P53 modulators

Abstract

Described are p53 modulators represented by the structural formula I: and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated dysfunctional p53.

Description

136867-01020 P53 MODULATORS RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 632,063, filed April 10, 2024, and U.S. Provisional Application Serial No. 63 / 632,482, filed April 10, 2024. The entire teachings of the aforementioned application are incorporated herein by reference. BACKGROUND

[0002] The p53 protein is a tetrameric transcription factor that prevents mutation to the genome by regulating the expression of a subgroup of target genes. Activation of p53 initiates pathways involved in apoptosis, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence in order to avoid propagation of damaged cells.

[0003] Tumor suppressor protein p53 is also a transcription factor that plays an important role in human cancers. Tumor initiation and maintenance depend upon inactivation of p53 pathways, which otherwise would deter uncontrolled cell growth. Consequently, p53 is the most frequently mutated gene in human cancers. It was estimated that more than half of all human tumors have mutant p53. The majority of those tumors that harbor mutant p53 are found to express full-length p53 protein with a single residue missense mutation in the p53 DNA-binding core domain (DBD). However, structural mutations remote from the DBD are also common. The Y220C mutation, which occurs in approximately 1.5% all human cancers, is such a structurally destabilizing mutation at codon 220, resulting in structural instability and loss of DNA binding at body temperature due to loss of beneficial lipophilic contacts of the tyrosine-220 residue as seen in wt-p53. The p53 Y220C mutation is associated with many cancers, including breast cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer.

[0004] The frequency and aggressive nature of cancers exhibiting p53 malfunction coupled with the potential benefits of restoring wild type p53 function has driven a widespread effort to identify compounds that restore normal p53 expression and activity. Nonetheless, there is still a critical need in the art for the development of new small molecule reactivators targeting p53 mutants (e.g., Y220C mutant) with high specificity and activity as well as low toxicity. 1 ME152734335v.1136867-01020 SUMMARY

[0005] Provided herein are compounds having the formula I:and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5are as described herein. In one aspect, the described compounds of Formula I and pharmaceutically acceptable salts thereof modulate P53 e.g, by re-activating p53 Y220C mutant, and are useful in treating p53 Y220C mutant-dependent disorders or diseases (e.g, treating a cancer).

[0006] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the described compounds of Formula I, as well as methods for their preparation are also included.

[0007] In certain aspects, the compounds described herein exhibit enhanced potency due to the inclusion of a halo substitution (i.e., R4) on the azabicyclooctanyl. DETAILED DESCRIPTION

[0008] In a first aspect, provided is a compound having the formula I:or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl; R2is -CH2NHC(O)RA, 4- to 6-membered heterocyclyl, or 5- to 7-membered heteroaryl, wherein each of said 4- to 6-membered heterocyclyl, -CH2C(O)NRCRD, and 5- to 7-membered heteroaryl are optionally substituted with 1 to 3 groups selected from RA1; R3is halo(C1-C4)alkyl; R4is halo; 2 ME152734335v.1136867-01020 R5is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -C(O)RC, -C(O)ORD, and -C(O)NRCRD; RAis selected from (C3-C6)cycloalkyl, 4- to 9-membered heterocyclyl, and 5- to 10- membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from RB; each RA1is independently selected from hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; each RBis independently selected from hydroxy, hydroxy[halo(C1-C4)alkyl], (C1- C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, hydroxy[halo(C1-C4)alkyl], -ORE, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl[deuterated(C1- C4)alkoxy], (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, wherein said (C3- C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1- C4)alkoxy; RCand RDare each independently hydrogen or (C1-C4)alkyl; and REis hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, deuterated(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, or halo(C1- C4)alkyl. Alternatively, as part of a first aspect, R1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl; each RBis independently selected from hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, hydroxy[halo(C1-C4)alkyl], -ORE, -(C1- C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl[deuterated(C1-C4)alkoxy], (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and REis hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, or halo(C1-C4)alkyl. 3 ME152734335v.1136867-01020

[0009] In a second aspect, the compound of Formula I is of the Formula Ia:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0010] In a third aspect, R3in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is CH2CF3, wherein the variables are as described above for Formula I.

[0011] In a fourth aspect, R4in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the variables are as described above for Formula I or the third aspect.

[0012] In a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, -CH2C(O)NRCRD, and 4- to 6-membered heterocyclyl, wherein the remaining variables are as described above for Formula I or the third or fourth aspect. Alternatively, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, and 4- to 6-membered heterocyclyl, wherein the variables are as described above for Formula I or the third or fourth aspect. In another alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from hydrogen and (C1-C4)alkyl, wherein the variables are as described above for Formula I or the third or fourth aspect. In another alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the variables are as described above for Formula I or the third or fourth aspect. In another alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, wherein the variables are as described above for Formula I or the third or fourth aspect. In another alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is CH3or CH2CH3, wherein the variables are as described above for Formula I or the third or fourth aspect. In another 4 ME152734335v.1136867-01020 alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is CH3, wherein the variables are as described above for Formula I or the third or fourth aspect. In another alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, CH3, CH(CH3)2, (CH2)2OH, CD3, -CH2C(O)NHCH3, and . In another alternative, as part of a fifth aspect, R1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, CH3, CH(CH3)2, (CH2)2OH, CD3, and , wherein the variables are as described above for Formula I or the third or fourth aspect.

[0013] In a sixth aspect, RC, and RDin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, are hydrogen and CH3respectively, wherein the variables are as described above for Formula I or any one of the third to fifth aspects

[0014] In a seventh aspect, R5in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the variables are as described above for Formula I or any one of the third to sixth aspects.

[0015] In an eighth aspect, R2in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 groups selected from RA1, wherein the variables are as described above for Formula I or any one of the third to seventh aspects. Alternatively, as part of an eighth aspect, R2in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is pyrrolidinyl optionally substituted with one RA1, wherein the variables are as described above for Formula I or any one of the third to seventh aspects.

[0016] In a ninth aspect, RA1in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is hydroxy, wherein the variables are as described above for Formula I or any one of the third to eighth aspects.

[0017] In a tenth aspect, R2in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is -CH2NHC(O)RA, wherein the variables are as described above for Formula I or any one of the third to ninth aspects.

[0018] In an eleventh aspect, RAin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from (C3-C6)cycloalkyl, 4- to 9- membered heterocyclyl, and 5- to 7-membered heteroaryl, each of which is optionally 5 ME152734335v.1136867-01020 substituted with 1 to 3 groups selected from RB, wherein the variables are as described above for Formula I or any one of the third to seventh or tenth aspects. Alternatively, as part of an eleventh aspect, RAin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from cyclopropyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, 2,3- dihydropyrazolo[5,1-b]oxazolyl, 1,2,3-triazolyl, pyrazolyl, 5,6-dihydro-8H-imidazo[5,1- c][1,4]oxazinyl, isoxazolyl, and imidazolyl, each of which is optionally substituted with 1 to 3 groups selected from RB, wherein the variables are as described above for Formula I or any one of the third to seventh or tenth aspects. In another alternative, as part of an eleventh aspect, RAin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from cyclopropyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, 2,3- dihydropyrazolo[5,1-b]oxazolyl, pyrazolyl, and imidazolyl, each of which is optionally substituted with 1 to 3 groups selected from RB, wherein the variables are as described above for Formula I or any one of the third to seventh or tenth aspects. Alternatively, as part of an eleventh aspect, RAin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from structures represented by: 6 ME152734335v.1136867-01020wherein the variables are as described above for Formula I or any one of the third to seventh or tenth aspects. Alternatively, as part of an eleventh aspect, RAin the compound of 7 ME152734335v.1136867-01020 Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from structures represented by:wherein the variables are as described above for Formula I or any one of the third to seventh or tenth aspects.

[0019] In a twelfth aspect, each RBin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is independently selected from hydroxy, (C1- 8 ME152734335v.1136867-01020 C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, hydroxy[halo(C1-C4)alkyl], -ORE, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1- C4)alkyl[deuterated(C1-C4)alkoxy], and 4- to 6-membered heterocyclyl, wherein said (C3- C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1- C4)alkoxy; and REis selected from (C1-C4)alkyl, deuterated(C1-C4)alkoxy, -(C1-C4)alkyl(C1- C4)alkoxy, hydroxy(C1-C4)alkyl, deuterated(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the variables are as described above for Formula I or any one of the third to seventh, tenth or eleventh aspects. Alternatively, as part of a twelfth aspect, each RBin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, -ORE, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, and 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and REis selected from (C1-C4)alkyl, deuterated(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the variables are as described above for Formula I or any one of the third to seventh, tenth or eleventh aspects.

[0020] In a thirteenth aspect, REin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is CD3, CH3, CH2CH3, CH2CH2OMe or CH2C(CH3)2OH, wherein the variables are as described above for Formula I or any one of the third to seventh, or tenth to twelfth aspects.

[0021] In a fourteenth aspect, each RBin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is independently selected from OH, CH3, C(CH3)3, CH2CHF2, CH2CF3, CD3, CH2C(CH3)2OH, CH2CH2OH, CH2OH, fluoro, OCH3, OCD3, OCH2CH3, CH2CH2OMe, CH2CH2OCD3, OCH2CHF2, CH2CH(OH)(CF3), OCHF2, CH2CH(OH)(CHF2), cyclopropyl, (CH2)2OCH3, oxetanyl, and 1,1-dioxide thietanyl, wherein the variables are as described above for Formula I or any one of the third to seventh, or eleventh to thirteenth aspects. Alternatively, as part of a fourteenth aspect, each RBin the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, is independently selected from CH3, C(CH3)3, CH2CHF2, CH2CF3, CD3, CH2C(CH3)2OH, CH2OH, fluoro, OCH3, OCD3, OCH2CHF2, OCHF2, cyclopropyl, (CH2)2OCH3, oxetanyl, and 1,1-dioxide thietanyl, wherein the variables are as described above for Formula I or any one of the third to seventh, or eleventh to thirteenth aspects. 9 ME152734335v.1136867-01020

[0022] In a fifteenth aspect, the compound of Formula I is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein: R1is (C1-C3)alkyl; R2is -CH2NHC(O)RA; RAis pyrazolyl optionally substituted with 1 or 2 groups selected from RB; each RBis independently selected from (C1-C3)alkyl, deuterated(C1-C3)alkyl, -ORE, and hydroxy(C1-C4)alkyl; and REis (C1-C4)alkyl or deuterated(C1-C4)alkyl.

[0023] In a sixteenth aspect, the compound of Formula I or II of the Formula IIa:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula II.

[0024] In a seventeenth aspect, R1in the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, is CH3, wherein the remaining variables are as described above for Formula II.

[0025] In an eighteenth aspect, R2in the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, is selected from10 ME152734335v.1136867-01020, wherein the remaining variables are as described above for Formula II or the seventeenth aspect.

[0026] In a nineteenth aspect, each RBin the compound of Formula II or IIa, or a pharmaceutically acceptable salt thereof, is independently selected from CH3, CH2C(CH3)2OH, CD3, and OCD3, wherein the remaining variables are as described above for Formula II or the seventeenth or eighteenth aspects.

[0027] When used in connection to describe a chemical group that may be construed as possibility having multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -(C1-C4)alkyl(C1- C4)alkoxy mean that the point of attachment for this group occurs on the a carbon atom of the (C1-C4)alkyl group.

[0028] The number of carbon atoms in a group is specified herein by the prefix “Cx-C-xx”, wherein x and xx are integers. For example, "(C1-C4)alkyl" is an alkyl group which has from 1 to 4 carbon atoms.

[0029] "Alkyl", when used alone or part of a larger moiety, refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, an alkyl comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, or n-hexyl.

[0030] "Alkoxy" refers to OR, where oxygen is singularly bonded to R, and R is an alkyl group. Examples of alkoxy include methoxy, ethoxy, isopropoxy, and the like.

[0031] A “deuterated” alkyl or alkoxy group means that one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of deuterium atoms at all sites of enrichment with the number of hydrogen plus deuterium atoms at all of the sites of enrichment. For example, a compound with two deuterated methyl group has a 98.0% enrichment when 98.0% of the hydrogen atoms on the two methyl group have been replaced with deuterium.

[0032] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I). 11 ME152734335v.1136867-01020

[0033] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0034] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g, –OCHF2 or –OCF3.

[0035] “Cycloalkyl” refers to a completely saturated monocyclic or bicyclic hydrocarbon group. Unless otherwise specified, a cycloalkyl has 3-10 ring carbon atoms, alternatively 3-6 ring carbon atoms. A cycloalkyl can be monocyclic, fused bicyclic and bridged bicyclic. A monocyclic cycloalkyl has 3-6 ring carbon atoms (i.e, (C3-C6)cycloalkyl) and includes cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, cyclopentyl, cyclopheptyl and cyclooctyl.

[0036] "Heteroaryl" refers to an aromatic 5- to 10-membered mono or bicyclic cyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g, N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. As intended herein, a monocyclic heteroaryl, has 5 to 7 ring atoms, and includes e.g, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. A bicyclic heteroaryl has 8 to 10 ring atoms, i.e, is 8 to 10 membered. Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiofuranyl, quinolinyl, isoquinolinyl and the like.

[0037] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g, fused or bridged) ring system which has from 4- to 12-ring members, e.g, 4-10 ring members, at least one of which is a heteroatom, and up to 4 (e.g, 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N can be oxidized (e.g, N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Examples of 4-7 membered monocyclic heterocyclyls include, but are not limited to, oxetanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, 1,1-dioxide thietanyl, and dihydropyranyl. A fused bicyclic heterocyclyl has a 4-7 membered heterocyclyl which shares two adjacent ring atoms with a 4-7 membered heterocyclyl or a 3-7 membered cycloalkyl, i.e, a 4 to 7 membered 12 ME152734335v.1136867-01020 heterocyclyl fused to a 4 to 7 membered heterocyclyl or a 3 to 7 membered carbocyclyl. Examples include cyclopropylpyrrolidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, 2,3- dihydropyrazolo[5,1-b]oxazolyl, and the like. A “bridged bicyclic heterocyclyl” has 7-10 members and comprises a 5 to 7 membered heterocyclyl which shares three ring atoms with a 5 to 7 membered heterocyclyl or a 5 to 7 membered non-aromatic cycloalkyl. Examples of nitrogen containing bridged bicyclics include azabicyclo[2.2.1]hepantyl, azabicyclo[3.2.1]octanyl, azabicyclo [3.3.1]nonanyl, diazabicyclo[2.2.1]hepantyl, diazabicyclo[3.2.1]octanyl and diazabicyclo [3.3.1]nonanyl. Examples of oxygen containing bridged bicyclics include oxobicyclo[2.2.1]hepantyl, oxobicyclo[3.2.1]octanyl, oxobicyclo [3.3.1]nonanyl, oxa-azabicyclo[2.2.1]hepantyl, oxa-azabicyclo[3.2.1]octanyl and oxa- azabicyclo [3.3.1]nonanyl.

[0038] If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non- hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions.

[0039] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e, each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. 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 13 ME152734335v.1136867-01020 (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.

[0040] 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.

[0041] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g, as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0042] 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.

[0043] 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. 14 ME152734335v.1136867-01020

[0044] The described compounds include all tautomeric forms.

[0045] To the extent that a chemical name is not consistent with the drawn structure, the structure takes priority.

[0046] 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.

[0047] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0048] 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.

[0049] In cases where a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

[0050] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

[0051] Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic 15 ME152734335v.1136867-01020 bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocycloalkyl amines, diheterocycloalkyl amines, triheterocycloalkyl amines, or mixed di- and tri-amines where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines can include, isopropylamine, trimethyl amine, diethyl amine, tri(iso- propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethyl¬aminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like. Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.

[0052] In one aspect, the compounds described herein or pharmaceutically acceptable salts or compositions can be used for reactivating mutated p53. “Reactivating mutated p53” refers to increasing the ability of a mutated p53 protein to bind to DNA at physiologically relevant temperatures, where that mutated p53 protein has decreased ability to bind to DNA at physiologically relevant temperatures compared with wild type p53 protein. A subject in need of inhibition of p53 includes, for example, a subject with a cancer characterized by dysfunctional p53. A dysfunctional p53 includes, for example, p53 with an inactivating mutation and / or mutated p53 with decreased ability to bind to DNA at physiologically relevant temperatures compared with wild type p53 protein. Inactivating p53 mutations included Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or a combination thereof. Alternatively, the p53 mutation is V157F, R175H, 16 ME152734335v.1136867-01020 Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof. In another alternative, the p53 mutation is Y220C.

[0053] In one aspect, provided are methods of re-activating p53 Y220C mutant in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such. In another aspect, provided is an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for re-activating p53 Y220C mutant e.g, in a subject in need. In yet another aspect, provided is the use of an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for the manufacture of a medicament for re-activating p53 Y220C mutant e.g, in a subject in need.

[0054] Also provided are methods for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such. In another aspect, provided is an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for treating cancer e.g, in a subject in need. In yet another aspect, provided is the use of an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for the manufacture of a medicament for treating cancer e.g, in a subject in need.

[0055] In some aspects, the cancer is characterized by dysfunctional p53. In some aspects, the cancer is characterized by an inactivating p53 mutation. In some aspects, the p53 mutation is Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or a combination thereof. In some aspects, the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof. In some aspects, the p53 mutation is Y220C.

[0056] Cancers which can be treated with the described compounds or pharmaceutically acceptable salts thereof or pharmaceutically acceptable salts thereof or the described pharmaceutical compositions include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive 17 ME152734335v.1136867-01020 neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, prostate cancer, rectal cancer, renal cell carcinoma, skin cancers, skin carcinoma merkel cell, small intestine cancer or throat cancer.

[0057] In one aspect, the described compounds or pharmaceutically acceptable salts thereof or described pharmaceutical compositions can be part of a combination therapies with one or more other therapeutic agents.

[0058] In some aspects, one or more other therapeutic agents can be an immune checkpoint inhibitor. In some aspects, the checkpoint inhibitors include but are not limited to anti programed cell death receptor-1 (aPD-1) monoclonal antibodies such as pembrolizumab, nivolumab, cemiplimab, or anti programed cell death receptor-1 ligand (aPD-L1) monoclonal antibodies such as atezolizumab, dostarlimab, durvalumab and avelumab, or anti cytotoxic T lymphocyte-associated antigen (anti-CTLA4) monoclonal antibodies such as ipilimumab and tremelimumab, or anti lymphocyte activated gene-3 (LAG-3) monoclonal antibodies such as relatlimab.

[0059] In some aspects, the one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL).

[0060] In some aspects, the one or more other therapeutic agent is an inhibitor of interaction between p53 and MDM2. Said MDM2 inhibitors include but are not limited to navtemadlin (AMG-232, KRG 232, Amgen), idasanutlin (RG7388, Hoffman‐La Roche), milademetan (RAIN-32), MK-8242 (Merck), SAR405838, NVP-CGM097, RG7112, and DS- 3032b.

[0061] In some aspects, the one or more other therapeutic agent is an MDM2 targeted protein degrader such as MD-224. 18 ME152734335v.1136867-01020

[0062] In some aspects, the one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some aspects, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[0063] In some aspects, the one or more other therapeutic agent is a CDK inhibitor such as a CDK4 / CDK6 inhibitor. In some aspects, a CDK 4 / 6 inhibitor is selected from Palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, Gl Therapeutics). In some aspects, a CDK inhibitor is a CDK9 selective inhibitor selected from dinaciclib, AT-7519, P276-00, AZD- 4573, alvocidib / flavopiridol, CYC065, atuveciclib, BAY-1251152, voruciclib or GFH009.

[0064] In some aspects, the one or more other therapeutic agent is an inhibitor of antiapoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie / Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott). Other therapeutic agents targeting BCL family proteins via E3 ligase-mediated target protein degradation may be used in the present invention.

[0065] In some aspects, the one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.

[0066] In some aspects, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0067] In some aspects, the one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some aspects, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin- bound paclitaxel (ABRAXANE®; Abraxis / Celgene), cabazitaxel (JEVTANA®, Sanofi- Aventis), and SID530 (SK Chemicals, Co.). 19 ME152734335v.1136867-01020

[0068] In some aspects, the one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[0069] In some aspects, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacytidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate. (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EElSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidinebased nucleoside analog and thymidine phosphorylase inhibitor, LONSEIRF®, Taiho Oncology).

[0070] In some aspects, the one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some aspects, a PBK inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202(formerly RP5230, TG Therapeutics).

[0071] In some aspects, the one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech / Roche) an anti-VEGF monoclonal 20 ME152734335v.1136867-01020 antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv- aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech / Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis / Genentech / Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech / Roche / Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech / Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRErVICA®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (RYE)APT®, Novartis).

[0072] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP- 547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / T akeda).

[0073] In some aspects, the one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some aspects, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).

[0074] In some aspects, the one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib 21 ME152734335v.1136867-01020 (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).

[0075] In some aspects, the one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and Osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).

[0076] In some aspects, the one or more other therapeutic agent is an aromatase inhibitor. In some aspects, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).

[0077] In some aspects, the one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).

[0078] In some aspects, the one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).

[0079] Pharmaceutical compositions are described that include one or more compounds provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some aspects, the described compounds or pharmaceutically acceptable salts thereof can be used in combination with other agents known to have beneficial activity targeting diseases or disorders listed above. For example, described compounds or pharmaceutically acceptable salts thereof can be administered alone or in combination with one or more anti-cancer or antiviral agent.

[0080] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described 22 ME152734335v.1136867-01020 herein are found in e.g, Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co, Easton, Pa. In one aspect, the route of administration for the described compounds, salts, and compositions is oral administration.

[0081] The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g, when administered in combination with an anti-cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed, 2003).

[0082] The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g, inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g, 0.1 mg to about 50 g per day).

[0083] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.

[0084] The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an aspect, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred aspects, the pharmaceutical composition is formulated for intravenous administration. 23 ME152734335v.1136867-01020

[0085] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with described compounds. EXEMPLIFICATION

[0086] The following examples are intended to be illustrative and are not meant in any way to be limiting.

[0087] Unless otherwise specified, abbreviations used herein will have the meaning as commonly used in the art, some of which are provided below: AcOH - acetic acid Aq. - Aqueous ACN – Acetonitrile br s – Broad singlet BuLi - n-Butyllithium °C – degree Celsius CBz – benzyloxycarbonyl CDCl3 – Deuterated chloroform CD3CN – Deuterated acetonitrile Cs2CO3– Cesium carbonate d – Doublet dd – Doublet of doublet δ – Delta 24 ME152734335v.1136867-01020 DCC - N,N′-Dicyclohexylcarbodiimide DCM – Dichloromethane DIPA – N,N-diisopropylamine DMF – N, N-Dimethylformamide DMSO–d6 – Deuterated dimethyl sulfoxide ESI – Electrospray ionization EtOH – ethanol Et3N - Triethylamine EA – Ethyl acetate FA – Formic acid19F NMR – Fluorine-19 nuclear magnetic resonance g – Gram GCMS – Gas chromatography-mass spectrometry h or hr – Hour1H – Proton1H NMR – Proton nuclear magnetic resonance H2O – Water HCl – Hydrochloric acid HCHO – Formaldehyde HPLC – High performance liquid chromatography Hz – Hertz J – Coupling constant LCMS – Liquid chromatography mass spectrometry M+– Molecular ion m – Multiplet MeCN - Acetonitrile MeOH – Methanol MeOD – deuterated methanol mg – Milligrams min – Minutes MHz – Mega Hertz (frequency) mL – Milliters mm – Millimeters 25 ME152734335v.1136867-01020 mmol – Millimoles MS – Mass spectroscopy MTBE - methyl tert-butyl ether NaBH3CN - Sodium cyanoborohydride NH2OH – Hydroxylamine NH4HCO3- Ammonium bicarbonate NaIO4- Sodium periodate Sat.NaHCO3 - Saturated sodium hydrogencarbonate Na2SO4 - Sodium sulfate Pd(PPh3)4- Tetrakis(triphenylphosphine)palladium(0) PE – Petroleum ether % – Percentage pH – potential of Hydrogen ppm – Parts per million q – Quartet Rt– Retention time rt – room temperature RuO2.H2O – Ruthenium oxide hydrate s – Singlet t – Triplet TBAF – Tetrabutylammonium fluoride THF – Tetrahydrofuran TLC – Thin layer chromatography Prep TLC – Preparative thin layer chromatography μL – Microliters μm – Millimeters μmol – Micromoles Xphos - dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane XPhos Pd G3 - (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino- 1,1′-biphenyl)]palladium(II) methanesulfonate 26 ME152734335v.1136867-01020

[0088] Intermediate 1. (2R,4S)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid

[0089] Step 1. Di-t-butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate

[0090] To a stirred solution of (2R,4S)-1-(t-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (50 g, 0.21 mol, 1 equiv)^in^dry THF (750 mL)^was added^t-butyl (E)-N, N'- diisopropylcarbamimidate (65 g, 0.32 mol, 1.5 equiv)^dropwise at^rt^under^nitrogen^atmosphere. The resulting mixture was stirred for 2.5^h^at 60^°C. Then additional^(E)-N,N'-diisopropylcarbamimidate (43.3 g, 0.21 mol, 1 equiv)^was added, The resulting mixture was stirred for 16^h^at 60^°C. The resulting mixture was allowed to cool down to rt. The resulting mixture was filtered, the filter cake was washed with^EA^(3 × 500^mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^MTBE in PE^(0% - 50%) to afford^di-t-butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (162 g, 65%)^as a solid. LCMS [M + H]+m / z: 288.20.

[0091] Step 2. Di-t-butyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate

[0092] To a stirred solution of di-t-butyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (90 g, 0.31 mol, 1 equiv) in dry DCM (900 mL) were added N1, N1, N8, N8- tetramethylnaphthalene-1,8-diamine (201.3 g, 0.93 mol, 3 equiv) and Me3OBF4 (92.8 g, 0.62 mol, 2 equiv) at rt under nitrogen atmosphere. The resulting mixture was stirred for 3 h at rt and then 64 mL MeOH was added. The resulting mixture was stirred for another 10 min, 5 L 0.5 M HCl (aq.) was added. The reaction mixture was filtered, the filter cake was washed with EA (500 mL). The resulting mixture was extracted with EA (3 × 2 L). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MTBE in PE^(0% - 50%) to afford di-t-butyl (2R,4S)-4- methoxypyrrolidine-1,2-dicarboxylate (80 g, 84%) as a solid. LCMS [M + H]+m / z: 302.10.

[0093] Step 3. Di-t-butyl (2R,4S)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate

[0094] To a stirred mixture of^di-t-butyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate (40 g, 0.13 mol, 1 equiv)^in^EA (800 mL) was added NaIO4(140.3 g, 0.65 mol, 5 equiv)^in^H2O (600 mL)^dropwise at 0^°C^under^nitrogen^atmosphere. Then^RuO2.H2O (3.9 g, 0.026 mol, 0.2 equiv)^was added. The resulting mixture was stirred for 24^h^at^rt^under^nitrogen^atmosphere. ~ 44% SM remained based on LCMS (200 nm). 27 ME152734335v.1136867-01020 Additional NaIO4 (28.1 g, 1 equiv.) and RuO2.H2O (0.8 g, 0.04 eq.) was added. The resulting reaction was stirred for another 24 h at rt. ~26% SM remained based on LCMS (200 nm). Additional NaIO4(56.1 g, 2 eq.) and RuO2.H2O (1.6 g, 0.08 eq.) was added, the resulting reaction was stirred for another 24 h at rt. ~ 5% SM remained based on LCMS (200 nm). The resulting mixture was extracted with EA (3 × 2 L). The combined organic layers were added IPA (320 mL) and then stirred for 30 min. The resulting mixture was washed with H2O (1.2 L). The combined organic layers were dried over Na2SO4and concentrated under reduce pressure. The residue (75 g crude) was purified by trituration with hexane (225 mL). This resulted in Di-t-butyl (2R,4S)-4-methoxy-5-oxopyrrolidine-1,2-dicarboxylate (58 g, 69%) as a solid. LCMS [2M + Na + H]+m / z:.653.40.

[0095] Step 4. (2R,4S)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid

[0096] To a stirred solution of di-t-butyl (2R,4S)-4-methoxy-5-oxopyrrolidine-1,2- dicarboxylate (23 g) in DCM (240 mL) was added TFA (60 mL) dropwise at 0 °C. The resulting mixture was stirred for 8 h at 30 °C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in 75 mL DCM and extracted with H2O (75 mL), the aqueous layer was washed with DCM (50 mL), then the aqueous layer was concentrated under vacuum. This resulted in (2R,4S)-4-methoxy-5-oxopyrrolidine-2-carboxylic acid (9.6 g, 82%) as a solid. LCMS [M + H]+m / z: 159.95.

[0097] Intermediate 2: 7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2- carbonitrile

[0098] Step 1. 7-bromo-2-iodobenzo[b]thiophene

[0099] To a stirred solution of DIPA (72.5 mL, 516.2 mmol) in THF (180 mL) was added n-BuLi (2.5 M in hexane, 206.5 mL, 516.2 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added solution of 7-bromo-1-benzothiophene (100 g, 28 ME152734335v.1136867-01020 469.3 mmol) in THF (360 mL) dropwise at -78 °C. The resulting mixture was stirred for 30 min at -78°C. To the above mixture was added solution of I2 (119.1 g, 469.3 mmol) in THF (210 mL) dropwise at -78 °C. The resulting mixture was stirred for 30 min at -78 °C. The reaction was quenched with an aq. solution of sodium sulfite (1.0 M, 100 mL) at -78 °C. The resulting mixture was extracted with CH2Cl2 (3 x 1000 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (1:10) to afford 7-bromo-2-iodobenzo[b]thiophene (90 g) as a solid. GCMS (M)+m / z: 337.9.

[0100] Step 2. 7-bromo-2-iodobenzo[b]thiophene-3-carbaldehyde

[0101] To a stirred solution of 7-bromo-2-iodobenzo[b]thiophene (90 g, 265.5 mmol) and dichloromethyl methyl ether (61.0 g, 531.0 mmol) in DCM (1.2 L) was added TiCl4 (44.4 mL, 398.2 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at rt. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (9:1) to afford 7-bromo-2- iodobenzo[b]thiophene-3-carbaldehyde (54 g) as a solid. GCMS (M)+m / z: 365.8.

[0102] Step 3. 7-bromo-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene

[0103] A solution of 7-bromo-2-iodobenzo[b]thiophene-3-carbaldehyde (54 g, 147.1 mmol) and 2,2-difluoro-2-(triphenylphosphaniumyl)acetate (104.8 g, 294.3 mmol, 2 in DMF (450 mL) was stirred for 30 min at 80 °C under nitrogen atmosphere. To the above mixture was added TBAF (1.0 M in THF, 295.0 mL, 295.0 mmol) and H2O (0.6 mL, 33.3 mmol) at 80 °C. The resulting mixture was stirred for 30 min at 80 °C. The resulting mixture was diluted with water (2000 mL). The resulting mixture was extracted with EA (3 x 2000 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 7-bromo-2-iodo-3-(2,2,2- trifluoroethyl)benzo[b]thiophene (33 g) as a solid. GCMS (M)+m / z: 419.9.

[0104] Step 4. 7-bromo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile

[0105] A mixture of 7-bromo-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene (500 mg, 1.19 mmol, Zn(CN)2 (139.4 mg, 1.2 mmol) and Pd(PPh3)4 (137.4 mg, 0.1 mmol) in DMF (5 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was 29 ME152734335v.1136867-01020 diluted with water (30 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 7- bromo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile (253 mg) as a solid. GCMS (M)+m / z: 319.0.

[0106] Step 5. T-butyl (1S,2R,3R,5R)-3-((2-cyano-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate

[0107] A mixture of 7-bromo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile (10 g, 31.2 mmol, 1 equiv.), t-butyl (1S,2R,3R,5R)-3-amino-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (8.4 g, 34.3mmol, 1.1 equiv.), XPhos (1.5 g, 3.1 mmol, 0.1 equiv.), XPhos Pd G3 (2.6 g, 3.1 mmol, 0.1 equiv.) and Cs2CO3(20.4 g, 62.5 mmol, 2 equiv.) in toluene (200 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. LCMS showed incompletion of the reaction. Then additional XPhos (0.74 g, 1.6 mmol, 0.05 equiv.) and XPhos Pd G3 (1.3 g, 1.6 mmol, 0.05 equiv.) was added to the reaction mixture. The resulting mixture was stirred at 100 °C for additional 8 h. The reaction mixture was filtered, the filter cake was washed with DCM (2 × 100 mL). The filtrate was concentrated under reduced pressure. Note: The reaction was conducted in 10 g×2 parallel batches and then purified together. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford t-butyl (1S,2R,3R,5R)-3- ((2-cyano-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (16.4 g, 54%) as a yellow solid. LCMS: [M + H]+m / z: 484.15.

[0108] Step 6. 7-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- (2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile

[0109] To a stirred solution of t-butyl (1S,2R,3R,5R)-3-((2-cyano-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate (16.4 g, 34 mmol, 1 equiv.) in DCM (160 mL) was added trifluoroacetic acid (40 mL) dropwise at 0 °C. The resulting mixture was stirred at rt for 1 h. The resulting mixture was concentrated under reduced pressure. The resulted in 7-(((1S,2S,3R,5R)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile 30 ME152734335v.1136867-01020 (21.8 g, crude TFA salt) as a yellow solid, which was used directly without further purification. LCMS: [M + H]+m / z: 384.05.

[0110] Step 7. 7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile

[0111] To a stirred solution of 7-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile (15 g TFA salt, ca. 23.29 mmol, 1 equiv.) in methanol (100 mL) was added Et3N (4 mL) dropwise at 0 °C. Then AcOH (1 mL) and HCHO (37 wt% in H2O, 1.88 g, 23.29 mmol, 1 equiv.) were added. The resulting mixture was stirred at rt for 30 min. To the above reaction mixture was added NaBH3CN (2.92 g, 41.67 mmol, 2 equiv.) in portions at 0 °C. The resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. Note: this batch was purified with another 6.8 g batch together. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0.1% TEA) (0%-10%) to afford 7- (((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-(2,2,2- trifluoroethyl)benzo[b]thiophene-2-carbonitrile (13 g, 97% yield over 2 steps) as a solid. LCMS: [M + H]+m / z: 398.10.

[0112] Step 8. (Z)-7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- yl)amino)-N'-hydroxy-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carboximidamide

[0113] To a stirred mixture of 7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carbonitrile (11.5 g, 28.8 mmol, 1 equiv.) in EtOH (150 mL) was added NH2OH (50 wt% in H2O, 15 mL) at 0 °C under air atmosphere. The resulting mixture was stirred at 50 °C for 1 h under air atmosphere. The resulting mixture was concentrated under vacuum to remove EtOH. Then 100 mL water was added to above mixture, the precipitated solids were collected by filtration and washed with water (3 × 20 mL). Note: this batch was purified with other two smaller scale batches (500 mg + 1 g) together. The collected solids were further purified by trituration with EtOH (50 mL). This resulted in (Z)-7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-N'-hydroxy-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2- carboximidamide (9.7 g, 68%) as a solid. LCMS: [M + H]+m / z: 431.20. 31 ME152734335v.1136867-01020

[0114] Intermediate 3:

[0115] Step 1. t-butyl (1S,2R,3R,5R)-2-fluoro-3-((2-((Z)-N'-hydroxycarbamimidoyl)- 3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate

[0116] A mixture of t-butyl (1S,2R,3R,5R)-3-[2-cyano-3-(2,2,2-trifluoroethyl)-1- benzothiophen-7-yl]amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (1.9 g, 3.9 mmol, 1.0 equiv) and NH2OH(50% in water) (1.9 mL) in EtOH (20 mL) was stirred at 50 °C for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated (2.0 g) as a solid.

[0117] Step 2. t-butyl (1S,2R,3R,5R)-2-fluoro-3-((2-(5-((3-methoxy-1-methyl-1H- pyrazole-4-carboxamido)methyl)-1,2,4-oxadiazol-3-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0118] To a stirred mixture of t-butyl (1S,2R,3R,5R)-2-fluoro-3-(2-[(Z)-N'- hydroxycarbamimidoyl]-3-(2,2,2-trifluoroethyl)-1-benzothiophen-7-yl-amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.348 mmol, 1 equiv) and methyl 2-[(3- methoxy-1-methylpyrazol-4-yl)formamido]acetate (134.6 mg, 0.59 mmol, 1.7 equiv) in toluene (15 mL) was added dicesium(1+) carbonate (340.6 mg, 1.04 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for additional 1 h. The reaction was monitored by LCMS. The resulting mixture was 32 ME152734335v.1136867-01020 filtered, the filter cake was washed with DCM (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the title compound (205 mg) as a solid.

[0119] Step 3. N-((3-(7-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-3- methoxy-1-methyl-1H-pyrazole-4-carboxamide

[0120] To a stirred solution of t-butyl (1S,2R,3R,5R)-2-fluoro-3-[2-(5-[(3-methoxy-1- methylpyrazol-4-yl)formamido]methyl}-1,2,4-oxadiazol-3-yl)-3-(2,2,2-trifluoroethyl)-1- benzothiophen-7-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (205 mg, 0.296 mmol, 1 equiv) in DCM (8 mL) was added TFA (2 mL) dropwise at 0 °C .The resulting mixture was stirred at room temperature for 1 h .The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 5% to 95% gradient in 30 min; detector, UV 254 nm. The title compound was isolated as a solid (150 mg).

[0121] Example 1-1

[0122] Step 1. N-((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan- 3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)-1,2,4-oxadiazol-5-yl)methyl)- 3-methoxy-1-methyl-1H-pyrazole-4-carboxamide

[0123] A mixture of (Z)-7-[(1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- yl]amino-N'-hydroxy-3-(2,2,2-trifluoroethyl)-1-benzothiophene-2-carboximidamide (1 g, 2.3 mmol, 1 equiv.), (3-methoxy-1-methyl-1H-pyrazole-4-carbonyl)glycine (990 mg, 4.6 mmol, 2 equiv.) and DCC (958.6 mg, 4.6 mmol, 2 equiv.) in 1,4-dioxane (10 mL) was stirred at 100 °C for 8 h. The resulting mixture was filtered, the filter cake was washed with DCM (2 × 10 mL). The filtrate was concentrated under reduced pressure. Note: The reaction was conducted in 1 g×5 parallel batches and then purified together. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0.1% TEA) (0%-10%) to afford 3.8 g crude product, which was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L 33 ME152734335v.1136867-01020 NH4HCO3), 5% to 95% gradient in 25 min; detector, UV 254 nm. The title compound was isolated (3.08 g, 43%) as a solid.

[0124] The compounds in the table below were synthesized as described in Example 1 from appropriate intermediates.34 ME152734335v.1136867-0102035 ME152734335v.1136867-01020

[0125] Example 2-236 ME152734335v.1136867-01020

[0126] Step 1. t-butyl ((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)-1,2,4- oxadiazol-5-yl)methyl)carbamate

[0127] A mixture of (Z)-7-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan- 3-yl)amino)-N'-hydroxy-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-2-carboximidamide (813.9 mg, 4.6 mmol, 2 equiv), (t-butoxycarbonyl)amino]acetic acid (813.9 mg, 4.6 mmol, 2 equiv) and N-(N-cyclohexylcarboximidoyl)cyclohexanamine (958.6 mg, 4.6 mmol, 2 equiv) in 1,4-dioxane (20 mL) was stirred at 100 °C for 1 h. The resulting mixture was allowed to cool, then filtered, the filter cake was washed with DCM (3 x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 5% to 95% gradient in 30 min; detector, UV 254 nm affording 630 mg of the title compound. LCMS: [M +H]+= 570.2.

[0128] Step 2. (1S,2R,3R,5R)-N-(2-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-3- amine

[0129] To a stirred solution of t-butyl N-[3-(7-[(1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl]amino-3-(2,2,2-trifluoroethyl)-1-benzothiophen-2-yl)-1,2,4- oxadiazol-5-yl]methylcarbamate (900 mg, 1.580 mmol, 1 equiv) in DCM (10 mL) was added trifluoroacetic acid (2.5 mL, 0.009 mmol, 0.05 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 5% to 95% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (630 mg) as a solid. LCMS: [M +H]+= 470.2

[0130] The compounds in the table below were synthesized as described in Example 2-2 from appropriate intermediates.37 ME152734335v.1136867-0102038 ME152734335v.1136867-0102039 ME152734335v.1136867-0102040 ME152734335v.1136867-0102041 ME152734335v.1136867-0102042 ME152734335v.1136867-0102043 ME152734335v.1136867-0102044 ME152734335v.1136867-0102045 ME152734335v.1136867-0102046 ME152734335v.1136867-0102047 ME152734335v.1136867-0102048 ME152734335v.1136867-0102049 ME152734335v.1136867-0102050 ME152734335v.1136867-0102051 ME152734335v.1136867-0102052 ME152734335v.1136867-0102053 ME152734335v.1136867-0102054 ME152734335v.1136867-01020

[0131] Example 3-155 ME152734335v.1136867-01020

[0132] Step 1. N-((3-(7-(((1S,2R,3R,5R)-2-fluoro-8-(2-hydroxyethyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide

[0133] To a stirred mixture of N-[3-(7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan- 3-yl]amino-3-(2,2,2-trifluoroethyl)-1-benzothiophen-2-yl)-1,2,4-oxadiazol-5-yl]methyl-3- methoxy-1-methylpyrazole-4-carboxamide (35 mg, 0.059 mmol, 1 equiv) and 2- bromoethanol (11.0 mg, 0.088 mmol, 1.5 equiv) in pyridine (2 mL) was added (3- [[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (16.95 mg, 0.088 mmol, 1.5 equiv) in portions at room temperature . The resulting mixture was stirred at 50°C for 16h.The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The title compound was isolated as a solid.

[0134] The compounds in the table below were synthesized as described in Example 3-1 from appropriate intermediates.56 ME152734335v.1136867-01020

[0135] Biological assays to measure the activities of p53-Y220C reactivators

[0136] Biochemical p53-Y220C and DNA binding assay.

[0137] The compounds described herein can bind to p53-Y220C and increase the ability of the mutant p53 to bind to DNA at higher temperatures. His-tagged p53-Y220C DNA binding domain containing amino acid 94-312 is used to measure DNA binding activities in vitro with the sequence described below. (SEQ ID NO: 1: MHHHHHHENLYFQGSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFC QLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPP QHLIRVEGNLRVEYLDDRNTFRHSVVVPCEPPEVGSDCTTIHYNYMCNSSCMGGMN RRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKR ALPNNT. Biotin labeled double strand DNA (dsDNA) containing consensus p53 binding sequence (SEQ ID NO: 2: Forward: 5’-(biotin)-ATTAGGCATGTCTAGGCATGTCTAGG- 3’; Reverse: 5’-(biotin)-CCTAGACATGCCTAGACATGCCTAAT-3’) is used to measure protein-DNA binding activities. Compounds, His-tagged p53-Y220C DBD proteins (100 nM), and biotinylated dsDNA (200 nM) were mixed in ice-cold assay buffer containing DPBS, 20 mM NaCl, and 0.5% BAS, and incubated at 4oC overnight in 384-well plate. Plates were transferred to incubator at 27 to 29oC with constant shaking for 60 minutes. Equal volume of Homogeneous Time-Resolved Fluorescence (HTRF) dyes containing mAb anti-6HIS Tb cryptate gold and d2 labeled streptavidin in the assay buffer was added to each well and incubated at 27 to 29oC with constant shaking for 60 minutes. The plate was read using Envision multimode plate reader. Reference compound 1 was used as high control and DMSO was used as low control. The percentage activation (A%) of protein-DNA binding by compounds was normalized by setting up high control (reference compound) as 500% and low control (DMSO) as 0% (A%=(HTRF ratio of compound -HTRF ratio of low control) / (HTRF ratio of high control – HTRF ratio of low control)*500). 10 points dose titration curves for each compound were analyzed by 4 parameter curve fit and inflection point (IP) was reported. Reference compound 1 is shown below Table 1.

[0138] Compounds described herein are active in the HTRF assay, the data for which is shown in Table 1. 57 ME152734335v.1136867-01020 Table 158 ME152734335v.1136867-01020Reference compound 1 (HTRF = A; IP < 100 nM)59 ME152734335v.1

Claims

136867-01020 CLAIMS Listing of Claims:

1. A compound having the formula I:or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, 4- to 6-membered heterocyclyl, - CH2C(O)NRCRDand 5- to 7- membered heteroaryl; R2is -CH2NHC(O)RA, 4- to 6-membered heterocyclyl, or 5- to 7-membered heteroaryl, wherein each of said 4- to 6-membered heterocyclyl and 5- to 7-membered heteroaryl are optionally substituted with 1 to 3 groups selected from RA1; R3is halo(C1-C4)alkyl; R4is halo; R5is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -C(O)RC, -C(O)ORD, and -C(O)NRCRD; RAis selected from (C3-C6)cycloalkyl, 4- to 9-membered heterocyclyl, and 5- to 10- membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from RB; each RA1is independently selected from hydroxyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; each RBis independently selected from hydroxy, hydroxy[halo(C1-C4)alkyl], (C1- C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, hydroxy[halo(C1-C4)alkyl], -ORE, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl[deuterated(C1- C4)alkoxy], (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, wherein said (C3- C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1- C4)alkoxy; RCand RDare each independently hydrogen or (C1-C4)alkyl; and 60 ME152734335v.1136867-01020 REis hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, deuterated(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, or halo(C1- C4)alkyl.

2. The compound of Claim 1, wherein R1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl; each RBis independently selected from hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, hydroxy[halo(C1-C4)alkyl], -ORE, -(C1- C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl[deuterated(C1-C4)alkoxy], (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and REis hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, or halo(C1-C4)alkyl.

3. The compound of Claim 1 or 2, wherein the compound is of the Formula Ia:or a pharmaceutically acceptable salt thereof.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3is CH2CF3.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R4is fluoro.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, -CH2C(O)NRCRDand 4- to 6-membered heterocyclyl. 61 ME152734335v.1136867-01020 7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein RCis hydrogen; and RDis CH3.

8. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen, (C1-C4)alkyl, deuterated(C1-C4)alkyl, hydroxy(C1-C4)alkyl, and 4- to 6-membered heterocyclyl.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen and (C1-C4)alkyl.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

11. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R1is (C1-C4)alkyl.

12. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein R1is CH3 or CH2CH3.

13. The compound of Claim 12, or a pharmaceutically acceptable salt thereof, wherein R1is CH3.

14. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen, CH3, CH(CH3)2, (CH2)2OH, CD3, -15. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1is selected from hydrogen, CH3, CH(CH3)2, (CH2)2OH, CD3, and. 62 ME152734335v.1136867-01020 16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 groups selected from RA1.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is pyrrolidinyl optionally substituted with one RA1.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein RA1is hydroxy.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R2is -CH2NHC(O)RA.

21. The compound of any one of Claims 1 to 16 and 20, or a pharmaceutically acceptable salt thereof, wherein RAis selected from (C3-C6)cycloalkyl, 4- to 9-membered heterocyclyl, and 5- to 7-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from RB.

22. The compound of any one of Claims 1 to 16 and 20, or a pharmaceutically acceptable salt thereof, wherein RAis selected from cyclopropyl, 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazinyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 1,2,3-triazolyl, pyrazolyl, 5,6-dihydro- 8H-imidazo[5,1-c][1,4]oxazinyl, isoxazolyl, and imidazolyl, each of which is optionally substituted with 1 to 3 groups selected from RB.

23. The compound of any one of Claims 1 to 16 and 20, or a pharmaceutically acceptable salt thereof, wherein RAis selected from cyclopropyl, 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazinyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, pyrazolyl, and imidazolyl, each of which is optionally substituted with 1 to 3 groups selected from RB. 63 ME152734335v.1136867-01020 24. The compound of any one of Claims 1 to 16, and 21 to 23, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1-C4)alkyl, halo, hydroxy(C1-C4)alkyl, hydroxy[halo(C1-C4)alkyl], -ORE, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl[deuterated(C1-C4)alkoxy], and 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and REis selected from (C1-C4)alkyl, deuterated(C1-C4)alkoxy, -(C1-C4)alkyl(C1- C4)alkoxy, hydroxy(C1-C4)alkyl, deuterated(C1-C4)alkyl, and halo(C1-C4)alkyl.

25. The compound of any one of Claims 1 to 16, and 21 to 23, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from C1-C4)alkyl, halo(C1-C4)alkyl, deuterated(C1- C4)alkyl, halo, hydroxy(C1-C4)alkyl, -ORE, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C1-C4)alkoxy, and 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 or 2 groups selected from cyano, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and REis selected from (C1-C4)alkyl, deuterated(C1-C4)alkyl, and halo(C1-C4)alkyl.

26. The compound of any one of Claims 1 to 16, and 21 to 25, or a pharmaceutically acceptable salt thereof, wherein REis CD3, CH3, CH2CH3, CH2CH2OMe or CH2C(CH3)2OH.

27. The compound of any one of Claims 1 to 16 and 21 to 26, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from OH, CH3, C(CH3)3, CH2CHF2, CH2CF3, CD3, CH2C(CH3)2OH, CH2CH2OH, CH2OH, fluoro, OCH3, OCD3, OCH2CH3, CH2CH2OMe, CH2CH2OCD3, OCH2CHF2, CH2CH(OH)(CF3), OCHF2, CH2CH(OH)(CHF2), cyclopropyl, (CH2)2OCH3, oxetanyl, and 1,1-dioxide thietanyl.

28. The compound of any one of Claims 1 to 16 and 21 to 26, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from CH3, C(CH3)3, CH2CHF2, CH2CF3, CD3, CH2C(CH3)2OH, CH2OH, fluoro, OCH3, OCD3, OCH2CHF2, OCHF2, cyclopropyl, (CH2)2OCH3, oxetanyl, and 1,1-dioxide thietanyl. 64 ME152734335v.1136867-01020 29. The compound of Claim 1 or 2, wherein the compound is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein: R1is (C1-C3)alkyl; R2is -CH2NHC(O)RA; RAis pyrazolyl optionally substituted with 1 or 2 groups selected from RB; each RBis independently selected from (C1-C3)alkyl, deuterated(C1-C3)alkyl, -ORE, and hydroxy(C1-C4)alkyl; and REis (C1-C4)alkyl or deuterated(C1-C4)alkyl.

30. The compound of Claim 29, wherein the compound is of the Formula IIa:or a pharmaceutically acceptable salt thereof.

31. The compound of Claim 29 or 30, or a pharmaceutically acceptable salt thereof, wherein R1is CH3.

32. The compound of any one of Claims 29 to 31, or a pharmaceutically acceptable salt thereof, wherein R2is selected from. 65 ME152734335v.1136867-01020 33. The compound of any one of Claims 29 to 31, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from CH3, CH2C(CH3)2OH, CD3, and OCD3.

34. The compound of Claim 1, wherein the compound is selected from ,, 66 ME152734335v.1136867-0102067 ME152734335v.1136867-01020 , ,, 68 ME152734335v.1136867-01020, 69 ME152734335v.1136867-01020 , ,, 70 ME152734335v.1136867-01020 ,, 71 ME152734335v.1136867-01020 ,, 72 ME152734335v.1136867-01020 , ,, 73 ME152734335v.1136867-01020 , ,, 74 ME152734335v.1136867-01020 ,, 75 ME152734335v.1136867-01020 ,, 76 ME152734335v.1136867-01020 , ,or a pharmaceutically acceptable salt of any of the foregoing.

35. A pharmaceutical composition comprising: i) the compound of any one of Claims 1- 34 or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier. 77 ME152734335v.1136867-01020 36. A method of treating a subject with cancer, comprising administering to the subject an effective amount of the compound of Claims 1-34 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of Claim 35.

37. The method of Claim 36, wherein the cancer is characterized by dysfunctional p53.

38. The method of Claim 36, wherein the cancer is characterized by an inactivating p53 mutation.

39. The method of Claim 38, wherein the p53 mutation is Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or a combination thereof.

40. The method of Claim 38, wherein the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof.

41. The method of Claim 38, wherein the p53 mutation is Y220C.

42. The method of any one of Claims 36 to 41, wherein the cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS- related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, prostate cancer, rectal cancer, renal cell carcinoma, skin cancers, skin carcinoma merkel cell, small intestine cancer or throat cancer.

43. A method for re-activating p53 Y220C mutant in a subject in need thereof, comprising administering to the subject an effective amount of the compound of Claims 1 to 34 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 35. 78 ME152734335v.1

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