 2012, 134, 6810-6818) that has been shown to bind TP53 Y220C via X-ray crysallography and stabilize the mutant protein as judged by differential scanning fluorimetry (DSF), nuclear magnetic resonance (NMR), and isothermal calorimetry (ITC), has an IC50= 9.7 µM in the TR-FRET assay described above. PK9301, PK9323, and PK5196 are all reversible TP53 Y220C ligands / stabilizers and as such display time-independent activity in the TR-FRET assay described above. Identical or nearly identical IC50values are observed at both the 4h and 24h time points. Covalent ligands / modifiers generally have time-dependent activity since covalent modification of the protein leads to a lasting, cumulative effect as the reaction with the target protein progresses. Compounds of Formula I often display time-dependent displacement of the TR-FRET binding probe, BP1, from TP53 Y220C distinguishing them from reversible TP53 Y220C ligands / stabilizers / correctors. We believe in certain instances that covalent modification of mutant TP53 Y220C may lead to more durable stabilization of the mutant protein and result in more robust restoration of wild-type TP53 function relative to reversible ligands. This covalent mechanism of action may be advantageous for small molecule therapies targeted towards medical conditions, such as cancer, associated with or ascribed to the TP53 Y220C mutant protein. Table 1. Example No. TR-FRET IC50 - TR-FRET IC50 - % inhibition (4h) % inhibition (24h) 1 C – A C – A 2 C – A B – A 3 C – A B – A 4 B – A A – A 5 C – A B – A 6 C – A B – A 7 C – A B – A 8 B – A A – A 9 C – A B – A 10 C – A C – A 11 E – C C – A . 43ME151606857v.1132266-01220

[0003] While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0004] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. 44ME151606857v.1

Claims

132266-01220 Listing of Claims:

1. A compound having the Formula I:or a pharmaceutically acceptable salt thereof, wherein R1is selected from optionally substituted alkyl; R2is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRaRb, -ORc, -NHC(O)Rc, -C(O)NRdRe, -C(O)Rf, and -SRg; R3is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRa1Rb1, -ORc1, -NHC(O)Rc1, - C(O)NRd1Re1, -C(O)Rf1, and -SRg1; X is selected from halo, -S(O)2alkyl, and –S(O)alkyl; one of A, Y, or Z is N and the two remaining variables that are not N are -CH-; Ra, Ra1, Rb, Rb1, Rc, and Rc1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted heterocyclyl; Rdand Reare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’, -C(O)OR’, -C(O)NR’R’’, -S(O)R’, and -S(O)2R’; or Rdand Retogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; Rd1and Re1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, - S(O)R’1, and -S(O)2R’1; or Rd1and Re1together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; Rfand Rf1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and 45ME151606857v.1132266-01220 R’ R’1, R’’, and R’’1are each independently selected from hydrogen and optionally substituted (C1-C4)alkyl.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein A is N.

3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

4. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is halo.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X is bromo or chloro.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1is halo(C1-C4)alkyl or cyano(C1-C4)alkyl.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is –CH2CH3or –CH2CN.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3is optionally substituted alkyl.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is -(C1-C4)alkylheterocyclyl or -(C1-C4)alkylNRg1Rh1, where Rg1and Rh1are each independently selected from hydrogen and (C1-C4)alkyl. 46ME151606857v.1132266-01220 12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3is -(C1-C4)bicyclicheterocylyl or -(C1-C4)alkylNRg1Rh1, wherein Rg1and Rh1are each independently selected from hydrogen and (C1-C4)alkyl.

13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3is selected from14. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, -SO2(C1-C3)alkyl, and -SO(C1-C3)alkyl.

15. The compound of Claim 1 or 14, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, -SO2CH3, and -SOCH3.

16. The compound of any one of Claims 1, 14, and 15, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, and -SO2CH3.

17. The compound of any one of Claims 1 and 14 to 16, or a pharmaceutically acceptable salt thereof, wherein X is chloro.

18. The compound of any one of Claims 1 and 14 to 17, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyano(C1-C4)alkyl, and -(C1-C4)alkyl(C3-C6)cycloalkyl).

19. The compound of any one of Claims 1 and 14 to 18, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl and halo(C1-C4)alkyl.

20. The compound of any one of Claims 1 and 14 to 19, or a pharmaceutically acceptable salt thereof, wherein R1is selected from -CH2CH3, -CH2CF3, -CH2CF2CH3, and -CH2CF2CF3. 47ME151606857v.1132266-01220 21. The compound of any one of Claims 1 and 14 to 20, or a pharmaceutically acceptable salt thereof, wherein R1is -CH2CF3.

22. The compound of any one of Claims 1 and 14 to 21, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7- membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1- C4)alkyl[4- to 6-membered heterocyclyl], -NRaRb, -ORc, -(C1-C4)alkylORc, -C(O)Rf, - C(O)NRdRe, -(C1-C4)alkylNRdRe, -(C1-C4)alkylC(O)Rf, -(C1-C4)alkylC(O)NRdRe, and -SRg, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5; Ra, Rb, and Rcare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, - (C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6; Rdand Reare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -(C1-C4)alkylOR’, -(C1-C4)alkylNR’R’’, -(C1-C4)alkylC(O)NR’R’’, -(C1- C4)alkylC(O)R’, -(C1-C4)alkylC(O)OR’, -(C1-C4)alkylS(O)R’, -(C1-C4)alkylS(O)2R’, (C1- C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], -C(O)R’, -C(O)OR’, -C(O)NR’R’’, -S(O)R’, and -S(O)2R’, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7; or Rdand Retogether with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7; Rfis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, 48ME151606857v.1132266-01220 wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8; Ra, R6, R7, and R8are each independently selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -NR’R’’, -(C1- C4)alkylNR’R’’ -(C1-C4)alkylC(O)NR’R’’, oxo, -(C1-C4)alkylOR’, -C(O)R’, -S(O)R’, and - S(O)2R’; and R’ and R’’ are each independently selected from hydrogen, (C1-C4)alkyl, and (C3- C6)cycloalkyl.

23. The compound of any one of Claims 1 and 14 to 22, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NRaRb, -ORc, - C(O)NRdRe, -(C1-C4)alkylNRdRe, and -(C1-C4)alkylC(O)NRdRe, wherein for each occurrence of 5- to 7-membered heteroaryl, phenyl, (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5.

24. The compound of any one of Claims 1 and 14 to 23, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NRaRb, -ORc, -C(O)NRdRe, -(C1- C4)alkylNRdRe, and -(C1-C4)alkylC(O)NRdRe, wherein said cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R5.

25. The compound of any one of Claims 1 and 14 to 24, or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, and Rcare each independently selected from hydrogen, (C1- C4)alkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, and -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl, said groups are each optionally substituted with 1 to 3 groups selected from R6.

26. The compound of any one of Claims 1 and 14 to 25, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each independently selected from (C1-C4)alkyl and halo(C1-C4)alkyl. 49ME151606857v.1132266-01220 27. The compound of any one of Claims 1 and 14 to 26, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3,28. The compound of any one of Claims 1 and 14 to 27, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, chloro, and -OCH2CF3.

29. The compound of any one of Claims 1 and 14 to 28, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

30. The compound of any one of Claims 1 and 14 to 29, or a pharmaceutically acceptable salt thereof, wherein R3is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylORc1, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -NRa1Rb1, - NHC(O)Rc1, -ORc1, -(C1-C4)alkylORc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1- C4)alkylC(O)Rf1, -(C1-C4)alkylC(O)NRd1Re1, and -SRg1, wherein for each occurrence of (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5a; Ra1, Rb1, and Rc1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6- 50ME151606857v.1132266-01220 membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a; Rd1, Re1, Rg1, and Rh1, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, -(C1-C4)alkylC(O)OR’1, -(C1-C4)alkylS(O)R’1, -(C1-C4)alkylS(O)2R’1, (C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6- membered heterocyclyl], -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, -S(O)R’1, and -S(O)2R’1, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7a; or Rd1and Re1together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7a; Rf1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8a; R5a, R6a, R7a, and R8aare each independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, cyano, -- (C1-C4)alkylNR’1R’’1, -(C1-C4)alkylC(O)NR’1R’’1, oxo, -(C1-C4)alkylOR’1, -C(O)R’1, - S(O)R’1, and -S(O)2R’1; and R’1and R’’1are each independently selected from hydrogen, (C1-C4)alkyl, (C3- C6)cycloalkyl, and 4- to 7-membered heterocyclyl.

31. The compound of any one of Claims 1 and 14 to 30, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -(C1- C4)alkyl[5- to 7-membered heteroaryl], 4- to 6-membered heterocyclyl, -(C1-C4)alkylORc1, - NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, and -(C1-C4)alkylNRg1Rh1, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and 4- to 9- membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R5a.

32. The compound of any one of Claims 1 and 14 to 31, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkylORc1, 4- to 6-membered heterocyclyl, - 51ME151606857v.1132266-01220 (C1-C4)alkyl[4- to 9-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, - C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, wherein said 4- to 6-membered heterocyclyl and 4- to 9-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R5a.

33. The compound of any one of Claims 1 and 14 to 32, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, - C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1-C4)alkyl[piperazinyl], -(C1- C4)alkyl[piperidinyl], -(C1-C4)alkyl[morpholinyl], -(C1-C4)alkyl[pyrrolindyl], -(C1- C4)alkyl[diazepanyl], -(C1-C4)alkyl[azetindinyl], piperazinyl, and tetrahydropyridinyl, wherein said piperidinyl, morpholinyl, pyrrolindyl, diazepanyl, tetrahydropyridinyl, azetindinyl, and each occurrence of piperazinyl are optionally substituted with 1 to 3 groups selected from R5a.

34. The compound of any one of Claims 1 and 14 to 34, or a pharmaceutically acceptable salt thereof, wherein R5ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, - NR’1R’’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkylOR’1, and -C(O)R’1.

35. The compound of any one of Claims 1 and 14 to 34, or a pharmaceutically acceptable salt thereof, wherein R5ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, -N[(C1- C4)alkyl]2, -(C1-C4)alkylN[(C1-C4)alkyl]2, -(C1-C4)alkylOH, -(C1-C4)alkylO(C1-C4)alkyl, and -C(O)(C1-C4)alkyl.

36. The compound of any one of Claims 1 and 14 to 35, or a pharmaceutically acceptable salt thereof, wherein Rc1is selected from 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R6a.

37. The compound of any one of Claims 1 and 14 to 36, or a pharmaceutically acceptable salt thereof, wherein Rc1is piperidinyl or pyridinyl, each optionally substituted with 1 to 3 groups selected from R6a.

38. The compound of any one of Claims 1 and 14 to 37, or a pharmaceutically acceptable salt thereof, wherein R6ais (C1-C4)alkyl. 52ME151606857v.1132266-01220 39. The compound of any one of Claims 1 and 14 to 38, or a pharmaceutically acceptable salt thereof, wherein Ra1and Rb1are each independently selected from hydrogen, -(C1- C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein for each occurrence of 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a.

40. The compound of any one of Claims 1 and 14 to 39, or a pharmaceutically acceptable salt thereof, wherein Ra1and Rb1are each independently selected from hydrogen and -(C1- C4)alkyl[5- to 7-membered heteroaryl], wherein said 5- to 7-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R6a.

41. The compound of any one of Claims 1 and 14 to 40, or a pharmaceutically acceptable salt thereof, wherein Ra1is hydrogen and Rb1is -(C1-C4)alkyl[pyridinyl], wherein said pyridinyl is optionally substituted with 1 to 3 groups selected from R6a.

42. The compound of any one of Claims 1 and 14 to 41, or a pharmaceutically acceptable salt thereof, wherein Rf1is 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R8a.

43. The compound of any one of Claims 1 and 14 to 42, or a pharmaceutically acceptable salt thereof, wherein Rf1is piperazinyl optionally substituted with 1 to 3 groups selected from R8a.

44. The compound of any one of Claims 1 and 14 to 43, or a pharmaceutically acceptable salt thereof, wherein R8ais (C1-C4)alkyl.

45. The compound of any one of Claims 1 and 14 to 44, or a pharmaceutically acceptable salt thereof, wherein Rd1and Re1are each independently selected from hydrogen, -(C1- C4)alkylNR’1R’’1, (C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein said 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, are each optionally substituted with 1 to 3 groups selected from R7a. 53ME151606857v.1132266-01220 46. The compound of any one of Claims 1 and 14 to 45, or a pharmaceutically acceptable salt thereof, wherein Rd1and Re1are each independently selected from hydrogen, -(C1- C4)alkylN[(C1-C4)alkyl]2, (C1-C4)alkyl[pyridinyl], and piperidinyl, wherein said pyridinyl and piperidinyl, are each optionally substituted with 1 to 3 groups selected from R7a.

47. The compound of any one of Claims 1 and 14 to 46, or a pharmaceutically acceptable salt thereof, wherein Rg1and Rh1are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, -C4)alkylC(O)NR’1R’’1, -(C1-C4)alkylC(O)R’1, (C1-C4)alkylphenyl, -(C1-C4)alkyl[5- to 7- membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein said phenyl, 5- to 7- membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R7a.

48. The compound of any one of Claims 1 and 14 to 47, or a pharmaceutically acceptable salt thereof, wherein Rg1and Rh1are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkyl[pyridinyl], -(C1-C4)alkylO(C1-C4)alkyl, (C1- C4)alkylphenyl, -(C1-C4)alkylN[(C1-C4)alkyl]2, piperidinyl, pyrrolidinyl, -(C1- C4)alkylC(O)N[(C1-C4)alkyl]2, halo(C1-C4)alkyl, -(C1-C4)alkylC(O)(morpholinyl), wherein said phenyl, pyridinyl, piperidinyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R7a.

49. The compound of any one of Claims 1 and 14 to 48, or a pharmaceutically acceptable salt thereof, wherein R7ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, (C1-C4)alkoxy, and cyano.

50. The compound of any one of Claims 1 and 14 to 49, or a pharmaceutically acceptable54ME151606857v.1132266-0122051. The compound of Claim 1, wherein the compound is selected from 55ME151606857v.1132266-01220or a pharmaceutically acceptable salt thereof.

52. A compound according to any one of Claims 1 to 51, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

53. A method of treating a condition responsive to the activation of wild-type tumor suppressor protein TP53 function in a subject in need thereof, comprising administering to 56ME151606857v.1132266-01220 the subject a therapeutically effective amount of a compound according to any one of Claims 1 to 51, or a pharmaceutically acceptable salt thereof, or the composition of Claim 52.

54. The method of Claim 53, wherein the condition is a cancer.

55. The method of Claim 53 or 54, wherein the condition is a cancer harboring a Y220C mutation.

56. The method of any one of Claims 53 to 55, wherein the cancer is a solid tumor or a heme malignancy.

57. The method of any one of Claims 53 to 56, wherein the cancer is selected from lung cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, glioma, glioblastoma, endometrial cancer, esophageal cancer, gastric cancer, prostate cancer, head and neck cancer, bladder cancer, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), sarcoma, and melanoma. 57ME151606857v.1

Images