Pyrido[3,2-b]indole-3-carbonitrile 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

132266-01320 COMPOUNDS AND COMPOSITION FOR TARGETING TP53-Y220C MUTANTS RELATEDAPPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 618,999, 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, X, and Y 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 1ME151606866v.1132266-01320 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; Y is -CH- or N; X is selected from halo, -S(O)2alkyl, and –S(O)alkyl; 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, - 2ME151606866v.1132266-01320 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, 3ME151606866v.1132266-01320 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. 4ME151606866v.1132266-01320

[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 5ME151606866v.1132266-01320 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. 6ME151606866v.1132266-01320

[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 7ME151606866v.1132266-01320 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 selected from chloro, bromo, fluoro, -SO2(C1-C3)alkyl, and -SO(C1- C3)alkyl., 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 8ME151606866v.1132266-01320 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, 9ME151606866v.1132266-01320 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 10ME151606866v.1132266-01320 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; 11ME151606866v.1132266-01320 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 12ME151606866v.1132266-01320 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 13ME151606866v.1132266-01320 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, - 14ME151606866v.1132266-01320 (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, 15ME151606866v.1132266-01320Formula I or any one of the second to nineteenth embodiments. 16ME151606866v.1132266-01320

[0051] In a twenty-first 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.

[0052] In a twenty-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 or the twenty-first embodiment. Alternatively, as part of a twenty-second embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is chloro or fluoro, wherein the remaining variables are as described above for Formula I or the twenty-first embodiment.

[0053] In a twenty-third embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is halo(C1-C3)alkyl, wherein the remaining variables are as described above for Formula I or the twenty-second embodiment. Alternatively, as part of a twenty-third embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CH2CF3, 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, 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-third embodiment. Alternatively, as part of a twenty-fourth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is -(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-third embodiment. Alternatively, as part of a twenty-fourth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is -(C1-C4)bicyclicheterocylyl, -(C1- C4)monocyclicheterocylyl 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 one of the twenty-first to twenty-third embodiment. Alternatively, as part of a twenty-fourth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from,17ME151606866v.1132266-01320 , wherein the remaining variables are as described above for Formula I or any one of the twenty-first to twenty-third embodiment. .

[0055] 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

[0056] 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.

[0057] 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.

[0058] 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)

[0059] Specific cancers treatable by the present compounds, salts, and compositions include, but are not limited to, solid tumors, heme malignancy, ovarian, esophageal, 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. 18ME151606866v.1132266-01320

[0060] 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.

[0061] 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.

[0062] In some aspects, the pharmaceutical compositions are administered orally.

[0063] 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. EXEMPLIFICATIONChemical Synthesis

[0064] 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.

[0065] Scheme 1. 19ME151606866v.1132266-01320

[0066] 4-Chloro-3-cyano-pyridoindoles like S10 may be prepared via a nine-step process beginning with the appropriate 3-carboxyindole S1. Curtius rearrangement of S1, followed by treatment with t-butylalcohol, and deprotection with acid provides the 3-aminoindole intermediate S3. Reaction of S3 with diethyl 2-(ethoxymethylene)malonate provides intermediate S4 which can be converted to the chloropyridoindole intermediate S5 with POCl3. Alkylation of S5 with trifluoroethyltriflate provides S6. Suzuki coupling with potassium ((dimethylamino)methyl)trifluoroborate provides S7. Hydrolysis of S7 followed by amide coupling with ammonia provides intermediate S9, which can be converted to the target 4-chloro-3-cyano-pyridoindoles via dehydration with POCl3.

[0067] Scheme 2. 20ME151606866v.1132266-01320

[0068] 4-Chloro-3-cyano-pyridoindoles like S19 may also be prepared via a eight-step process beginning with intermediate S11. Treatmeant of S11 with sodium methoxide provides the methyl ether S12 which can be converted to intermediate S13 via a Suzuki coupling with a vinyl-boronate ester. Saponification of S13, followed by amide coupling of S14, provides the primary amide S15. S15 can be converted to the aldehyde intermediate S16 by oxidative cleavage with OsO4 and NaIO4. Treatment of S16 with POCl3 converts the primary amide to the nitrile and the methyl ether to the aryl chloride present in intermediate S17. Reductive amination of S17, followed by deprotection provides the target compound S19.

[0069] Scheme 3.

[0070] 4-Fluoro-3-cyano-pyridoindoles like S25 may be prepared via a five-step sequence, largely following the processes outlinedin schemes 1 and 2. 4-Chloro-3-cyano- 21ME151606866v.1132266-01320 pyridoindoles like S24 may be converted to the 4-fluoro-3-cyano-pyridoindole target compounds by treatment with cesium fluoride, tetramethylammonium chloride, and 18- crown-6.

[0071] Scheme 4.

[0072] 4-Chloro-3-cyano-pyrrolodipyridines like S37 can be prepared in an eleven-step sequence beginning with the 5-bromoazaindole S26. Nitration of S26 followed by reduction affords intermediate S28. Reaction of S28 with diethyl 2-(ethoxymethylene)malonate provides intermediate S29 which can be converted to the chloropyrrolodipyridine intermediate S30 with POCl3. Saponification of the ester followed by mixed anhydride formation and treatment with ammonia provides the primary amide intermediate S32. Dehydration of S32 with trifluoroacetic anhydride provides S33, which can be converted to intermediate S34 by alkylation with trifluoroethyltriflate. Suzuki coupling with a vinyl- boronate ester followed by oxidative cleavage provides intermediate S36. Intermediate S36 can be converted to target compounds like S37 via reductive amination.

[0073] Abbreviations: ACN = acetonitrile AcOH = acetic acid Boc2O = di-tert-butyl dicarbonate 22ME151606866v.1132266-01320 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-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine

[0074] Scheme 1, step 1. tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate:

[0075] To a solution of 5-bromo-1H-indole-3-carboxylic acid (24.0 g, 99.9 mmol, 1.0 equiv.) and DPPA (30.2 g, 109.9 mmol, 23.8 mL, 1.1 equiv.) in THF (500 mL) was added TEA (15.3 mL, 109.9 mmol, 1.1 equiv.). The mixture was stirred at RT for 16 hours. Then tert-butylalcohol (500 mL) was added to the reaction solution and the mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (150 mL) and H2O (150 mL). The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel 23ME151606866v.1132266-01320 column chromatography (4-15% ethyl acetate in petroleum ether) to afford the title compound (12.0 g, 39% yield) as a yellow solid.

[0076] Scheme 1, step 2. 5-bromo-1H-indol-3-amine:

[0077] To a mixture of tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (12.0 g, 38.5 mmol, 1.0 equiv.) in EtOAc (60.0 mL) was added HCl (9.64 mL, 1.0 equiv.; 4M in EtOAc) atat RT under an atmosphere of nitrogen. The mixture was stirred at RT for 6 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc to afford the title compound (8.14 g, 100% yield; hydrochloride salt) as a yellow solid.

[0078] LCMS [M+1, M+3] = 211.0, 212.9.

[0079] Scheme 1, step 3. diethyl 2-[[(5-bromo-1H-indol-3yl)amino]methylene] propanedioate:

[0080] To a mixture of 5-bromo-1H-indol-3-amine (8.14 g, 32.89 mmol, 1 equiv. HCl) in DMF (100.0 mL) was added diethyl 2-(ethoxymethylene)propanedioate (9.36 mL, 46.3 mmol, 1.46 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to RT and diluted with EtOAc and H2O. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (3-20% ethyl acetate in petroleum ether) to afford the title compound (9.6 g, 65% yield) as a yellow solid.

[0081] LCMS [M+1, M+3] = 381.1, 383.1.

[0082] Scheme 1, step 4. Ethyl 8-bromo-4-chloro-5H-pyrido[3,2-b]indole-3-carboxylate:

[0083] To a mixture of diethyl 2-[[(5-bromo-1H-indol-3-yl)amino]methylene]- propanedioate (19.0 g, 49.8 mmol, 1.0 equiv.) in dioxane (190 mL) was added POCl3 (69.4 mL, 747.6 mmol, 15.0 equiv.) in one portion at RT under an atmosphere of nitrogen. The reaction mixture was stirred at 90oC for 24 hours. The reaction mixture was cooled to RT and concentrated. The solid was washed with MTBE (10 mL) to afford the title compound (16.0 g, 87% yield; hydrochloride salt) as a brown solid.

[0084] LCMS [M+1, M+3] = 352.9, 354.9.

[0085] Scheme 1, step 5. Ethyl 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carboxylate:

[0086] To a solution of ethyl 8-bromo-4-chloro-5H-pyrido[3,2-b]indole-3-carboxylate hydrochloride (1.1 g, 2.8 mmol, 1.0 equiv.) in THF (5.0 mL) was added NaH (451 mg, 11.2 mmol, 4.0 equiv.; 60% dispersion in oil). The mixture was stirred at RT for 1 hour, and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (982 mg, 4.23 mmol, 1.5 equiv.) was added dropwise as a solution in THF (5.0 mL). The mixture was stirred at RT for 12 hours. The 24ME151606866v.1132266-01320 reaction mixture was quenched with a saturate aqueous solution of NH4Cl at RT, and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE at RT and filtered with vacuum to afford the title compound (0.7 g, 57% yield) as a brown solid.

[0087] LCMS [M+1, M+3] = 352.9, 354.9.

[0088] Scheme 1, step 6. Ethyl 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carboxylate:

[0089] A mixture of ethyl 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole- 3-carboxylate (1.0 g, 2.30 mmol, 1.0 equiv.), potassium ((dimethylamino)methyl)trifluoroborate (341 mg, 2.07 mmol, 0.9 equiv.), Cs2CO3 (2.24 g, 6.89 mmol, 3.0 equiv.), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (60 mg, 91.8 μmol, 0.04 equiv.) in H2O (2.0 mL) and 2-methylbutan-2-ol (10.0 mL) was degassed with nitrogen, and then the mixture was stirred at 80°C for 8 hours under an atmosphere of nitrogen. 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. The residue was purified by silica gel column chromatography (0-3% methanol in DCM) to afford the title compound (435 mg, 46% yield) as a yellow solid.

[0090] LCMS [M+1, M+3] = 414.1, 416.1.

[0091] Scheme 1, step 7. 4-Chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carboxylic acid:

[0092] To a solution of ethyl 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carboxylate (38.0 mg, 91.8 μmol, 1.0 equiv.) in THF (0.4 mL) and H2O (0.1 mL) was added LiOH·H2O (7.7 mg, 183.6 μmol, 2.0 equiv.). The mixture was stirred at RT for 2 hours. The reaction mixture was partitioned between EtOAc (15.0 mL) and H2O (15.0 mL). The aqueous phase was separated and lyophilized. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150mm x 40mm x 10µm; mobile phase: 1-35% acetonitrile in water (+NH4HCO3)) to afford the title compound (30.0 mg, 85% yield) as a white solid.

[0093] LCMS [M+1, M+3] = 386.3, 388.3.

[0094] 1H NMR (400 MHz, METHANOL-d4) δ 8.61 (s, 1H), 8.40 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 5.68 (q, J = 8.2 Hz, 2H), 4.53 (s, 2H), 2.92 (s, 6H)

[0095] Scheme 1, step 8. 4-Chloro-8-[(dimethylamino) methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carboxamide: 25ME151606866v.1132266-01320

[0096] To a solution of 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrido [3,2-b]indole-3-carboxylic acid (100.0 mg, 259.2 μmol, 1.0 equiv.) in DMF (1.0 mL) was added DIEA (226 μL, 1.3 mmol, 5.0 equiv.) and BOP (172 mg, 389 μmol, 1.5 equiv.) at RT and the mixture was stirred at RT for 10 minutes. Then NH3·H2O (100 μL, 777.6 μmol, 3.0 equiv.; 30% solution in water) was added to the mixture and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with EtOAc and water. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge C18150mm x 50mm x 10µm; mobile phase: 20-50% acetonitrile in water (+ 10mM NH4HCO3)) to afford the title compound (15.0 mg, 15% yield) as a white solid.

[0097] LCMS [M+1, M+3] = 385.1, 387.0.

[0098] Scheme 1, step 9. 4-Chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrido [3,2-b]indole-3-carbonitrile:

[0099] POCl3 (0.5 mL) was added to a flask containing 4-chloro-8- [(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrido[3,2-b] indole-3-carboxamide (10.0 mg, 25.9 μmol, 1.0 equiv.). The mixture was stirred at 100°C for 1 hour. The reaction mixture was diluted with EtOAc and water. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to afford the title compound (9.90 mg, 17% yield) as a white solid.

[0100] LCMS [M+1, M+3] = 367.1, 369.1.

[0101] NMR (400 MHz, CHLOROFORM-d) δ 8.78 (s, 1H), 8.32 (s, 1H), 7.97 - 7.81 (m, 1H), 7.63 - 7.51 (m, 1H), 5.51 - 5.29 (m, 2H), 3.85 - 3.65 (m, 2H), 2.55 - 2.28 (m, 6H). Example 2. 4-chloro-8-(piperazin-1-ylmethyl)-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carbonitrile

[0102] Scheme 2, step 1. Methyl 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carboxylate: 26ME151606866v.1132266-01320

[0103] A mixture of ethyl 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole- 3-carboxylate (3.0 g, 6.9 mmol, 1.0 equiv.) and NaOMe (1.9 g, 34.4 mmol, 5.0 equiv.) in MeOH (20.0 mL) was degassed with nitrogen and then the mixture was stirred at 80°C for 5 hours under an atmosphere of nitrogen. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was triturated with water (100 mL) at RT to afford the title compound (2.0 g, 70% yield) as a yellow solid.

[0104] LCMS: [M+1, M+3] = 417.0, 419.1.

[0105] Scheme 2, step 2. Methyl 4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrido[3,2- b] indole-3-carboxylate:

[0106] A mixture of methyl 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carboxylate (2.0 g, 4.8 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (886.0 mg, 5.8 mmol, 975.8 μL, 1.2 equiv.), Pd(PPh3)4 (443.2 mg, 383.5 μmol, 0.08 equiv.), and K2CO3(2.0 g, 14.4 mmol, 4.6 mL, 3.0 equiv.) in dioxane (12.0 mL) and H2O (3 mL) was degassed with nitrogen and then the mixture was stirred at 90°C for 5 hours under an atmosphere of nitrogen. The reaction mixture was cooled to RT and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-5% ethyl acetate in petroleum ether) to afford the title compound (1.4 g, 80% yield) as a yellow solid.

[0107] LCMS: [M+1] = 365.0.

[0108] Scheme 2, step 3. 4-Methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrido[3,2-b]indole- 3-carboxylic acid:

[0109] A mixture of methyl 4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrido[3,2- b]indole-3-carboxylate (1.4 g, 3.8 mmol, 1.0 equiv.), LiOH·H2O (161 mg, 3.8 mmol, 1.0 equiv.), in THF (10.0 mL), MeOH (2.0 mL) and H2O (3.0 mL) was degassed with nitrogen and then the mixture was stirred at 50°C for 16 hours. The mixture was concentrated to remove THF and MeOH, then the pH of the residue was adjusted to pH = 3-4 with HCl (1 M). The crude product was filtered and triturated with water to afford the title compound (1.4 g, 96% yield) as a white solid.

[0110] LCMS: [M+1] = 351.1.

[0111] Scheme 2, step 4. 4-Methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrido[3,2-b]indole- 3-carboxamide: 27ME151606866v.1132266-01320

[0112] A mixture of 4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrido[3,2-b]indole-3- carboxylic acid (1.4 g, 3.9 mmol, 1.0 equiv.), BOP (2.6 g, 5.8 mmol, 1.5 equiv.) and DIEA (1.5 g, 11.6 mmol, 2.0 mL, 3.0 equiv.) in DMF (14.0 mL) was degassed with nitrogen and the mixture was stirred at RT for 30 minutes. Then NH4Cl (412 mg, 7.7 mmol, 2.0 equiv.) was added to the mixture and the mixture was stirred at RT for 3 hours under an atmosphere of nitrogen. The reaction mixure was poured into water (100 mL) and stirred at RT for 20 minutes. The precipiatea was filtered off and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-5% methanol in DCM) to give product. It was combined with the filter cake product to afford the title compound (800 mg, 59% yield) as a white solid.

[0113] LCMS: [M+1] = 350.1.

[0114] Scheme 2, step 5. 8-formyl-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carboxamide:

[0115] A mixture of 4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrido[3,2-b]indole-3- carboxamide (800 mg, 2.3 mmol, 1.0 equiv.), NaIO4(2.0 g, 9.2 mmol, 4.0 equiv.), 2,6- dimethylpyridine (534 μL, 4.6 mmol, 2.0 equiv.) and K2OsO4.2H2O (16.9 mg, 45.8 μmol, 0.02 equiv.) in dioxane (1.5 mL) and H2O (0.75 mL) was degassed with nitrogen and then the mixture was stirred at RT for 16 hours. The reation was diluted with water (50 mL) and ethyl acetate (50 mL). The mixture was stirred at RT for 30 minutes and the precipitate was filtered and dried to afford the title compound (500 mg, 75% yield) as a yellow solid.

[0116] LCMS: [M+1] = 352.0.

[0117] Scheme 2, step 6. 4-Chloro-8-formyl-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole- 3-carbonitrile:

[0118] A mixture of 8-formyl-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carboxamide (500 mg, 1.4 mmol, 1.0 equiv.), in dichlorophosphoryloxybenzene (15.0 mL) was degassed with nitrogen and the mixture was stirred at 110°C for 3 hours. The reaction mixture was cooled to RT and then poured into a saturated aqueous solution of NaHCO3(800 ml). The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc at RT to afford the title compound (170 mg, 59% yield) as a yellow solid.

[0119] LCMS: [M+1, M+3] = 338.0, 340.0. 28ME151606866v.1132266-01320

[0120] Scheme 2, step 7. tert-Butyl 4- chloro-3-cyano-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indol-8-yl]methyl]piperazine-1-carboxylate:

[0121] A mixture of 4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carbonitrile (50.0 mg, 148.1 μmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (55.2 mg, 296.1 μmol, 2.0 equiv.) in AcOH (0.03 mL) and methanol (3.0 mL) was degassed with nitrogen. The mixture was stirred at RT for 16 hours. NaBH3CN (19 mg, 296 μmol, 2.0 equiv.) was added and the mixture was stirred for an additional 16 hours at RT. The reaction mixture was poured into water (20 mL). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, ethyl acetate) to afford the title compound (20 mg, 27% yield) as a white solid.

[0122] LCMS: [M+1, M+3] = 508.2, 510.2.

[0123] Scheme 2, step 8. 4-chloro-8-(piperazin-1-ylmethyl)-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile:

[0124] HCl (1.0 mL; 4M in dioxane) was added to a flask containing tert-butyl 4-[[4- chloro-3-cyano-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indol-8-yl]methyl]piperazine-1- carboxylate (20.0 mg, 39.4 μmol, 1.0 equiv.). The mixture was stirred at RT for 5 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (10.0 mg, 56% yield, hydrochloride salt) as a white solid.

[0125] LCMS: [M+1, M+3] = 407.9, 409.9.

[0126] 1H NMR (400 MHz, DMSO-d6) δ 9.72 (br s, 1H), 9.02 (s, 1H), 8.62 (br s, 1H), 8.14 - 8.10 (m, 2H), 5.82 (q, J = 8.8 Hz, 2H), 4.70 - 4.45 (m, 2H), 3.70 - 3.50 (m, 4H), 3.40 - 3.10 (m, 4H). Example 3. 4-chloro-8-(3,6-diazabicyclo[3.1.1]heptan-3-ylmethyl)-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile

[0127] Scheme 2, step 7. tert-Butyl 3- chloro-3-cyano-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indol-8-yl]methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate:

[0128] To a solution of 4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carbonitrile (50.0 mg, 148.0 μmol, 1.0 equiv) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane- 29ME151606866v.1132266-01320 6-carboxylate (58.7 mg, 296.1 μmol, 2.0 equiv) in DMF (0.5 mL) was added TMSCl (113 μL, 888 μmol, 6.0 equiv) in one portion at RT under an atmosphere of nitrogen. The mixture was stirred at RT for 30 minutes. NaBH(OAc)3(94.1 mg, 444.2 μmol, 3.0 equiv) was then added and the reaction mixture was stirred at RT for 2 hours. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, ethyl acetate) to afford the title compound (30.0 mg, 39% yield) as a colorless oil.

[0129] LCMS [M+1, M+3] = 520.2, 522.2.

[0130] Scheme 2, step 8. 4-Chloro-8-(3,6-diazabicyclo[3.1.1]heptan-3-ylmethyl)-5- (2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile:

[0131] To a solution of tert-butyl 3-[[4-chloro-3-cyano-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indol-8-yl]methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (30.0 mg, 57.7 μmol, 1.0 equiv) in CF3CH2OH (0.9 mL) was dropwise add TMSCl (0.15 mL) at 0°C over a period of 5 minutes under an atmosphere of nitrogen and the reaction mixture was stirred at RT for 1 hour. The reaction was concentrated under reduced pressure and the residue was lyophilized to afford the title compound (17.4 mg, 69% yield) as a white solid.

[0132] LCMS [M+1, M+3] = 420.3, 422.3.

[0133] 1H NMR (400 MHz, DMSO-d6) δ 9.51 - 9.21 (m, 1H), 9.01 (s, 1H), 8.76 - 8.53 (m, 1H), 8.31 - 7.99 (m, 2H), 5.82 (q, J = 8.6 Hz, 2H), 4.95 - 4.65 (m, 1H), 4.33 (br s, 2H), 4.24 - 3.98 (m, 2H), 3.81 - 3.58 (m, 1H), 3.29 - 2.96 (m, 1H), 2.93 - 2.75 (m, 1H), 2.65 - 2.56 (m, 1H), 2.04 - 1.95 (m, 1H). Example 4. 4-chloro-8-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile

[0134] Scheme 2, step 7. tert-Butyl 3- chloro-3-cyano-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indol-8-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:

[0135] A mixture of 4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carbonitrile (50.0 mg, 148.1 μmol, 1.0 equiv.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (62.9 mg, 296.1 μmol, 2.0 equiv.), TMSCl (112.7 μL, 888 μmol, 6.0 equiv.) and 30ME151606866v.1132266-01320 in DMF (0.5 mL) was degassed with nitrogen, and then the mixture was stirred at RT for 30 minutes. Then NaBH(OAc)3 (94.1 mg, 444.2 μmol, 3.0 equiv.) was added and the reaction mixture was stirred at RT for 5 hours. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (55 mg, 65% yield) as a white solid.

[0136] LCMS [M+1, M+3] = 534.3, 536.3.

[0137] Scheme 2, step 8. 4-chloro-8-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile:

[0138] To a solution of TMSCl (0.05 mL) and CF3CH2OH (0.45 mL) was added a solution of tert-butyl 3-[[4-chloro-3-cyano-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indol-8- yl]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 93.6 μmol, 1.0 equiv.) in CF3CH2OH (0.5 mL) dropwise at 0°C under an atmosphere of nitrogen. The mixture was stirred at RT for 30 minutes. The mixture was concentrated in vacuum. Then water (5.0 mL) was added to the residue and lyophilization of this mixture afforded the title compound (40 mg, 89% yield) as a white solid.

[0139] LCMS [M+1, M+3] = 434.0, 435.9.

[0140] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.85 (br s, 1H), 8.25 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 5.78 (q, J = 8.8 Hz, 2H), 3.93 (br s, 2H), 3.76 (s, 2H), 2.73 (br d, J = 11.2 Hz, 2H), 2.55 (br s, 2H), 2.05 - 1.85 (m, 4H). Example 5. 4-Chloro-8-[(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile

[0141] Scheme 2, step 8. 4-Chloro-8-[(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl]- 5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile:

[0142] To a mixture of 4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carbonitrile (100 mg, 296.1 μmol, 1.0 equiv.) and 2-methyl-2,7-diazaspiro[3.5]nonane hydrochloride (104.6 mg, 592.3 μmol, 2.0 equiv.) in DCE (1.0 mL) was added TEA (165 μL, 1.2 mmol, 4.0 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at RT for 30 minutes, then NaBH(OAc)3 (125.5 mg, 592.3 μmol, 2.0 equiv.) was added to the 31ME151606866v.1132266-01320 mixture and the resulting mixture was stirred at RT for 2 hours. The reaction mixture was concentrated in vacuum. The residue was purified by preparative TLC (SiO2, 10:1 DCM: MeOH + 1% NH3·H2O). The residue was re-purified by preparative TLC (SiO2, 3:1:1 petroleum ether: ethyl acetate: ethanol + 3% NH3·H2O) to afford the title compound (40.0 mg, 29% yield) as a white solid.

[0143] LCMS [M+1, M+3] = 462.2, 464.1.

[0144] 1H NMR (400 MHz, METHANOL-d4) δ 8.88 (s, 1H), 8.54 (s, 1H), 8.02 - 7.92 (m, 2H), 5.71 (q, J = 8.4 Hz, 2H), 4.51 (br s, 2H), 4.40 - 3.96 (m, 4H), 3.51 - 3.35 (m, 2H), 3.28 - 3.10 (m, 2H), 2.97 (s, 3H), 2.45 - 2.05 (m, 4H). Example 6. 4-fluoro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carbonitrile

[0145] Scheme 3, step 1. 8-Bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carboxylic acid:

[0146] A mixture of ethyl 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole- 3-carboxylate (120 mg, 275.5 μmol, 1.0 equiv.), NaOMe (248.0 mg, 1.4 mmol, 5.0 equiv.; 30% solution in MeOH) in MeOH (2.0 mL) was degassed with nitrogen, and then the mixture was stirred at 80°C for 5 hours under an atmosphere of nitrogen. H2O (0.1 mL) was added and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to RT and concentrated under reduced pressure. Then water (5 mL) was added to the residue and the pH of the mixture was adjusted to pH = 4-5 with an aqueous solution of HCl (1 M). The resulting precipitate was filtered off to afford the title compound (110 mg, 99% yield) as a yellow solid.

[0147] LCMS: [M+1, M+3] = 403.0, 404.9.

[0148] Scheme 3, step 2. 8-Bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2- b]indole-3-carboxamide:

[0149] A mixture of 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carboxylic acid (2.3 g, 5.7 mmol, 1.0 equiv.), BOP (2.8 g, 6.3 mmol, 1.1 equiv.), DIEA (2.0 mL, 11.5 mmol, 2.0 equiv.) in DMF (23.0 mL) was degassed with nitrogen, and then the mixture was stirred at RT for 2 hours. NH4Cl (613.0 mg, 11.5 mmol, 2.0 eq) was added and 32ME151606866v.1132266-01320 the mixture was stirred at RT for 2 hours. The reaction mixture was poured into water and stirred for 5 min. The resulting precipitate was triturated and the solid was filtered to afford the title compound (2.0 g, 87% yield) as a yellow solid.

[0150] LCMS: [M+1, M+3] = 402.3, 404.3.

[0151] Scheme 3, step 3. 8-Bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole- 3-carbonitrile:

[0152] A mixture of 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carboxamide (2.0 g, 5.0 mmol, 1.0 eq), in dichlorophosphoryloxybenzene (2.0 mL) was degassed with nitrogen, and then the mixture was stirred at 110°C for 3 hours. The mixture was poured into a saturated aqueous solution of NaHCO3(200 mL) and ethyl acetate (100 mL) and stirred for 5 minutes. The organic phase was separated and NaHCO3 (100 mL) was added to the organic phase then stirred at 20°C for 5 minutes. This procedure was repeated several times until the pH of the solution was greater than 7. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MeCN (50 mL) at RT. The precipitate was filtered off and purified by preparative HPLC (column: Phenomenex luna C18 (250mm x 70mm x 15 µm); mobile phase: 70-100% acetonitrile in water (+0.2% formic acid)) to give crude product. The crude product was triturated with MeCN (5 mL) at RT and filtered to afford the titl compound (1.6 g, 41% yield) as a brown solid.

[0153] Scheme 3, step 4. 4-Chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile:

[0154] A mixture of 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrido[3,2-b]indole-3- carbonitrile (500 mg, 1.3 mmol, 1.0 equiv.), potassium 1-methyl-4-((trifluoro-l4- boraneyl)methyl)piperazine (850 mg, 3.9 mmol, 3.0 equiv.) , Cs2CO3 (1.3 g, 3.9 mmol, 3.0 equiv.), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (25.2 mg, 38.6 μmol, 0.03 equiv.) in 2-methylbutan-2-ol (15.0 mL) and H2O (1.5 mL) was degassed with nitrogren and then the mixture was stirred at 65°C for 16 hours under an atmosphere of nitrogen. The reaction mixture was cooled to RT and water (20 mL) and ethyl acetate (50 mL) were added. The mixture was stirred for 5 minutes and then filtered. The precipitate was the starting material. HCl (1 M, 80 mL) was added to the filtrate and the mixture was stirred for 15 minutes. Na2CO3 was added until the pH of the mixture was pH = 7. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 DCM: MeOH + 0.3% NH3·H2O) to afford the title compound (200 mg, 37% yield) as a white solid. 33ME151606866v.1132266-01320

[0155] LCMS: [M+1, M+3] = 422.2, 424.2.

[0156] Scheme 3, step 5. 4-Fluoro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile:

[0157] To a mixture of 4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrido[3,2-b]indole-3-carbonitrile (50.0 mg, 118.5 μmol, 1.0 equv.) in MeCN (1.0 mL) was added 1,4,7,10,13,16-hexaoxacyclooctadecane (3.1 mg, 11.8 μmol, 0.1 equiv.), cesium fluoride (54.0 mg, 355.6 μmol, 13.1 μL, 3 eq), and tetramethylammonium chloride (1.3 mg, 11.8 μmol, 0.1 eq) at RT under an atmosphere of nitrogen. The mixture was stirred at 60°C for 1.5 hours. The reaction mixture was poured into water (10 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (10 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 C18150mm x 50mm x 10µm; mobile phase: 30-60% acetonitrile in water (+ 10mM NH4HCO3)) to afford the title compound (25.0 mg, 26% yield) as a white solid.

[0158] LCMS: [M+1] = 406.1.

[0159] 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 0.4 Hz 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 1.6, 8.8 Hz, 1H), 5.53 (q, J = 9.2 Hz, 2H), 3.66 (s, 2H), 2.50 - 2.30 (m, 8H), 2.14 (s, 3H). Example 7. 4-Chloro-8-((2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3-carbonitrile

[0160] Scheme 4, step 1. 5-Bromo-3-nitro-1H-pyrrolo[2,3-c]pyridine:

[0161] To a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (5.0 g, 25.3 mmol, 1.0 equiv.) in H2SO4 (25 mL) was added HNO3 (1.6 g, 25.3 mmol, 1.1 mL, 1.0 equiv.) at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was poured into H2O (10 mL) and the pH was adjusted to greated than 7 with powdered NaOH. The resulting precipitate was filtered and dried under reduced pressure to afford the title compound (6.0 g, 98% yield) as a yellow solid.

[0162] LCMS [M+1, M+3] = 242.0, 244.0.

[0163] Scheme 4, step 2. 5-Bromo-1H-pyrrolo[2,3-c]pyridin-3-amine: 34ME151606866v.1132266-01320

[0164] To a solution of 5-bromo-3-nitro-1H-pyrrolo[2,3-c]pyridine (6.0 g, 24.7 mmol, 1.0 equiv.) in THF (100 mL) and H2O (10 mL) was added iron (0) (6.9 g, 123.9 mmol, 5.0 equiv.) and NH4Cl (9.28 g, 173.5 mmol, 7.0 equiv.) at RT. The mixture was stirred at 50°C for 12 hours. The mixture filtered and filtrate was concentrated under reduced pressure to afford the title compound (3.6 g, 68% yield) as a yellow solid.

[0165] LCMS [M+1, M+3] = 212.1, 214.1.

[0166] Scheme 4, step 3. Diethyl 2-[[(5-bromo-1H-pyrrolo[2,3-c]pyridin-3- yl)amino]methylene]propanedioate:

[0167] A solution of 5-bromo-1H-pyrrolo[2,3-c]pyridin-3-amine (3.60 g, 16.9 mmol, 1.0 equiv.) and diethyl 2-(ethoxymethylene)propanedioate (3.60 g, 16.9 mmol, 3.43 mL, 1.0 equiv.) in toluene (40 mL) was stirred at 130°C for 2 hours. The reaction mixture was filtered to give a filter cake, and the cake was washed with THF (10.0 mL) to afford the title compound (5.0 g, 77% yield) as a yellow solid.

[0168] LCMS [M+1, M+3] = 356.0, 358.0.

[0169] Scheme 4, step 4. Ethyl 8-bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carboxylate:

[0170] POCl3(30.0 mL) was added to a flask containing diethyl 2-(((5-bromo-1H- pyrrolo[2,3-c]pyridin-3-yl)amino)methylene)malonate (5.0 g, 13.0 mmol, 1.0 equiv.) and the mixture was stirred at 130°C for 48 hours. The reaction was cooled to RT and then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-40% THF in petroleum ether) to afford the title compound (4.0 g, 86% yield) as a yellow solid.

[0171] LCMS [M+1, M+3] = 354.0, 356.0.

[0172] Scheme 4, step 5. 8-Bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carboxylic acid:

[0173] To a solution of ethyl 8-bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carboxylate (4.0 g, 11.2 mmol, 1.0 equiv.) in THF (32.0 mL) and H2O (8.0 mL) was added NaOH (1.3 g, 33.8 mmol, 3.0 equiv.). The mixture was stirred at 50°C for 12 hours. The reaction was diluted with H2O (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (3.0 g, 57.0% yield; 70% purity) as a yellow oil. This material was used in the next step without further purification.

[0174] LCMS [M+1, M+3] = 326.1, 328.1. 35ME151606866v.1132266-01320

[0175] Scheme 4, step 6. 8-Bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carboxamide:

[0176] To a 0°C solution of 8-bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carboxylic acid (2.00 g, 6.1 mmol, 1.0 equiv.) in THF (30.0 mL) was added TEA (2.5 mL, 18.3 mmol, 3.0 equiv.). Isobutyl chloroformate (1.6 mL, 12.2 mmol, 2.0 equiv.) was then slowly added to the mixture at 0°C and then the mixture was allowed to warm to RT and stirred for 12 hours. Then NH3(10.0 mL; 0.4 M in THF) was added and the mixture was stirred at RT for 2 hours. The reaction was diluted with H2O (5.0 mL) and extracted with ethyl acetate (3 x 5.0 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 9-100% ethyl acetate in petroleum ether) to afford the title compound (1.0 g, 50% yield) as a yellow solid.

[0177] LCMS [M+1, M+3] = 325.0, 327.0.

[0178] Scheme 4, step 7. 8-Bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carbonitrile:

[0179] To a solution of 8-bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carboxamide (500.0 mg, 1.54 mmol, 1.0 equiv.) in DCM (5.0 mL) was added TEA (214 μL, 1.54 mmol, 1.0 equiv.) at 0°C. Then trifluoroacetic anhydride (213 μL, 1.54 mmol, 1.0 equiv.) was added slowly and the mixture was warmed to RT and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate in petroleum ether) to afford the title compound (300.0 mg, 64% yield) as a white solid.

[0180] LCMS [M+1, M+3] = 307.0, 309.0 .

[0181] Scheme 4, step 8. 8-Bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,2- b:5,4-c']dipyridine-3-carbonitrile:

[0182] To a solution of 8-bromo-4-chloro-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3- carbonitrile (300.0 mg, 975.5 μmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (339.6 mg, 1.46 mmol, 1.5 equiv.) in DMF (3.0 mL) was added K2CO3 (269.6 mg, 1.95 mmol, 2.0 equiv.) and then the mixture was stirred at RT for 2 hours. H2O (2.0 ml) was added to the reaction mixture and a precipitate formed. The precipitate was filtered off and dried under reduced pressure to afford the title compound (250.0 mg, 66% yield) as a yellow solid.

[0183] LCMS [M+1, M+3] = 388.9, 390.9. 36ME151606866v.1132266-01320

[0184] Scheme 4, step 9. 4-Chloro-5-(2,2,2-trifluoroethyl)-8-vinyl-5H-pyrrolo[3,2-b:5,4- c']dipyridine-3-carbonitrile:

[0185] To a solution of 8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,2-b:5,4- c']dipyridine-3-carbonitrile (250.0 mg, 641.7 μmol, 1.0 equiv.) in H2O (1.0 mL) and THF (4.0 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (98.8 mg, 641.7 μmol, 1.0 equiv.), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (41.8 mg, 64.1 μmol, 0.1 equiv.) and K3PO4(272 mg, 1.28 mmol, 2.0 equiv.) under an atmosphere of nitrogen. Then the mixture was stirred at 50°C for 12 hours. The reaction was cooled to RT, diluted with H2O (5.0 mL), and extracted with ethyl acetate (3 x 5.0 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 (10-100% THF in petroleum ether) to afford the title compound (170.0 mg, 79% yield) as a yellow solid.

[0186] LCMS [M+1, M+3] = 336.9, 338.9.

[0187] Scheme 4, step 10. 4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,2- b:5,4-c']dipyridine-3-carbonitrile:

[0188] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)-8-vinyl-5H-pyrrolo[3,2-b:5,4- c']dipyridine-3-carbonitrile (200.0 mg, 594.0 μmol, 1.0 equiv.) in dioxane (5.0 mL) and H2O (1.0 mL) was added K2OsO4·H2O (10.9 mg, 29.7 μmol, 0.05 equiv.), NaIO4 (1.02 g, 4.75 mmol, 8.0 equiv.) and 2,6-dimethylpyridine (277 μL, 2.38 mmol, 4.0 equiv.) and the mixture was stirred at RT for 2 hours. The reaction mixture was poured into water (2.0 mL) and the aqueous phase was extracted with ethyl acetate (2 x 2.0 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 (10-100% ethyl acetate in petroleum ether) to afford the title compound (170.0 mg, 85% yield) as a white solid.

[0189] LCMS [M+1, M+3] = 339.0, 341.1.

[0190] Scheme 4, step 11. 4-chloro-8-((2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl)- 5-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine-3-carbonitrile:

[0191] To a solution of 4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,2-b:5,4- c']dipyridine-3-carbonitrile (70.0 mg, 206.6 μmol, 1.0 equiv.) in THF (0.5 mL) was added 2- methyl-2,7-diazaspiro[3.5]nonane (43.4 mg, 310.0 μmol, 1.5 equiv.) and titanium (IV) isopropoxide (305 μL, 1.03 mmol, 5.0 equiv.) at RT. Then the mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to RT and then NaBH(OAc)3 (131 mg, 620.0 μmol, 37ME151606866v.1132266-01320 3.0 equiv.) was added and the mixture was stirred at RT for 1 hour. The reaction was quenched with MeOH (5.0 mL) and H2O (2.0 mL) and stirred at RT for 10 min. The reaction was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18100mm x 40 mm x 5 µm; mobile phase: 20-50% acetonitrile in water (+0.04% HCl)) to afford the title compound (36.0 mg, 38% yield; hydrochloride salt) as a white solid.

[0192] LCMS [M+1, M+3] = 463.2, 465.2.

[0193] 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.11 (s, 1H), 8.68 (s, 1H), 5.96 (q, J = 8.8 Hz, 2H), 4.61 (br s, 2H), 4.06 (s, 1H), 3.74 - 3.62 (m, 3H), 3.47 - 3.01 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 2.43 (br s, 1H), 2.20 (br s, 1H), 2.06 (br s, 2H).

[0194] 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 38ME151606866v.1132266-01320

[0195] 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.

[0196] 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). 39ME151606866v.1132266-01320

[0197] 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.

[0198] 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.

[0199] 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).

[0200] LCMS [M+1] = 425.1.

[0201] 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. 40ME151606866v.1132266-013201H 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).

[0202] LCMS [M+1] = 408.2.

[0203] 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.

[0204] 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). LCMS [M+1] = 378.3.

[0205] 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 41ME151606866v.1132266-01320 × 15 um); mobile phase: 40-75% ACN in water (+NH4HCO3 modifier)) to afford the title compound (480 mg, 26% yield) as a white solid.

[0206] 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).

[0207] LCMS [M+1] = 488.4.

[0208] 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.

[0209] 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.

[0210] 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 42ME151606866v.1132266-01320 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.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).

[0211] LCMS [M+1] = 812.3.

[0212] 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.

[0213] LCMS [M+1] = 712.4.

[0214] 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. 43ME151606866v.1132266-01320

[0215] 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

[0216] 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 5 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%.

[0217] 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. 44ME151606866v.1132266-01320 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 5. 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 C – A B – A 5 C – A B – A 6 B – A A – A 7 B – A A – A .

[0218] 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 45ME151606866v.1132266-01320 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.

[0219] 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. 46ME151606866v.1

Claims

132266-01320 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; Y is -CH- or N; X is selected from halo, -S(O)2alkyl, and –S(O)alkyl; 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 47ME151606866v.1132266-01320 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 X is selected from chloro, bromo, fluoro, -SO2(C1-C3)alkyl, and -SO(C1-C3)alkyl.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, -SO2CH3, and -SOCH3.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, and -SO2CH3.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is chloro.

6. The compound of any one of Claims 1 to 5, 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).

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl and halo(C1-C4)alkyl.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1is selected from -CH2CH3, -CH2CF3, -CH2CF2CH3, and -CH2CF2CF3.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is -CH2CF3.

10. The compound of any one of Claims 1 to 9, 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, - 48ME151606866v.1132266-01320 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, 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.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7- 49ME151606866v.1132266-01320 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.

12. The compound of any one of Claims 1 to 11, 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.

13. The compound of any one of Claims 1 to 10, 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.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each independently selected from (C1-C4)alkyl and halo(C1- C4)alkyl.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3,, , , , , , , 50ME151606866v.1132266-01320 ,16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, chloro, and -OCH2CF3.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

18. The compound of any one of Claims 1 to 17, 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- 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, -(C1-C4) - - (O)NR’1R’’1, - 1-C4)alkylC(O)R’1(C , -(C1-C4) - - alkylS(O)2R’1, 51ME151606866v.1132266-01320 (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],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)alkylC(O)NR’1R’’1,- -S(O)2R’1; andand R’’1are each independently selected from hydrogen, (C1-C4)alkyl, (C3- C6)cycloalkyl, and 4- to 7-membered heterocyclyl.

19. The compound of any one of Claims 1 to 18, 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.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R3is 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.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, - 52ME151606866v.1132266-01320 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.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R5ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, - ’1’’1 ’1’’1 ’1’1.

23. The compound of any one of Claims 1 to 22, 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.

24. The compound of any one of Claims 1 to 23, 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.

25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Rc1is piperidinyl or pyridinyl, each optionally substituted with 1 to 3 groups selected from R6a.

27. The compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R6ais (C1-C4)alkyl.

28. The compound of any one of Claims 1 to 27, 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. 53ME151606866v.1132266-01320 29. The compound of any one of Claims 1 to 28, 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.

30. The compound of any one of Claims 1 to 29, 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.

31. The compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Rf1is 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R8a.

32. The compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Rf1is piperazinyl optionally substituted with 1 to 3 groups selected from R8a.

33. The compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R8ais (C1-C4)alkyl.

34. The compound of any one of Claims 1 to 33, 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.

35. The compound of any one of Claims 1 to 34, 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.

36. The compound of any one of Claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Rg1and Rh1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR’1, -(C1-C4)alkylNR’1R’’1, -(C1-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- 54ME151606866v.1132266-01320 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.

37. The compound of any one of Claims 1 to 36, 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.

38. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R7ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, (C1-C4)alkoxy, and cyano.

39. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R3is selected from –CH2NHCH3, –CH2N, - ,, , , , 55ME151606866v.1132266-01320 , , ,40. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

41. The compound of Claim 1 or 40, or a pharmaceutically acceptable salt thereof, wherein X is halo.

42. The compound of any one of Claims 1, 40, and 41, or a pharmaceutically acceptable salt thereof, wherein X is chloro or fluoro.

43. The compound of any one of Claims 1 and 40 to 42, or a pharmaceutically acceptable salt thereof, wherein R1is halo(C1-C3)alkyl.

44. The compound of any one of Claims 1 and 40 to 43, or a pharmaceutically acceptable salt thereof, wherein R1is CH2CF3.

45. The compound of any one of Claims 1 and 40 to 44, or a pharmaceutically acceptable salt thereof, wherein R3is optionally substituted alkyl. 56ME151606866v.1132266-01320 46. The compound of any one of Claims 1 and 40 to 45, 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.

47. The compound of any one of Claims 1 and 40 to 46, or a pharmaceutically acceptable salt thereof, wherein R3is -(C1-C4)bicyclicheterocylyl, -(C1-C4)monocyclicheterocylyl or - (C1-C4)alkylNRg1Rh1, wherein Rg1and Rh1are each independently selected from hydrogen and (C1-C4)alkyl.

48. The compound of any one of Claims 1 and 40 to 47, or a pharmaceutically acceptable salt thereof, wherein R3is selected from ,49. The compound of Claim 1, wherein the compound is selected from, 57ME151606866v.1132266-0132050. A compound according to any one of Claims 1 to 49, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

51. 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 the subject a therapeutically effective amount of a compound according to any one of Claims 1 to 49, or a pharmaceutically acceptable salt thereof, or the composition of Claim 50.

52. The method of Claim 51, wherein the condition is a cancer.

53. The method of Claim 51 or 52, wherein the condition is a cancer harboring a Y220C mutation.

54. The method of any one of Claims 51 to 53, wherein the cancer is a solid tumor or a heme malignancy. 58ME151606866v.1132266-01320 55. The method of any one of Claims 51 to 54, 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. 59ME151606866v.1

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