Compositions and methods for use in the treatment of cancer and other indications

Abstract

Provided herein are methods of treating diseases, disorders, or conditions including cancers, where the methods comprise administration of Compound 1, or a pharmaceutically acceptable salt thereof, as described herein. Such methods may comprise the treatment of lung cancer, breast cancer, or colorectal cancer.

Description

PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1COMPOSITIONS AND METHODS FOR USE IN THE TREATMENT OF CANCER AND OTHER INDICATIONSCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 702,041, filed October 1, 2024, which is incorporated in its entirety for all purposes.BACKGROUND

[0002] An estimated over 600,000 Americans will have died from cancer in 2021, corresponding to more than 1600 deaths per day (Cancer Facts and Figures 2021). The greatest number of deaths are from cancers of the lung, prostate, and colorectum in men, and cancers of the lung, breast, and colorectum in women. Almost one-quarter of all cancer deaths are due to lung cancer, 82% of which is directly caused by cigarette smoking. The 5- year survival rate for lung cancer patients is only about 20%.

[0003] The aberrant activation of the phosphoinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in treating cancers. PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration.

[0004] The frequency of PI3K oncogenic events has fueled the development and testing of PI3K inhibitors. Most PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance. Additional methods of treating cancers including lung, breast, and colorectal cancers are needed.SUMMARY

[0005] The present disclosure provides methods of treating diseases, disorders, and conditions such as cancers with a compound capable of disrupting, inhibiting, and / or preventing an interaction between a PI3K protein (e.g., PI3Ka) and a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). The methods may comprise administering a compound (e.g., Compound 1, alsoPage 1 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 known as BBO-10203), or a pharmaceutically acceptable salt thereof (e.g., as described herein) to a subject in need thereof.

[0006] In a first aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (X):or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of the compound, and the cancer is described herein.

[0007] In some embodiments, the compound is Compound 1:or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the compound is Compound 1:Page 2 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1(Compound 1).

[0009] In a second aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1 :a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0010] In a third aspect, the present disclosure provides a method of treating colorectal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1:Page 3 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0011] In a fourth aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, method comprising administering to the subject a therapeutically effective amount of Compound 1:a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0012] In some embodiments of any one of the first to fourth aspects, the method comprises administering a therapeutically effective amount of Compound 1 to the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 schematically illustrates the overall study design of the study described in Example 4.

[0014] FIGs. 2A-2C show that BBO-10203 has broad in vitro activity and potently inhibits pAKT signaling across a panel of cell lines with HER2 amplification (9 cell lines), KRASPage 4 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 mutations (35 cell lines), or PIK3CA mutations (22 cell lines). (nM=nanomolar; pAKT=phosphorylated AKT)

[0015] FIGs. 3A-3F show that BBO- 10203 is orally bioavailable and can achieve near complete inhibition of signaling in tumors without risk of hyperglycemia or hyperinsulinemia. FIG. 3A shows the pharmacokinetics of BBO- 10203 in mice. FIGs. 3B- 3C show the dose and time response pharmacodynamics for BBO- 10203 in a KYSE-410 cell line-derived xenograft model following one dose of BBO-10203. FIG. 3B shows high levels of pAKT inhibition is achieved with a single dose of 30 mg / kg of BBO-10203 at 8 hours. FIG. 3C shows pAKT inhibition is suppressed for up to 24 hours after administration of one dose of 30 or 100 mg / kg BBO-10203. (One-way ANOVA with Dunnett’s test vs vehicle; *=p<0.0001). FIGs. 3D-3F demonstrate that unlike PI3Ka kinase domain inhibitors, BBO- 10203 does not affect glucose metabolism. FIG. 3D shows blood glucose levels at the time of and after administration of a single dose of vehicle, the PI3Ka kinase domain inhibitor alpelisib, and BBO-10203 in fasted male mice after an oral glucose tolerance test. (One-way ANOVA with Dunnett’s test vs vehicle, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). FIG. 3E shows the blood glucose concentration AUC calculated from the data in FIG. 3D was elevated following administration of alpelisib but not BBO-10203. Hyperglycemia is observed in alpelisib but not in BBO-10203 treated mice. (One-way ANOVA with Dunnett’s test vs vehicle, *p<0.001, **p<0.0001). FIG. 3F shows c-peptide levels at 150 minutes after compound administration in the oGTT. Hyperinsulinemia is observed in alpelisib but not BBO-10203 treated mice. (One-way ANOVA with Dunnett’s test vs vehicle: *p<0.001).(AUC=area under the curve; iv=intravenous administration; min*mg / dL=minutes times milligrams per deciliter; mg / dL=milligrams per deciliter; mg / kg=milligrams per kilogram; min=minutes; ng / mL=nanograms per milliliter; pAKT=phosphorylated AKT;PK=pharmacokinetics; pM=picomolar; po=per os or oral administration; QD=quaque die or once daily; pM=micromolar; veh=vehicle).

[0016] FIGs. 4A-4B show that strong efficacy is observed in a xenograft model with HER2 amplification and a KRAS G12C mutation and that BBO-10203 drives efficacy by reducing tumor cell proliferation. FIG. 4A shows changes in tumor volume in a KYSE-410 cell line- derived xenograft model featuring HER2 amplification and a KRAS G12C mutation. Dose dependent, significant efficacy was observed and there was tumor regression with 30 mg / kg of BBO-10203. (Two-way repeated measures ANOVA with Dunnett’s test vs vehicle,Page 5 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1*p<0.0001). FIG. 4B shows significantly reduced tumor cell proliferation at 24 hours following a single oral dose of 30 mg / kg BBO-10203 in the KYSE-410 model, as indicated by a significant reduction in BrdU incorporation in tumor cells by IHC. (One-way ANOVA with Dunnett’s test vs vehicle, *p<0.01). (BrdU=5-Bromo-2’-deoxyuridine;IHC=immunohistochemistry; mg / kg=milligrams per kilogram; mm =cubic millimeters; QD=quaque die or once daily; pm2 / p m2=micrometer squared over micrometer squared).DETAILED DESCRIPTIONDefinitions

[0017] Unless specifically indicated otherwise, the group “as used herein in any one of formulae of compounds as disclosed herein, refers to methyl.

[0018] Unless specifically indicated otherwise, the wavy line in each moiety as used herein,Ofor example in a moiety H , refers to the attachment to the remainder of the molecule.

[0019] Unless specifically indicated otherwise, a dosage amount (e.g., a total daily dosage of from about 10 mg to about 2000 mg, etc.) refers to an amount of the compound (e.g., Compound 1) in its free base (or free acid) form. By way of example, when the hydrochloric acid (HC1) salt of Compound 1 is dosed, the amount of the HC1 salt of Compound 1 required to provide a 1000 mg dose of Compound 1 is 1056.9 mg. One skilled in the art understands the necessary conversion when a pharmaceutically acceptable salt of the compound (e.g., Compound 1 ) is administered in any one of embodiments as described herein.

[0020] When ranges of values are disclosed, and the notation “from m ... to m” or “between m . . . and n2” is used, where m and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 p M (micromolar),” which is intended to include 1 p M, 3 p M, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).Page 6 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1

[0021] ‘ ‘About,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures. In some embodiments, “about” means a range extending to + / - 10% of the specified value. In some embodiments, “about” means a range of + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1% of the specified value. In some embodiments, “about” means a range of + / - 10% of the specified value. In some embodiments, “about” means a range of + / - 5% of the specified value. In some embodiments, “about” means the specified value.

[0022] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0023] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropisomeric, or epimeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure; and the D- and L-isomers of each compound are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Table 1 and Table 2 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commerciallyPage 7 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 available starting materials that contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation, such as conversion to a mixture of diastereomers followed by separation via, e.g., recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by various techniques. Unless otherwise stated, all tautomeric forms (e.g., rapidly interconverting forms) of provided compounds are within the scope of the disclosure.

[0024] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0025] As used herein, the term “aliphatic” or “aliphatic group” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (e.g., multiple bonds, such as double or triplebonds). Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.

[0026] As used herein, the term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, CMO, C1-8, C1-6, C1-4, C1-3, or C1-2). Examples of alkyl groups include methyl, ethyl, propyl (e.g., n- propyl), isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, isoamyl, hexyl, heptyl, octyl, and nonyl. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH2- )•Page 8 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0027] As used herein, the term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Examples of alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0028] As used herein, the term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Examples of alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2 -pentynyl, isopentynyl,1.3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3 -hexadiynyl,1.4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hexatriynyl.

[0029] As used herein, the term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. A bicyclic ring system may comprise first and second rings that are fused together and / or share one or more atoms. The term “aryl” may be used interchangeably with the term “aryl ring(s).” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system. Examples of aryl groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents as defined herein. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl or tetrahydronaphthyl, and the like. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0030] As used herein, the terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. A carbocycle may comprise fused ring systems, bridged ring systems, and / or spiro ring systems (e.g., a system including two rings sharing a single carbon atom). Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,Page 9 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 cycloheptenyl, cyclooctyl, cyclooctenyl, norbomyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic Cs-Cs hydrocarbon, or an optionally substituted Ce-Cio bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0031] As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

[0032] As used herein, the terms “heteroaryl”, “heteroaromatic”, and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 14 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Examples of bicyclic heteroaromatic groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, indazolyl, indolizinyl, benzimidazolyl, benzthiazolyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiadiazolyl, tetrazolopyridazinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, chromonyl, coumarinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Examples of tricyclic heterocyclic groups include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenazinyl, phenanthridinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl”Page 10 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. It will be appreciated that certain tautomeric forms of a heteroaryl ring can exist and are encompassed by the term “heteroaryl.” Such tautomeric forms include, for example, pyridin-2(lf / )-one.

[0033] As used herein, the term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon); the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)). In some embodiments, a heteroatom is selected from oxygen, sulfur, and nitrogen.

[0034] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to one or more carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be unsubstituted or substituted with one or more substituents (e.g., as described herein). Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are unsubstituted or substituted with one or more substituents (e.g., as described herein).Page 11 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0035] As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0036] As described herein, compounds of this disclosure may contain “optionally substituted” moieties (e.g., moieties bearing one or more substituents). In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0037] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)O^IR°; -(CH2)O-40R°: -0(CH2)o-4R°, - 0-(CH2)O^C(0)OR°; -(CH2)O^CH(OR°)2; -(CH2)O ISR°; -(CH2)o iPh, which may be substituted with R°; -(CH2)o^iO(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o^iO(CH2)o-i -pyridyl which may be substitutedPage 12 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 with R°; -NO2; -CN; -N3; -(CH2)OMN(R°)2; -(CH2)OMN(R°)C(0)R°; -N(R°)C(S)R°; - (CH2)O .IN(R0)C(0)NR02; -N(RO)C(S)NR°2; -(CH2)OMN(R°)C(0)OR0; - N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)OMC(0)R°; - C(S)R°; -(CH2)OMC(0)OR°; -(CH2)(MC(O)SR°; -(CH2)oMC(0)OSiR°3; -(CH2)OMOC(0)R0; -OC(O)(CH2)0MSR°; -(CH2)OMSC(0)R°; -(CH2)(MC(O)NRO2; -C(S)NRO2; -C(S)SR°; - SC(S)SR°, -(CH2)OMOC(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2K4SSR0; -(CH2)OMS(0)2R°; -(CH2)OMS(0)2OR°; -(CH2)OMOS(0)2R°; - S(O)2NR°2; -(CH2)OMS(0)R°; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; - C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR°3; -(CM straight or branched alkylene)O-N(R°)2; or -(CIM straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci- 6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0038] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0 2Re, -(haloR*), -(CH2)o-2OH, -(CH2)O 2OR*, -(CH2)O_2CH(OR*)2, -O(haloR’), -CN, -N3, -(CH2)o-2C(0)R*, -(CH2)0-2C(O)OH, -(CH2)o-2C(O)OR-, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, - NO2, -SiR*3, -OSiR*3, -C(O)SR*. -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0039] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*2, =NNHC(O)R*,Page 13 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1=NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S- wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] Suitable substituents on the aliphatic group of R* include halogen, - R’, -(haloR*), -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR , or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -RfC(O)CH2C(wherein each Rfis independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ', taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0042] Suitable substituents on the aliphatic group of R ' are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^i aliphatic, -CH2Ph, -0(CH2)o-iPh, or aPage 14 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 13- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] ‘ ‘Tautomer”, as used herein, alone or in combination, refers to one of two or more isomers that rapidly interconvert. Generally, this interconversion is sufficiently fast so that an individual tautomer is not isolated in the absence of another tautomer. The ratio of the amount of tautomers can be dependent on solvent composition, ionic strength, and pH, as well as other solution parameters. The ratio of the amount of tautomers can be different in a particular solution and in the microenvironment of a biomolecular binding site in said solution. Examples of tautomers that are well known in the art include keto I enol, enamine I imine, and lactam I lactim tautomers. Examples of tautomers that are well known in the art also include 2-hydroxypyridine / 2( I f / J-pyridone and 2-aminopyridine / 2( l H)-iminopyridone tautomers.

[0044] Asymmetric centers may exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this disclosure. Additionally, the compounds provided herein may comprise conformational isomers, which compounds comprise groups that can orient in different conformations in relation to another moiety. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solventsPage 15 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0045] As used herein, the term “therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease, disorder, or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amounts will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0046] As used herein, the term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0047] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy (e.g., therapeutic agent) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. Treatment may also refer to any other indicia of success in the treatment or amelioration of an injury, pathology, disease, disorder, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, disease, disorder, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; and / or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / orPage 16 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. Treatment may also be preemptive in nature; i.e., it may include prevention of a disease, disorder, or condition, prevention of onset of one or more symptoms of a disease, disorder, or condition, and / or prevention of escalation of a disease, disorder, or condition. Prevention of a disease, disorder, or condition may involve complete protection from disease, and / or prevention of disease progression (e.g., to a later stage of the disease, disorder, or condition). For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease, disorder, or condition to a clinically significant or detectable level. As used herein, when used in connection with the occurrence of a disease, disorder, and / or condition, “prevent” or “prevention” refers to reducing the risk of developing the disease, disorder, or condition; delaying onset of one or more characteristics or symptoms of the disease, disorder, or condition; and / or preventing escalation of a disease, disorder, or condition. Prevention of a disease, disorder, or condition may involve complete protection from disease and / or prevention of disease progression (e.g., to a later stage of the disease, disorder, or condition). For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease, disorder, or condition to a clinically significant or detectable level. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0048] As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Non-limiting examples of patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, hamsters, guinea pigs, cats, dogs, goats, pigs, sheep, cows, deer, horses, non-human primates, and / or humans). In some embodiments, a patient or subject is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.Page 17 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1

[0049] As used herein, the term “composition” refers to a discrete physical entity that comprises one or more specified components (e.g., a product comprising one or more specified ingredients (e.g., in specified amounts) or a product that results, directly or indirectly, from combination of specified ingredients in specified amounts). Unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc. A composition may comprise one or more pharmaceutically acceptable components, such as a carrier, diluent, or excipient. By “pharmaceutically acceptable” it is generally meant the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0050] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disin tegrants, lubricants, coatings, sweeteners, flavors, and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0051] As used herein, the term “a compound capable of disrupting, inhibiting, and / or preventing an interaction” between two proteins (e.g., a small GTPase and a PI3Ka protein) means a compound that interrupts (e.g., transiently or permanently) the formation of a protein-protein complex. Disruption, inhibition, and / or prevention of an interaction between two proteins can be complete or partial and can occur via any means, including alteration of the quartenary structure of one or both proteins, alteration of the chemical structure of one or both proteins by, for example, chemical modification, or the non-covalent association of a compound at the protein-protein interface. In certain embodiments herein, a compound that is capable of disrupting, inhibiting, and / or preventing an interaction between two proteins (e.g., a small GTPase and a PI3Ka protein) demonstrates (i) modification of > 75%, 50% < modification < 75%, or 25% < modification < 50% of PIK3CA protein in the assay of Example 2, infra', and / or (ii) pAKT inhibition IC50 value of < 0.1 pM or 0.1 pM < IC50 value < 1 pM, or 1 pM < IC50 value < 3 pM in the assay of Example 3, infra. In some embodiments herein, “partial disruption, inhibition, or prevention of an interaction” between two proteins refers to (i) 25% < modification < 50% of PIK3CA protein in the assay of Example 2, infra; and / or (ii) pAKT inhibition IC50 value of 1 pM < IC50 value < 3 pM in the assay of Example 3, infra.Page 18 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0052] ‘ ‘Treatment cycle” refers to the period of time in which a subject receives the treatment at a prescribed dose level (e.g., 100 milligrams (mg), 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1200 mg, etc.) and dosing interval (e.g., once a day, twice a day, etc.).

[0053] ‘ ‘Adverse event,” as used herein, is any untoward medical occurrence in a subject, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Examples of adverse events include, but are not limited to, nausea or vomiting; diarrhea lasting longer than 3 days; adrenal insufficiency; interstitial lung disease; pneumonitis; photosensitivity; higher than normal alkaline phosphatase, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) levels; anemia; febrile neutropenia; thrombocytopenia; or hematologic reactions.

[0054] “Initial dose” refers to a dose level (e.g., 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1200 mg, etc.) prescribed for a treatment cycle to be given to the subject at the prescribed interval (e.g., once a day, twice a day, etc.). As used herein, “initial dose level” is intended to encompass the dosing standard for the duration of the treatment cycle in the absence of an adverse event.

[0055] “Reduced dose,” as used herein, is intended to encompass a dose level (e.g., 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, etc.) prescribed for the duration of an adverse event in the place of the initial dose level unless and until the adverse event is resolved. A subject may revert to the initial dose level from a reduced dose once the adverse event is resolved.

[0056] The compounds disclosed herein can exist as therapeutically acceptable salts (also referred to herein as “pharmaceutically acceptable salts”). The present disclosure includes compounds provided herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.

[0057] The terms “therapeutically acceptable salt” and “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitablePage 19 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0058] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, / V,N-dimethylaniline, -methylpiperidine, / V-methy 1 morpholine, dicyclohexylamine, procaine, dibenzylamine, N, A-dibenzylphenethylamine, 1-ephenamine, and 7V,A’-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.Page 20 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0059] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

[0060] ‘ ‘A,” “an,” or “a(n)”, when used in reference to a group of substituents or “substituent group” herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is unsubstituted or substituted with at least one alkyl and / or at least one aryl, wherein each alkyl and / or aryl is optionally different. In another example, where a compound is substituted with “a” substituent group, the compound is substituted with at least one substituent group, wherein each substituent group is optionally different.PI3K and Small GTPase Proteins

[0061] The aberrant activation of the phosphoinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in treating cancers. PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration. Upon activation, PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2). Signaling proteins such as Ser / Thr kinase AKT (e.g., Protein Kinase B (PKB)) can bind to PIP3 and thereby localize to the cell membrane. Phosphorylated AKT activates or inhibits several signaling proteins through direct phosphorylation including the mammalian target of rapamycin complex 1 (mTORCl), which acts as a regulator of cell growth and survival pathways, cyclin DI , GSK3(B), BAD, MDM2, FOXO, TSC1 / 2, and PRAS40. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulates this pathway by dephosphorylating PIP3 to PIP2 and thus prevents activation of downstream kinases.

[0062] Based on the sequence homology and substrate preference, PI3Ks have been grouped into three separate classes (e.g., classes I, II, and III). Class I PI3Ks are further divided into two subclasses, IA and IB depending on their modes of regulation. Class IA PI3Ks are heterodimers comprising pl 10 catalytic and p85 regulatory subunits, and are most clearly implicated in human cancer. Class IA PI3K contains pl 10a, pl lOp, and pl 105 catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while pl 10y produced by PIK3CG represents the only catalytic subunit in classPage 21 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1IB PI3K. The expression of PI3K isoforms (e.g., PI3Ka, PI3K0, PI3K6, and PI3Ky) is specific to cell types. The pl 10a and [3 isoforms are expressed in all cell types, whereas pllOS expression is mainly confined to leukocytes. The pl 10y isoform is expressed primarily in the myeloid cell lineage.

[0063] PIK3CA gene encodes the 1068 amino acid pl 10a protein that contains five domains: an N-terminal adaptor binding domain (ABD) that binds to regulatory subunit p85a, a RAS-binding domain (RBD), a C2 domain, a helical domain, and a kinase catalytic domain. RAS contributes directly to the activation of the PI3K pathway through direct binding of RAS proteins (e.g., HRAS, NRAS, and KRAS) to a RAS-binding domain (RBD) in the pl 10a catalytic subunit of PI3Ka. Activating mutations in the KRAS and PIK3CA genes are frequently detected in cancer, making these two proteins important targets for drug discovery. Somatic missense mutations in the PIK3CA gene have been reported in many human cancer types including breast, colon, liver, stomach, endometrial, bladder, and lung cancers. The most frequent hotspot mutations in PIK3CA are E542K, E545K, H1047R, and H1047L, and they account for 80-90% of all PIK3CA mutations detected in human malignancies. These PIK3CA mutations lead to increased catalytic activity of pl 10a, which causes downstream effects such as unregulated cell growth, proliferation, and survival.

[0064] Mutations in RAS proteins are found in over 20% of all human cancers. RAS proteins function as molecular switches that cycle between an active, GTP-bound state and an inactive, GDP-bound state. In the active state, RAS proteins interact with various effector proteins including PI3K, RAF kinase, and RalGDS, leading to activation of multiple downstream signaling pathways. Oncogenic RAS mutations are predominantly found at amino acid positions G12, G13, and Q61, and these mutations impair GTPase activities leading to the accumulation of active RAS proteins. The most common oncogenic RAS mutations are G12C, G12D, G12S, G12V, G12R, G13D, and Q61H.

[0065] RAS signaling through PI3K is necessary for normal lymphatic development and RAS -induced transformation, especially in lung cancer, where the interaction between mutant RAS and pl lOa-RBD is essential for tumor initiation and maintenance. RAS interactions with pl lOa-RBD have been shown to be crucial for epidermal growth factor (EGF) signaling to P13K. Recent studies have shown that disrupting the RAS-PI3K interaction inhibits AKT and RAC1 activation in EGFR-mutant lung cancer cells, leading to reduced growth andPage 22 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 survival and inhibiting EGFR-mutant-induced tumor onset. These results suggest that the binding of pl 10a to endogenous RAS proteins in EGFR-driven lung adenocarcinoma is critical in tumors driven by upstream activators of the RAS pathways and not just those in which RAS is mutationally activated.

[0066] Small GTPases (e.g., other than RAS) are also expected to bind the RBD of PI3Ka resulting in activation of signaling. The small GTPases Rael and CDC42 have been shown to bind the RBD of PI3KJ3 and are hypothesized to also be capable of binding the RBD of PI3Ka. Accordingly, in some embodiments, the present disclosure encompasses the recognition that disrupting an interaction between PI3Ka and any small GTPase that binds the RBD of PI3Ka may be a useful therapeutic strategy for treating cancers and other indications. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins (including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).

[0067] The frequency of oncogenic PIK3CA hotspot mutations across cancers has fueled the development and testing of numerous PI3K (e.g., PI3Ka) inhibitors. Most PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance. In 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (BYL719; Novartis Pharma AG), an inhibitor specific to the PI3Ka isoform, combined with fulvestrant for the treatment of patients diagnosed with HR+ / HER2- PIK3CA-mutation. The therapeutic window of PI3K inhibitors is mainly limited by isoform selectivity and off- tumor toxicity. Moreover, hyperglycemia and hyperinsulinemia have been observed as major doselimiting toxicides for pl 10a inhibitors, which prevent the use of sufficiently high doses to fully suppress PI3Ka signaling in the tumor. Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3Ka inhibition, as inhibition of the PI3K / AKT pathway reduces glucose uptake, which in turn leads to increased secretion of insulin and subsequent activation of insulin / insulin-like growth factor I receptor in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of the PI3Ka inhibitor. Indeed, hyperglycemia was observed in 65% of patients in a Phase III clinical trial of alpelisib, leading to significant dose interruptions.Page 23 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0068] To overcome the limitations of current PI3Ka inhibitors, novel strategies to target PI3Ka need to be explored. Previous studies have suggested that inhibiting the RAS- llOa(RBD) interaction has minimal toxicity in adult animals while effectively causing tumor regression. As described in International Patent Application No.PCT / US2023 / 012521, filed February 7, 2023, which is herein incorporated by reference in its entirety, this therapeutic approach may be effective in various cancers including RAS- mutant-driven cancers and / or those driven by mutations or amplification of receptor tyrosine kinases (RTKs). This therapeutic modality may provide certain advantages over known PI3Ka inhibitors (e.g., those that target the ATP binding pocket of PI3Ka). For example, compounds capable of disrupting, inhibiting, and / or preventing an interaction between a protein such as a small GTPase or other protein and PI3Ka protein (e.g., the RAS-binding domain of a PI3Ka protein) may avoid hyperglycemia and insulin-driven resistance common to PI3Ka inhibitors, e.g., because such technologies target activation of PI3Ka by RAS, which is mostly present in transformed cells.

[0069] Accordingly, the present disclosure provides methods and uses of a compound or a form (e.g., salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof), in the treatment of or in the manufacture of a medicament for use in the treatment of a disease, disorder, or condition such as a cancer (e.g., as described herein).

[0070] In an aspect, the present disclosure provides a method, comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein to a subject in need thereof.

[0071] In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of binding to PI3Ka, such that (i) the interaction between the small GTPase and PI3Ka is at least partially disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of PI3Ka is not significantly inhibited. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of binding to PI3Ka, such that the interaction between the small GTPase and PI3Ka is at least partially disrupted, inhibited, and / or prevented. In some embodiments, the compound, or the formPage 24 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1(e.g., pharmaceutically acceptable salt) thereof, is capable of binding to PI3Ka, such that the kinase activity of PI3Ka is not significantly inhibited.

[0072] In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof: (i) demonstrates modification of > 75%, 50% < modification < 75%, or 25% < modification < 50% of PIK3CA protein in the assay of Example 2; and / or (ii) pAKT inhibition IC50 value of < 0. 1 pM, 0. 1 pM < IC50 value < 1 pM, or 1 pM < IC50 value < 3 pM in the assay of Example 3. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof: (i) demonstrates modification of > 75% or 50% < modification < 75% of PIK3CA protein in the assay of Example 2; and / or (ii) pAKT inhibition IC50 value of < 0.1 pM or 0. 1 pM < IC50 value < 1 pM in the assay of Example 3. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof: (i) demonstrates modification of > 75% of PIK3CA protein in the assay of Example 2; and / or (ii) pAKT inhibition IC50 value of < 0.1 pM in the assay of Example 3. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof: (i) demonstrates modification of > 75% of PIK3CA protein in the assay of Example 2; and (ii) pAKT inhibition IC50 value of < 0.1 pM in the assay of Example 3.

[0073] In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, comprises an electrophilic moiety. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of interacting with a Cys242 residue in the catalytic subunit of PI3Ka.

[0074] In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of irreversibly binding the PI3Ka protein. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of reversibly binding the PI3Ka protein.

[0075] In some embodiments, the PI3Ka protein is aberrantly activated.

[0076] In some embodiments, the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, EHOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.Page 25 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0077] In some embodiments, the small GTPase is Rael, CDC42, or a RAS protein. In some embodiments, the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITE In some embodiments, the RAS protein comprises a mutation in codon 12, 13, or 61. In some embodiments, the RAS protein is KRAS. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61 IP, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12V, or G12R mutation. In some embodiments, the KRAS protein comprises a G12C or G12D mutation. In some embodiments, the KRAS protein is a wild-type KRAS protein. In some embodiments, the RAS protein is HRAS. In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein is a wild-type HRAS protein. In some embodiments, the RAS protein is NRAS. In some embodiments, the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein is a wild-type NRAS protein.

[0078] In some embodiments, the compound is a compound described herein, such as a compound according to Formula (I), or Compound 1, or a pharmaceutically acceptable salt thereof.Compounds

[0079] In some embodiments, the compound is a compound according to Formula (I):or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject in need thereof, wherein:Ring A is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 26 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Ring B is selected from phenyl, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered bicyclic carbocyclic ring; a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl, heteroaryl, and heterocyclic rings is optionally fused to Ring E;Ring D is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl and heteroaryl rings is optionally fused to Ring F;Ring E is selected from a 5- to 6-membered carbocyclic ring; a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5;Ring F is selected from phenyl; a 5- to 6-membered carbocyclic ring; a 5- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W and y instances of R2;R1is selected from -L-W, Ring D', or a bivalent Ci-6 aliphatic chain substituted with Ring D'; each -L-W is -CN, or: each L is independently a bivalent straight or branched Ci-s aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -Page 27 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, - N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN; each Ring D' is independently a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D' is substituted with t instances of -L- W ; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and Ci-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2) Cy, - OCH2CH2OR, and optionally substituted C1-6 aliphatic; each Cy is independently a 5- to 6-memhered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, - N(R)2, -SR, -C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -C(O)N(R)2, - C(O)N(R)(CH2)xCy, -(CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, - N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, -P(O)R2, (CH2)xCy, -O(CH2)xCy, and optionally substituted Ci-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, - SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatomsPage 28 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci- 6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10- membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1 ; r is 0, 1, or 2; s is 0, 1 , 2, or 3; t is 0, 1, or 2; u is 0 or 1 ; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; and y is 0, 1, or 2.

[0080] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the compound of Formula (I) is described in International Patent Application No. PCT / US2023 / 012521, filed February 7, 2023, which is incorporated herein in its entirety for all purposes.

[0082] In some embodiments, the compound is a compound according to Formula (I-a-v’):Page 29 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring E, Ring F, R2, R2, R3, R4, R5, Rs, L, W, m, n, p, r, s, y, and u are as defined above for Formula (I) and described in classes and subclasses in PCT / US2023 / 012521, both singly and in combination. In some embodiments, the compound is a compound of Formula (I-a-v’) or a pharmaceutically acceptable salt thereof, as described in classes and subclasses herein, both singly and in combination.

[0083] In some embodiments of Formula (I) or (I-a-v’), Ring A is phenyl.

[0084] In some embodiments, the compound is a compound according to Formula (I-a-v’):or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring D is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and phenyl;Page 30 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Ring E is selected from a 5- to 6-membered carbocyclic ring; a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring F is a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each L is independently selected from-C(O)CClH-, -C(O)CC1F-, -C(O)CH=CH-, - N(R)C(O)CH=CH-, -C(O)C(=CH2)-, -C(O)C(=CHCH3)-, -C(O)CH=CH-CH2- , -C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(R)-, -CH2N(R)C(O)CH=CH- , -CH2CH2N(R)C(O)CH=CH-, -C(O)C< -C(0)CCCH2-, and - SO2CH=CH-, and each W is independently hydrogen, halogen, or -CN; each R2and R2is independently selected from halogen and Ci-6 alkyl; each R3is independently selected from halogen, -OR, -O(CH2)vCy, and -O-(Ci-4 alkylene)-OR; each Cy is independently a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and Ci-6 alkyl;Page 31 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 each of R5and Rsis independently selected from oxo, =NH, halogen, -OR, -N(R)2, and Ci -6 alkyl unsubstituted or substituted with one or more substituents selected from halogen, -OR, and -N(R)r; each R6is independently selected from oxo, halogen, -OR, and Ci-6 alkyl unsubstituted or substituted with one or more halogen or -OR; and each R is independently hydrogen or Ci-6 alkyl unsubstituted or substituted with one or more halogen; m is 1, 2, or 3; n is 0 or 1 ; p is 0, 1, or 2; r is 0 or 1 ; s is 0, 1, 2, or 3; u is 1; each v is independently 0, 1, or 2; and y is 0, 1, or 2,

[0085] In some embodiments, the compound is a compound of Formula (IF):or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, Ring E, L, R2, R3, R4, R5, R5, W, m, n, p, s, and y are as defined above for Formula (I) or (I-a-v’) and described in classes and subclasses in PCT / US2023 / 012521, both singly and in combination. In some embodiments, the compoundPage 32 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 is a compound of Formula (IF) or a pharmaceutically acceptable salt thereof, as described in classes and subclasses herein, both singly and in combination.

[0086] In some embodiments of Formula (I-a-v’) or (IF), the moiety

[0087] In some embodiments, the compound is a compound of Formula (IF1 ):or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, Ring E, L, R2, R3, R4, Rs, Rs, W, n, p, s, and y are as defined above for Formula (I) or (I-a-v’) and described in classes and subclasses in PCT / US2023 / 012521, both singly and in combination. In some embodiments, the compound is a compound of Formula (IF1) or a pharmaceutically acceptable salt thereof, as described in classes and subclasses herein, both singly and in combination.

[0088] In some embodiments, the compound is represented by Formula (IFl):Page 33 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1or a pharmaceutically acceptable salt thereof, wherein:Ring C is phenyl;Ring E is a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R2is independently halogen or C 1-4 alkyl; each R3is independently halogen or -O-(Ci-4 alkylene)-OR; each R4is independently halogen or C1-4 alkyl; each of R5and R5is independently halogen or C1-4 alkyl; each R independently hydrogen or C 1-4 alkyl; n is 0 or 1 ; p is O or l; s is 0 or 1 ; and y is 0, 1 or 2.Page 34 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0089] In some embodiments of Formula (I-a-v’), (IF), or (IF1), the moiety

[0090] In some embodiments of Formula (IF1), the moiety

[0091] In some embodiments of any one of formulae described herein, one R3is -O-(Ci-4 alkylene)-OR; R is C1-4 alkyl; and the remaining R3are each halogen.Page 35 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0092] In some embodiments of Formula (IF1), the moietyis selected fromalkylene)-OR; and R is Ci-4 alkyl. In some

[0093] In some embodiments of Formula (IF) or (IF1), the moietyselected from:Page 36 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0094] In some embodiments of Formula (IF) or (IF1), the moiety

[0095] In some embodiments of Formula (IF1), the moiety

[0096] In some embodiments of any one of formulae described herein, n is 0. In some embodiments of any one of formulae described herein, n is 1. In some embodiments of any one of formulae described herein, n is 1; and R4is F.Page 37 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0097] In some embodiments of any one of formulae (I-a-v’), (IF), and (IF1), the moiety

[0098] In some embodiments of any one of Formula (I), (I-a-v’), (IF), and (IF1), Ring C is

[0100] In some embodiments of Formula (IF1), the moietyselected from:Page 38 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1,o

[0102] In some embodiments of a compound of Formula (IF1), -L-W is

[0103] In some embodiments of Formula (IF) or (IF1 ), the moietyselected from:Page 39 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Page 40 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0105] In some embodiments, the compound is represented by Formula (X):or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound is Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof.

[0107] Compound 1 is described in International Patent Application No. PCT / US2023 / 012521, filed February 7, 2023. The synthesis of Compound 1 is described inSynthetic Example 70 of PCT / US2023 / 012521, which is reproduced herein. Compound 1 may be referred to as l-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(l-methyl-Page 41 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 lH-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin- 5(4H)-yl)prop-2-en-l-one. Compound 1 is also known as BBO-10203.

[0108] In some embodiments, the compound is administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977). Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci^ialkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0109] It will be appreciated that compounds described herein may be provided and / or utilized in any available form (e.g., a salt form) and that all such forms are contemplated by the present disclosure. The present disclosure also contemplates forms such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers of the compounds provided herein.Page 42 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1

[0110] In some embodiments, provided compounds are prepared as described in International Patent Application No. PCT / US2023 / 012521. In some embodiments, Compound 1 is prepared as described in Example 1 herein.Compositions[OHl] The compound, or form (e.g., pharmaceutically acceptable salt) thereof, may be a component of a composition that optionally includes one or more other components, such as one or more pharmaceutically acceptable excipients. In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I-a, I-a-z, I-a-zz”, I-a-v', IA, IA1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, and IF1 as described in PCT / US2023 / 012521). In some embodiments, a composition comprises and / or delivers a compound of Formula (IF1) as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises and / or delivers Compound 1, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of Formulae I-a, Faz’, I-a-zz”, I-a-v', IA, IA1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, and IF1, as described in PCT / US2023 / 012521, such as Compound 1, or a pharmaceutically acceptable salt thereof) and further comprises a pharmaceutically acceptable carrier. In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound of Formula (IF1) as described herein, or a pharmaceutically acceptable salt thereof, and further comprises a pharmaceutically acceptable carrier. In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound of Compound 1 , or a pharmaceutically acceptable salt thereof, and further comprises a pharmaceutically acceptable carrier. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is included in a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is formulated for oral administration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a tablet or capsule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a tablet. Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desiredPage 43 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti- adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art.

[0113] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0114] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein.Uses and Methods of Treatment

[0115] The present disclosure provides uses for compounds and compositions described herein (e.g., compounds of Formulae I-a, I-a-z, I-a-zz’, I-a-v', IA, IA1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, and IF1, as described in PCT / US2023 / 012521, such as Compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapeutic agents for use in the treatment, amelioration, delaying progress of, amelioration or elimination of a symptom of, and / orPage 44 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 inhibition of a disease or disorder, as described herein). In some embodiments, provided compounds and compositions are useful as medicaments. Accordingly, in an aspect, the present disclosure provides a method, comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered orally. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is formulated as a tablet or capsule. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0118] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered once, twice, thrice, or four times daily. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered twice daily.

[0119] In some embodiments, administration of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) occurs according to a treatment cycle. In some embodiments, the treatment cycle is 21 days. In some embodiments, the treatment cycle is 28 days.

[0120] In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is at least about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475Page 45 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 mg, or 1500 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is at least about 50 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is at least about 100 mg.

[0121] In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is at most about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is at most about 1200 mg.

[0122] In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is between about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70-1500 mg, about 80-1500 mg, about 90-1500 mg, about 100- 1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, about 300-1500 mg, about 325-1500 mg, about 350-1500 mg, about 375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525-1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about 1000-1500 mg, about 1025-1500 mg, about 1050-1500 mg, about 1075-1500 mg, 1100-1500 mg, about 1125-1500 mg, about 1150-1500 mg, about 1175-1500 mg, about 1200-1500 mg,Page 46 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 about 1225-1500 mg, about 1250-1500 mg, about 1275-1500 mg, about 1300-1500 mg, about 1325-1500 mg, about 1350-1500 mg, about 1375-1500 mg, about 1400-1500 mg, about 1425-1500 mg, about 1450-1500 mg, about 1475-1500 mg, about 1-1200 mg, about 10-1200 mg, about 20-1200 mg, about 30-1200 mg, about 40-1200 mg, about 50-1200 mg, about 60- 1200 mg, about 70-1200 mg, about 80-1200 mg, about 90-1200 mg, about 100-1200 mg, about 125-1200 mg, about 150-1200 mg, about 175-1200 mg, about 200-1200 mg, about 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475-1200 mg, about 500-1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725- 1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, about 875-1200 mg, about 900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000- 1200 mg, about 1025-1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1-1000 mg, about 10-1000 mg, about 20-1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100- 1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550-1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825- 1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg, about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50- 750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100- 750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200-750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375-750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575- 750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675-750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20-500 mg, aboutPage 47 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 130-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70-500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200-500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400- 500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1-300 mg, about 10-300 mg, about 20-300 mg, about 30-300 mg, about 40-300 mg, about 50-300 mg, about 60-300 mg, about 70-300 mg, about 80-300 mg, about 90-300 mg, about 100-300 mg, about 125-300 mg, about 150-300 mg, about 175-300 mg, about 200-300 mg, about 225-300 mg, about 250-300 mg, about 275-300 mg, about 1-150 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40-150 mg, about 50-150 mg, about 60-150 mg, about 70-150 mg, about 80- 150 mg, about 90-150 mg, about 100-150 mg, about 125-150 mg, about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475- 525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1 , or a pharmaceutically acceptable salt thereof) is between about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg.

[0123] In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, or 1200 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable saltPage 48 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 100 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 150 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 300 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 500 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 750 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 1000 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is about 1200 mg.

[0124] In some embodiments, when the subject experiences an adverse event, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered to the subject at a reduced dose comprising 50% of the initial dose level that was administered to the subject. In some embodiments, when the subject experiences a second adverse event, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered to the subject at reduced dose comprising 25% of the initial dose level that was administered to the subject. In some embodiments, the subject is treated with the reduced dose until the adverse event is resolved. In some embodiments, the subject resumes the initial dose level after the adverse event is resolved. In some embodiments, the adverse event is nausea, vomiting, diarrhea lasting longer than 3 days, anemia, febrile neutropenia, thrombocytopenia with or without clinically significant bleeding, or a hematologic adverse reaction.

[0125] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered in a unit dosage form. In some embodiments, the unit dosage form is a tablet. In some embodiments, the tablet comprises about 25 milligrams (mg), about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound, or the pharmaceuticallyPage 49 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof (e.g., Compound 1, or a pharmaceutically acceptable salt thereof).

[0126] In some embodiments, administration of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) treats a disease, disorder, or condition in the subject. In some embodiments, the disease, disorder, or condition is a cancer.

[0127] As used herein, “cancer” (and also, “malignancy”, “neoplasm”, “tumor”, and “carcinoma”), refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, a tumor may be or comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. In some embodiments, a cancer may be characterized by a solid tumor. In some embodiments, a cancer may be characterized by a hematologic tumor. Numerous different types of cancers are known.

[0128] In some embodiments, the disease, disorder, or condition (e.g., cancer) is associated with an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, the disease, disorder, or condition (e.g., cancer) is ameliorated by disruption of an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein.

[0129] In some embodiments, a cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non- Hodgkin’ s lymphomas; multiple myeloma; and hematopoieticPage 50 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. Additional exemplary types of cancer include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi’s sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphatic system cancer, lymphomas, lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myelomas, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinomas, paraganglioma, parathyroid tumors, pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm’s tumor. In some embodiments, the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, melanoma, glioblastoma, sarcomas, and pancreatic cancer. In some embodiments, a cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0130] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is KRAS mutant NSCLC. In some embodiments, the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS. In some embodiments, the NSCLC is KRAS G12C mutant NSCLC. In some embodiments, the subject does not have tumors withPage 51 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

[0131] In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is KRAS mutant colorectal cancer. In some embodiments, the subject does not have a BRAF V600E mutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) tumors.

[0132] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is HR+ / HER2- breast cancer or HER2+ breast cancer. In some embodiments, the cancer is HR+ / HER2- breast cancer. In some embodiments, the cancer is HER2+ breast cancer. In some embodiments, the subject has had at least 2 prior lines of anti-HER2- directed therapy, or 1 prior line where there is no other regionally available standard of care. In some embodiments, the subject has left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks before administration of the compound.

[0133] In some embodiments, the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). In some embodiments, the cancer is characterized by a mutant KRAS protein. In some embodiments, the cancer is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor. In some embodiments, the cancer is a KRAS G12C positive cancer resistant to a KRAS G12C inhibitor. In some embodiments, the cancer is a KRAS G12C positive cancer characterized by acquired and / or intrinsic resistance to a KRAS G12C inhibitor. In some embodiments, the cancer is a KRAS G12C positive cancer resistant to a KRAS G12C inhibitor that inhibits the inactive state (e.g., GDP-bound state) of KRAS. In some embodiments, the cancer is a KRAS G12C positive cancer resistant to sotorasib, adagrasib, or divarasib.

[0134] In some embodiments, a cancer is associated with and / or characterized by aberrant activation of PI3Ka. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61HPage 52 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HR AS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in a PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, EllOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0135] In some embodiments, a cancer is characterized by one or more mutations. In some such embodiments, a subject may be diagnosed with cancer and / or selected for therapy based on the detection of one or more mutations in a biological sample obtained from the subject. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., KRAS, HRAS, or NRAS). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. InPage 53 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 some embodiments, a cancer is characterized by a mutation in a PI3Ka protein. In some embodiments, the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family (e.g., HER2 and / or HER3), Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). In some embodiments, a cancer is characterized by a mutation in or a deletion of a PTEN protein. In some embodiments, a cancer has demonstrable sensitivity to Avastin. For example, a cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, a cancer is ER positive (e.g., having estrogen receptors). In some embodiments, a cancer is PR positive (e.g., having progesterone receptors).

[0136] In some embodiments, the subject has progression on or disease recurrence after, all available standard of care treatments or would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. In some embodiments, the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy. In some embodiments, the cancer is a measurable disease by RECIST v 1.1.

[0137] In some embodiments, a subject has previously undergone a treatment regimen for a cancer. In some embodiments, a subject has previously entered remission from a cancer.

[0138] In some embodiments, the subject has not previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0139] In some embodiments, the subject has previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0140] In some embodiments, the subject is a human. In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject has been diagnosed with the cancer. In some embodiments, the subject has adequate organ function as follows: a. Hematological:Page 54 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1- Absolute neutrophil count (ANC) >1 500 / microliter ( L)- Platelets >100 000 / pL- Hemoglobin >9 grams per deciliter (g / dL) without transfusion for at least 2 weeks before enrollment or without erythropoiesis-stimulating agents (eg, Epo, Procrit®) for at least 6 weeks before enrollment. b. Renal:- Creatinine clearance >50 milliliters per minute (mL / min) calculated using the Cockcroft- Gault formula [(140 - age) x (weight in kilogram ((kg) x (0.85 if female) / 72 x (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection c. Hepatic:- Serum total bilirubin <1.5 x institutional upper limit of normal (ULN) or <2.0 x ULN if the subject has a diagnosis of Gilbert syndrome or <3.0 x ULN for subjects with liver metastases.- Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic -pyruvic transaminase (SGPT) <3.0xULN or AST and / or ALT <3.0xULN with documented liver metastases. d. Coagulation:- International normalized ratio (INR) or prothrombin time (PT) <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants.- aPTT <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.

[0141] In some embodiments, provided methods comprise administering a compound, or a pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) to a subject in need thereof, according to a regimen such that the subject does not experience hyperglycemia or insulin-driven resistance.Page 55 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0142] In some embodiments, the present disclosure provides a compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition comprising the same for use in the manufacture of a medicament. In some embodiments, a provided compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition comprising the same is useful in the manufacture of a medicament for treating a disease, disorder, or condition (e.g., cancer) associated with or ameliorated by an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Ka protein. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RITE In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Ka protein is a wild-type PI3Ka protein. In some embodiments, a PI3Ka protein is a mutant PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 I E, KI 1 IN, E81 K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions are useful in the manufacture of a medicament for treating a disease, disorder, or condition described herein. In some embodiments, providedPage 56 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 compounds or compositions are useful in the manufacture of a medicament for treating a cancer or other indication described herein.

[0143] In some embodiments, the present disclosure provides compounds (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or compositions comprising the same for use in treating a disease, disorder, or condition in a subject in need thereof. In some embodiments, a provided compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition comprising the same is useful in treating a disease, disorder, or condition associated with or ameliorated by an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Ka protein. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RITE In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Ka protein is a wild-type PI3Ka protein. In some embodiments, a PI3Ka protein is a mutant PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M 10431, KI HE, KI UN, E81K, E545A, E545G, N1044K, EHOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K,Page 57 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions are useful for treating a disease, disorder, or condition described herein. In some embodiments, provided compounds or compositions are useful for treating a cancer or other indication as described herein.

[0144] In some embodiments, a provided compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agents or modalities to a subject receiving the other agent or modality in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although, in some embodiments, two or more agents may be administered together in a combination composition.

[0145] In some embodiments, a provided compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition is administered to a subject who is receiving or has received one or more additional therapeutic agents (e.g., an anti-cancer agent and / or a therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care). Exemplary anti-cancer agents include, but are not limited to, an alkylating agent, an antimitotic, a checkpoint inhibitor, an anti-metabolite, a plant alkaloid, a terpenoid, a cytotoxic agent, an antibiotic, a topoisomerase inhibitor, an aromatase inhibitor, an angiogenesis inhibitor, an anti-steroid, an anti- androgen, an mTOR inhibitor, monoclonal antibodies, a kinase inhibitor, a HIF2a inhibitor, or a tyrosine kinase inhibitor. An alkylating agent may be, for example, armustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, or cyclophosphamidePage 58 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1(ENDOXAN). An anti-metabolite may be, for example, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate (RHEUMATREX), or raltitrexed. An antimitotic may be, for example, a taxane such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL), or a vinca alkaloid such as vincristine (ONCOVIN), vinblastine, vindesine, or vinorelbine (NAVELBINE). A checkpoint inhibitor may be an anti-PD-1 or anti-PD-Ll antibody such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, or MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); or an agent that targets LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin- like receptor), 4- IBB (tumor necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3), or 0X40 (tumor necrosis factor receptor superfamily member 4). A topoisomerase inhibitor may be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), or etoposide (EPOSIN). A cytotoxic antibiotic may be, for example, actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or plicamycin. An aromatase inhibitor may be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN). An angiogenesis inhibitor may be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN). An anti-steroid or anti-androgen may be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON). A tyrosine kinase inhibitor may be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA). An mTOR inhibitor may be, for example, everolimus, temsirolimus (TORISEL), or sirolimus. Monoclonal antibody may be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). A kinase inhibitor may be, for example, a BRAF inhibitor, MEK inhibitor, or a KRAS inhibitor (e.g., KRAS G12C inhibitor, such as sotorasib, adagrasib, or BBO-8520). Additional examples of agents that may be useful in combination with a compound provided herein include, but are not limited to, amsacrine; Bacillus Calmette-Guerin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxy viridin;Page 59 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,r'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone.

[0146] In an aspect, the present disclosure provides a method of treating a disease, disorder, or condition (e.g., cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0147] In an aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the NSCLC is KRAS mutant NSCLC. In some embodiments, the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS. In some embodiments, the NSCLC is KRAS G12C mutant NSCLC. In some embodiments, the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

[0148] In an aspect, the present disclosure provides a method of treating colorectal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is KRAS mutant colorectal cancer. In some embodiments, the subject does not have a BRAF V600E mutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMR) / microsatellite instability-high (MSLH) tumors.

[0149] In an aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is HR+ / HER2- breast cancer or HER2+ breast cancer. In somePage 60 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 embodiments, the cancer is HR+ / HER2- breast cancer. In some embodiments, the cancer is HER2+ breast cancer. In some embodiments, the subject has had at least 2 prior lines of anti- HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care. In some embodiments, the subject has left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks before administration of the compound.

[0150] In some embodiments, for any of the preceding aspects, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is formulated as a tablet or capsule. In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0151] In some embodiments, for any of the preceding aspects, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily. In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is administered twice daily.

[0152] In some embodiments, for any of the preceding aspects, administration of Compound 1, or the pharmaceutically acceptable salt thereof, occurs according to a treatment cycle. In some embodiments, the treatment cycle is 21 days. In some embodiments, the treatment cycle is 28 days.

[0153] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is at least about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is at least about 50 mg. In some embodiments, thePage 61 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is at least about 100 mg.

[0154] In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is administered in a total daily dosage of at least about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg,725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, or 1200 mg of Compound 1. In some embodiments, the total daily dosage is at least about 50 mg of Compound 1. In some embodiments, the total daily dosage is at least about 100 mg of Compound 1. In some embodiments, the total daily dosage is at least about 150 mg of Compound 1. In some embodiments, the total daily dosage is at least about 300 mg of Compound 1. In some embodiments, the total daily dosage is at least about 500 mg of Compound 1. In some embodiments, the total daily dosage is at least about 750 mg ofCompound 1. In some embodiments, the total daily dosage is at least about 1000 mg of Compound 1.

[0155] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is at most about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0156] In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is administered in a total daily dosage of at most about 100 milligram (mg), 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg,Page 62 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg of Compound 1. In some embodiments, the total daily dosage is at most about 1000 mg of Compound 1. In some embodiments, the total daily dosage is at most about 1200 mg of Compound 1.

[0157] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is between about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70-1500 mg, about 80-1500 mg, about 90-1500 mg, about 100- 1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, about 300-1500 mg, about 325-1500 mg, about 350-1500 mg, about 375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525-1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about 1000-1500 mg, about 1025-1500 mg, about 1050-1500 mg, about 1075-1500 mg, 1100-1500 mg, about 1125-1500 mg, about 1150-1500 mg, about 1175-1500 mg, about 1200-1500 mg, about 1225-1500 mg, about 1250-1500 mg, about 1275-1500 mg, about 1300-1500 mg, about 1325-1500 mg, about 1350-1500 mg, about 1375-1500 mg, about 1400-1500 mg, about 1425-1500 mg, about 1450-1500 mg, about 1475-1500 mg, about 1-1200 mg, about 10-1200 mg, about 20-1200 mg, about 30-1200 mg, about 40-1200 mg, about 50-1200 mg, about 60- 1200 mg, about 70-1200 mg, about 80-1200 mg, about 90-1200 mg, about 100-1200 mg, about 125-1200 mg, about 150-1200 mg, about 175-1200 mg, about 200-1200 mg, about 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475-1200 mg, about 500- 1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725-1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, about 875-1200 mg, aboutPage 63 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000- 1200 mg, about 1025-1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1-1000 mg, about 10-1000 mg, about 20-1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100- 1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550-1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg, about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50- 750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100- 750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200-750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375-750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575- 750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675-750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20-500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70-500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200-500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400- 500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1-300 mg, about 10-300 mg, about 20-300 mg, about 30-300 mg, about 40-300 mg, about 50-300 mg, about 60-300 mg, about 70-300 mg, about 80-300 mg, about 90-300 mg, about 100-300 mg, about 125-300 mg, about 150-300 mg, about 175-300 mg, about 200-300 mg, about 225-300 mg, about 250-300 mg, about 275-300 mg, about 1-150 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40-150 mg, about 50-150 mg, about 60-150 mg, about 70-150 mg, about 80-150 mg, about 90-150 mg, about 100-150 mg, about 125-150 mg, about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-Page 64 of 18513005782vlPATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg. In some embodiments, the total daily dosage of Compound 1 , or a pharmaceutically acceptable salt thereof, is between about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900- 1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg.

[0158] In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is administered in a total daily dosage in an range of about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70-1500 mg, about 80-1500 mg, about 90- 1500 mg, about 100-1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, about 300-1500 mg, about 325-1500 mg, about 350-1500 mg, about 375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525-1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about 1000-1500 mg, about 1025-1500 mg, about 1050-1500 mg, about 1075- 1500 mg, 1100-1500 mg, about 1125-1500 mg, about 1150-1500 mg, about 1175-1500 mg, about 1200-1500 mg, about 1225-1500 mg, about 1250-1500 mg, about 1275-1500 mg, about 1300-1500 mg, about 1325-1500 mg, about 1350-1500 mg, about 1375-1500 mg, about 1400-1500 mg, about 1425-1500 mg, about 1450-1500 mg, about 1475-1500 mg, about 1- 1200 mg, about 10-1200 mg, about 20-1200 mg, about 30-1200 mg, about 40-1200 mg, about 50-1200 mg, about 60-1200 mg, about 70-1200 mg, about 80-1200 mg, about 90-1200 mg, about 100-1200 mg, about 125-1200 mg, about 150-1200 mg, about 175-1200 mg, about 200-1200 mg, about 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475- 1200 mg, about 500-1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725-1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, aboutPage 65 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1875-1200 mg, about 900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000-1200 mg, about 1025-1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1- 1000 mg, about 10-1000 mg, about 20-1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100-1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550-1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700- 1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg, about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50-750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100-750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200- 750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375-750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575-750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675- 750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20- 500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70- 500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200-500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400-500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1- 300 mg, about 10-300 mg, about 20-300 mg, about 30-300 mg, about 40-300 mg, about SO- SOO mg, about 60-300 mg, about 70-300 mg, about 80-300 mg, about 90-300 mg, about 100- 300 mg, about 125-300 mg, about 150-300 mg, about 175-300 mg, about 200-300 mg, about 225-300 mg, about 250-300 mg, about 275-300 mg, about 1-150 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40-150 mg, about 50-150 mg, about 60-150 mg, about 70-150 mg, about 80-150 mg, about 90-150 mg, about 100-150 mg, about 125-150 mg, about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg,Page 66 of 18513005782vlPATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900- 1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg of Compound 1. In some embodiments, the total daily dosage is in an arrange of about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975- 1025 mg, about 1100-1300 mg, or about 1175-1225 mg of Compound 1.

[0159] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, or 1200 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 500 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 750 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1000 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1200 mg.

[0160] In some embodiments, Compound 1, or the pharmaceutically acceptable salt thereof, is administered in a total daily dosage of about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg,750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000Page 67 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg of Compound 1. In some embodiments, the total daily dosage is about 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, or 1200 mg of Compound 1. In some embodiments, the total daily dosage is about 100 mg of Compound 1. In some embodiments, the total daily dosage is about 150 mg of Compound 1. In some embodiments, the total daily dosage is about 300 mg of Compound 1. In some embodiments, the total daily dosage is about 500 mg of Compound 1. In some embodiments, the total daily dosage is about 750 mg of Compound 1. In some embodiments, the total daily dosage is about 1000 mg of Compound 1. In some embodiments, the total daily dosage is about 1200 mg of Compound 1.

[0161] In some embodiments, when the subject experiences an adverse event, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at a reduced dose comprising 50% of the initial dose level that was administered to the subject. In some embodiments, when the subject experiences a second adverse event, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject at reduced dose comprising 25% of the initial dose level that was administered to the subject. In some embodiments, the subject is treated with the reduced dose until the adverse event is resolved. In some embodiments, the subject resumes the initial dose level after the adverse event is resolved. In some embodiments, the adverse event is nausea, vomiting, diarrhea lasting longer than 3 days, anemia, febrile neutropenia, thrombocytopenia with or without clinically significant bleeding, or a hematologic adverse reaction.

[0162] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a unit dosage form. In some embodiments, the unit dosage form is a tablet. In some embodiments, the tablet comprises about 25 milligrams (mg), about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 50 mg or about 150 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 25 milligrams (mg), about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of Compound 1. In some embodiments, the tablet comprises about 50 mg of Compound 1. In some embodiments, the tablet comprises about 100 mg of Compound 1. In some embodiments, the tablet comprises about 150 mg of Compound 1.Page 68 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0163] In some embodiments, the subject has progression on or disease recurrence after, all available standard of care treatments or would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. In some embodiments, the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy. In some embodiments, the cancer is a measurable disease by RECIST v 1.1.

[0164] In some embodiments, a subject has previously undergone a treatment regimen for a cancer. In some embodiments, a subject has previously entered remission from a cancer.

[0165] In some embodiments, the subject has not previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0166] In some embodiments, the subject has previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0167] In some embodiments, the subject is a human. In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject has been diagnosed with the cancer. In some embodiments, the subject has adequate organ function as follows: a. Hematological:- Absolute neutrophil count (ANC) >1 500 / microliter (pL)- Platelets >100 000 / pL- Hemoglobin >9 grams per deciliter (g / dL) without transfusion for at least 2 weeks before enrollment or without erythropoiesis-stimulating agents (eg, Epo, Procrit®) for at least 6 weeks before enrollment. b. Renal:- Creatinine clearance >50 milliliters per minute (mL / min) calculated using the Cockcroft- Gault formula [(140 - age) x (weight in kilogram ((kg) x (0.85 if female) / 72 x (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection c. Hepatic:- Serum total bilirubin <1.5 x institutional upper limit of normal (ULN) or <2.0 x ULN if the subject has a diagnosis of Gilbert syndrome or <3.0 x ULN forPage 69 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 subjects with liver metastases.- Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic -pyruvic transaminase (SGPT) <3.0xULN or AST and / or ALT <3.0xULN with documented liver metastases. d. Coagulation:- International normalized ratio (INR) or prothrombin time (PT) <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants.- aPTT <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.Monotherapy of BBO-10203

[0168] In a first aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (X):or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of the compound.

[0169] In some embodiments, the compound is Compound 1:Page 70 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of Formula (X) is Compound 1.

[0171] In some embodiments, the cancer is described according to any one of embodiments herein in Section - Uses and Methods of Treatment.

[0172] In some embodiments, the cancer is breast cancer, lung cancer, endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, melanoma, glioblastoma, sarcomas, or pancreatic cancer.

[0173] In some embodiments, the cancer is breast cancer, lung cancer, or colorectal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) cancer. In some embodiments, the cancer is colorectal cancer.

[0174] In some embodiments, the cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified cancer. In some embodiments, the cancer is HER2 positive cancer. In some embodiments, the cancer is HER2 amplified cancer.

[0175] In some embodiments, the cancer is a hormone receptor (HR) positive cancer. In some embodiments, the cancer is HR positive and HER2 negative cancer. In some embodiments, the cancer is HR positive and HER2 positive cancer.

[0176] In some embodiments, the cancer is an estrogen receptor (ER) positive cancer. In some embodiments, the cancer is ER positive and HER2 negative cancer. In some embodiments, the cancer is ER positive and HER2 positive cancer.Page 71 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0177] In some embodiments, the cancer is ER negative cancer. In some embodiments, the cancer is ER negative and HER2 positive cancer.

[0178] In some embodiments, the cancer is characterized by a mutation in a HER2 protein.

[0179] In some embodiments, the cancer is characterized by a mutation in a KRAS protein.

[0180] In some embodiments, the cancer is characterized by a mutation in a KRAS protein and further characterized by amplified HER2.

[0181] In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation.

[0182] In some embodiments, the cancer is characterized by a G12C, G12D, G12V, and / or G13D mutation in a KRAS protein. In some embodiments, the cancer is characterized by KRAS G12C mutation. In some embodiments, the cancer is a KRAS G12C positive cancer.Breast Cancer

[0183] In some embodiments, the cancer is breast cancer.

[0184] In a second aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.Page 72 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0185] In some embodiments, the breast cancer is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the breast cancer is described in Example 4.

[0186] In some embodiments, the breast cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified breast cancer. In some embodiments, the breast cancer is HER2 positive breast cancer. In some embodiments, the breast cancer is HER2 amplified breast cancer.

[0187] In some embodiments, the breast cancer is a hormone receptor (HR) positive breast cancer. In some embodiments, the breast cancer is HR positive and HER2 negative breast cancer. In some embodiments, the breast cancer is HR positive and HER2 positive breast cancer.

[0188] In some embodiments, the breast cancer is an estrogen receptor (ER) positive breast cancer. In some embodiments, the breast cancer is ER positive and HER2 negative breast cancer. In some embodiments, the breast cancer is ER positive and HER2 positive breast cancer.

[0189] In some embodiments, the breast cancer is ER negative breast cancer. In some embodiments, the breast cancer is ER negative and HER2 positive breast cancer.

[0190] In some embodiments, the breast cancer is characterized by a mutation in a HER2 protein.

[0191] In some embodiments, the breast cancer is an advanced or metastatic breast cancer.

[0192] In some embodiments, the subject is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the subject is described in Example 4. In some embodiments, the subject meets inclusion criteria, as described in Example 4. In some embodiments, the subject meets both inclusion and exclusive criteria, as described in Example 4.

[0193] In some embodiments, the subject has had at least 2 prior lines of anti-HER2- directed therapy, or 1 prior line where there is no other regionally available standard of care.Page 73 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0194] In some embodiments, the subject has progression after or intolerance of at least 2 prior lines of anti-HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care.

[0195] For treating HER2 positive breast cancer, in some embodiments, the subject has had at least 2 prior lines of anti-HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care.

[0196] For treating HER2 positive breast cancer, in some embodiments, the subject has progression after or intolerance of at least 2 prior lines of anti-HER2 -directed therapy, or 1 prior line where there is no other regionally available standard of care.

[0197] For treating HR positive and HER2 negative breast cancer, the subject has progression on or disease recurrence after available standard of care (SoC) treatments; or the subject is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

[0198] For treating all types of breast cancer, in some embodiments, the subject has left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA), documented within 4 weeks prior to administration of the compound or Compound 1.Colorectal Cancer

[0199] In some embodiments, the cancer is colorectal cancer.

[0200] In a third aspect, the present disclosure provides a method of treating colorectal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1 :Page 74 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0201] In some embodiments, the colorectal cancer is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the colorectal cancer is described in Example 4.

[0202] In some embodiments, the colorectal cancer is characterized by a mutation in a KRAS protein.

[0203] In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation.

[0204] In some embodiments, the colorectal cancer is characterized by a G12C, G12D, G12V, and / or G13D mutation in a KRAS protein. In some embodiments, the colorectal cancer is characterized by KRAS G12C mutation. In some embodiments, the colorectal cancer is a KRAS G12C positive cancer.

[0205] In some embodiments, the colorectal cancer is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor. In some embodiments, the colorectal cancer is resistant to a KRAS G12C inhibitor. In some embodiments, the colorectal cancer is resistant to sotorasib, adagrasib, or divarasib.

[0206] In some embodiments, the colorectal cancer is an advanced or metastatic colorectal cancer.Page 75 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0207] In some embodiments, the subject is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the subject is described in Example 4. In some embodiments, the subject meets inclusion criteria, as described in Example 4. In some embodiments, the subject meets both inclusion and exclusive criteria, as described in Example 4.

[0208] In some embodiments, the subject has progression on or disease recurrence after available standard of care (SoC) treatments; or the subject is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

[0209] In some embodiments, the subject does not have a BRAF V600E mutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMR) / microsatellite instability- high (MSI-H) tumors.Non-small Cell Lung Cancer (NSCLC)

[0210] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0211] In a furth aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, method comprising administering to the subject a therapeutically effective amount of Compound 1:or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0212] In some embodiments, the NSCLC is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the NSCLC is described in Example 4.Page 76 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0213] In some embodiments, the NSCLC is characterized by a mutation in a KRAS protein.

[0214] In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation.

[0215] In some embodiments, the NSCLC is characterized by a G12C, G12D, G12V, and / or G13D mutation in a KRAS protein. In some embodiments, the NSCLC is characterized by KRAS G12C mutation. In some embodiments, the NSCLC is a KRAS G12C positive cancer.

[0216] In some embodiments, the NSCLC is characterized by a mutation in a KRAS protein and further characterized by amplified HER2.

[0217] In some embodiments, the NSCLC is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor. In some embodiments, the NSCLC is resistant to a KRAS G12C inhibitor. In some embodiments, the NSCLC is resistant to sotorasib, adagrasib, or divarasib.

[0218] In some embodiments, the NSCLC is an advanced or metastatic NSCLC.

[0219] In some embodiments, the subject is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the subject is described in Example 4. In some embodiments, the subject meets inclusion criteria, as described in Example 4. In some embodiments, the subject meets both inclusion and exclusive criteria, as described in Example 4.

[0220] In some embodiments, the subject has progression on or disease recurrence after available standard of care (SoC) treatments; or the subject is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

[0221] In some embodiments, the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS 1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).Page 77 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0222] For treating all types of cancer (e.g., breast cancer, colorectal cancer, and NSCLC), in some embodiments, the subject has not previously been treated with the compound of Formula (X), Compound 1, or a pharmaceutically acceptable salt thereof.

[0223] For treating all types of cancer (e.g., breast cancer, colorectal cancer, and NSCLC), in some embodiments, the subject is a human. In some embodiments, the subject is an adult of at least 18 years old.Compound of Formula (X) and Compound 1

[0224] In some embodiments, the compound of Formula (X), Compound 1, or a pharmaceutically acceptable salt thereof, is capable of:1) disrupting, inhibiting, and / or preventing an interaction between a small GTPase and aPI3Ka protein;2) interacting with a Cys242 residue in the catalytic subunit of PI3Ka; and / or3) irreversibly binding to the PI3Ka protein.

[0225] In some embodiments, the small GTPase and a PI3Ka protein are each described according to any one of embodiments herein in Section - PI3K and Small GTPase Proteins.

[0226] In some embodiments, the small GTPase is Rael, CDC42, or a RAS protein.

[0227] In some embodiments, the small GTPase is a RAS protein.

[0228] In some embodiments, the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MR AS, or RITE

[0229] In some embodiments, the RAS protein is KRAS, NRAS, or HRAS.

[0230] In some embodiments, the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, EllOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

[0231] In some embodiments, the PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.Administration

[0232] In some embodiments, the administration of the compound of Formula (X), Compound 1, or a or a pharmaceutically acceptable salt thereof is described according to anyPage 78 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the administration of Compound 1 (or a pharmaceutically acceptable salt thereof) is described in Example 4.

[0233] In some embodiments, the compound of Formula (X), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount, with a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0234] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount, with a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0235] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 50 mg to about 2000 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 1500 mg, from about 50 mg to about 1200 mg, from about 100 mg to about 1200 mg, from about 150 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 750 mg to about 1200 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 100 mg to about 750 mg, from about 150 mg to about 750 mg, from about 300 mg to about 750 mg, from about 500 mg to about 750 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 150 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 150 mg, or from about 100 mg to about 150 mg of the compound of Formula (X) or Compound 1 .

[0236] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 50 mg to about 2000 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 1500 mg, from about 50 mg to about 1200 mg, from about 100 mg to about 1200 mg, from about 150 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 750 mg to about 1200 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 100 mg to about 750 mg, from about 150 mg to about 750 mg, from about 300 mg to about 750 mg, from about 500Page 79 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 mg to about 750 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 150 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 150 mg, or from about 100 mg to about 150 mg of the compound of Compound 1.

[0237] In some embodiments, the therapeutically effective amount is a total daily dosage of about 50 mg, about 100 mg, about 150 mg, about 300 mg, about 500 mg, about 750 mg, about 1000 mg, or about 1200 mg of the compound of Formula (X) or Compound 1.

[0238] In some embodiments, the therapeutically effective amount is a total daily dosage of about 50 mg, about 100 mg, about 150 mg, about 300 mg, about 500 mg, about 750 mg, about 1000 mg, or about 1200 mg of Compound 1.

[0239] In some embodiments, the therapeutically effective amount is a total daily dosage of about 50 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 100 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 150 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 300 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 500 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 750 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 1000 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 1200 mg of Compound 1.

[0240] In some embodiments, the compound of Formula (X), Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0241] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0242] In some embodiments, the compound of Formula (X), Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

[0243] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily. In some embodiments, Compound 1, or aPage 80 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.Treatment

[0244] In some embodiments, the treatment (e.g., treatment cycle, duration, dose escalation or de-escalation) is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the treatment is described in Example 4.

[0245] In some embodiments, the treatment comprises one or more treatment cycles; and the administration of the compound of Formula (X) or Compound 1 comprises a dose escalation or de-escalation after a previous treatment cycle, wherein the dose escalation or de- escalation is determined by a dose-limiting toxicity (DLT) assessment.

[0246] In some embodiments, the treatment comprises one or more treatment cycles; and the administration of Compound 1 comprises a dose escalation or de-escalation after a previous treatment cycle, wherein the dose escalation or de-escalation is determined by a dose-limiting toxicity (DLT) assessment (as described herein).

[0247] In some embodiments of any one of the first to fourth aspects and the embodiments thereof, the method comprises administering a therapeutically effective amount of Compound 1 to the subject, wherein the therapeutically effective amount is described herein.Embodiments

[0248] Embodiment 1. A method, comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein to a subject in need thereof.

[0249] Embodiment 2. The method of embodiment 1, wherein the compound, or pharmaceutically acceptable salt thereof, is capable of binding to PI3Ka, such that (i) the interaction between the small GTPase and PI3Ka is at least partially disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of PI3Ka is not significantly inhibited.

[0250] Embodiment 3. The method of embodiment 2, wherein the compound, or pharmaceutically acceptable salt thereof, is capable of binding to PI3Ka, such that thePage 81 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 interaction between the small GTPase and PI3Ka is at least partially disrupted, inhibited, and / or prevented.

[0251] Embodiment 4. The method of embodiment 2 or 3, wherein the compound, or pharmaceutically acceptable salt thereof, is capable of binding to PI3Ka, such that the kinase activity of PI3Ka is not significantly inhibited.

[0252] Embodiment 5. The method of any one of embodiments 1-4, wherein the compound, or pharmaceutically acceptable salt thereof, demonstrates (i) modification of > 75%, 50% < modification < 75%, or 25% < modification < 50% of PIK3CA protein in the assay of Example 2; and / or (ii) pAKT inhibition IC50 value of < 0.1 pM or 0.1 pM < IC50 value < 1 pM, or 1 pM < IC50 value < 3 pM in the assay of Example 3.

[0253] Embodiment 6. The method of embodiment 5, wherein the compound, or pharmaceutically acceptable salt thereof, demonstrates (i) modification of > 75% or 50% < modification < 75% of PIK3CA protein in the assay of Example 2; and / or (ii) pAKT inhibition IC50 value of < 0.1 pM or 0.1 pM < IC50 value < 1 pM in the assay of Example 3.

[0254] Embodiment 7. The method of embodiment 6, wherein the compound, or pharmaceutically acceptable salt thereof, demonstrates (i) modification of > 75% of PIK3CA protein in the assay of Example 2; and / or (ii) pAKT inhibition IC50 value of < 0.1 pM in the assay of Example 3.

[0255] Embodiment 8. The method of any one of embodiments 1-7, wherein the compound, or pharmaceutically acceptable salt thereof, comprises an electrophilic moiety.

[0256] Embodiment 9. The method of embodiment 8, wherein the compound, or pharmaceutically acceptable salt thereof, is capable of interacting with a Cys242 residue in the catalytic subunit of PI3Ka.

[0257] Embodiment 10. The method of any one of embodiments 1-9, wherein the compound, or pharmaceutically acceptable salt thereof, is capable of irreversibly binding the PI3Ka protein.

[0258] Embodiment 11. The method of any one of embodiments 1-9, wherein the compound, or pharmaceutically acceptable salt thereof, is capable of reversibly binding the PI3Ka protein.Page 82 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0259] Embodiment 12. The method of any one of embodiments 1-11, wherein the PI3Ka protein is aberrantly activated.

[0260] Embodiment 13. The method of any one of embodiments 1-12, wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

[0261] Embodiment 14. The method of embodiment 13, wherein the PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0262] Embodiment 15. The method of any one of embodiments 1-14, wherein the small GTPase is Rael, CDC42, or a RAS protein.

[0263] Embodiment 16. The method of embodiment 15, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITE

[0264] Embodiment 17. The method of embodiment 16, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

[0265] Embodiment 18. The method of embodiment 16 or 17, wherein the RAS protein is KRAS.

[0266] Embodiment 19. The method of embodiment 18, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q611P, Q61R, and / or Q61H mutation.

[0267] Embodiment 20. The method of embodiment 19, wherein the KRAS protein comprises a G12C, G12D, G12V, or G12R mutation.

[0268] Embodiment 21. The method of embodiment 20, wherein the KRAS protein comprises a G12C or G12D mutation.

[0269] Embodiment 22. The method of embodiment 18, wherein the KRAS protein is a wild-type KRAS protein.

[0270] Embodiment 23. The method of embodiment 16 or 17, wherein the RAS protein is HRAS.Page 83 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0271] Embodiment 24. The method of embodiment 23, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, GI3R. G13S, GEV, Q61K, Q61L, Q61P, Q61R, and / or Q61H.

[0272] Embodiment 25. The method of embodiment 23, wherein the HRAS protein is a wild-type HRAS protein.

[0273] Embodiment 26. The method of embodiment 16 or 17, wherein the RAS protein is NRAS.

[0274] Embodiment 27. The method of embodiment 26, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H.

[0275] Embodiment 28. The method of embodiment 26, wherein the NRAS protein is a wild-type NRAS protein.

[0276] Embodiment 29. The method of any one of embodiments 1-28, wherein the compound is a compound of Formula I:or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:Ring A is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is selected from a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and phenyl;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered bicyclic carbocyclic ring; a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, andPage 84 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 sulfur; and a 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl, heteroaryl, and heterocyclic rings is optionally fused to Ring E;Ring D is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and phenyl, wherein each of the heteroaryl and phenyl rings is optionally fused to Ring F;Ring E is selected from a 5- to 6-membered carbocyclic ring; a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5;Ring F is selected from phenyl; a 5- to 6-membered carbocyclic ring; a 5- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W and y instances of R2;R1is selected from -L-W, Ring D', or a bivalent Ci-6 aliphatic chain substituted with Ring D'; each -L-W is -CN, or: each L is independently a bivalent straight or branched Ci-8 aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)- , -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, - C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN;Page 85 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 each Ring D' is independently a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D' is substituted with t instances of -L- W ; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and Ci-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, - OCH2CH2OR, and optionally substituted C1-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, - N(R)2, -SR, -C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -C(O)N(R)2, - C(O)N(R)(CH2)xCy, -(CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, - N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, -P(O)R2, -(CH2)xCy, -O(CH2)xCy, and optionally substituted C1-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, - SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci- 6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3Page 86 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10- membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1 ; r is 0, 1, or 2; s is 0, 1, 2, or 3; t is 0, 1, or 2; u is 0 or 1 ; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; and y is 0, 1, or 2.

[0277] Embodiment 30. The method of embodiment 29, wherein the compound is a compound according to Formula I-a-v':or a salt (e.g., pharmaceutically acceptable salt) thereof.

[0278] Embodiment 31. The method of embodiment 29 or 30, wherein the compound is a compound according to Formula IF or IF1:Page 87 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1or a salt (e.g., pharmaceutically acceptable salt) thereof.

[0279] Embodiment 32. The method of embodiment 29 or 30, wherein Ring A is phenyl.

[0280] Embodiment 33. The method of embodiment 32, wherein Ring A is selected

[0281] Embodiment 34. The method of any one of embodiments 29-33, wherein at least one R3is selected from halogen, -OR, -O(CH2)vCy, and -O-(Ci-4 alkylene)-OR.

[0282] Embodiment 35. The method of any one of embodiments 29-34, wherein Ring C is phenyl.

[0283] Embodiment 36. The method of any one of embodiments 29-35, wherein Ring C is fused to Ring E.

[0284] Embodiment 37. The method of embodiment 35 or 36, wherein Ring E is selected from a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5.Page 88 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0285] Embodiment 38. The method of any one of embodiments 29-37, wherein

[0286] Embodiment 39. The method of any one of embodiments 29-38, wherein eachRsis independently selected from Ci-6 aliphatic.

[0287] Embodiment 40. The method of any one of embodiments 29-39, wherein Ring D is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0288] Embodiment 41. The method of any one of embodiments 29-40, wherein Ring D is fused to Ring F.

[0289] Embodiment 42. The method of any one of embodiments 29-41, wherein q is 0.

[0290] Embodiment 43. The method of any one of embodiments 29-42, wherein eachR2is independently selected from Ci-6 alkyl.Page 89 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0291] Embodiment 44. The method of any one of embodiments 29-43, wherein y is 1 or 2 and r is 0.

[0292] Embodiment 45. The method of any one of embodiments 29-44, wherein each -L-W is independently selected from -C(O)CH=CH2, -C(O)CF=CH2, -NHC(O)CF=CH2, and -NHC(O)CH=CH2.

[0293] Embodiment 46. The method of any one of embodiments 29-45, whereinPage 90 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0294] Embodiment 47. The method of any one of embodiments 1-46, wherein the compound is Compound 1 :Page 91 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1(Compound 1), or a pharmaceutically acceptable salt thereof.

[0295] Embodiment 48. The method of embodiment 47, wherein the compound is Compound 1.

[0296] Embodiment 49. The method of any one of embodiments 1-48, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered orally.

[0297] Embodiment 50. The method of any one of embodiments 1-49, wherein the compound, or the pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0298] Embodiment 51. The method of any one of embodiments 1-50, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily.

[0299] Embodiment 52. The method of any one of embodiments 1-51, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once daily.

[0300] Embodiment 53. The method of any one of embodiments 1-51, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered twice daily.

[0301] Embodiment 54. The method of any one of embodiments 1-53, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, occurs according to a treatment cycle.

[0302] Embodiment 55. The method of embodiment 54, wherein the treatment cycle is 21 days.

[0303] Embodiment 56. The method of embodiment 54, wherein the treatment cycle is 28 days.Page 92 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0304] Embodiment 57. The method of any one of embodiments 1-56, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg,625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg,1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0305] Embodiment 58. The method of embodiment 57, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 mg.

[0306] Embodiment 59. The method of embodiment 57, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 100 mg.

[0307] Embodiment 60. The method of any one of embodiments 1-59, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg,625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg,1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0308] Embodiment 61. The method of embodiment 60, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0309] Embodiment 62. The method of any one of embodiments 1-61, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is between about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70-1500 mg, about 80-1500 mg, about 90-1500 mg, about 100-1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, about 300-1500 mg, about 325-1500 mg, about 350-1500 mg, aboutPage 93 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525-1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about 1000-1500 mg, about 1025-1500 mg, about 1050-1500 mg, about 1075-1500 mg, 1100-1500 mg, about 1125-1500 mg, about 1150-1500 mg, about 1175-1500 mg, about 1200-1500 mg, about 1225-1500 mg, about 1250-1500 mg, about 1275-1500 mg, about 1300-1500 mg, about 1325-1500 mg, about 1350-1500 mg, about 1375-1500 mg, about 1400-1500 mg, about 1425-1500 mg, about 1450-1500 mg, about 1475-1500 mg, about 1-1200 mg, about 10-1200 mg, about 20-1200 mg, about 30-1200 mg, about 40-1200 mg, about 50-1200 mg, about 60-1200 mg, about 70- 1200 mg, about 80-1200 mg, about 90-1200 mg, about 100-1200 mg, about 125-1200 mg, about 150-1200 mg, about 175-1200 mg, about 200-1200 mg, about 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475-1200 mg, about 500-1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725-1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, about 875-1200 mg, about 900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000-1200 mg, about 1025- 1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1-1000 mg, about 10-1000 mg, about 20- 1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100-1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550- 1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg,Page 94 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50-750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100-750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200-750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375- 750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575-750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675-750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20-500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70-500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200- 500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400-500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1-300 mg, about 10-300 mg, about 20-300 mg, about 30-300 mg, about 40-300 mg, about 50-300 mg, about 60-300 mg, about 70-300 mg, about 80-300 mg, about 90-300 mg, about 100-300 mg, about 125-300 mg, about 150-300 mg, about 175-300 mg, about 200-300 mg, about 225-300 mg, about 250-300 mg, about 275- 300 mg, about 1-150 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40- 150 mg, about 50-150 mg, about 60-150 mg, about 70-150 mg, about 80-150 mg, about 90- 150 mg, about 100-150 mg, about 125-150 mg, about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975-1025 mg, about HOODOO mg, or about 1175-1225 mg.

[0310] Embodiment 63. The method of any one of embodiments 1-62, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is between about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900- 1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg.

[0311] Embodiment 64. The method of any one of embodiments 1-63, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,Page 95 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0312] Embodiment 65. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, or 1200 mg.

[0313] Embodiment 66. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0314] Embodiment 67. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150 mg.

[0315] Embodiment 68. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg.

[0316] Embodiment 69. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg.

[0317] Embodiment 70. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750 mg.

[0318] Embodiment 71. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1000 mg.

[0319] Embodiment 72. The method of any one of embodiments 1-64, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1200 mg.Page 96 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0320] Embodiment 73. The method of any one of embodiments 1-72, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in a unit dosage form.

[0321] Embodiment 74. The method of embodiment 73, wherein the unit dosage form is a tablet.

[0322] Embodiment 75. The method of embodiment 74, wherein the tablet comprises about 25 milligrams (mg), about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0323] Embodiment 76. The method of embodiments 74 or 75, wherein the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0324] Embodiment 77. The method of any one of embodiments 1-76, wherein, when the subject experiences an adverse event, the compound is administered to the subject at a reduced dose comprising 50% of the initial dose level that was administered to the subject.

[0325] Embodiment 78. The method of any one of embodiments 1-77, wherein, when the subject experiences a second adverse event, the compound is administered to the subject at reduced dose comprising 25% of the initial dose level that was administered to the subject.

[0326] Embodiment 79. The method of embodiments 77 or 78, wherein the subject is treated with the reduced dose until the adverse event is resolved.

[0327] Embodiment 80. The method of any one of embodiments 77-79, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0328] Embodiment 81. The method of any one of embodiments 77-80, wherein the adverse event is nausea, vomiting, diarrhea lasting longer than 3 days, anemia, febrile neutropenia, thrombocytopenia with or without clinically significant bleeding, or a hematologic adverse reaction.

[0329] Embodiment 82. The method of any one of embodiments 1-81, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, treats a disease, disorder, or condition in the subject.Page 97 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0330] Embodiment 83. The method of embodiment 82, wherein the disease, disorder, or condition is a cancer.

[0331] Embodiment 84. The method of embodiment 83, wherein the cancer is selected from the group consisting of pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non-Hodgkin’ s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas.

[0332] Embodiment 85. The method of embodiment 83, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, melanoma, glioblastoma, sarcomas, and pancreatic cancer.

[0333] Embodiment 86. The method of embodiment 83, wherein the cancer is lung cancer.

[0334] Embodiment 87. The method of embodiment 83, wherein the cancer is non-small cell lung cancer (NSCLC).

[0335] Embodiment 88. The method of embodiment 87, wherein the NSCLC is KRAS mutant NSCLC.

[0336] Embodiment 89. The method of embodiment 88, wherein the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS.

[0337] Embodiment 90. The method of embodiment 88 or 89, wherein the NSCLC isKRAS G12C mutant NSCLC.Page 98 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0338] Embodiment 91. The method of any one of embodiments 82-90, wherein the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

[0339] Embodiment 92. The method of embodiment 83, wherein the cancer is colorectal cancer.

[0340] Embodiment 93. The method of embodiment 92, wherein the cancer is KRAS mutant colorectal cancer.

[0341] Embodiment 94. The method of embodiment 92 or 93, wherein the subject does not have a BRAF V600E mutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) tumors.

[0342] Embodiment 95. The method of embodiment 83, wherein the cancer is breast cancer.

[0343] Embodiment 96. The method of embodiment 95, wherein the cancer is HR+ / HER2- breast cancer or HER2+ breast cancer.

[0344] Embodiment 97. The method of embodiment 95 or 96, wherein the cancer is HR+ / HER2- breast cancer.

[0345] Embodiment 98. The method of embodiment 95, wherein the cancer is human epidermal growth factor receptor 2 (HER2) positive (Her2+) breast cancer.

[0346] Embodiment 99. The method of embodiment 98, wherein the subject has had at least 2 prior lines of anti-HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care.

[0347] Embodiment 100. The method of embodiment 98 or 99, wherein the subject has left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks before administration of the compound.

[0348] Embodiment 101. The method of any one of embodiments 98-100, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases).Page 99 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0349] Embodiment 102. The method of any one of embodiments 98-101, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified cancer.

[0350] Embodiment 103. The method of any one of embodiments 98-102, wherein the cancer is characterized by a mutant KRAS protein.

[0351] Embodiment 104. The method of any one of embodiments 98-103, wherein the cancer is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor.

[0352] Embodiment 105. The method of any one of embodiments 98-104, wherein the cancer is a KRAS G12C positive cancer resistant to a KRAS G12C inhibitor.

[0353] Embodiment 106. The method of embodiment 105, wherein the cancer is a KRAS G12C positive cancer characterized by acquired and / or intrinsic resistance to a KRAS G12C inhibitor.

[0354] Embodiment 107. The method of embodiment 106, wherein the cancer is a KRAS G12C positive cancer resistant to a KRAS G12C inhibitor that inhibits the inactive state (e.g., GDP-bound state) of KRAS.

[0355] Embodiment 108. The method of any one of embodiments 104-107, wherein the cancer is a KRAS G12C positive cancer resistant to sotorasib, adagrasib, or divarasib.

[0356] Embodiment 109. The method of any one of embodiments 1-108, wherein the subject has progression on or disease recurrence after, all available standard of care treatments or would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

[0357] Embodiment 110. The method of any one of embodiments 83-109, wherein the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy.

[0358] Embodiment 111. The method of any one of embodiments 83-110, wherein the cancer is a measurable disease by RECIST vl.l.

[0359] Embodiment 112. The method of any one of embodiments 83-111, wherein the subject has previously undergone a treatment regimen for cancer.Page 100 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0360] Embodiment 113. The method of any one of embodiments 83-112, wherein the subject has previously entered remission from cancer.

[0361] Embodiment 114. The method of any one of embodiments 83-113, wherein the subject has not previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0362] Embodiment 115. The method of any one of embodiments 83-114, wherein the subject has previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0363] Embodiment 1 16. The method of any one of embodiments 1-115, wherein the subject is a human.

[0364] Embodiment 117. The method of any one of embodiments 1-116, wherein the subject is at least 18 years of age.

[0365] Embodiment 118. The method of any one of embodiments 1-117, wherein the subject has been diagnosed with the cancer.

[0366] Embodiment 119. The method of any one of embodiments 1-118, wherein the subject has adequate organ function as follows: a) Hematological: Absolute neutrophil count (ANC) >1 500 / microliter (p L); Platelets >100 000 / L; Hemoglobin >9 grams per deciliter (g / dL) without transfusion for at least 2 weeks before enrollment or without erythropoiesisstimulating agents (eg, Epo, Procrit®) for at least 6 weeks before enrollment b) Renal: Creatinine clearance >50 milliliters per minute (mL / min) calculated using the Cockcroft- Gault formula [(140 - age) x (weight in kilogram ((kg) x (0.85 if female) / 72 x (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection; c) Hepatic: Serum total bilirubin <1.5 x institutional upper limit of normal (ULN) or <2.0 x ULN if the subject has a diagnosis of Gilbert syndrome or <3.0 x ULN for subjects with liver metastases; Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) <3.0xULN or AST and / or ALT <3.0xULN with documented liver metastases; andPage 101 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 d) Coagulation: International normalized ratio (INR) or prothrombin time (PT)<1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants; aPTT <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.

[0367] Embodiment 120. The method of any one of embodiments 1-119, further comprising administering an additional therapeutic agent.

[0368] Embodiment 121. A method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effectiveor a pharmaceutically acceptable salt thereof.

[0369] Embodiment 122. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1or a pharmaceutically acceptable salt thereof.

[0370] Embodiment 123. A method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1Page 102 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1(Compound 1), or a pharmaceutically acceptable salt thereof.

[0371] Embodiment 124. The method of embodiment 123, wherein the NSCLC is KRAS mutant NSCLC.

[0372] Embodiment 125. The method of embodiments 123 or 124, wherein the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS.

[0373] Embodiment 126. The method of any one of embodiments 123-125, wherein theNSCLC is KRAS G12C mutant NSCLC.

[0374] Embodiment 127. The method of any one of embodiments 123-126, wherein the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

[0375] Embodiment 128. A method of treating colorectal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1(Compound 1), or a pharmaceutically acceptable salt thereof.

[0376] Embodiment 129. The method of embodiment 128, wherein the cancer is KRAS mutant colorectal cancer.Page 103 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0377] Embodiment 130. The method of embodiment 128 or 129, wherein the subject does not have a BRAE V600E mutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMR) / microsatellite instability -high (MSI-H) tumors.

[0378] Embodiment 131. A method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1(Compound 1), or a pharmaceutically acceptable salt thereof.

[0379] Embodiment 132. The method of embodiment 131, wherein the cancer isHR+ / HER2- breast cancer or HER2+ breast cancer.

[0380] Embodiment 133. The method of embodiment 131 or 132, wherein the cancer isHR+ / HER2- breast cancer.

[0381] Embodiment 134. The method of embodiment 131 or 132, wherein the cancer isHer2+ breast cancer.

[0382] Embodiment 135. The method of any one of embodiments 131-134, wherein the subject has had at least 2 prior lines of anti-HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care.

[0383] Embodiment 136. The method of any one of embodiments 131-135, wherein the subject has left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks before administration of the compound.

[0384] Embodiment 137. The method of any one of embodiments 121-136, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered orally.

[0385] Embodiment 138. The method of any one of embodiments 121-137, wherein the compound, or the pharmaceutically acceptable salt thereof, is formulated as a tablet.Page 104 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0386] Embodiment 139. The method of any one of embodiments 121-138, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily.

[0387] Embodiment 140. The method of any one of embodiments 121-139, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once daily.

[0388] Embodiment 141. The method of any one of embodiments 121-139, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered twice daily.

[0389] Embodiment 142. The method of any one of embodiments 121-142, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, occurs according to a treatment cycle.

[0390] Embodiment 143. The method of embodiment 142, wherein the treatment cycle is21 days.

[0391] Embodiment 144. The method of embodiment 143, wherein the treatment cycle is 28 days.

[0392] Embodiment 145. The method of any one of embodiments 121-144, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg,350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg,875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg,1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0393] Embodiment 146. The method of any one of embodiments 121-145, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 mg.

[0394] Embodiment 147. The method of any one of embodiments 121-145, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 100 mg.Page 105 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0395] Embodiment 148. The method of any one of embodiments 121-147, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0396] Embodiment 149. The method of any one of embodiments 121-148, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0397] Embodiment 150. The method of any one of embodiments 121-149, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is between about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70- 1500 mg, about 80-1500 mg, about 90-1500 mg, about 100-1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, about 300-1500 mg, about 325-1500 mg, about 350-1500 mg, about 375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525- 1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about 1000-1500 mg, about 1025- 1500 mg, about 1050-1500 mg, about 1075-1500 mg, 1100-1500 mg, about 1125-1500 mg, about 1150-1500 mg, about 1175-1500 mg, about 1200-1500 mg, about 1225-1500 mg, about 1250-1500 mg, about 1275-1500 mg, about 1300-1500 mg, about 1325-1500 mg, about 1350-1500 mg, about 1375-1500 mg, about 1400-1500 mg, about 1425-1500 mg, about 1450-1500 mg, about 1475-1500 mg, about 1-1200 mg, about 10-1200 mg, about 20-1200 mg, about 30-1200 mg, about 40-1200 mg, about 50-1200 mg, about 60-1200 mg, about 70- 1200 mg, about 80-1200 mg, about 90-1200 mg, about 100-1200 mg, about 125-1200 mg,Page 106 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 about 150-1200 mg, about 175-1200 mg, about 200-1200 mg, about 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475-1200 mg, about 500-1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725-1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, about 875-1200 mg, about 900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000-1200 mg, about 1025- 1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1-1000 mg, about 10-1000 mg, about 20- 1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100-1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550- 1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg, about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50-750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100-750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200-750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375- 750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575-750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675-750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20-500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70-500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200- 500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400-500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1-300 mg, about 10-300 mg, about 20-300 mg,Page 107 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 about 30-300 mg, about 40-300 mg, about 50-300 mg, about 60-300 mg, about 70-300 mg, about 80-300 mg, about 90-300 mg, about 100-300 mg, about 125-300 mg, about 150-300 mg, about 175-300 mg, about 200-300 mg, about 225-300 mg, about 250-300 mg, about 275- 300 mg, about 1-150 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40- 150 mg, about 50-150 mg, about 60-150 mg, about 70-150 mg, about 80-150 mg, about 90- 150 mg, about 100-150 mg, about 125-150 mg, about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975-1025 mg, about HOODOO mg, or about 1175-1225 mg.

[0398] Embodiment 151. The method of any one of embodiments 121-150, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is between about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900-1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg.

[0399] Embodiment 152. The method of any one of embodiments 121-151, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg,1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0400] Embodiment 153. The method of any one of embodiments 121-152, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, or 1200 mg.

[0401] Embodiment 154. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg.Page 108 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0402] Embodiment 155. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150 mg.

[0403] Embodiment 156. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg.

[0404] Embodiment 157. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg.

[0405] Embodiment 158. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750 mg.

[0406] Embodiment 159. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1000 mg.

[0407] Embodiment 160. The method of any one of embodiments 121-153, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1200 mg.

[0408] Embodiment 161. The method of any one of embodiments 121-160, wherein, when the subject experiences an adverse event, the compound is administered to the subject at a reduced dose comprising 50% of the initial dose level that was administered to the subject.

[0409] Embodiment 162. The method of any one of embodiments 121-161, wherein, when the subject experiences a second adverse event, the compound is administered to the subject at reduced dose comprising 25% of the initial dose level that was administered to the subject.

[0410] Embodiment 163. The method of embodiment 161 or 162, wherein the subject is treated with the reduced dose until the adverse event is resolved.Page 109 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0411] Embodiment 164. The method of any one of embodiments 161-163, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0412] Embodiment 165. The method of any one of embodiments 161-164, wherein the adverse event is nausea, vomiting, diarrhea lasting longer than 3 days, anemia, febrile neutropenia, thrombocytopenia with or without clinically significant bleeding, or a hematologic adverse reaction.

[0413] Embodiment 166. The method of any one of embodiments 121-165, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in a unit dosage form.

[0414] Embodiment 167. The method of embodiment 166, wherein the unit dosage form is a tablet.

[0415] Embodiment 168. The method of embodiment 167, wherein the tablet comprises about 25 milligrams (mg), about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0416] Embodiment 169. The method of embodiment 167 or 168, wherein the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0417] Embodiment 170. The method of any one of embodiments 121-169, wherein the subject has progression on or disease recurrence after, all available standard of care treatments or would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

[0418] Embodiment 171. The method of any one of embodiments 121-170, wherein the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy.

[0419] Embodiment 172. The method of any one of embodiments 121-171, wherein the cancer is a measurable disease by RECIST vl.l.

[0420] Embodiment 173. The method of any one of embodiments 121-172, wherein the subject has previously undergone a treatment regimen for cancer.Page 110 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0421] Embodiment 174. The method of any one of embodiments 121-173, wherein the subject has previously entered remission from cancer.

[0422] Embodiment 175. The method of any one of embodiments 121-174, wherein the subject has not previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0423] Embodiment 176. The method of any one of embodiments 121-174, wherein the subject has previously been treated with a compound capable of disrupting, interacting, and / or preventing an interaction between a small GTPase and a PI3Ka protein.

[0424] Embodiment 177. The method of any one of embodiments 121-176, wherein the subject is a human.

[0425] Embodiment 178. The method of any one of embodiments 121-177, wherein the subject is at least 18 years of age.

[0426] Embodiment 179. The method of any one of embodiments 121-178, wherein the subject has been diagnosed with the cancer.

[0427] Embodiment 180. The method of any one of embodiments 121-179, wherein the subject has adequate organ function as follows: a) Hematological: Absolute neutrophil count (ANC) >1 500 / microliter (p L); Platelets >100 000 / L; Hemoglobin >9 grams per deciliter (g / dL) without transfusion for at least 2 weeks before enrollment or without erythropoiesisstimulating agents (eg, Epo, Procrit®) for at least 6 weeks before enrollment b) Renal: Creatinine clearance >50 milliliters per minute (mL / min) calculated using the Cockcroft- Gault formula [(140 - age) x (weight in kilogram ((kg) x (0.85 if female) / 72 x (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection; c) Hepatic: Serum total bilirubin <1.5 x institutional upper limit of normal (ULN) or <2.0 x ULN if the subject has a diagnosis of Gilbert syndrome or <3.0 x ULN for subjects with liver metastases; Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) <3.0xULN or AST and / or ALT <3.0xULN with documented liver metastases; andPage 111 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 d) Coagulation: International normalized ratio (INR) or prothrombin time (PT)<1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants; aPTT <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.Embodiment 181. The method of any one of embodiments 121-180, further comprising administering an additional therapeutic agent.EXAMPLES

[0428] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0429] Selected abbreviations used in the preceding sections and the Examples are summarized in Table 1.Table 1. Abbreviations.Page 112 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Page 113 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Page 114 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Materials and Methods

[0430] Preparative thin layer chromatography (PTLC) separations described herein were typically performed on 20 x 20 cm plates (500-pm thick silica gel).

[0431] Chromatographic purifications were typically performed using Biotage Isolera. One automated system running Biotage Isolera One 2.0.6 software (Biotage LLC, Charlotte, NC). Flow rates were the default values specified for the column in use. Reverse phase chromatography was performed using elution gradients of water and acetonitrile on KP-C18- HS Flash-i- columns (Biotage LLC) of various sizes. Typical loading was between 1:50 and 1: 1000 crude sample: RP SiO2 by weight. Normal phase chromatography was performed using elution gradients of various solvents (e.g., hexane, ethyl acetate, methylene chloride, methanol, acetone, chloroform, MTBE, etc.). The columns were SNAP Cartridges containing KP-SIL or SNAP Ultra (25 pm spherical particles) of various sizes (Biotage LLC). Typical loading was between 1: 10 to 1: 150 crude sample: SiCh by weight. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0432] 1HNMR analyses of intermediates and exemplified compounds were typically performed on a Bruker Ascend TM 400 spectrometer (operating at 400 MHz), Bruker Ascend 500 MHz Avance Neo Spectrometer (Bruker-Biospin) or Bruker Avance Neo Nanobay (operating at 400 MHz) at 298 °K following standard operating procedure suggested by manufacturer. Reference frequency was set using TMS as an internal standard. ChemicalPage 115 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 shift values (5) are reported in parts per million (ppm) with splitting patterns abbreviated to: s (singlet), br. s (broad singlet), d (doublet), dd (double doublet), t (triplet), and m (multiplet). The coupling constant (J) is given in Hz. Typical deuterated solvents were utilized as indicated in the individual examples.

[0433] LCMS analysis was typically performed using one of the following conditions:

[0434] (1) LCMS spectra were taken on an Agilent Technologies 6120B Quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) with 0.1% formic acid, and water (B) with 0.1% formic acid, and the eluent gradient was from 5-95% A in 6.0 min, 5%- 40% A in 6.0 min, 80-100% A in 6.0 min. using a poroshell 120 EC-C18 50 mm x 3.0 mm x 2.7 pVl capillary column; Flow Rate: 0.7 mL / min. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius (°C) unless otherwise noted.

[0435] (2) LCMS spectra were taken on an Agilent Technologies 1290-6420 Triple Quadrupole spectrometer: The mobile phase for the LC was acetonitrile (A) with 0.05% formic acid, and water (B) with 0.05% formic acid, and the eluent gradient was from 5-95% A in 5.0 min, using a ZORBAX SB-C18 50 mm x 2.1 mm x 1.8 pM capillary column; Flow Rate: 0.3 mL / min. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius unless otherwise noted.

[0436] (3) LC-MS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C18 4.6 mm x 150 mm x 3.5 pM RapidResol column with a mobile phase of water (0. 1 % formic acid) I MeCN (0.1% formic acid) and a gradient of 5-95% MeCN over 10 minutes at a flow rate of 1 mL / min. Accurate mass data was obtained using a Thermo Fisher extractive plus EMR orbitrap LCMS system. Exact mass values were calculated by ChemCalc.

[0437] (4) LCMS spectra were taken on an alliance Waters 2695 coupled to a Waters 2487 Dual Wavelength Absorbance Detector and a Waters Micromass-ZQ-2000 single quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was from 5-100% A in 10.0 minute using a Kromasil 100-5-C18 150 mm x 4.6 mm x 5 pm column. Mass spectra (MS) were measured byPage 116 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius unless otherwise noted.

[0438] (5) LCMS spectra were taken on Waters Micromass-ZQ 2000 Quadrupole spectrometer. The mobile phase for the LC was (A) 0.1% formic acid in water; (B) Acetonitrile 100% and the eluent gradient was from 10-90% B in 10.0 min, 90% up to 12 min B, 12-13 min 90-10% B, 13-15 min 90-10% B using Phenomenex Gemini-C18 (50 mm x 4.6 mm x 5 pm); Flow Rate: 0.5 mL / min. Mass spectra (MS) were measured by Electrospray Ion-Mass spectroscopy (ESI).

[0439] Typically, analytical HPLC spectrometry conditions were as follows:

[0440] LC1: Agilent Technologies 1260 Infinity coupled, Column: poroshell 120 EC-C18 150 mm x 4.6 mm x 4 pm; Temperature: 40 °C; Eluent: 5:95 v / v acetonitrile / water + 0.02% trifluoroacetic acid in 20 min; Flow Rate: 1.2 mL / min; Detection: VWD, 190-600 nm.

[0441] LC2: Shimadzu 2010 CHT, Column Waters X-select CSH C18 (150 x 4.6) mm x 3.5 pm, Temperature: 30 °C; MP-A 10mm ammonium acetate Buffer, MP-B: Acetonitrile (100%), Flow Rate: 1.0 mL / min; Detection: VWD, 270 nm. Gradient elevation: time / B con: 0 / 5, 2 / 5, 20 / 50, 25 / 50, 30 / 90, 35 / 90, 37 / 05, 40 / 05.

[0442] LC3: Shimadzu LC-2010A HT, Column: XBRIDGE-C18 3.5 pm 2.1 x 50 mm; Temperature: 45 °C; Mobile phase: water (0.05%TFA)-ACN (0.05%TFA), ACN from 0 to 60% over 7 minutes, 7-8 min, ACN from 60% to 100%; Flow Rate: 0.8 mL / min; Detection: PDA, 214 nm, 254 nm.

[0443] LC4: Shimadzu LC-2050c, Column: XBRIDGE-C18 3.5 pm 2.1 x 50 mm;Temperature: 45 °C; Mobile phase: water (0.05%TFA)-ACN (0.05%TFA), ACN from 0 to 60% over 7 minutes, 7-8 min, ACN from 60% to 100%; Flow Rate: 0.8 mL / min; Detection: VWD, PDA, 214 nm, 254 nm.PDA, 214 nm, 254 nm.

[0444] Preparative HPLC was carried out with one of the following conditions:

[0445] Condition 1: GILSON Preparative HPLC System; Column: Ultimate XB-C18, 21.2 mm x 250 mm, 5 pm; Mobile phase: Water with 0.1% trifluoroacetic acid; MeCN with 0.1% trifluoroacetic acid; Method: 15 minutes gradient elution; Initial organic: 10% to 30%; Final organic: 60% to 80%; UV1: 240; UV2: 230; Flow: 15 mL / min.Page 117 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0446] Condition 2: CIS-Reverse phase preparative HPLC was performed using a Waters purification system with 2489 UV / Vis detector, 2545 Gradient module, and Fraction collector III controlled by Waters Chromescope vl.6. The preparative HPLC column used was a Waters XBridge® Prep Cl 8 5uM OBD™ 19 x 250 mm column with a mobile phase of water / MeCN or water (0.1% TFA) I MeCN (0.1% TFA).

[0447] Condition 3: Shimadzu Preparative HPLC System; Column: Phenomenex Luna C18, 21.1 mm x 250 mm, 10 pm; Mobile phase; MP-A 10mm ammonium acetate Buffer, MP-B: Methanol (100%), 35 minutes gradient elution UV: 254; Flow: 10 mL / min. Gradient elevation: time / B con: 0 / 50, 25 / 90, 30 / 90, 32 / 50, 35 / 50.

[0448] Chiral supercritical fluid chromatography (SFC) was carried out with one of the following conditions:

[0449] Condition 1: SFC Thar prep 80; Column: CHIRALPAK® AD-H 250 mm x 20 mm, 5 pm; Mobile phase: 40% EtOH / CCh (contining 0.2% NH4OH); 40 g / min.

[0450] Condition 2: SFC Thar prep 80; Column: CHIRALPAK® OD-H 250 mm x 20 mm, 5 pm; Mobile phase: 40% MeOH / CCL (contining 0.2% NH4OH); 40 g / min.

[0451] Condition 3: SFC Thar prep 80; Column: CHIRALPAK® IC 250 mm x 20 mm, 5 pm; Mobile phase: 40% IPA / CO2 (containing 0.2% DEA); 40 g / min.

[0452] Compound names were generated with ChemDraw Professional.

[0453] The compounds provided herein, including in various forms such as salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc., may be prepared according to various methods including those set forth in the following examples.Example 1: Synthesis of l-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(l- methyl-lH-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)prop-2-en-l-one (Compound 1).Page 118 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1

[0454] Step A: Preparation of tert-butyl (R)-2-((S)-7-(2,4-difluoro-6-(2- methoxyethoxy)phenyl)-4-(l-methyl-lH-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl- 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate: To a solution of tert-butyl (R)-2-((S)- 7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2- c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (5.00 g, 7.10 mmol) and (l-methylindazol-5-yl)boronic acid (1.50 g, 8.51 mmol) in 1,4-dioxane (50 mL) / water (5 mL) was added Na2CO3 (1.50 g, 14.2 mmol) and tetrakis(triphenylphosphine)palladium (0.410 g, 0.355 mmol). The reaction mixture was stirred at 100 °C for 3 h under Ar. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:petroleum ether = 1:1) to give tert-butyl (R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(l-methyl- lH-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine- 5(4H)-carboxylate (4.0 g, 82% yield). LCMS ESI (+) m / z 687.3 (M+H).

[0455] Step B: Preparation of (S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(l- methyl-lH-indazol-5-yl)-6-((R)-4-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)thieno[3,2-c]pyridine 2,2,2-trifluoroacetate: To a solution of tert-butyl (R)-2-((S)-7-(2,4- difluoro-6-(2-methoxyethoxy)phenyl)-4-(l-methyl-lH-indazol-5-yl)thieno[3,2-c]pyridin-6- yl)-4-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (50 mg, 0.073 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at rt for 2 h. The solution was concentrated to dryness to give (S)-7-(2,4-difluoro-6-(2- methoxyethoxy )phenyl)-4-(l-methyl-lH-indazol-5-yl)-6-((R)-4-methyl-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)thieno[3,2-c]pyridine 2,2,2-trifluoroacetate (62 mg, crude), which was used in the next step without further purification. LCMS ESI (+) m / z 587.3 (M+H).

[0456] Step C: Preparation l-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4- (l-methyl-lH-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)prop-2-en-l-one: To a solution of (S)-7-(2,4-difluoro-6-(2- methoxyethoxy)phenyl)-4-(l-methyl- lH-indazol-5-yl)-6-((R)-4-methy 1-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)thieno[3,2-c]pyridine 2,2,2-trifluoroacetate (62 mg crude, 0.073 mmol) in ethyl acetate / water (2 mL / 2 mL) was added Na2COs aqueous solution to adjust the pH to 8. Sodium bicarbonate (9.0 mg, 0.11 mmol) was added. The mixture was cooled to 0 °C. A solution of acryloyl chloride (0.0070 mL, 0.086 mmol) in DCM (0.1 mL)Page 119 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 was added and the mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous N 2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM:MeOH= 20: 1) to give l-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4- (l-methyl-lH-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)prop-2-en-l-one (42 mg, 86% yield) as a white solid’H NMR (400 MHz, CD3OD) 8 8.49 (d, J = 1.4 Hz, 1H), 8.27 (s, 1H), 8.01 - 8.16 (m, 2H), 7.82 - 7.97 (m, 2H), 7.01 (d, J = 10.7 Hz, 1H), 6.76 - 6.90 (m, 2H), 6.30 (d, J = 16.8 Hz, 1H), 6.05 (s, 1H), 5.83 (dd, J = 1.7, 10.6 Hz, 1H), 5.41 - 5.76 (m, 1H), 4.08 - 4.39 (m, 6H), 3.46 (t, J = 4.5 Hz, 2H), 3.09 (s, 3H), 1.35-1.53 (m, 3H). LCMS ESI (+) m / z 641.0 (M+H).Example 2: Covalent modification assay using MALDI-TOF MS

[0457] Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis of covalent modification of Cys242 in human PIK3CA (157- 299) was performed. Initially 3.33 pM protein target and 1:7.5 protein to compound ratio were used; later the target protein concentration was adjusted to I pM with 1:5 protein to compound ratio for more potent compounds.

[0458] Reaction: 3.33 pM or 1 pM of PIK3CA (157-299) protein (produced in-house by Protein Expression Laboratory, FNLCR / Leidos Biomed) in 20 mM HEPES buffer containing 150 mM NaCl, 2 mM MgCh, pH 7.3 was prepared freshly before assay. Twelve-pL aliquots of protein were dispensed onto low volume 384- well plate, then 470 nL DMSO and 30 nL of tested compounds from 10 mM DMSO stocks were added to appropriate wells using ECHO 555 acoustic liquid handler (Labcyte Inc.). For each reaction / assay, three blanks were prepared by mixing 12 pL of protein solution with 500 nL DMSO. The wells content was carefully mixed by aspiration, and then the plate was sealed by an adhesive cover, centrifuged at 931 g for 1 minute, and kept in the dark at room temperature until 15 min, 30 min, 2 h, or 4 h collections.

[0459] Target pretreatment: Before each assay MALDI target (Bruker MPT 384 ground steel BC) was pre-treated by pipetting on each spot 0.75 pL of saturated sinapinic acid in acetonitrile (ACN). This step significantly improves the uniformity of sample crystallization across the plate resulting in enhanced sensitivity.Page 120 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0460] Sample preparation: At collection time point, 2 p L of reaction mixtures were pipetted out into 20 pL MALDI matrix solution (saturated solution of sinapinic acid in 1:1 ACN:water solution containing 0.15% trifluoroacetic acid (TFA)) deposited on 384 well polypropylene plate. The resulting solution was mixed by aspiration, centrifuged at 931 g for 1 minute, then 1.5 pL aliquots were dispensed on pre-treated MALDI target using Beckman Coulter Biomek FXP96 / 384-Span-8 Laboratory Automation Workstation. Finally, the MALDI target was dried under a mild vacuum to produce spots with a fine crystalline structure.

[0461] Measurements: MALDI-TOF measurements were performed on Bruker Daltonics rapifleX Tissuetyper TOF-TOF mass spectrometer using linear mode and mass ranging from 16.0 to 19.6 kDa. Detector gain was set to 0.64x (459 V), sample rate to 5 GS / s, real-time smoothing to medium (175 MHz), laser smart beam pattern was set to “Custom” single smartbeam beam scan with a scan range of 40 pm on both X and Y axis, and the laser frequency was 10000 Hz. Spectra were automatically collected using the custom AutoXecute method. Laser power was auto adjusted using fuzzy control. The peak selection range was set to be between 16.0 and 18.5 kDa. Peak evaluation uses a half-width parameter set to be smaller than 40 Da for processed spectrograms (centroid peak detection; smoothed by SavitzkyGolay algorithm using 7 m / z width and 2 cycles; baseline was subtracted using a median algorithm with flatness 1 and median level 0). Fuzzy control used Proteins / Oligonucleotides protocol with minimum half-width 1 / 10 times above threshold. Up to 40000 satisfactory shots were collected in 10000 short steps. Dynamic termination was implemented to finish data collection when the peak signal / noise ratio was reaching a value of 1000.

[0462] Spectra processing: Spectra were smoothed by SavitzkyGolay algorithm using 7 m / z width and three cycles. Centroid peak detection algorithm was used with signal to noise threshold set to 6, relative intensity threshold 3%, peak width 10 m / z, and median baseline subtraction using flatness of 1 and the median level of 0.1. Peak intensity and area under the peak were evaluated and recorded for all peaks between 16.0 and 19.5 kDa.

[0463] Calculation of percent modification: Percent modification was calculated as a ratio of peak height for protein modified by compound to the sum of the peak height of remaining protein plus peak height for protein modified by a compound. If multiple modifications werePage 121 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 observed each was calculated as a ratio of peak height for given modification versus the sum of peak heights for all observed protein species.

[0464] Data are reported from a 4 h reaction time point. Compounds are characterized based on percent of modification of PIK3CA protein as follows: “A” means percent of modification of PIK3CA protein > 75%; “B” means 50% < percent of modification < 75%; “C” means 25% < percent of modification < 50%; “D” means percent of modification < 25%.

[0465] Data for Compound 1 is collected using 3.33 pM protein target and 1:7.5 protein to compound ratio. Compound 1 demonstrates > 75% percent of modification of PIK3CA (“A”).Example 3: Matrix-Assisted Cell-based pAKT HTRF assay in BT474 cells

[0466] On Day 1, cells were seeded into 96-well plates at 2.5x104 cells / well in complete growth media (DMEM, 10% FBS). On Day 2, cells were treated with compounds at 0.25% DMSO. The source plate was created with compounds diluted in media at 5-fold the final assay concentration. The compounds are run in a 9-point concentration curve starting at 3 pM, with a 3-fold dilution between concentrations. 20 pL was transferred onto the cell plates (final volume in wells was 100 pL). Plates were harvested after 4 hr incubation by aspirating media and adding kit-supplied lx supplemented lysis buffer to all wells (75 pL per well). Plates were then placed on a plate shaker and incubated at 850 rpm for an additional 30 min. The antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit supplied detection buffer, then mixed the diluted antibodies solutions (1: 1 v:v). 4 pL of this solution was then added to a 384-well detection plate (Perkin Elmer; 6008230). Samples were homogenized by pipetting up and down and then transferred (16 pL of cell lysates) from the 96-well cell culture plate to two wells of the HTRF 384-well detection plate containing the antibody solution. Plates were centrifuged (524 g for 1 min) and allowed to incubate between 4 and 24 h at room temperature. The maximum signal is reached after 4 h incubation time and remains stable over a period of 24 hours. Therefore, readings can be made between 4 and 24 h of incubation. Plates were centrifuged again (524 g for 1 min), and analyzed on the EnVision plate reader using the following settings: Excitation 320 nM, Bandwidth 75 nM; Emission 615 nM, Bandwidth 85 nM, Gain 100%, Flashes 100, Lag 60 ps.Page 122 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0467] Compounds are characterized based on pAKT inhibition IC50 values as follows: “A” means IC50 < 0.1 pM; “B” means IC50 > 0.1 pM and < 1 pM; “C” means IC50 > 1 pM and < 3 pM; “D” means IC50 > 3 pM.

[0468] Compound 1 demonstrates pAKT inhibition IC50 of < 0.1 pM (“A”).Example 5: In vitro Activity of Compound 1 (BBO-10203)

[0469] The effect of BBO- 10203 on pAKT signaling was evaluated in a diverse panel of 62 human cell cancer lines bearing HER2 amplification, KRAS mutations, or PI3KCA mutations. The majority of cell lines had one of these alterations, and four cell lines had two of these alterations. pAKT was assessed by homogeneous time resolved fluorescence (HTRF). BBO-10203 displayed potent inhibition of pAKT with a mean EC50 of 3.2 nM and mean Emax of 57% inhibition across all 62 cell lines. In the 9 cell lines with HER2 amplification, the mean EC50 was 4.6 nM with a mean Emax of 74% (FIG. 2A). In the 35 cell lines with a KRAS mutation, the mean EC50 was 3.3 nM with a mean Emax of 58% (FIG. 2B). In the 22 cell lines with a PIK3CA mutation, the mean EC50 was 2.7 nM with a mean Emax of 53% (FIG. C). These results demonstrated that BBO-10203 is potent in cell lines with HER2 amplification, KRAS mutations, or PIK3CA mutations.Example 4: A Phase la / lb Study of the PI3Kot:RAS Breaker Compound 1 in Subjects with Advanced Solid Tumors

[0470] The present example describes a Dose Escalation and Dose Expansion Study of Compound 1 in subjects with advanced solid tumors.

[0471] Compound 1 is being developed for treatment of patients with various cancers including advanced breast cancer (aBC) that are either HER2-positive or HR-positive (ERpositive and progesterone receptor-positive or -negative), and patients with advanced colorectal cancer (aCRC) or advanced non-small cell lung cancer (aNSCLC) that harbor mutations in KRAS. Intracellular signaling mediated by both the RAS-MAPK and the PI3K- AKT pathway are known to drive tumorigenesis in each of the above-mentioned cancers.

[0472] In patients with HR -positive aBC, dysregulated PI3K signaling due to aberrations in PIK3CA and / or AKT genes is associated with reduced response to endocrine therapies in earlier lines of treatment. In fact, approval of a PI3Ka inhibitor, alpelisib and more recently that of an AKT specific inhibitor, capivasertib, both in combination with standard of carePage 123 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1(SoC) endocrine therapy, in the HR-positive aBC patient population underscores the therapeutic relevance of inhibiting this pathway. In the SOLAR- 1 study, which led to the approval of alpelisib in combination with fulvestrant, patients with PIK3CA-mutated tumors had a progression-free survival (PFS) of 11 months in the alpelisib plus fulvestrant arm compared with 5.7 months in the placebo plus fulvestrant arm (Piqray United States Prescribing Information (USPI)). In the more recent CAPItello-291 study, which led to the approval of capivasertib in combination with fulvestrant in patients with AKT-pathway alterations (including PIK3CA mutations), PFS was 7.3 months in the capivasertib plus fulvestrant arm compared with 3.1 months in the placebo plus fulvestrant arm (Truqap USPI). Despite approval of both of these agents that target the PI3K / AKT signaling pathway, each is associated with significant dose limiting toxicities (DLTs); significant among these is the occurrence of hyperglycemia in 65% of alpelisib-treated patients (Piqray USPI) and 18% of capivasertib-treated patients (with 37% increased fasting glucose and 58% increased random glucose) (Truqap USPI). The adverse event (AE) profile of these 2 agents resulted in frequent rates of dose reductions, interruptions, and discontinuations. For example, with alpelisib, the rate of dose reductions due to AEs was 55% (Piqray USPI) and the rate of dose interruption with capivasertib was 39%, with 10% of subjects discontinuing treatment due to AEs despite the use of intermittent dosing (Truqap USPI).

[0473] A major implication of this is suboptimal target inhibition allowing for resurgence of tumor growth, thereby limiting treatment response and disease control. Hyperglycemia in response to inhibition of the PI3K / AKT signaling pathway is due in part to the role of phosphorylated AKT in regulating proteins involved in glucose uptake in response to insulin signaling (Goncalves 2018). Thus, there is an urgent need for agents that allow for sustained inhibition of cellular proliferation downstream of the PI3K signaling axis while avoiding the hyperglycemia associated with inhibition of AKT-mediated glucose homeostasis.

[0474] Compound 1 covalently modifies pl 10a, the catalytic subunit of PI3K, thereby inhibiting its interaction with RAS. Inhibition of the PI3Ka:RAS interaction allows for specifically targeting cellular proliferation as evidenced by activity of Compound 1 in animal models of various tumors, including those for breast, colorectal, and lung cancers. Cell lines that express HER2 or those that are mutant for KRAS are particularly sensitive to inhibition of PI3Ka:RAS interactions. Thus, in addition to testing the activity of Compound 1 in HRpositive aBC as described above, this trial will also enroll patients with HER2-positive aBCPage 124 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 and KRAS mutant aCRC and aNSCLC. In patients with HER2-positive aBC, dysregulated PI3K activity is often associated with resistance to HER2-targeted therapies (Swain 2023;Eichhorn 2008; Berns 2007); similarly, patients with KRAS mutant aCRC and aNSCLC have suboptimal outcomes in response to treatment with current SoC regimens (Zeineddine 2023; Soria 2018; Peters 2017).Synopsis

[0475] The study will include a Phase la dose escalation / cohort expansion. Phase la objectives and endpoints are summarized in Table 2.Table 2. Overview of Phase la objectives and endpoints.Page 125 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0476] Study centers'. Approximately 30 study centers worldwide.

[0477] Number of Subjects Planned: Overall, approximately up to 153 subjects are planned for enrollment.

[0478] Phase la Dose Escalation Monotherapy cohorts: Up to approximately 30DLT-evaluable subjects (3 to 5 per cohort), unless additional dose levels are recommended by the Safety Review Committee (SRC), in which case more subjects may be enrolled during escalation at each dose level. In addition, up to 6 subjects per dose level (up to approximately 36 total unless additional dose levels [not to exceed the highest planned dose] are recommended by the SRC) may be enrolled to backfill dose levels that have been determined to be safe.

[0479] Phase la Dose Escalation Cohort Expansion: Up to 20 additional subjects with HER2-positive aBC will be enrolled into any monotherapy cohort that has been found to be safe and is at a dose level that is predicted to provide exposures necessary to drive efficacy. This is estimated to be approximately up to 40 subjects in total but may increase if the SRC recommends cohort expansion at more than 2 dose levels. The dose at which cohort expansion will start will be based on SRC review of safety, PK and PD (including target occupancy), and efficacy data.Study population’.Page 126 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0480] Inclusion criteria: To be included in the study, subjects must meet the eligibility criteria listed below for all subjects and for subjects enrolled in the individual phases of the study, as applicable.All SubjectsAge:2. Subjects must be >18 years old at signing of informed consent.Type of Subject and Disease Characteristics:3. Locally advanced and unresectable or metastatic (ie, advanced) disease and / or lesions that are not amenable to definitive radiotherapy.4. Measurable disease by RECIST vl.l. a. Subjects with disease limited to the bone are eligible if there is at least 1 measurable soft tissue component according to RECIST vl. l.5. Must provide archival formalin-fixed paraffin embedded (FFPE) tumor tissue before enrollment. Sample is to be from the most recent biopsy, if available. If archival tumor tissue is not available, a fresh tumor tissue biopsy is required (except for subjects with bone-only disease). a. For dose escalation only: subjects who do not have adequate archival tissue and for whom biopsy is contraindicated may be enrolled after approval by the medical monitor.6. Minimum life expectancy of > 12 weeks according to the investigator’ s judgement.7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or1.8. Adequate organ function as defined below. a. Hematological:- Absolute neutrophil count (ANC) >1 500 / pL.- Platelets >100 000 / pL.- Hemoglobin >9 g / dL without transfusion for at least 2 weeks before enrollment or without erythropoiesis-stimulating agents (eg, Epo, Procrit®) for at least 6 weeks before enrollment. b. Renal:- Creatinine clearance >50 mL / min calculated using the Cockcroft- Gault formula [(140 - age) x (weight in kg) x (0.85 if female) / 72 x (serumPage 127 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 creatinine in mg / dL)] or measured using 24-hour urine collection. c. Hepatic:- Serum total bilirubin <1.5 x institutional upper limit of normal (ULN) or <2.0 x ULN if the subject has a diagnosis of Gilbert syndrome or <3.0 x ULN for subjects with liver metastases.- Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic -pyruvic transaminase (SGPT) <3.0xULN or AST and / or ALT <3.0xULN with documented liver metastases. d. Coagulation:- International normalized ratio (INR) or prothrombin time (PT) <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of intended use of anticoagulants.- aPTT <1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.9. Willing and able to comply with study visits and study procedures.10. Able to swallow tablets intact without chewing or crushing.Informed Consent:11. Subjects must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.Subjects Enrolled in Phase la Compound 1 Monotherapy Dose Escalation / Cohort Expansion Subjects with HER2-positive aBC:12. Histologically documented HER2-positive aBC, with HER2-positivity defined by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) methodology according to American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines at any time during their disease. Enrollment based on HER2-positive status in a tumor sample from the most recent progression or recurrence is strongly encouraged.13. Must have had at least 2 prior lines of anti-HER2-directed therapy. Only 1 prior line isPage 128 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 acceptable where there is no other regionally available standard of care (SoC).14. Left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks before the first dose of study treatment.15. If brain metastases are found on a screening contrast brain magnetic resonance imaging (MRI), the following apply for eligibility: a. Subjects with untreated brain metastases not needing immediate local therapy are allowed. However, for subjects with untreated CNS lesions >2.0 cm found on screening contrast brain MRI, discussion with and approval from the medical monitor is required before enrollment. b. Subjects with previously treated prior history of brain metastases: see Exclusion Criterion 10.Subjects with HR-positive, HER2-negative aBC:16. Histologically documented HR-positive (estrogen receptor [ER]-positive and progesterone receptor-positive or -negative), and HER2-negative aBC tumor according to ASCO-CAP guidelines based on most recent available tumor biopsy.17. Must have progression on, or disease recurrence after, all available SoC treatments or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate SoC therapy.18. LVEF >50% as assessed by ECHO or MUGA documented within 4 weeks before the first dose of study treatment.Subjects with KRAS mutant aCRC:19. Histologically documented locally advanced or metastatic CRC that is positive for KRAS mutation at any time during their disease.20. Must have progression on or disease recurrence after available SoC treatments or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate SoC therapy.Subjects with KRAS mutant aNSCLC:21. Histologically documented locally advanced or metastatic NSCLC that is positive for KRAS mutation at any time during their disease.22. Must have progression on or disease recurrence after available SoC treatments or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate SoC therapy.Page 129 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Subjects with HER2-positive aBC Enrolled in Phase la Dose Escalation Cohorts23. Histologically documented HER2-positive aBC, with HER2-positivity defined by ISH or FISH or IHC methodology according to ASCO-CAP guidelines at any time during their disease. Enrollment based on HER2-positive status in a tumor sample from the most recent progression or recurrence is strongly encouraged.24. Progression after or intolerance of at least 2 prior lines of HER2-targeted therapy. Only 1 prior line is acceptable where there is no other regionally available SoC.25. LVEF >50%, as assessed by ECHO or MUGA, documented within 4 weeks before the first dose of study treatment.26. If brain metastases are found on a screening contrast MRI, the following apply for eligibility: a. Subjects with untreated brain metastases not needing immediate local therapy are allowed. However, for subjects with untreated CNS lesions >2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required before enrollment. b. Subjects with previously treated brain metastases: see Exclusion Criterion 10.

[0481] Exclusion criteria: Subjects are excluded from the study if any of the following criteria apply:Subjects with HER2-Positive aBC1. Have had more than 1 prior line of therapy with an antibody-drug conjugate. Subjects with HR-Positive, HER2-Negative aBC2. Have potentially immediately life-threatening visceral organ involvement. Subjects with KRAS mutant aCRC3. Have BRAFV600Emutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMRj / microsatellite instability-high (MSI-H) tumors.Subjects with KRAS Mutant aNSCLC4. Have tumors with other targetable driver mutations (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).All SubjectsMedical Conditions:5. Have active hepatitis B infection (hepatitis B surface antigen [hBsAg] or hepatitis BPage 130 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 virus [HBV] DNA) or hepatitis C infection (hepatitis C virus [HCV] antibody and positive HCV RNA).6. Known positive HIV test.7. Have any other life-threatening illness, medical condition, clinically meaningful ongoing toxicity from prior therapy, active uncontrolled infection, or organ system dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating subject’s safety, or interfere with or compromise the integrity of the study outcomes.8. Have any of the following cardiac -related issues or findings: a. History of significant cardiovascular disease, such as cerebrovascular accident, myocardial infarction, or unstable angina, within the last 6 months before starting study treatment. b. Clinically significant cardiac disease, including New York Heart Association (NYHA) Class II or higher heart failure. c. History of LVEF <50% or less than the institutional normal range (whichever is higher) within the previous 12 months before starting study treatment as measured by ECHO (or MUGA scan). d. Resting QT interval corrected for heart rate (QTc) >470 msec, derived as the average from 3 electrocardiograms (ECGs) at screening. e. Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (eg, third-degree heart block, Mobitz Type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation). f. Subjects with a pacemaker may be allowed on study after review and agreement between the treating physician and medical monitor.9. Have a diagnosis of another invasive malignancy within the previous 2 years from time of informed consent other than curatively treated non-melanomatous skin cancer, superficial urothelial carcinoma, in situ cervical cancer, or any other curatively treated or closely monitored malignancy that is not expected to require treatment for recurrence or progress during the course of the study.10. Have untreated brain metastases (for HER2 -positive aBC, see exception in tumorspecific Inclusion Criteria). a. Subjects with treated and stable brain metastases are allowed provided that subjects who have had brain metastases resected or have received radiationPage 131 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 therapy ending at least 2 weeks before Cycle 1 Day 1 (C1D1) if they are neurologically stable and meet all of the following criteria before first dose of study treatment:- Residual neurological symptoms related to the CNS treatment Grade <2.- On a stable or decreasing dose of <10 mg daily prednisone (or equivalent) for at least 2 weeks before C IDE- Follow-up MRI shows no clinically relevant new or progressing lesions, b. Subjects with spinal cord compression or leptomeningeal metastases are not allowed.11. Have active gastrointestinal illness or inability to ingest the medication in its intended form that would preclude absorption of Compound 1 (eg, swallowing issues, refractory nausea, post gastrectomy, short bowel / malabsorption syndrome, uncontrolled Crohn’s disease, celiac disease with villous atrophy, or chronic gastritis).12. Pregnant or lactating subjects or subjects expecting to conceive children within the projected duration of the trial, starting with the Screening visit through 90 days after the last dose of Compound 1.13. Are on dialysis.14. Have a history of allogeneic bone marrow transplant.15. Have a history of coagulopathies such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if applicable).Prior / Concomitant Therapy:16. Have undergone major surgery within 4 weeks before C1D1.Note: This does not include subjects who have had procedures such as peripherally inserted central catheter line placement, thoracentesis, paracentesis, biopsies, or abscess drainage.17. Have Grade >1 unresolved toxicities from prior surgery or any antitumor therapy with the exception of alopecia.18. Have participated in an interventional clinical study within the last 4 weeks OR, if applicable, be within 5-times the half-life of the investigational study drug(s), whichever is lesser, before the C1D1 visit. Subjects should always adhere to other eligibility criteria that apply to specified concomitant medication regarding washoutPage 132 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 periods as specified below.19. Have received radiotherapy or proton therapy with a limited field of radiation for palliation within 2 weeks of the start of study treatment, OR radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the start of study treatment. Palliative radiotherapy to nontarget lesions may be allowed on a case-by-case basis by the medical monitor in consultation with the investigator.20. Have taken any of the following: a. Strong inducers or inhibitors of cytochrome P450 (CYP)3A within 14 days or 5 half-lives of the agent (whichever is longer) before C1D1, or food products containing the fruit or juice from grapefruit, star fruit, pomegranates, or Seville oranges within 3 days before C1D1.AND / OR b. Known CYP3A substrates with a narrow therapeutic window, within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, before C1D1.AND / OR c. Strong acid-reducing agents (protein-pump inhibitors) within 3 days of CID 1 and for the study duration.Sex and Contraceptive / Barrier Requirements:21. Contraceptive use by study participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. Male subjects are excluded if any of the following apply:- Unwilling to refrain from donating sperm during the study treatment period and for at least 120 days after the last dose of study drug.- Unwilling or unable to practice acceptable methods of birth control during the study treatment period and for at least 120 days after the last dose of study drug. Acceptable methods of birth control for men include sexual abstinence (refraining from heterosexual intercourse) only if it is the usual and customary lifestyle of the patient; vasectomy with testing showing there is no sperm in the semen; bilateral tubal ligation or occlusion in the partner; or a male condom (with female partner use of an additional highly effective contraceptive method with a failure rate of < 1% per year as described in Appendix 4, Section 10.4 of the protocol, Contraceptive and BarrierPage 133 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Guidance) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. b. Female subjects are excluded if any of the following apply:- Pregnant or breastfeeding or planning to become pregnant or to breastfeed.- Positive highly sensitive serum pregnancy test during screening or within 48 hours before the first dose of study drug (WOCBP only).- Is a WOCBP and is unwilling to use a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency (see Appendix 4, Section 10.4 of the protocol, Contraceptive and Barrier Guidance), during the study treatment period and for at least 90 days after the last dose of study drug or to refrain from egg (ova, oocytes) donation for the purpose of reproduction during this period.The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study drug. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.Other Exclusions:22. Have a history of hypersensitivity to active or inactive excipients of Compound 1 or drugs with a similar chemical structure or class to Compound 1.23. Have a history of hypersensitivity to active or inactive excipients or any of the other anticancer agents required for treatment in this study except for Grade 1 or 2 infusion reactions to trastuzumab that were successfully managed.Study Drug, Dose, and Administration'.

[0482] Investigational product (all cohorts): Compound 1 administered continuously as oral tablets once daily in 21 day cycles starting on CID 1.

[0483] Duration of Treatment'. Compound 1 will be administered until disease progression, unacceptable toxicity, withdrawal of consent, or until other treatment discontinuation criteria are met.

[0484] Study Design: This is a multicenter, open-label, Phase 1 study to evaluate the safety and preliminary antitumor activity of Compound 1, a PI3Ka:RAS inhibitor, in subjects withPage 134 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 locally advanced unresectable or metastatic (ie, advanced) solid tumors. Subjects will have received prior therapy according to tumor-specific entry criteria detailed in the inclusion and exclusion criteria. The study will utilize an SRC to oversee the safety of subjects enrolled in the study. The membership, roles and responsibilities, and decision-making procedures of the SRC are defined in the SRC Charter.

[0485] In the Phase la Compound 1 Monotherapy Dose Escalation / Cohort Expansion part of the study, a Bayesian optimal interval (BO1N) design will be used to evaluate increasing doses of Compound 1 in subjects with 4 tumor types (HER2 positive aBC; HR -positive, HER2-negative aBC; KRAS mutant aCRC; and KRAS mutant aNSCLC). Six potential dose cohorts are planned, according to a modified Fibonacci dose incremental scheme, for evaluation, 150 mg (starting dose), 300 mg, 500 mg, 750 mg, 1000 mg, and 1200 mg, if required, as detailed in Table 3.Table 3. Dosing of Compound 1 in Phase la Study.Abbreviations: DL=dose level; DLT=dose-limiting toxicity; SRC=safety review committee.aNumber of DLT-evaluable subjects required for each dose level is 3 to 5; backfill of each cohort that has been determined to be safe will be allowed for up to 6 subjects if a higher dose level is not open to enrollment.bAdditional dose levels may be implemented after SRC review of the totality of the available data and after the SRC approves or makes a recommendation regarding the next dose cohort.cDe-escalation to a dose lower than the starting dose (DL-1) may be recommended based on SRC evaluation of all available data for DLL

[0486] The DLT assessment period for Compound 1 monotherapy cohorts will be 21 days after the first dose of study drug (1 treatment cycle). For each dose level, the SRC will evaluate all safety data (including DLTs) and all available PK, PD, and efficacy (ifPage 135 of 18513005782v1PATENTAttorney Docket No. 2014229-0162 Client Ref. No. Thera-24. WO 1 applicable) data at the end of the DLT assessment period before opening the next dose level cohort. The SRC will make dosing and escalation or de escalation decisions in accordance with the escalation and de-escalation rules of the BOIN design using a target toxicity rate of 27% with escalation and de-escalation thresholds of <21.3% and >32.2%, respectively. Approximately 30 DLT-evaluable subjects (3 to 5 per cohort) are required for the Phase la Compound 1 Monotherapy Dose Escalation part of the study, unless additional dose levels or dose schedules are recommended by the SRC, in which case more subjects may be enrolled during escalation at each dose level. Backfill of each cohort that has been determined to be safe will be allowed for up to 6 subjects if a higher dose level is not open to enrollment. Intrasubject dose escalation may be allowed for subjects with SD or better after 2 treatment cycles if a higher dose level has been determined to be safe.

[0487] In Phase la Cohort Expansion, to collect additional safety, efficacy, and PK and PD data, up to 20 subjects with HER2 -positive aBC will be enrolled into any monotherapy cohort that has been found to be safe and is at a dose level that is predicted to provide exposures necessary to drive efficacy. This is estimated to be up to 40 subjects in total but may increase if the SRC recommends cohort expansion at more than 2 dose levels. The dose at which cohort expansion will start will be based on SRC review of safety, PK and PD (including target occupancy), and efficacy data. Intrasubject dose escalation will not be allowed for HER2-positive subjects enrolled into the cohort expansion.

[0488] Each phase of the study will consist of a Screening period of up to 30 days; a Treatment period; End of Treatment (EOT) and Safety Follow-Up visits at no later than 14 days and at 30 days after the last dose of study treatment, respectively; and a Long-Term Follow-Up period that will continue for up to 24 months after the last dose of study treatment or until the End of Study.

[0489] After providing informed consent, all subjects will undergo screening assessments to determine eligibility, including confirmation of available appropriate archival tumor tissue sample or new tumor biopsy for retrospective testing of relevant HER2 expression status and KRAS, as applicable. Catalytic a subunit of phosphoinositide 3-kinase (PIK3CA) mutation is not required for trial eligibility, but mutational status will be assessed retrospectively and collected if previously performed. All subjects will be enrolled based on the documented results of local testing. Subjects who meet all eligibility criteria will be enrolled.Page 136 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1

[0490] Safety, efficacy (tumor response), PK, and PD assessments will be completed as detailed in the Schedules of Activities (SoAs). All subjects will be evaluated radiographically for tumor response using RECIST vl.l and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) (subjects with brain metastases at baseline) at the protocol-required time points, regardless of study treatment dosing delays or discontinuations, until disease progression is confirmed by the investigator. Subjects who discontinue study treatment for reasons other than disease progression will continue to have radiographic assessments every 12 weeks (±7 days) until disease progression, the initiation of other anticancer therapies, death, or the subject withdraws consent for radiographic assessment, whichever occurs first.

[0491] Subjects in Compound 1 monotherapy cohorts will undergo an EOT visit as soon as possible after the decision to discontinue Compound 1 and no later than 14 days after the last dose of Compound 1. A Safety Follow-Up visit will be conducted 30 (+7) days after the last dose of study treatment unless 1 of the following occurs: death, loss to follow-up, initiation of new anticancer therapy, or withdrawal of consent.

[0492] Long-term follow-up for survival status and new anticancer therapy information will be via telephone contact every 12 weeks after the EOT visit until 24 months after the last dose of study treatment or until the End of Study. Long-term follow-up also applies to subjects who discontinue study treatment for reasons other than radiographic progression but withdraw consent for further tumor assessments.

[0493] Statistical Considerations: Descriptive statistics will be employed to analyze the data.

[0494] The mean, standard deviation, first quartile (QI), median, third quartile (Q3), minimum, and maximum will be summarized for continuous variables; frequency counts and percentages will be presented for categorical variables. Summaries will be displayed by study phase, dose level, and time point, as appropriate.

[0495] Efficacy analyses will be conducted on the modified intent to treat (mITT) population, unless otherwise specified. Efficacy data (eg, ORR, CBR, DOR, PFS, OS) will be summarized.

[0496] Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Tabulations of TEAEs will be prepared by study part (i.e., dosePage 137 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 escalation and dose expansion) and dose level, as appropriate. Treatment-emergent adverse events will be defined as AEs that first occur or worsen in severity after the first administration of study treatment through 30 days after the last administration of study treatment. The maximum severity and frequency of TEAEs will be summarized. Treatment- emergent adverse events will be tabulated by severity grade, and relationship to study drug. Also, TEAEs leading to permanent discontinuation of study drug, nonfatal SAEs, and SAEs leading to death will be listed and summarized. For each continuous laboratory parameter, results will be categorized as low, normal, or high based on the laboratory normal ranges. Frequencies and percentages will be presented by study part and dose level for the shifts in these categories (e.g., low to normal, low to high, high to low) from baseline to each post treatment assessment time point. Additionally, for each continuous hematology and chemistry parameter, descriptive statistics will be presented by dose level for the changes from baseline to each post-treatment assessment time point. Descriptive statistics will be presented by study part and dose level for the changes in vital signs, and ECGs from baseline to each posttreatment assessment time point. Demographic and other baseline data will be listed by subject and summarized descriptively.

[0497] Descriptive statistics will be provided for continuous variables, and frequency tables will be used to summarize categorical variables. The best overall response, CBR, and the proportions of subjects who experienced CR, PR, SD, and progressive disease in subjects with measurable disease will be displayed along with the corresponding 95% exact Cfs.

[0498] The Kaplan-Meier method will be used to estimate the DOR for responders, PFS, and OS. These time to-event variables will be summarized using the QI, median, and Q3 as well as the minimum and maximum time-to-event, along with their 95% Cis, calculated by Kaplan- Meier method, and will be displayed graphically.

[0499] Pharmacokinetic parameters of Compound 1 will be determined based on individual plasma concentration-time profiles using noncompartmental methods. Descriptive statistics will be summarized for each PK parameter by time point and dose level. Pharmacokinetic and PD parameters will be summarized descriptively. Geometric means, geometric CVs, and geometric mean ratios of these parameters will be presented, as appropriate.

[0500] Prior and concomitant medications or procedures will be summarized according to frequency and percentage using the World Health Organization (WHO) Drug Dictionary byPage 138 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 anatomical therapeutic chemical (ATC) classification system terms per safety analysis set. Any medication started before the first dose of study drug is defined as a prior medication; otherwise, it is a concomitant medication.

[0501] Baseline characteristics and demographic variables will be summarized descriptively.

[0502] An overview of the study design is included in FIG. 1. In the figure, the following abbreviations are used: aBC=advanced breast cancer; aCRC=advanced colorectal cancer; AE=adverse event; aNSCLC=advanced non-small cell lung cancer; BOIN=Bayesian optimal interval; DL=dose level; DLT=dose-limiting toxicity; HER2=human epidermal growth factor receptor 2; HER2 =HER2-negative; HER2+=HER2-positive; HR+=hormone receptor-positive (estrogen receptor-positive and progesterone receptor- positive or -negative); KRAS=Kirsten rat sarcoma viral oncogene homolog; PD=pharmacodynamic; PK=pharmacokinetics;QD=once daily; SoC=standard of care; SRC=safety review board.aDose escalation will follow a BOIN design. Six dose cohorts are planned, according to a modified Fibonacci dose incremental scheme. Additional lower DLs for BBO- 10203 may be implemented after SRC review of all available data and after the SRC approves or makes recommendation regarding the next DL. The DLT assessment period for all monotherapy cohorts is 21 days after first dose of study drug.bTo collect additional safety, efficacy, and PK and PD data, up to 20 subjects with HER2-positive aBC will be enrolled into any cohort that has been found to be safe and is at a dose level that is predicted to provide exposures necessary to drive efficacy. The dose at which cohort expansion will start will be based on SRC review of safety, PK and PD (including target occupancy), and efficacy data.

[0503] Table 4 includes a schedule of activities for the Phase la study.Page 139 of 18513005782v1Table 4. Schedule of activities for Compound 1 Monotherapy cohorts; Phase la (dose escalation and cohort expansion).PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Abbreviations and Footnotes of Table 4Abbreviations: aBC=advanced breast cancer; aCRC=advanced colorectal cancer; AE=adverse event; AKT= protein kinase B; aNSCLC=advanced non-small cell lung cancer; aPTT=activated partial thromboplastin;; C=cycle; CEA= carcinoembryonic antigen; CNS=central nervous system; CR=complete response; CRC=colorectal cancer;CT=computed tomography; D=day; DLT=dose-limiting toxicity; ECG=electrocardiogram; ECHO=echocardiogram; ECOG PS=Eastern Cooperative Oncology Group performance status; EDC=electronic data capture; EOT=end-of-treatment; ER=estrogen receptor; FDG=fluorodeoxyglucose; FSH=follicle-stimulating hormone; HbAlc= hemoglobin Ale; HBV=hepatitis B virus; HCV=hepatitis C virus; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; ICF=informed consent form; INR=international normalized ratio; KRAS=Kirsten rat sarcoma viral oncogene; MRI=magnetic resonance imaging; MUGA=multigated acquisition scan; NA=not applicable; NGS=next generation sequencing; NSCLC=non-small cell lung cancer; PET=positron emission tomography; PIK3CA=catalytic a subunit of phosphoinositide 3-kinase; PK=pharmacokinetic(s); PR=partial response; PT=prothrombin time; PTEN=phosphatase and tensin homolog;RANO-BM=Response Assessment in Neuro-Oncology Brain Metastases;RECISTvl.l=Response Evaluation Criteria in Solid Tumors, version 1.1; SAE=serious adverse event; T3= triiodothyronine; T4= thyroxine; TSH= thyroid stimulating hormone; WOCBP=women of childbearing potential.Note: Unscheduled visits are permitted if clinically indicated in the opinion of the investigator and should be logged in EDC.aScreening: Screening assessments are to be completed within 30 days before the first dose of study drug, except for the radiological tumor assessment (see footnote *n’ below). Screening assessments that are conducted within 2 days before C1D1 can be used to satisfy the Day 1 (baseline) requirement.bCycle 1 / Cycle 2 : A window of - 1 day is allowed for the following assessments scheduled during Cycles 1 and 2: abbreviated physical examination, weight, ECOG PS, vital signs, serum chemistry, hematology, coagulation, and urinalysis. There is no window allowed for other assessments scheduled for Cycles 1 and 2. After Cycle 2, a ±2-day window is allowed for all scheduled assessments. Note: exception is WOCBP who must have a negative serum pregnancy test within 48 hours before dosing on Day 1 of each treatment cycle.Page 143 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1cEOT visit: To be completed as soon as possible after the decision to discontinue Compound 1 for any reason and no later than 14 days after last dose. If the EOT visit occurs 30 days from the last dose of Compound 1, at the time of the Safety Follow-Up visit, the EOT visit procedures (ECG and treatment compliance assessments) should be performed.dSafety Follow-Up visit: To be completed 30 (+7) days after the last dose of study drug.eLong-term follow-up: Upon documented disease progression, subjects will be followed approximately every 12 weeks (telephone contact) from the EOT visit up to 24 months after last dose of study drug or until the End of Study for survival status and new anticancer therapy information. Survival follow up also applies to subjects who discontinue study drug for reasons other than radiographic progression but withdraw consent for further tumor assessments.f24-hour PK sample collection time point: To be collected before Compound 1 dosing on C1D2 and ClD16.8ICF : Informed consent must be obtained before any screening procedures are performed.hArchival tumor sample / Documented advanced disease: All subjects will be enrolled based on documented results of local testing for HER2 expression, HR (ER and progesterone receptor) expression and KRAS mutational status, as applicable, according to the requirements for the tumor type (ie, HER2 -positive aBC; HR-positive, HER2-negative aBC; KRAS mutant aNSCLC; or KRAS mutant aCRC). Local results of PIK3CA / PTEN / AKT mutational status (if previously performed) should also be collected and will be retrospectively confirmed. Laboratory test reports for all local results must be provided. For all subjects (except those with bone-only disease), archival or fresh (if no archival is available) tumor tissue sample must be provided for confirmation of tumor biomarkers status at the sponsor designated laboratory.1Physical examination: Full physical examination includes, at a minimum, assessment of the skin, cardiovascular, respiratory, gastrointestinal, and neurological systems. Abbreviated physical examination should be symptom-driven.jAssessment to be completed predose on days when study drug is administered at the study center. Note: At study visits where vital signs, ECGs, and blood sample collections are scheduled, the assessments should preferably be performed in that order and before Compound 1 administration.kPregnancy test: WOCBP with serum pregnancy test at all indicated time points. Subjects must have a negative test within 48 hours before dosing on Day 1 of every cycle. If thePage 144 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 serum pregnancy test results are not available at the time of dosing, a urine pregnancy test should be performed and later confirmed with the serum pregnancy test.1FSH / Estradiol: Female subjects who are not surgically sterile to confirm menopausal state. Estradiol levels for female subjects <60 years with HR-positive, HER2-negative aBC.mLaboratory assessments: A list of hematology, serum chemistry, urinalysis parameters, and additional required laboratory tests is provided elsewhere.nRadiologic tumor assessments (CT / MRI scans): To be performed at screening within 28 days of C1D1 (baseline). Subjects with history of brain metastases or signs or symptoms of brain metastases and all subjects with HER2 -positive aBC, must have baseline brain MRI performed at screening. If MRI is contraindicated, then CT with contrast of the brain is acceptable. Radionuclide bone scan is required at screening only for all subjects with HRpositive, HER2-negative aBC; refer to footnote “p” for details on radionuclide bone scans for all subjects and possible additional radiologic assessments for subjects with bone disease. Subsequent scheduled radiographic disease assessments should include all sites of disease identified at baseline or suspected to have developed during the study.° Radiologic tumor assessment (CT / MRT scans) after C1D1 : To be performed every 6 weeks (±7 days); scans can be obtained early for clinical deterioration at the discretion of the investigator. After lyear, radiologic tumor assessment may be increased to every 12 weeks (±7 days). Each radiologic assessment must include the chest, abdomen, pelvis, and all other known sites of disease. Tumor burden assessments will be performed based on RECIST vl.l guidelines. For subjects with CNS metastases at baseline, assessments will also be made by RANO-BM. Radiographic response (CR and PR) requires confirmation by a repeat consecutive assessment no sooner than 4 weeks after the first detection of response. Subjects will continue to be evaluated for tumor response at the required time points independent of treatment delays or discontinuations, until radiographic disease progression is confirmed by the investigator. Subjects who discontinue study drug for reasons other than radiographic progression will continue to have radiographic assessments every 12 weeks (±7 days) until radiographic progression, or the initiation of subsequent anticancer therapies, or death, or the subject withdraws consent for radiographic assessment, whichever occurs first. All baseline and on-treatment radiographic scans will be collected and held centrally for possible future independent radiology review.pRadionuclide bone scan: Whole body radionuclide bone scan (or PET or PET / CT according to local standard for clinical trials; FDG-PET is acceptable) and confirmatoryPage 145 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 imaging (CT scan with bone windows, MRI, or x-ray) is required within 12 weeks of enrollment for subjects with HR-positive, HER2-negative aBC and at screening for subjects with other tumor types with known or suspected bone metastases. Repeat bone scan as clinically indicated or if necessary to confirm CR. Note: subjects with HR-positive, HER2- negative aBC with measurable bone lesions identified at baseline as the only site of disease will have radiological tumor assessments using x-ray / CT scan / MRI every 6 weeks (±7 days) and every 12 weeks (±7 days) after 1 year, regardless of study drug dosing delays or discontinuations, until disease progression is confirmed by the investigator.qECHO / MUGA: Not required at screening if it has been performed in the last 4 weeks.rCompound 1 administration: Subjects will take Compound 1 orally at their assigned dose once daily in the morning in each 21-day treatment cycle. Study drug will be administered at the study center on C1D1 (first dose) and at all on-site study visits when PK sampling is scheduled.sAdverse Events: Only SAEs will be collected from signing of the ICF through the first dose of study treatment on CID 1. All AEs and SAEs will be collected after first dose of study treatment (Cl DI ) through the Safety Follow-Up visit at 30 (+7) days after last dose of study treatment. AE information will be collected at study visits or over the phone.Study Design

[0504] This is a multicenter, open-label, Phase 1 study to evaluate the safety and preliminary antitumor activity of Compound 1, a PI3Ka:RAS inhibitor, in subjects with locally advanced unresectable or metastatic (ie, advanced) solid tumors. Pharmacokinetic and PD parameters will also be assessed. The study will be conducted at approximately 30 study centers worldwide.

[0505] Subjects will have received prior therapy according to tumor-specific entry criteria detailed elsewhere herein. A schema of the overall design of the study is provided in FIG. 1. Study procedures are summarized in Table 4. This study will utilize a safety review committee (SRC) to oversee the safety of subjects enrolled in the study.

[0506] In the Phase la Compound 1 Monotherapy Dose Escalation / Cohort Expansion part of the study, a Bayesian optimal interval (BOIN) design will be used to evaluate increasing doses of Compound 1 in subjects with 4 tumor types: HER2 -positive aBC; HR-positive (ERpositive and progesterone receptor-positive or -negative), HER2-negative aBC; KRAS mutant aCRC; and KRAS mutant aNSCLC. Based on review of all available data forPage 146 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1Compound 1 at different doses in the monotherapy part of the study, the maximum tolerated dose (MTD), if reached, will be determined to be the highest dose tested that is determined to be safe by the SRC and a starting Compound 1 dose and dosing regimen may be selected for evaluation in a Dose Escalation cohort.

[0507] Each phase of the study will consist of a Screening period of up to 30 days; a Treatment period; end of treatment (EOT) and Safety Follow-Up visits at no later than 14 days and at 30 days after the last dose of study treatment, respectively; and a Long-Term Follow-Up period that will continue for up to 24 months after the last dose of study treatment or until the End of Study.

[0508] After providing informed consent, all subjects will undergo screening assessments to determine eligibility, including confirmation of available appropriate archival tumor tissue sample or new tumor biopsy for retrospective testing of relevant HER2 expression status and KRAS or PIK3CA mutations, as applicable. Mutational status of PIK3CA (if previously performed) will also be collected. All subjects will be enrolled based on the documented results of local testing. Subjects who meet all eligibility criteria will be enrolled.

[0509] Safety, efficacy (tumor response), PK, and PD assessments will be completed. All subjects will be evaluated radiographically for tumor response using RECIST vl.l and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) (subjects with brain metastases at baseline), regardless of study treatment dosing delays or discontinuations, until disease progression is confirmed by the investigator. Subjects who discontinue study treatment for reasons other than disease progression will continue to have radiographic assessments every 12 weeks (±7 days) until disease progression, the initiation of other anticancer therapies, death, or the subject withdraws consent for radiographic assessment, whichever occurs first.

[0510] Subjects in Compound 1 monotherapy cohorts will undergo an EOT visit as soon as possible after the decision to discontinue Compound 1 and no later than 14 days after the last dose of Compound 1. A Safety Follow-Up visit will be conducted 30 (+7) days after the last dose of study treatment unless 1 of the following occurs: death, loss to follow-up, initiation of new anticancer therapy, or withdrawal of consent.

[0511] Long-term follow-up for survival status and new anticancer therapy information will be via telephone contact every 12 weeks after the EOT visit until 24 months after the lastPage 147 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 dose of study treatment or until the End of Study. Long-term follow-up also applies to subjects who discontinue study treatment for reasons other than radiographic progression but withdraw consent for further tumor assessments.Phase la Dose Escalation: Compound 1 Monotherapy Dose Escalation / Cohort Expansion

[0512] In the Phase la Compound 1 Monotherapy Dose Escalation / Cohort Expansion part of the study, increasing doses of Compound 1 will be evaluated in subjects with the following 4 tumor types:HER2 -positive aBC.HR-positive, HER2-negative aBC.KRAS mutant aCRC.KRAS mutant aNSCLC.

[0513] Subjects enrolled in Phase la Compound 1 Monotherapy Dose Escalation / Cohort Expansion cohorts must have had progression on or disease recurrence after available So...

Claims

PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (X):or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of the compound.

2. The method of claim 1, wherein the compound is Compound 1:or a pharmaceutically acceptable salt thereof.

3. The method of any one of claims 1 to 2, wherein the compound is Compound 1:Page 176 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1(Compound 1).

4. The method of any one of claims 1 to 3, wherein the cancer is a solid tumor.

5. The method of any one of claims 1 to 4, wherein the cancer is breast cancer, lung cancer, endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, melanoma, glioblastoma, sarcomas, or pancreatic cancer.

6. The method of any one of claims 1 to 5, wherein the cancer is breast cancer, lung cancer, or colorectal cancer.

7. The method of any one of claims 1 to 6, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified cancer.

8. The method of any one of claims 1 to 6, wherein the cancer is a hormone receptor (HR) positive and HER2 negative cancer.

9. The method of any one of claims 1 to 6, wherein the cancer is characterized by a mutation in a HER2 protein.

10. The method of any one of claims 1 to 8, wherein the cancer is characterized by a mutation in a KRAS protein.

11. The method of claim 10, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.Page 177 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 112. The method of claim 10 or 11, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation.

13. The method of any one of claims 1 to 12, wherein the cancer is breast cancer.

14. A method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1:or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

15. The method of claim 13 or 14, wherein the breast cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified breast cancer.

16. The method of claim 15, wherein the breast cancer is estrogen receptor (ER) positive and HER2 positive breast cancer.

17. The method of claim 15, wherein the breast cancer is ER negative and HER2 positive breast cancer.

18. The method of claim 13 or 14, wherein the breast cancer is a hormone receptor (HR) positive and HER2 negative breast cancer.

19. The method of claim 18, wherein the breast cancer is ER positive and HER2 negative breast cancer.

20. The method of any one of claims 13 to 19, wherein the breast cancer is an advanced breast cancer or metastatic breast cancer.Page 178 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 121. The method of any one of claims 15 to 17, wherein the subject has had at least 2 prior lines of anti-HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care.

22. The method of any one of claims 15 to 17, wherein the subject has progression after or intolerance of at least 2 prior lines of anti-HER2-directed therapy, or 1 prior line where there is no other regionally available standard of care.

23. The method of claim 18 or 19, wherein the subject has progression on or disease recurrence after available standard of care (SoC) treatments; or the subject is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

24. The method of any one of claims 14 to 23, wherein the subject has left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA), documented within 4 weeks prior to administration of the compound or Compound 1.

25. The method of any one of claims 1 to 12, wherein the cancer is colorectal cancer.

26. A method of treating colorectal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1:or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

27. The method of claim 25 or 26, wherein the colorectal cancer is characterized by a mutation in a KRAS protein.Page 179 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 128. The method of claim 27, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation.

29. The method of any one of claims 25 to 27, wherein the colorectal cancer is characterized by a G12C, G12D, G12V, and / or G13D mutation in a KRAS protein.

30. The method of claim 29, wherein the colorectal cancer is a KRAS G12C positive cancer.

31. The method of any one of claims 25 to 30, wherein the colorectal cancer is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor.

32. The method of claim 31, wherein the colorectal cancer is resistant to a KRAS G12C inhibitor.

33. The method of any one of claims 25 to 32, wherein the colorectal cancer is resistant to sotorasib, adagrasib, or divarasib.

34. The method of any one of claims 25 to 33, wherein the colorectal cancer is an advanced or metastatic colorectal cancer.

35. The method of any one of claims 26 to 34, wherein the subject has progression on or disease recurrence after available standard of care (SoC) treatments; or the subject is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

36. The method of any one of claims 26 to 35, wherein the subject does not have a BRAF V600E mutation, HER2 amplification (HER2amp), or deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) tumors.

37. The method of any one of claims 1 to 12, wherein the cancer is non-small cell lung cancer (NSCLC).

38. A method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 :Page 180 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

39. The method of claim 37 or 38, wherein the NSCLC is characterized by a mutation in a KRAS protein.

40. The method of claim 39, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation.

41. The method of any one of claims 37 to 39, wherein the NSCLC is characterized by a G12C, G12D, and / or G12V mutation in a KRAS protein.

42. The method of claim 41, wherein the NSCLC is a KRAS G12C positive cancer.

43. The method of any one of claims 37 to 42, wherein the NSCLC is resistant to a KRASG12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor.

44. The method of claim 43, wherein the NSCLC is resistant to a KRAS G12C inhibitor.

45. The method of any one of claims 37 to 44, wherein the NSCLC is resistant to sotorasib, adagrasib, or divarasib.

46. The method of any one of claims 37 to 45, wherein the NSCLC is an advanced or metastatic NSCLC.Page 181 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 147. The method of any one of claims 38 to 46, wherein the subject has progression on or disease recurrence after available standard of care (SoC) treatments; or the subject is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.

48. The method of any one of claims 38 to 47, wherein the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

49. The method of any one of claims 1 to 48, wherein the subject has not previously been treated with the compound, Compound 1 , or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 1 to 49, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is capable of:1) disrupting, inhibiting, and / or preventing an interaction between a small GTPase and aPI3Ka protein;2) interacting with a Cys242 residue in the catalytic subunit of PI3Ka; and / or3) irreversibly binding to the PI3Ka protein.

51. The method of claim 50, wherein the small GTPase is Rael, CDC42, or a RAS protein.

52. The method of claim 50 or 51, wherein the small GTPase is a RAS protein.

53. The method of claim 52, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MR AS, or RITE54. The method of claim 52 or 53, wherein the RAS protein is KRAS, NRAS, or HRAS.

55. The method of any one of claims 50 to 54, wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M 10431, KI HE,KI UN, E81K, E545A, E545G, N1044K, EllOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

56. The method of any one of claims 50 to 55, wherein the PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.Page 182 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 157. The method of any one of claims 1 to 56, wherein the subject is a human.

58. The method of any one of claims 1 to 57, wherein the subject is an adult of at least 18 years old.

59. The method of any one of claims 1 to 58, wherein the therapeutically effective amount is a total daily dosage of from about 50 mg to about 2000 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 1500 mg, from about 50 mg to about 1200 mg, from about 100 mg to about 1200 mg, from about 150 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 750 mg to about 1200 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 100 mg to about 750 mg, from about 150 mg to about 750 mg, from about 300 mg to about 750 mg, from about 500 mg to about 750 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 150 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 150 mg, or from about 100 mg to about 150 mg of the compound or Compound 1.

60. The method of claim 59, wherein the therapeutically effective amount is a total daily dosage of about 50 mg, about 100 mg, about 150 mg, about 300 mg, about 500 mg, about 750 mg, about 1000 mg, or about 1200 mg of the compound or Compound 1.

61. The method of any one of claims 1 to 60, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

62. The method of any one of claims 1 to 61, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

63. The method of any one of claims 1 to 62, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily.

64. The method of any one of claims 1 to 63, wherein the treating comprises one or more treatment cycles; and the administration of the compound or Compound 1 comprises a dosePage 183 of 18513005782v1PATENTAttorney Docket No. 2014229-0162Client Ref. No. Thera-24. WO 1 escalation or de-escalation after a previous treatment cycle, wherein the dose escalation or de- escalation is determined by a dose-limiting toxicity (DLT) assessment.Page 184 of 18513005782v1

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