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, in combination with a HER2 receptor antagonist, as described herein. Such methods may comprise the treatment of breast cancer, including HER2+ breast cancer.

Description

PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 COMPOSITIONS AND METHODS FOR USE IN THE TREATMENT OF CANCER AND OTHER INDICATIONS CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 702,044, 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., PI3Kα) and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a HER2 receptor antagonist. The methods may comprise administering a compound (e.g., Compound 1, also known as BBO-10203), or a pharmaceutically acceptable Page 1 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 salt thereof (e.g., as described herein), and a HER2 receptor antagonist to a subject in need thereof.

[0006] In a first aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of a compound represented by Formula (IF1): , or aii) a therapeutically effective amount of a HER2 receptor antagonist, wherein the compound of Formula (IF1), the HER2 receptor antagonist, the cancer, and the subject are each described herein.

[0007] In some embodiments, the compound of Formula (IF1) is Compound 1: 1), or a

[0008] In a second aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of Compound 1: Page 2 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 1), or aii) a wherein the HER2 receptor antagonist, the breast cancer, and the subject are each described herein.

[0009] In a third aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of Compound 1: 1), or aii) a therapeutically effective amount of a HER2 receptor antagonist, wherein the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto.

[0010] In a fourth aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of Compound 1: Page 3 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 1), or aii) a wherein the HER2 receptor antagonist is tucatinib. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG.1 schematically illustrates the overall study design of the study described in Example 4.

[0012] FIGs.2A-2B show that strong anti-proliferative effects are observed with the combination of BBO-10203 and the HER2-targeted antibody trastuzumab in ER+ HER2+ cell breast cancer lines. FIG.2A shows changes in percent cell confluence in the ER+ HER2+ breast cancer BT-474 cell line featuring HER2 amplification and a PIK3CA K111N mutation. FIG.2B shows changes in percent cell confluence in the ER+ HER2+ breast cancer ZR-75-30 cell line featuring HER2 amplification.

[0013] FIGs.3A-3B show that strong efficacy is observed with the combination of BBO- 10203 and the HER2-targeted antibody trastuzumab in HER2+ breast cancer xenograft models. FIG.3A shows changes in tumor volume (mean + / - SEM) in the ER+ HER2+ breast cancer BT-474 cell line-derived xenograft model featuring HER2 amplification and a PIK3CA K111N mutation (n=10 per group). FIG.3B shows changes in tumor volume (mean + / - SEM) in the ER- HER2+ breast cancer MDA-MB-453 cell line-derived xenograft model featuring a PIK3CA H1047R mutation (n=9 per group).

[0014] FIG.4 shows that strong efficacy is observed with the combination of BBO-10203 and the HER2 inhibitor tucatinib in the ER+ HER2+ breast cancer BT-474 xenograft model, which features HER2 amplification and a PIK3CA K111N mutation. Changes in tumor Page 4 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 volume (mean + / - SEM) in the BT-474 cell line-derived xenograft model (n=10 per group) are shown.

[0015] FIG.5 shows that strong efficacy is observed with the combination of BBO-10203 and the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan in the ER- HER2+ breast cancer JIMT-1 xenograft model, which features HER2 amplification and a PIK3CA C420R mutation. Changes in tumor volume (mean + / - SEM) in the JIMT-1 cell line-derived xenograft model (n=10 per group) are shown. DETAILED DESCRIPTION Definitions

[0016] Unless specifically indicated otherwise, the group “ ” as used herein in any oneof formulae of compounds as disclosed herein, refers to methyl.

[0017] Unless specifically indicated otherwise, the wavy line in each moiety as used herein, for example in a , refers to the attachment to the remainder of the molecule.

[0018] 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 (HCl) salt of Compound 1 is dosed, the amount of the HCl 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.

[0019] When ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1… and n2” is used, where n1and n2are 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 Page 5 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 “from 1 to 3 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0020] “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.

[0021] 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.

[0022] 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. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as mixtures thereof. Page 6 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Individual stereoisomers of compounds can be prepared synthetically from commercially 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.

[0023] 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.

[0024] 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 triple bonds). 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.

[0025] 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, C1-10, 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 7 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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 8 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C6-C10 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.

[0030] As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

[0031] 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 π 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 9 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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(1H)-one.

[0032] 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.

[0033] 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 10 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0034] 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.

[0035] 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., refers to at ,). Unless otherwise indicated, an “optionallyat 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.

[0036] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, – O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted Page 11 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; – (CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)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; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -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.

[0037] 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)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0– CH(OR^) , -O(haloR^), –CN, –N , –(CH ) C(O)R^, –(CH ) C(O)OH, –(CH ) 2 2 3 2 0–2 2 0–2 2 0– C(O)OR^, –(CH ) SR^, –(CH ) SH, –(CH ) NH , –(CH ) NHR^, –(CH ) NR^ 2 2 0–2 2 0–2 2 0–2 2 2 0–2 2 0–2 2, – NO , –SiR^ , –OSiR^ , -C(O)SR^ –(C straight or branched alkylene)C(O)OR^, or –SSR^2 3 3 , 1–4 ^ wherein each R is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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 =O and =S.

[0038] Suitable divalent substituents on a saturated carbon atom of an “optionally **substituted” group include the following: =O (“oxo”), =S, =NNR , =NNHC(O)R ,2 Page 12 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 =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, C1–6aliphatic 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, C1–6 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.

[0039] 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^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2 whereinas 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.

[0041] 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 C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a Page 13 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0042] “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 / enol, enamine / imine, and lactam / lactim tautomers. Examples of tautomers that are well known in the art also include 2-hydroxypyridine / 2(1H)-pyridone and 2-aminopyridine / 2(1H)-iminopyridone tautomers.

[0043] 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 solvents Page 14 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0044] 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).

[0045] 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.

[0046] 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 / or Page 15 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0047] 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 16 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0048] 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.

[0049] 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, disintegrants, lubricants, coatings, sweeteners, flavors, and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0050] 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 PI3Kα 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 quaternary 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 PI3Kα 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 µM or 0.1 µM ≤ IC50 value < 1 µM, or 1 µM ≤ IC50value ≤ 3 µM 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 µM ≤ IC50 value ≤ 3 µM in the assay of Example 3, infra. Page 17 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0051] “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.).

[0052] “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.

[0053] “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.

[0054] “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.

[0055] 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. Page 18 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[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 suitable 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 quaternized 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. Page 19 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[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, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N’-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[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 Page 20 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 proteins through direct phosphorylation including the mammalian target of rapamycin complex 1 (mTORC1), which acts as a regulator of cell growth and survival pathways, cyclin D1, 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 p110 catalytic and p85 regulatory subunits, and are most clearly implicated in human cancer. Class IA PI3K contains p110α, p110β, and p110δ catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3K. The expression of PI3K isoforms (e.g., PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) is specific to cell types. The p110α and β isoforms are expressed in all cell types, whereas p110δ expression is mainly confined to leukocytes. The p110γ isoform is expressed primarily in the myeloid cell lineage.

[0063] PIK3CA gene encodes the 1068 amino acid p110α protein that contains five domains: an N-terminal adaptor binding domain (ABD) that binds to regulatory subunit p85α, 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 p110α catalytic subunit of PI3Kα. 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 p110α, 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 Page 21 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 p110a-RBD is essential for tumor initiation and maintenance. RAS interactions with p110α-RBD have been shown to be crucial for epidermal growth factor (EGF) signaling to PI3K. 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 and survival and inhibiting EGFR-mutant-induced tumor onset. These results suggest that the binding of p110α 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 PI3Kα resulting in activation of signaling. The small GTPases Rac1 and CDC42 have been shown to bind the RBD of PI3Kβ and are hypothesized to also be capable of binding the RBD of PI3Kα. Accordingly, in some embodiments, the present disclosure encompasses the recognition that disrupting an interaction between PI3Kα and any small GTPase that binds the RBD of PI3Kα may be a useful therapeutic strategy for treating cancers and other indications. In some embodiments, a small GTPase is selected from Rac1, 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., PI3Kα) 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 PI3Kα isoform, combined with Page 22 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 dose- limiting toxicities for p110α inhibitors, which prevent the use of sufficiently high doses to fully suppress PI3Kα signaling in the tumor. Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3Kα 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 PI3Kα inhibitor. Indeed, hyperglycemia was observed in 65% of patients in a Phase III clinical trial of alpelisib, leading to significant dose interruptions.

[0068] To overcome the limitations of current PI3Kα inhibitors, novel strategies to target PI3Kα need to be explored. Previous studies have suggested that inhibiting the RAS- p110α(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 PI3Kα inhibitors (e.g., those that target the ATP binding pocket of PI3Kα). For example, compounds capable of disrupting, inhibiting, and / or preventing an interaction between a protein such as a small GTPase or other protein and PI3Kα protein (e.g., the RAS-binding domain of a PI3Kα protein) may avoid hyperglycemia and insulin-driven resistance common to PI3Kα inhibitors, e.g., because such technologies target activation of PI3Kα by RAS, which is mostly present in transformed cells.

[0069] Cell lines that express HER2 or those that are mutant for KRAS are particularly sensitive to inhibition of PI3Kα:RAS interactions. In subjects with HER2-positive (e.g., HER2+) breast cancer, PI3K pathway signaling is a resistance mechanism to HER2-targeted therapies. Notably, activation mutations in PIK3CA are reported in approximately 30% of HER2-positive breast cancers and are associated with poorer clinical outcomes to HER2- targeted therapies. Preclinical studies have demonstrated that inhibition of PI3K pathway signaling enhances the efficacy of HER2-targeted therapies in HER2-positive breast cancer Page 23 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 cell lines and in CDX and PDX models. However, simultaneous inhibition of HER2 and PI3K pathways has been difficult to achieve in the clinic due to the limited therapeutic window of current PI3K pathway inhibitors, primarily because of their impact on glucose homeostasis. Compounds provided herein may inhibit RAS-driven PI3Kα activation without causing hyperglycemia, and thus may have the potential to be safely used in combination with HER2-targeted therapies like trastuzumab in the clinic to treat patients with HER2- positive tumors.

[0070] 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 combination with a HER2-targeted therapy (e.g., a HER2 receptor antagonist) 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).

[0071] In an aspect, the present disclosure provides a method, comprising administering to a subject in need thereof i) a therapeutically effective amount of a compound capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein, or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of an additional therapeutic agent, wherein the additional therapeutic agent is a HER2 receptor antagonist. Compounds

[0072] In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of binding to PI3Kα, such that (i) the interaction between the small GTPase and PI3Kα is at least partially disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of PI3Kα is not significantly inhibited. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of binding to PI3Kα, such that the interaction between the small GTPase and PI3Kα is at least partially disrupted, inhibited, and / or prevented. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of binding to PI3Kα, such that the kinase activity of PI3Kα is not significantly inhibited.

[0073] 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 Biological Example 1; Page 24 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 and / or (ii) pAKT inhibition IC50 value of < 0.1 µM, 0.1 µM ≤ IC50 value < 1 µM, or1 µM ≤ IC50 value ≤ 3 µM in the assay of Biological Example 2. 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 Biological Example 1; and / or (ii) pAKT inhibition IC50value of < 0.1 µM or 0.1 µM ≤ IC50value < 1 µM in the assay of Biological Example 2. 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 Biological Example 1; and / or (ii) pAKT inhibition IC50 value of < 0.1 µM in the assay of Biological Example 2. 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 Biological Example 1; and (ii) pAKT inhibition IC50 value of < 0.1 µM in the assay of Biological Example 2.

[0074] 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 PI3Kα.

[0075] In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of irreversibly binding the PI3Kα protein. In some embodiments, the compound, or the form (e.g., pharmaceutically acceptable salt) thereof, is capable of reversibly binding the PI3Kα protein.

[0076] In some embodiments, the PI3Kα protein is aberrantly activated.

[0077] In some embodiments, the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0078] In some embodiments, the small GTPase is Rac1, CDC42, or a RAS protein. In some embodiments, the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1. 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 Page 25 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q611P, 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.

[0079] 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.

[0080] In some embodiments, the compound is a compound according to Formula (I): , or a salt (e.g.,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; Ring 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 Page 26 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 C1-6 aliphatic chain substituted with Ring D′; each –L-W is –CN, or: each L is independently a bivalent straight or branched C1-8aliphatic 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 Page 27 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 R2’is independently selected from oxo, halogen, -CN, -OR, and C1-6alkyl; 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 R5′is 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 C1-6aliphatic; 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; Page 28 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 each R is independently hydrogen or 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; 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.

[0081] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0082] 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.

[0083] In some embodiments, the compound is a compound according to Formula (I-a-v’): ,Page 29 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 or 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, R5’, 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.

[0084] In some embodiments of Formula (I) or (I-a-v’), Ring A is phenyl.

[0085] In some embodiments, the compound is a compound according to Formula (I-a-v’): , or a pharmaceuticallyRing 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 a 4- 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; 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; 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; Page 30 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 , -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-, -C(O)C≡CCH2-, and – SO2CH=CH-, and each W is independently hydrogen, halogen, or -CN; each R2and R2’is independently selected from halogen and C1-6 alkyl; each R3is independently selected from halogen, -OR, -O(CH2)vCy, and -O-(C1-4alkylene)-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 C1-6alkyl; each of R5and R5′is independently selected from oxo, =NH, halogen, -OR, -N(R)2, and C1-6alkyl unsubstituted or substituted with one or more substituents selected from halogen, -OR, and -N(R)2; each R6is independently selected from oxo, halogen, -OR, and C1-6alkyl unsubstituted or substituted with one or more halogen or -OR; and Page 31 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 each R is independently hydrogen or C1-6 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, .is a compound of Formula (IF): , or a salt (e.g.,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 compound is a compound of formula (IF) or a pharmaceutically acceptable salt thereof, as described in classes and subclasses herein, both singly and in combination. Page 32 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0087] In some embodiments of Formula (I-a-v’) or (IF), the is.embodiments, the compound is a compound of Formula (IF1): , or a salt (e.g., zwitterionic form, orstereoisomer thereof, wherein Ring C, Ring E, L, R2’, R3, R4, R5, R5’, 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.

[0089] In some embodiments, the compound is represented by Formula (IF1): , or a pharmaceuticallyRing C is phenyl; Page 33 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Ring E is a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ,or 4 each R4is independently halogen or C1-4alkyl; each of R5and R5′is independently halogen or C1-4 alkyl; each R independently hydrogen or C1-4alkyl; n is 0 or 1; p is 0 or 1; s is 0 or 1; and y is 0, 1 or 2.

[0090] In some embodiments of Formula (I-a-v’), (IF), or (IF1), the oror orPage 34 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 .0-2

[0091] In some embodiments of Formula (IF1), the.of any one of formulae described herein, one R3is –O–(C1-4 alkylene)–OR; R is C1-4alkyl; and the remaining R3are each halogen. (R3)0-2

[0093] In some embodiments of Formula (IF1), the is selectedfrom and ; R3is –O–(C1-4 alkylene)–OR; and R is C1-4 alkyl. In some Page 35 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 (R3)0-2

[0094] In some embodiments of Formula (IF) or (IF1), the or,Page 36 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 or

[0096] In some embodiments of Formula (IF1), the is.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.

[0098] In some embodiments of any one of formulae (I-a-v’), (IF), and (IF1), the moiety .one of Formula (I), (I-a-v’), (IF), and (IF1), Ring C is fused to ,Page 37 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 , .

[0101] In some embodiments of Formula (IF1), the is selected from:, .Page 38 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0102] In some embodiments of Formula (IF1), thesome embodiments of Formula (IF1), the is

[0103] In some embodiments of a compound of Formula (IF1), -L-W .

[0104] is selected, ,Page 39 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 ,some Page 40 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 , or a

[0107] In some embodiments, the compound is Compound 1: 1), or a

[0108] Compound 1 is described in International Patent Application No. PCT / US2023 / 012521, filed February 7, 2023. The synthesis of Compound 1 is described in Synthetic Example 70 of PCT / US2023 / 012521, which is reproduced herein. Compound 1 may be referred to as 1-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(1-methyl- 1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl)prop-2-en-1-one. Compound 1 is also known as BBO-10203.

[0109] 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 Page 41 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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+(C1–4alkyl)4salts. 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.

[0110] 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.

[0111] 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

[0112] 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-i, I-a-ii’, 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 Page 42 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0113] 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, I-a- i, I-a-ii’, 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 desired 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.

[0114] 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 Page 43 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0115] 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. HER2-targeting Agents

[0116] In some embodiments, the HER2 receptor antagonist comprises and / or delivers a monoclonal antibody. In some embodiments, the HER2 receptor antagonist comprises a monoclonal antibody. In some embodiments, the HER2 receptor antagonist is a monoclonal antibody. In some embodiments, the HER2 receptor antagonist comprises or is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is or comprises trastuzumab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera).

[0117] In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin). In some embodiments, the HER2 receptor antagonist is administered by intravenous infusion. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 4 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 2 mg / kg of the HER2 receptor antagonist over about 30 minutes once per week, optionally further comprising administering 6 mg / kg over 30-90 minutes every 3 weeks. In some embodiments, administration of the Page 44 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion and ii) subsequently administering about 6 mg / kg over 30-90 minutes every 3 weeks. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 6 mg / kg of the HER2 receptor antagonist over about 30-90 minutes once every 21 days. In some embodiments, when the subject experiences an adverse event that is an infusion related reaction, infusion is reduced, interrupted, or halted. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥16% absolute decrease from baseline or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused for at least 4 weeks if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease in LVEF from pretreatment values, and resumed if, within 4-8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%; or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form is a lyophilized powder for reconstitution. In some embodiments, the unit dosage form comprises about 150 milligrams (mg) or 420 mg of the HER2 receptor antagonist.

[0118] In some embodiments, the HER2 receptor antagonist is or comprises pertuzumab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is administered by intravenous infusion. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) an initial dose of about 840 milligrams over about 60 minutes and ii) subsequently administering about 420 mg over 30-60 minutes every 3 weeks. In some embodiments, when the subject experiences an Page 45 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) drops to less than 40% or is 40-45% with a 10% or greater absolute decrease below pretreatment values or (ii) discontinued if LVEF decline is persistent. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form comprises about 420 milligrams of the HER2 receptor antagonist in a 14 milliliter (mL) single-use vial.

[0119] In some embodiments, the HER2 receptor antagonist is or comprises margetuximab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is administered by intravenous infusion. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) an initial dose of about 15 milligrams per kilogram (mg / kg) over about 120 minutes and ii) subsequently administering about 15 mg / kg over about 30 minutes every 3 weeks. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from pretreatment values or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease from pretreatment values or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for LVEF decline. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form comprises about 250 milligrams of the HER2 receptor antagonist in a 10 milliliter (mL) single-use vial.

[0120] In some embodiments, the HER2 receptor antagonist is administered in combination with an endoglycosidase. In some embodiments, the HER2 receptor antagonist is trastuzumab administered in combination with an endoglycosidase. In some embodiments, the HER2 receptor antagonist is (i) trastuzumab hyaluronidase-oysk (Herceptin Hylecta) or (ii) pertusumab, trastuzumab hyaluronidase-zzxf (Phesgo). In some embodiments, the HER2 receptor antagonist is trastuzumab hyaluronidase-oysk (Herceptin Hylecta). In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering 600 milligram (mg) per 10,000 units (e.g., 600 mg trastuzumab and 10,000 units hyaluronidase) subcutaneously over approximately 2-5 minutes once every 21 days. In some embodiments, the HER2 receptor antagonist is administered Page 46 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 subcutaneously. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from pre-treatment values or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease from pre-treatment levels or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form comprises about 600 milligram (mg) trastuzumab per 10,000 units hyaluronidase per 5 milliliters (mL) (e.g., 120 mg / 2,000 units per mL) solution.

[0121] In some embodiments, the HER2 receptor antagonist is a HER2-directed antibody and topoisomerase inhibitor conjugate. In some embodiments, the HER2 receptor antagonist is trastuzumab, or a biosimilar thereto, conjugated to another entity. In some embodiments, the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu) or ado- trastuzumab emtansine (Kadcyla). In some embodiments, the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu). In some embodiments, the HER2 receptor antagonist is administered by intravenous infusion. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering 5.4 milligrams per kilogram (mg / kg) by intravenous infusion once every 21 days. In some embodiments, when the subject experiences an adverse reaction corresponding to the HER2 receptor antagonist, the dose is reduced to 4.4 mg / kg or 3.2 mg / kg. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering 3.6 milligrams per kilogram (mg / kg) by intravenous infusion once every 21 days. In some embodiments, when the subject experiences an adverse reaction corresponding to the HER2 receptor antagonist, the dose is reduced to 3 mg / kg or 2.4 mg / kg. In some embodiments, when the subject experiences an adverse event that is an infusion related reaction, infusion is reduced, interrupted, or halted. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) is 40-45% and exhibits 10-20% absolute decrease from baseline, and resumed if after 3 weeks LVEF recovers to within 10% from baseline at the same dose or discontinued if LVEF after 3 weeks has not recovered to within 10% from baseline; (ii) paused if LVEF is less than 40% or absolute decrease from baseline is greater than 20% and Page 47 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 discontinued if after 3 weeks LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed; (iii) discontinued if symptomatic congestive heart failure is observed. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) is 40 to ≤ 45% and exhibits ≥ 10% decrease from baseline, and resumed if after 3 weeks LVEF recovers to within 10% from baseline at the same dose or discontinued if LVEF after 3 weeks has not recovered to within 10% from baseline; and (ii) discontinued if symptomatic congestive heart failure, interstitial lung disease (ILD), or pneumonitis is observed. In some embodiments, the subject has a left ventricular ejection fraction (LVEF) of greater than 40% and does not have symptomatic congestive heart failure. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form is a lyophilized powder for reconstitution. In some embodiments, the unit dosage form comprises about 100 milligrams (mg) or 160 mg of the HER2 receptor antagonist.

[0122] In some embodiments, the HER2 receptor antagonist is a small molecule inhibitor. In some embodiments, the HER2 receptor antagonist is, neratinib, dacomitinib, lapatinib, or tucatinib. In some embodiments, the HER2 receptor antagonist is tucatinib.

[0123] In some embodiments, the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, dacomitinib, lapatinib, or tucatinib) is administered orally. In some embodiments, the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, dacomitinib, lapatinib, or tucatinib) is formulated as a tablet. In some embodiments, the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, dacomitinib, lapatinib, or tucatinib) is administered once, twice, thrice, or four times daily. In some embodiments, the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, dacomitinib, lapatinib, or tucatinib) is administered once daily. In some embodiments, the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, dacomitinib, lapatinib, or tucatinib) is administered twice daily.

[0124] In some embodiments, the total daily dosage of the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, dacomitinib, lapatinib, or tucatinib) is between about 10 milligrams (mg) and about 5000 mg. In some embodiments, the total daily dosage of the HER2 receptor antagonist (e.g., a small molecule inhibitor such as neratinib, Page 48 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 dacomitinib, lapatinib, or tucatinib) is about 10 mg, about 15 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In some embodiments, the total daily dosage of the HER2 receptor antagonist (e.g., tucatinib) is about 300 mg, 400 mg, 500 mg, or about 600 mg. In some embodiments, the total daily dosage of the HER2 receptor antagonist (e.g., neratinib) is about 80 mg, about 120 mg, about 160 mg, about 200 mg, or about 240 mg. In some embodiments, the total daily dosage of the HER2 receptor antagonist (e.g., dacomitinib) is about 45 mg. In some embodiments, the total daily dosage of the HER2 receptor antagonist (e.g., lapatinib) is about 7550 mg, 1000 mg, or 1250 mg. In some embodiments, about 150 milligrams (mg), about 200 mg, about 250 mg, or about 300 mg of the HER2 receptor antagonist (e.g., tucatinib) is administered to the subject twice daily. In some embodiments, about 300 mg of the HER2 receptor antagonist (e.g., tucatinib) is administered to the subject twice daily. In some embodiments, about 80 milligrams (mg), about 120 mg, about 160 mg, about 200 mg, or about 240 mg of the HER2 receptor antagonist (e.g., neratinib) is administered to the subject once daily. In some embodiments, about 240 mg of the HER2 receptor antagonist (e.g., neratinib) is administered to the subject once daily. In some embodiments, about 15 milligrams (mg), about 30 mg, or about 45 mg of the HER2 receptor antagonist (e.g., dacomitinib) is administered to the subject once daily. In some embodiments, about 45 mg of the HER2 receptor antagonist (e.g., dacomitinib) is administered to the subject once daily. In some embodiments, about 750 milligrams (mg), 1000 mg, or 1250 mg of the HER2 receptor antagonist (e.g., lapatinib) is administered to the subject once daily. In some embodiments, about 1250 mg of the HER2 receptor antagonist (e.g., lapatinib) is administered to the subject once daily. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form is a tablet. In some embodiments, the unit dosage form comprises about 15 milligrams (mg), about 30 mg, 40 mg, about 45 mg, about 50 mg, about 150 mg, or about 250 mg. Page 49 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Uses and Methods of Treatment

[0125] The present disclosure provides uses for compounds and compositions described herein (e.g., compounds of Formulae I-a, I-a-i, I-a-ii’, 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 combination with a HER2 receptor antagonist. In some embodiments, the present disclosure provides uses for compounds of Formula (IF1) as described herein, or a pharmaceutically acceptable salt thereof, and compositions comprising the compound of Formula (IF1) or a pharmaceutically acceptable salt thereof, in combination with a HER2 receptor antagonist. 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 / or inhibition of a disease or disorder, as described herein) in combination with a HER2 receptor antagonist. In some embodiments, provided compounds and compositions are useful as medicaments used in combination with a HER2 receptor antagonist. Accordingly, in an aspect, the present disclosure provides a method, comprising administering to a subject in need thereof i) a therapeutically effective amount of a compound capable of disrupting, inhibiting, and / or preventing an interaction between a protein (e.g., a small GTPase) and a PI3Kα protein (e.g., the RBD of a PI3Kα protein), or a pharmaceutically acceptable salt thereof and ii) a therapeutically effective amount of a HER2 receptor antagonist.

[0126] In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0127] 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.

[0128] 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. Page 50 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0129] 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.

[0130] 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, 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 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.

[0131] 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. Page 51 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0132] 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, 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, Page 52 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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- 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 Page 53 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0133] 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 salt 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.

[0134] In some embodiments, when the subject experiences an adverse event, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered Page 54 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0135] 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 pharmaceutically 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).

[0136] In some embodiments, administration of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and the HER2 receptor antagonist treats a disease, disorder, or condition in the subject. In some embodiments, the disease, disorder, or condition is a cancer.

[0137] 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. Page 55 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0138] In some embodiments, the disease, disorder, or condition (e.g., cancer) is associated with an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein.

[0139] 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 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. 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, Page 56 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0140] 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 with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

[0141] 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.

[0142] 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.

[0143] In some embodiments, the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases). In some embodiments, the cancer is a HER2 positive or HER2 Page 57 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 amplified cancer. 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.

[0144] In some embodiments, a cancer is associated with and / or characterized by aberrant activation of PI3Kα. 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 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. In some embodiments, a cancer is characterized by a mutation in a PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0145] 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 Page 58 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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. In some embodiments, a cancer is characterized by a mutation in a PI3Kα protein. In some embodiments, the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα 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, Alk, 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).

[0146] 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 Page 59 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 definitive radiotherapy. In some embodiments, the cancer is a measurable disease by RECIST v1.1.

[0147] 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.

[0148] 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 PI3Kα protein.

[0149] 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 PI3Kα protein.

[0150] In some embodiments, the subject has not previously been treated with a HER2 receptor antagonist.

[0151] In some embodiments, the subject has previously been treated with a HER2 receptor antagonist. In some embodiments, the subject has previously been treated with trastuzumab. In some embodiments, the subject has previously been treated with tucatinib.

[0152] 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) ≥1500 / microliter (µL) − Platelets ≥100000 / µL − 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) × (weight in kilogram ((kg) × (0.85 if female) / 72 × (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection. Page 60 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 c. Hepatic: − Serum total bilirubin ≤1.5 × institutional upper limit of normal (ULN) or ≤2.0 × ULN if the subject has a diagnosis of Gilbert syndrome or ≤3.0 × ULN for subjects with liver metastases. − Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) ≤3.0×ULN or AST and / or ALT ≤3.0×ULN with documented liver metastases. d. Coagulation: − International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × 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 × 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.

[0153] 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.

[0154] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered concomitantly.

[0155] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered sequentially.

[0156] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the HER2 receptor antagonist.

[0157] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the HER2 receptor antagonist. Page 61 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0158] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in jointly therapeutically effective amounts.

[0159] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in synergistically effective amounts.

[0160] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and / or the HER2 receptor antagonist is used at a dose different than when it is used alone. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is used at a dose lower than when it is used alone. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is used at a dose higher than when it is used alone. In some embodiments, the HER2 receptor antagonist is used at a dose lower than when it is used alone. In some embodiments, the HER2 receptor antagonist is used at a dose higher than when it is used alone.

[0161] In some embodiments, the present disclosure provides i) a compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition comprising the same and ii) a HER2 receptor antagonist (e.g., as described herein) for use in the manufacture of a medicament. In some embodiments, i) a provided compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) or composition comprising the same and ii) HER2 receptor antagonist (e.g., as described herein) 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, 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 PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. 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, Page 62 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions and a HER2 receptor antagonist (e.g., as described herein) are useful in the manufacture of a medicament for treating a disease, disorder, or condition described herein. In some embodiments, provided compounds or compositions and a HER2 receptor antagonist (e.g., as described herein) are useful in the manufacture of a medicament for treating a cancer or other indication described herein.

[0162] 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 combination with a HER2 receptor antagonist 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 combination with a HER2 receptor antagonist in treating a disease, disorder, or condition associated with or ameliorated by an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, 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 PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some Page 63 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, 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.

[0163] 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.

[0164] In an aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject i) a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and ii) a therapeutically effective amount of a HER2 receptor antagonist. 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 Page 64 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0165] In some embodiments, the HER2 receptor antagonist comprises and / or delivers a monoclonal antibody. In some embodiments, the HER2 receptor antagonist comprises a monoclonal antibody. In some embodiments, the HER2 receptor antagonist is a monoclonal antibody. In some embodiments, the HER2 receptor antagonist comprises or is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is or comprises trastuzumab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera).

[0166] In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin). In some embodiments, the HER2 receptor antagonist is administered by intravenous infusion. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 4 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 2 mg / kg of the HER2 receptor antagonist over about 30 minutes once per week, optionally further comprising administering 6 mg / kg over 30-90 minutes every 3 weeks. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion and ii) subsequently administering about 6 mg / kg over 30-90 minutes every 3 weeks. In some embodiments, administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 6 mg / kg of the HER2 receptor antagonist over about 30-90 minutes once every 21 days. In some embodiments, when the subject experiences an adverse event that is an infusion related reaction, infusion is reduced, interrupted, or halted. In some embodiments, when the subject experiences an Page 65 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥16% absolute decrease from baseline or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy. In some embodiments, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused for at least 4 weeks if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease in LVEF from pretreatment values, and resumed if, within 4-8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%; or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy. In some embodiments, the HER2 receptor antagonist is administered in a unit dosage form. In some embodiments, the unit dosage form is a lyophilized powder for reconstitution. In some embodiments, the unit dosage form comprises about 150 milligrams (mg) or 420 mg of the HER2 receptor antagonist.

[0167] 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.

[0168] 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.

[0169] 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. Page 66 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0170] 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, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is at least about 100 mg.

[0171] 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.

[0172] 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 Page 67 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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, 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, Page 68 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 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.

[0173] 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 Page 69 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0174] 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.

[0175] 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.

[0176] 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 Page 70 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 definitive radiotherapy. In some embodiments, the cancer is a measurable disease by RECIST v1.1.

[0177] 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.

[0178] 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 PI3Kα protein.

[0179] 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 PI3Kα protein.

[0180] 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) ≥1500 / microliter (µL) − Platelets ≥100000 / µL − 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) × (weight in kilogram ((kg) × (0.85 if female) / 72 × (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection. c. Hepatic: − Serum total bilirubin ≤1.5 × institutional upper limit of normal (ULN) or ≤2.0 × ULN if the subject has a diagnosis of Gilbert syndrome or ≤3.0 × ULN for subjects with liver metastases. − Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) ≤3.0×ULN or AST and / or ALT ≤3.0×ULN with Page 71 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 documented liver metastases. d. Coagulation: − International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × 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 × 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. Combination Therapy

[0181] In a first aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering: i) a therapeutically effective amount of a compound represented by Formula (IF1): , or aii) a therapeutically effective amount of a HER2 receptor antagonist, 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; Page 72 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 ,or 4 each R4is independently halogen or C1-4alkyl; each of R5and R5′is independently halogen or C1-4 alkyl; each R independently hydrogen or C1-4alkyl; n is 0 or 1; p is 0 or 1; s is 0 or 1; and y is 0, 1 or 2.

[0182] In some embodiments, the compound of Formula (IF1) is described in International Patent Application No. PCT / US2023 / 012521, which is incorporated herein in its entirety for all purposes.

[0183] In some embodiments, the compound of Formula (IF1) is described according to any one of embodiments herein in Section – Compounds.

[0184] In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound 1.

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

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

[0187] In some embodiments, the cancer is breast cancer, stomach cancer, esophageal cancer, or lung cancer. Page 73 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0188] In some embodiments, the cancer is resistant to a HER2 receptor antagonist, a PI3Kα inhibitor, or a combination thereof. In some embodiments, the cancer is resistant to a HER2 receptor antagonist as described herein. In some embodiments, the cancer is resistant to a PI3Kα inhibitor as described herein. In some embodiments, the cancer is resistant to a PI3Kα inhibitor, wherein the PI3Kα inhibitor is a compound of Formula (IF1) as described herein, or pharmaceutically acceptable salt thereof. In some embodiments, the cancer is resistant to Compound 1, or pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the cancer is breast cancer.

[0190] In a second aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, the method comprising administering: i) a therapeutically effective amount of a compound, which is Compound 1: 1), or aii) a therapeutically effective amount of a HER2 receptor antagonist.

[0191] In some embodiments, the HER2 receptor antagonist is described according to any one of embodiments herein in Section – HER2-targating agents.

[0192] In some embodiments, the HER2 receptor antagonist comprises a monoclonal antibody.

[0193] In some embodiments, the HER2 receptor antagonist comprises or is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist comprises trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto. In some embodiments, the HER2 receptor antagonist is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto. Page 74 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0194] In some embodiments, the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto.

[0195] In a third aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, the method comprising administering: i) a therapeutically effective amount of a compound, which is Compound 1: (Compound 1), or aii) a therapeutically effective amount of a HER2 receptor antagonist, wherein the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto.

[0196] In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera).

[0197] In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin).

[0198] In some embodiments, the HER2 receptor antagonist, is administered by intravenous infusion. In some embodiments, the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera), each of which is administered by intravenous infusion.

[0199] In some embodiments, the HER2 receptor antagonist is administered in combination with an endoglycosidase. In some embodiments, the HER2 receptor antagonist comprises trastuzumab, which is administered in combination with an endoglycosidase. Page 75 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0200] In some embodiments, the HER2 receptor antagonist is (i) trastuzumab and hyaluronidase-oysk (Herceptin Hylecta); or (ii) pertusumab / trastuzumab / hyaluronidase-zzxf (Phesgo).

[0201] In some embodiments, the HER2 receptor antagonist is trastuzumab and hyaluronidase-oysk (Herceptin Hylecta).

[0202] In some embodiments, the HER2 receptor antagonist, when administered in combination with an endoglycosidase, is administered subcutaneously. In some embodiments, the HER2 receptor antagonist comprising trastuzumab, when administered in combination with an endoglycosidase, is administered subcutaneously.

[0203] In some embodiments, the HER2 receptor antagonist is trastuzumab, or a biosimilar thereto, conjugated to another entity.

[0204] In some embodiments, the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu) or ado-trastuzumab emtansine (Kadcyla).

[0205] In some embodiments, the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu).

[0206] In some embodiments, the HER2 receptor antagonist, when conjugated to another entity, is administered by intravenous infusion. In some embodiments, the HER2 receptor antagonist comprising trastuzumab, when conjugated to another entity, is administered by intravenous infusion.

[0207] In some embodiments, the HER2 receptor antagonist is a small molecule inhibitor.

[0208] In some embodiments, the HER2 receptor antagonist is neratinib, dacomitinib, lapatinib, or tucatinib.

[0209] In some embodiments, the HER2 receptor antagonist is tucatinib.

[0210] In a fourth aspect, the present disclosure provides a method of treating breast cancer in a subject in need thereof, the method comprising administering: i) a therapeutically effective amount of a compound, which is Compound 1: Page 76 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 (Compound 1), or aii) a therapeutically effective amount of a HER2 receptor antagonist, wherein the HER2 receptor antagonist is tucatinib.

[0211] In some embodiments, the HER2 receptor antagonist as a small molecule inhibitor is administered orally. In some embodiments, tucatinib is administered orally.

[0212] With reference to any one of the second to fourth aspects, in some embodiments, the breast cancer is described according to any one of embodiments herein in Section – Uses and Methods of Treatment.

[0213] In some embodiments, the breast cancer is a human epidermal growth factor receptor 2 (HER2) positive breast cancer or HER2 amplified cancer.

[0214] In some embodiments, the breast cancer is a HER2 positive breast cancer. In some embodiments, the breast cancer is a HER2 amplified cancer.

[0215] In some embodiments, the breast cancer is an estrogen receptor (ER) positive and a HER2 positive breast cancer.

[0216] In some embodiments, the breast cancer is an estrogen receptor (ER) negative and a HER2 positive breast cancer.

[0217] In some embodiments, the breast cancer is an advanced or metastatic breast cancer.

[0218] In some embodiments, the breast cancer is resistant to a HER2 receptor antagonist, a PI3Kα inhibitor, or a combination thereof. In some embodiments, the breast cancer is resistant to a HER2 receptor antagonist as described herein. In some embodiments, the breast cancer is resistant to a PI3Kα inhibitor as described herein. In some embodiments, the breast Page 77 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 cancer is resistant to a PI3Kα inhibitor, wherein the PI3Kα inhibitor is a compound of Formula (IF1) as described herein, or pharmaceutically acceptable salt thereof. In some embodiments, the breast cancer is resistant to Compound 1, or pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is capable of: 1) disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein; 2) interacting with a Cys242 residue in the catalytic subunit of PI3Kα; and / or 3) irreversibly binding to the PI3Kα protein.

[0220] In some embodiments, the small GTPase and a PI3Kα protein are each described according to any one of embodiments herein in Section – PI3K and Small GTPase Proteins. In some embodiments, the compound (e.g., capable of 1) disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein; 2) interacting with a Cys242 residue in the catalytic subunit of PI3Kα; and / or 3) irreversibly binding to the PI3Kα protein) is described according to any one of embodiments herein in Section – Compounds.

[0221] In some embodiments, the small GTPase is Rac1, CDC42, or a RAS protein.

[0222] In some embodiments, the small GTPase is a RAS protein.

[0223] In some embodiments, the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0224] In some embodiments, the RAS protein is KRAS, NRAS, or HRAS.

[0225] In some embodiments, the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

[0226] In some embodiments, the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0227] In some embodiments, the subject is described according to any one of embodiments herein in Section – Uses and Methods of Treatment. Page 78 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0228] In some embodiments, the subject has not previously been treated with a HER2 receptor antagonist, a PI3Kα inhibitor, or a combination thereof. In some embodiments, the subject has not previously been treated with a HER2 receptor antagonist, a PI3Kα inhibitor, or a combination thereof, each of which is described herein.

[0229] 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.

[0230] In some embodiments, the subject has previously been treated with a HER2 receptor antagonist, a PI3Kα inhibitor, or a combination thereof. In some embodiments, the subject has previously been treated with a HER2 receptor antagonist, a PI3Kα inhibitor, or a combination thereof, each of which is described herein.

[0231] In some embodiments, the subject has previously been treated with trastuzumab or a biosimilar thereto.

[0232] In some embodiments, the subject has previously been treated with tucatinib.

[0233] In some embodiments, the subject has previously been treated with a PI3Kα inhibitor, wherein the PI3Kα inhibitor is a compound of Formula (IF1) according to any one of embodiments as described herein (see Section – Compounds), or pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the subject has previously been treated with Compound 1, or pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the subject is a human.

[0236] In some embodiments, the administration of the compound (as described herein) and the HER2 receptor antagonist is described according to any one of embodiments herein in Section – Uses and Methods of Treatment.

[0237] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0238] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered concomitantly. Page 79 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0239] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered sequentially.

[0240] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the HER2 receptor antagonist.

[0241] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the HER2 receptor antagonist.

[0242] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered concomitantly, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib.

[0243] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered sequentially, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib.

[0244] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the HER2 receptor antagonist, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib.

[0245] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the HER2 receptor antagonist, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib.

[0246] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in jointly therapeutically effective amounts. Page 80 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0247] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in synergistically effective amounts.

[0248] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and / or the HER2 receptor antagonist are each used at a dose lower than when it is used alone.

[0249] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in jointly therapeutically effective amounts, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib.

[0250] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in synergistically effective amounts, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib.

[0251] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and / or the HER2 receptor antagonist are each used at a dose lower than when it is used alone, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof; and the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto, or the HER2 receptor antagonist is tucatinib. Embodiments

[0252] Embodiment 1: A method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering: i) a therapeutically effective amount of a compound capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein, or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of an additional therapeutic agent, wherein the additional therapeutic agent is a HER2 receptor antagonist.

[0253] Embodiment 2: The method of embodiment 1, wherein the HER2 receptor antagonist comprises a monoclonal antibody. Page 81 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0254] Embodiment 3: The method of embodiment 1 or 2, wherein the HER2 receptor antagonist is a monoclonal antibody.

[0255] Embodiment 4: The method of any one of embodiments 1-3, wherein the HER2 receptor antagonist comprises or is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto.

[0256] Embodiment 5: The method of any one of embodiments 1-3, wherein the HER2 receptor antagonist is or comprises trastuzumab, or a biosimilar thereto.

[0257] Embodiment 6: The method of any one of embodiments 1-3, wherein the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera).

[0258] Embodiment 7: The method of embodiment 6, wherein the HER2 receptor antagonist is trastuzumab (Herceptin).

[0259] Embodiment 8: The method of any one of embodiments 1-7, wherein the HER2 receptor antagonist is administered by intravenous infusion.

[0260] Embodiment 9: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 4 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 2 mg / kg of the HER2 receptor antagonist over about 30 minutes once per week, optionally further comprising administering 6 mg / kg over 30-90 minutes every 3 weeks.

[0261] Embodiment 10: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion and ii) subsequently administering about 6 mg / kg over 30-90 minutes every 3 weeks.

[0262] Embodiment 11: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist Page 82 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 comprises administering i) a loading dose of about 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 6 mg / kg of the HER2 receptor antagonist over about 30-90 minutes once every 21 days.

[0263] Embodiment 12: The method of any one of embodiments 1-11, wherein when the subject experiences an adverse event that is an infusion related reaction, infusion is reduced, interrupted, or halted.

[0264] Embodiment 13: The method of any one of embodiments 1-11, wherein when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥16% absolute decrease from baseline or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy.

[0265] Embodiment 14: The method of any one of embodiments 1-11, wherein when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused for at least 4 weeks if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease in LVEF from pretreatment values, and resumed if, within 4-8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%; or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy.

[0266] Embodiment 15: The method of any one of embodiments 1-14, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0267] Embodiment 16: The method of embodiment 15, wherein the unit dosage form is a lyophilized powder for reconstitution.

[0268] Embodiment 17: The method of embodiment 15 or 16, wherein the unit dosage form comprises about 150 milligrams (mg) or 420 mg of the HER2 receptor antagonist.

[0269] Embodiment 18: The method of embodiment 17, wherein the HER2 receptor antagonist is or comprises pertuzumab, or a biosimilar thereto. Page 83 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0270] Embodiment 19: The method of any one of embodiments 1-18, wherein the HER2 receptor antagonist is administered by intravenous infusion.

[0271] Embodiment 20: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) an initial dose of about 840 milligrams over about 60 minutes and ii) subsequently administering about 420 mg over 30-60 minutes every 3 weeks.

[0272] Embodiment 21: The method of embodiment 20, wherein, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) drops to less than 40% or is 40-45% with a 10% or greater absolute decrease below pretreatment values or (ii) discontinued if LVEF decline is persistent.

[0273] Embodiment 22: The method of embodiment 20 or 21, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0274] Embodiment 23: The method of any one of embodiments 20-22, wherein the unit dosage form comprises about 420 milligrams of the HER2 receptor antagonist in a 14 milliliter (mL) single-use vial.

[0275] Embodiment 24: The method of any one of embodiments 20-23, wherein the HER2 receptor antagonist is or comprises margetuximab, or a biosimilar thereto.

[0276] Embodiment 25: The method of any one of embodiments 20-24, wherein the HER2 receptor antagonist is administered by intravenous infusion.

[0277] Embodiment 26: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) an initial dose of about 15 milligrams per kilogram (mg / kg) over about 120 minutes and ii) subsequently administering about 15 mg / kg over about 30 minutes every 3 weeks.

[0278] Embodiment 27: The method of embodiment 26, wherein, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from pretreatment values or LVEF is below institutional limits of normal Page 84 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 and exhibits ≥10% absolute decrease from pretreatment values or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for LVEF decline.

[0279] Embodiment 28: The method of embodiment 26 or 27, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0280] Embodiment 29: The method of embodiment 28, wherein the unit dosage form comprises about 250 milligrams of the HER2 receptor antagonist in a 10 milliliter (mL) single-use vial.

[0281] Embodiment 30: The method of any one of embodiments 1-29, wherein the HER2 receptor antagonist is administered in combination with an endoglycosidase.

[0282] Embodiment 31: The method of embodiment 30, wherein the HER2 receptor antagonist is trastuzumab administered in combination with an endoglycosidase.

[0283] Embodiment 32: The method of embodiment 30, wherein the HER2 receptor antagonist is (i) trastuzumab hyaluronidase-oysk (Herceptin Hylecta) or (ii) pertusumab, trastuzumab hyaluronidase-zzxf (Phesgo).

[0284] Embodiment 33: The method of embodiment 30, wherein the HER2 receptor antagonist is trastuzumab hyaluronidase-oysk (Herceptin Hylecta).

[0285] Embodiment 34: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering 600 milligram (mg) per 10,000 units (e.g., 600 mg trastuzumab and 10,000 units hyaluronidase) subcutaneously over approximately 2-5 minutes once every 21 days.

[0286] Embodiment 35: The method of embodiment 34, wherein the HER2 receptor antagonist is administered subcutaneously.

[0287] Embodiment 36: The method of embodiment 34 or 35, wherein, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from pre-treeatment values or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease from pre-treatment levels or (ii) discontinued if LVEF Page 85 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy.

[0288] Embodiment 37: The method of any one of embodiments 34-36, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0289] Embodiment 38: The method of embodiment 37, wherein the unit dosage form comprises about 600 milligram (mg) trastuzumab per 10,000 units hyaluronidase per 5 milliliters (mL) (e.g., 120 mg / 2,000 units per mL) solution.

[0290] Embodiment 39: The method of any one of embodiments 34-38, wherein the HER2 receptor antagonist is a HER2-directed antibody and topoisomerase inhibitor conjugate.

[0291] Embodiment 40: The method of any one of embodiments 34-39, wherein the HER2 receptor antagonist is trastuzumab, or a biosimilar thereto, conjugated to another entity.

[0292] Embodiment 41: The method of any one of embodiments 34-39, wherein the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu) or ado-trastuzumab emtansine (Kadcyla).

[0293] Embodiment 42: The method of any one of embodiments 34-39, wherein the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu).

[0294] Embodiment 43: The method of any one of embodiments 34-42, wherein the HER2 receptor antagonist is administered by intravenous infusion.

[0295] Embodiment 44: The method of any one of embodiments 1-8, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering 5.4 milligrams per kilogram (mg / kg) by intravenous infusion once every 21 days.

[0296] Embodiment 45: The method of embodiment 44, wherein, when the subject experiences an adverse reaction corresponding to the HER2 receptor antagonist, the dose is reduced to 4.4 mg / kg or 3.2 mg / kg.

[0297] Embodiment 46: The method of embodiment 44 or 45, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering 3.6 milligrams per kilogram (mg / kg) by intravenous infusion once every 21 days. Page 86 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0298] Embodiment 47: The method of any one of embodiments 44-46, wherein, when the subject experiences an adverse reaction corresponding to the HER2 receptor antagonist, the dose is reduced to 3 mg / kg or 2.4 mg / kg.

[0299] Embodiment 48: The method of any one of embodiments 44-47, wherein, when the subject experiences an adverse event that is an infusion related reaction, infusion is reduced, interrupted, or halted.

[0300] Embodiment 49: The method of any one of embodiments 44-48, wherein, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) is 40-45% and exhibits 10-20% absolute decrease from baseline, and resumed if after 3 weeks LVEF recovers to within 10% from baseline at the same dose or discontinued if LVEF after 3 weeks has not recovered to within 10% from baseline; (ii) paused if LVEF is less than 40% or absolute decrease from baseline is greater than 20% and discontinued if after 3 weeks LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed; (iii) discontinued if symptomatic congestive heart failure is observed.

[0301] Embodiment 50: The method of any one of embodiments 44-48, wherein, when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) is 40 to ≤ 45% and exhibits ≥ 10% decrease from baseline, and resumed if after 3 weeks LVEF recovers to within 10% from baseline at the same dose or discontinued if LVEF after 3 weeks has not recovered to within 10% from baseline; and (ii) discontinued if symptomatic congestive heart failure, interstitial lung disease (ILD), or pneumonitis is observed.

[0302] Embodiment 51: The method of embodiment 50, wherein the subject has a left ventricular ejection fraction (LVEF) of greater than 40% and does not have symptomatic congestive heart failure.

[0303] Embodiment 52: The method of any one of embodiments 44-51, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0304] Embodiment 53: The method of embodiment 52, wherein the unit dosage form is a lyophilized powder for reconstitution. Page 87 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0305] Embodiment 54: The method of embodiment 52 or 53, wherein the unit dosage form comprises about 100 milligrams (mg) or 160 mg of the HER2 receptor antagonist.

[0306] Embodiment 55: The method of any one of embodiments 44-54, wherein the HER2 receptor antagonist is a small molecule inhibitor.

[0307] Embodiment 56: The method of embodiment 55, wherein the HER2 receptor antagonist is, neratinib, dacomitinib, lapatinib, or tucatinib.

[0308] Embodiment 57: The method of embodiment 55 or 56, wherein the HER2 receptor antagonist is tucatinib.

[0309] Embodiment 58: The method of any one of embodiments 44-57, wherein the HER2 receptor antagonist is administered orally.

[0310] Embodiment 59: The method of any one of embodiments 44-58, wherein the HER2 receptor antagonist is formulated as a tablet.

[0311] Embodiment 60: The method of any one of embodiments 44-59, the HER2 receptor antagonist is administered once, twice, thrice, or four times daily.

[0312] Embodiment 61: The method of any one of embodiments 44-60, wherein the HER2 receptor antagonist is administered once daily.

[0313] Embodiment 62: The method of any one of embodiments 44-60, wherein the HER2 receptor antagonist is administered twice daily.

[0314] Embodiment 63: The method of any one of embodiments 44-62, wherein the total daily dosage of the HER2 receptor antagonist is between about 10 milligrams (mg) and about 5000 mg.

[0315] Embodiment 64: The method of any one of embodiments 44-63, wherein the total daily dosage of the HER2 receptor antagonist is about 10 mg, about 15 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. Page 88 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0316] Embodiment 65: The method of any one of embodiments 44-64, wherein the total daily dosage of the HER2 receptor antagonist is about 300 mg, 400 mg, 500 mg, or about 600 mg.

[0317] Embodiment 66: The method of any one of embodiments 44-64, wherein the total daily dosage of the HER2 receptor antagonist is about 80 mg, about 120 mg, about 160 mg, about 200 mg, or about 240 mg.

[0318] Embodiment 67: The method of any one of embodiments 44-64, wherein the total daily dosage of the HER2 receptor antagonist is about 45 mg.

[0319] Embodiment 68: The method of any one of embodiments 44-64, wherein the total daily dosage of the HER2 receptor antagonist is about 7550 mg, 1000 mg, or 1250 mg.

[0320] Embodiment 69: The method of any one of embodiments 44-64, wherein about 150 milligrams (mg), about 200 mg, about 250 mg, or about 300 mg of the HER2 receptor antagonist is administered to the subject twice daily.

[0321] Embodiment 70: The method of any one of embodiments 44-64, wherein about 300 mg of the HER2 receptor antagonist is administered to the subject twice daily.

[0322] Embodiment 71: The method of any one of embodiments 44-64, wherein about 80 milligrams (mg), about 120 mg, about 160 mg, about 200 mg, or about 240 mg of the HER2 receptor antagonist is administered to the subject once daily.

[0323] Embodiment 72: The method of any one of embodiments 44-64, wherein about 240 mg of the HER2 receptor antagonist is administered to the subject once daily.

[0324] Embodiment 73: The method of any one of embodiments 44-64, wherein about 15 milligrams (mg), about 30 mg, or about 45 mg of the HER2 receptor antagonist is administered to the subject once daily.

[0325] Embodiment 74: The method of embodiment 73, wherein about 45 mg of the HER2 receptor antagonist is administered to the subject once daily.

[0326] Embodiment 75: The method of any one of embodiments 44-64, wherein about 750 milligrams (mg), 1000 mg, or 1250 mg of the HER2 receptor antagonist is administered to the subject once daily. Page 89 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0327] Embodiment 76: The method of embodiment 75, wherein about 1250 mg of the HER2 receptor antagonist is administered to the subject once daily.

[0328] Embodiment 77: The method of any one of embodiments 44-76, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0329] Embodiment 78: The method of embodiment 77, wherein the unit dosage form is a tablet.

[0330] Embodiment 79: The method of embodiment 77 or 78, wherein the unit dosage form comprises about 15 milligrams (mg), about 30 mg, 40 mg, about 45 mg, about 50 mg, about 150 mg, or about 250 mg.

[0331] Embodiment 80: The method of any one of embodiments 1-79, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of binding to PI3Kα, such that (i) the interaction between the small GTPase and PI3Kα is at least partially disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of PI3Kα is not significantly inhibited.

[0332] Embodiment 81: The method of embodiment 70, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of binding to PI3Kα, such that the interaction between the small GTPase and PI3Kα is at least partially disrupted, inhibited, and / or prevented.

[0333] Embodiment 82: The method of embodiment 80, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of binding to PI3Kα, such that the kinase activity of PI3Kα is not significantly inhibited.

[0334] Embodiment 83: The method of any one of embodiments 1-82, wherein the compound, or pharmaceutically acceptable salt thereof, (i) demonstrates modification of ≥ 75%, 50% ≤ modification < 75%, or 25% ≤ modification < 50% of PIK3CA protein in the assay of Biological Example 1; and / or (ii) pAKT inhibition IC50 value of < 0.1 µM or 0.1 µM ≤ IC50value < 1 µM, or1 µM ≤ IC50value ≤ 3 µM in the assay of Biological Example 2.

[0335] Embodiment 84: The method of any one of embodiments 1-82, wherein the compound, or pharmaceutically acceptable salt thereof, (i) demonstrates modification of ≥ 75% or 50% ≤ modification < 75% of PIK3CA protein in the assay of Biological Example 1; Page 90 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 and / or (ii) pAKT inhibition IC50 value of < 0.1 µM or 0.1 µM ≤ IC50 value < 1 µM in the assay of Biological Example 2.

[0336] Embodiment 85: The method of embodiment 84, wherein the compound, or pharmaceutically acceptable salt thereof, (i) demonstrates modification of ≥ 75% of PIK3CA protein in the assay of Biological Example 1; and / or (ii) pAKT inhibition IC50 value of < 0.1 µM in the assay of Biological Example 2.

[0337] Embodiment 86: The method of any one of embodiments 1-85, wherein the compound, or a pharmaceutically acceptable salt thereof, comprises an electrophilic moiety.

[0338] Embodiment 87: The method of any one of embodiments 1-86, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of interacting with a Cys242 residue in the catalytic subunit of PI3Kα.

[0339] Embodiment 88: The method of any one of embodiments 1-87, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of irreversibly binding the PI3Kα protein.

[0340] Embodiment 89: The method of any one of embodiments 1-88, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of reversibly binding the PI3Kα protein.

[0341] Embodiment 90: The method of any one of embodiments 1-89, wherein the PI3Kα protein is aberrantly activated.

[0342] Embodiment 91: The method of any one of embodiments 1-90, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

[0343] Embodiment 92: The method of any one of embodiments 1-91, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0344] Embodiment 93: The method of any one of embodiments 1-92, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

[0345] Embodiment 94: The method of embodiment 93, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1. Page 91 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0346] Embodiment 95: The method of embodiment 93 or 94, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

[0347] Embodiment 96: The method of any one of embodiments 93-95, wherein the RAS protein is KRAS.

[0348] Embodiment 97: The method of embodiment 96, 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.

[0349] Embodiment 98: The method of embodiment 96 or 97, the KRAS protein comprises a G12C, G12D, G12V, or G12R mutation.

[0350] Embodiment 99: The method of any one of embodiments 96-98, wherein the KRAS protein comprises a G12C or G12D mutation.

[0351] Embodiment 100: The method of any one of embodiments 96-99, wherein the KRAS protein is a wild-type KRAS protein.

[0352] Embodiment 101: The method of embodiment 94, wherein the RAS protein is HRAS.

[0353] Embodiment 102: The method of embodiment 101, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H.

[0354] Embodiment 103: The method of embodiment 101 or 102, wherein the HRAS protein is a wild-type HRAS protein.

[0355] Embodiment 104: The method of embodiment 94, wherein the RAS protein is NRAS.

[0356] Embodiment 105: The method of embodiment 104, 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.

[0357] Embodiment 106: The method of embodiment 104 or 105, wherein the NRAS protein is a wild-type NRAS protein. Page 92 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0358] Embodiment 107: The method of any one of embodiments 1-106, wherein the compound is a compound of Formula (I): , or a salt (e.g., wherein:Ring A is selected a 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, 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 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′; Page 93 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 C1-6 aliphatic chain substituted with Ring D′; each –L-W is –CN, or: each L is independently a bivalent straight or branched C1-8aliphatic 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; 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 R2’is independently selected from oxo, halogen, -CN, -OR, and C1-6alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, - OCH2CH2OR, and optionally substituted C1-6aliphatic; 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 C1-6aliphatic; Page 94 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 each of R5and R5′is 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 C1-6aliphatic; 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 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; 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. Page 95 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0359] Embodiment 108: The method of embodiment 107, wherein the compound is a compound according to Formula (I-a-v'): or a salt (e.g.,

[0360] Embodiment 109: The method of embodiment 107 or 108, wherein the compound is a compound according to Formula (IF) or (IF1):

[0361] Embodiment 110: The method of embodiment 108 or 109, wherein Ring A is phenyl.

[0362] Embodiment 111: The method of embodiment 110, wherein Ring A is selected from .The method of any one of embodiments 108-111, wherein at least one R3is selected from halogen, -OR, -O(CH2)vCy, and -O-(C1-4alkylene)-OR. Page 96 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0364] Embodiment 113: The method of any one of embodiments 108-112, wherein Ring C is phenyl.

[0365] Embodiment 114: The method of any one of embodiments 108-113, wherein Ring C is fused to Ring E.

[0366] Embodiment 115: The method of embodiment 113 or 114, 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′.

[0367] Embodiment 116: The method of any one of embodiments 108-115, wherein ,

[0368] Embodiment 117: The method of any one of embodiments 108-116, wherein each R5is independently selected from C1-6 aliphatic. Page 97 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0369] Embodiment 118: The method of any one of embodiments 108-117, wherein Ring D is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0370] Embodiment 119: The method of any one of embodiments 108-118, wherein Ring D is fused to Ring F.

[0371] Embodiment 120: The method of any one of embodiments 108-119, wherein q is 0.

[0372] Embodiment 121: The method of any one of embodiments 108-120, wherein each R2’is independently selected from C1-6 alkyl.

[0373] Embodiment 122: The method of any one of embodiments 108-121, wherein y is 1 or 2 and r is 0.

[0374] Embodiment 123: The method of any one of embodiments 108-122, 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.

[0375] Embodiment 124: The method of any one of embodiments 108-123, wherein ,Page 98 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 ,Page 99 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1compound is Compound 1: (Compound 1), or a

[0377] Embodiment 126: The method of embodiment 125, wherein the compound is Compound 1.

[0378] Embodiment 127: The method of any one of embodiments 107-126, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered orally.

[0379] Embodiment 128: The method of any one of embodiments 107-127, wherein the compound, or the pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0380] Embodiment 129: The method of any one of embodiments 107-128, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily.

[0381] Embodiment 130: The method of any one of embodiments 107-129, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once daily. Page 100 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0382] Embodiment 131: The method of any one of embodiments 107-129, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered twice daily.

[0383] Embodiment 132: The method of any one of embodiments 107-131, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, occurs according to a treatment cycle.

[0384] Embodiment 133: The method of embodiment 132, wherein the treatment cycle is 21 days.

[0385] Embodiment 134: The method of embodiment 132, wherein the treatment cycle is 28 days.

[0386] Embodiment 135: The method of any one of embodiments 107-134, 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.

[0387] Embodiment 136: The method of embodiment 135, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 mg.

[0388] Embodiment 137: The method of embodiment 135, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 100 mg.

[0389] Embodiment 138: The method of any one of embodiments 107-137, 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, Page 101 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0390] Embodiment 139: The method of embodiment 138, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0391] Embodiment 140: The method of any one of embodiments 107-139, 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, 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- Page 102 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 475-525 mg, about 500-900 mg, Page 103 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0392] Embodiment 141: The method of embodiment 140, 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.

[0393] Embodiment 142: The method of any one of embodiments 107-141, 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.

[0394] Embodiment 143: The method of any one of embodiments 107-142, 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.

[0395] Embodiment 144: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0396] Embodiment 145: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150 mg.

[0397] Embodiment 146: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg. Page 104 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0398] Embodiment 147: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg.

[0399] Embodiment 148: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750 mg.

[0400] Embodiment 149: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1000 mg.

[0401] Embodiment 150: The method of any one of embodiments 107-143, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1200 mg.

[0402] Embodiment 151: The method of any one of embodiments 107-150, wherein the disease, disorder, or condition is a cancer.

[0403] Embodiment 152: The method of any one of embodiments 107-151, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in a unit dosage form.

[0404] Embodiment 153: The method of embodiment 152, wherein the unit dosage form is a tablet.

[0405] Embodiment 154: The method of embodiment 153, 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.

[0406] Embodiment 155: The method of embodiment 153 or 154, wherein the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0407] Embodiment 156: The method of any one of embodiments 107-155, wherein, when the subject experiences an adverse event that is not an infusion related reaction, the compound is administered to the subject at a reduced dose comprising 50% of the initial dose level that was administered to the subject. Page 105 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0408] Embodiment 157: The method of any one of embodiments 107-156, 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.

[0409] Embodiment 158: The method of embodiment 156 or 157, wherein the subject is treated with the reduced dose until the adverse event is resolved.

[0410] Embodiment 159: The method of any one of embodiments 156-158, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0411] Embodiment 160: The method of any one of embodiments 156-159, 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.

[0412] Embodiment 161: The method of any one of embodiments 107-160, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, treats a disease, disorder, or condition in the subject.

[0413] Embodiment 162: The method of embodiment 161, wherein the disease, disorder, or condition is a cancer.

[0414] Embodiment 163: The method of embodiment 162, 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. Page 106 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0415] Embodiment 164: The method of embodiment 162 or 163, 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 (e.g., heck and neck squamous cell carcinoma), prostate cancer, melanoma, glioblastoma, sarcomas, biliary cancer, and pancreatic cancer.

[0416] Embodiment 165: The method of any one of embodiments 162-164, wherein the cancer is lung cancer.

[0417] Embodiment 166: The method of embodiment 165, wherein the cancer is non-small cell lung cancer (NSCLC).

[0418] Embodiment 167: The method of embodiment 166, wherein the NSCLC is KRAS mutant NSCLC.

[0419] Embodiment 168: The method of embodiment 166 or 167, wherein the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS.

[0420] Embodiment 169: The method of any one of embodiments 166-168, wherein the NSCLC is KRAS G12C mutant NSCLC.

[0421] Embodiment 170: The method of any one of embodiments 162-164, wherein the cancer is colorectal cancer.

[0422] Embodiment 171: The method of any one of embodiments 162-164, wherein the cancer is breast cancer.

[0423] Embodiment 172: The method of embodiment 171, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive breast cancer.

[0424] Embodiment 173: The method of embodiment 171 or 172, 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.

[0425] Embodiment 174: The method of any one of embodiments 171-173, 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. Page 107 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0426] Embodiment 175: The method of any one of embodiments 162-164, wherein the cancer is gastric cancer.

[0427] Embodiment 176: The method of any one of embodiments 162-175, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

[0428] Embodiment 177: The method of any one of embodiments 162-176, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified cancer.

[0429] Embodiment 178: The method of any one of embodiments 162-177, wherein the cancer is characterized by a mutant KRAS protein.

[0430] Embodiment 179: The method of any one of embodiments 162-178, wherein the cancer is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor.

[0431] Embodiment 180: The method of any one of embodiments 162-179, wherein the cancer is a KRAS G12C positive cancer resistant to a KRAS G12C inhibitor.

[0432] Embodiment 181: The method of any one of embodiments 162-180, wherein the cancer is a KRAS G12C positive cancer characterized by acquired and / or intrinsic resistance to a KRAS G12C inhibitor.

[0433] Embodiment 182: The method of any one of embodiments 162-181, 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.

[0434] Embodiment 183: The method of any one of embodiments 162-182, wherein the cancer is a KRAS G12C positive cancer resistant to sotorasib, adagrasib, or divarasib.

[0435] Embodiment 184: The method of any one of embodiments 162-183, 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.

[0436] Embodiment 185: The method of any one of embodiments 162-184, wherein the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy. Page 108 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0437] Embodiment 186: The method of any one of embodiments 162-185, wherein the cancer is a measurable disease by RECIST v1.1.

[0438] Embodiment 187: The method of any one of embodiments 162-186, wherein the subject has previously undergone a treatment regimen for cancer.

[0439] Embodiment 188: The method of any one of embodiments 162-187, wherein the subject has previously entered remission from cancer.

[0440] Embodiment 189: The method of any one of embodiments 162-188, wherein the subject has not previously been treated with a HER2 receptor antagonist.

[0441] Embodiment 190: The method of any one of embodiments 162-188, wherein the subject has previously been treated with a HER2 receptor antagonist.

[0442] Embodiment 191: The method of any one of embodiments 162-190, wherein the subject was previously treated with trastuzumab.

[0443] Embodiment 192: The method of any one of embodiments 162-191, wherein the subject was previously treated with tucatinib.

[0444] Embodiment 193: The method of any one of embodiments 162-192, 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 PI3Kα protein.

[0445] Embodiment 194: The method of any one of embodiments 162-192, 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 PI3Kα protein.

[0446] Embodiment 195: The method of any one of embodiments 107-194, wherein the subject is a human.

[0447] Embodiment 196: The method of any one of embodiments 107-195, wherein the subject is at least 18 years of age.

[0448] Embodiment 197: The method of any one of embodiments 107-196, wherein the subject has been diagnosed with the cancer.

[0449] Embodiment 198: The method of any one of embodiments 107-194, wherein the subject has adequate organ function as follows: a) Hematological: Absolute neutrophil count Page 109 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 (ANC) ≥1500 / microliter (µL); Platelets ≥100000 / µL; 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) × (weight in kilogram ((kg) × (0.85 if female) / 72 × (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection; c) Hepatic: Serum total bilirubin ≤1.5 × institutional upper limit of normal (ULN) or ≤2.0 × ULN if the subject has a diagnosis of Gilbert syndrome or ≤3.0 × ULN for subjects with liver metastases; Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) ≤3.0×ULN or AST and / or ALT ≤3.0×ULN with documented liver metastases; and d) Coagulation: International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × 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 × 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.

[0450] Embodiment 199: The method of any one of embodiments 107-198, wherein the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered concomitantly.

[0451] Embodiment 200: The method of any one of embodiments 107-198, wherein the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered sequentially.

[0452] Embodiment 201: The method of any one of embodiments 107-198, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the HER2 receptor antagonist.

[0453] Embodiment 202: The method of any one of embodiments 107-198, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the HER2 receptor antagonist. Page 110 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0454] Embodiment 203: The method of any one of embodiments 107-202, wherein the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in jointly therapeutically effective amounts.

[0455] Embodiment 204: The method of any one of embodiments 107-203, wherein the compound, or the pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in synergistically effective amounts.

[0456] Embodiment 205: The method of any one of embodiments 107-204, wherein the compound, or the pharmaceutically acceptable salt thereof, and / or the HER2 receptor antagonists used at a dose different than when it is used alone.

[0457] Embodiment 206: The method of any one of embodiments 107-205, wherein the compound, or the pharmaceutically acceptable salt thereof, is used at a dose lower than when it is used alone.

[0458] Embodiment 207: The method of any one of embodiments 107-205, wherein the compound, or the pharmaceutically acceptable salt thereof, is used at a dose higher than when it is used alone.

[0459] Embodiment 208: The method of any one of embodiments 107-207, wherein the HER2 receptor antagonists used at a dose lower than when it is used alone.

[0460] Embodiment 209: The method of any one of embodiments 107-207, wherein the HER2 receptor antagonists used at a dose higher than when it is used alone.

[0461] Embodiment 210: A method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject i) a therapeutically effective amount of Compound 1: (Compound 1),Page 111 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of a HER2 receptor antagonist.

[0462] Embodiment 211: A method of treating a cancer in a subject in need thereof, comprising administering to the subject i) a therapeutically effective amount of Compound 1: (Compound 1), or a pharmaceuticallya therapeutically effective amount of a HER2 receptor antagonist.

[0463] Embodiment 212: The method of embodiment 211, wherein the cancer is breast cancer.

[0464] Embodiment 213: The method of embodiment 212, wherein the breast cancer is HER2+ breast cancer.

[0465] Embodiment 214: The method of any one of embodiments 211-213, 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.

[0466] Embodiment 215: The method of any one of embodiments 211-214, 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.

[0467] Embodiment 216: The method of any one of embodiments 211-215, wherein the HER2 receptor antagonist comprises or is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto.

[0468] Embodiment 217: The method of any one of embodiments 211-215, wherein the HER2 receptor antagonist is or comprises trastuzumab, or a biosimilar thereto. Page 112 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0469] Embodiment 218: The method of any one of embodiments 211-215, wherein the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera).

[0470] Embodiment 219: The method of any one of embodiments 211-215, wherein the HER2 receptor antagonist is trastuzumab (Herceptin).

[0471] Embodiment 220: The method of any one of embodiments 211-219, wherein the HER2 receptor antagonist is administered by intravenous infusion.

[0472] Embodiment 221: The method of any one of embodiments 211-220, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 4 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 2 mg / kg of the HER2 receptor antagonist over about 30 minutes once per week, optionally further comprising administering 6 mg / kg over 30-90 minutes every 3 weeks.

[0473] Embodiment 222: The method of any one of embodiments 211-220, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion and ii) subsequently administering about 6 mg / kg over 30-90 minutes every 3 weeks.

[0474] Embodiment 223: The method of any one of embodiments 211-220, wherein administration of the therapeutically effective amount of the HER2 receptor antagonist comprises administering i) a loading dose of about 8 milligrams per kilogram (mg / kg) of the HER2 receptor antagonist by intravenous infusion over about 90 minutes and ii) subsequently administering about 6 mg / kg of the HER2 receptor antagonist over about 30-90 minutes once every 21 days.

[0475] Embodiment 224: The method of any one of embodiments 211-223, wherein when the subject experiences an adverse event that is an infusion related reaction, infusion is reduced, interrupted, or halted. Page 113 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0476] Embodiment 225: The method of any one of embodiments 211-224, wherein when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥16% absolute decrease from baseline or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy.

[0477] Embodiment 226: The method of any one of embodiments 211-224, wherein when the subject experiences an adverse event that is left ventricular dysfunction, administration of the HER2 receptor antagonist is (i) paused for at least 4 weeks if left ventricular ejection fraction (LVEF) exhibits ≥16% absolute decrease from baseline or LVEF is below institutional limits of normal and exhibits ≥10% absolute decrease in LVEF from pretreatment values, and resumed if, within 4-8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%; or (ii) discontinued if LVEF decline is persistent (>8 weeks) or ≥3 suspensions of HER2 receptor antagonist are made for cardiomyopathy.

[0478] Embodiment 227: The method of any one of embodiments 211-226, wherein the HER2 receptor antagonist is administered in a unit dosage form.

[0479] Embodiment 228: The method of embodiment 227, wherein the unit dosage form is a lyophilized powder for reconstitution.

[0480] Embodiment 229: The method of embodiment 226 or 227, wherein the unit dosage form comprises about 150 milligrams (mg) or 420 mg of the HER2 receptor antagonist.

[0481] Embodiment 230: The method of any one of embodiments 211-229, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered orally.

[0482] Embodiment 231: The method of any one of embodiments 211-230, wherein the compound, or the pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0483] Embodiment 232: The method of any one of embodiments 211-231, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily. Page 114 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0484] Embodiment 233: The method of any one of embodiments 211-232, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered once daily.

[0485] Embodiment 234: The method of any one of embodiments 211-232, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered twice daily.

[0486] Embodiment 235; The method of any one of embodiments 211-234, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, occurs according to a treatment cycle.

[0487] Embodiment 236: The method of embodiment 235, wherein the treatment cycle is 21 days.

[0488] Embodiment 237: The method of embodiment 235, wherein the treatment cycle is 28 days.

[0489] Embodiment 238: The method of any one of embodiments 211-237, 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.

[0490] Embodiment 239: The method of any one of embodiments 211-238, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 mg.

[0491] Embodiment 240: The method of any one of embodiments 211-238, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 100 mg.

[0492] Embodiment 241: The method of any one of embodiments 211-240, 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, Page 115 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0493] Embodiment 242: The method of any one of embodiments 211-241, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0494] Embodiment 243: The method of any one of embodiments 211-242, 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, 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 Page 116 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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, 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- Page 117 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0495] Embodiment 244: The method of any one of embodiments 211-243, 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.

[0496] Embodiment 245: The method of any one of embodiments 211-244, 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.

[0497] Embodiment 246: The method of any one of embodiments 211-245, 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.

[0498] Embodiment 247: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0499] Embodiment 248: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150 mg. Page 118 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0500] Embodiment 249: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg.

[0501] Embodiment 250: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg.

[0502] Embodiment 251: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750 mg.

[0503] Embodiment 252: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1000 mg.

[0504] Embodiment 253: The method of any one of embodiments 211-246, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1200 mg.

[0505] Embodiment 254: The method of any one of embodiments 211-253, 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.

[0506] Embodiment 255: The method of any one of embodiments 211-254, 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.

[0507] Embodiment 256: The method of embodiment 254 or 255, wherein the subject is treated with the reduced dose until the adverse event is resolved.

[0508] Embodiment 257: The method of any one of embodiments 254-256, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0509] Embodiment 258: The method of any one of embodiments 254-257, 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. Page 119 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0510] Embodiment 259: The method of any one of embodiments 211-258, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in a unit dosage form.

[0511] Embodiment 260: The method of embodiment 259, wherein the unit dosage form is a tablet.

[0512] Embodiment 261: The method of embodiment 260, 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.

[0513] Embodiment 262: The method of embodiment 260 or 261, wherein the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0514] Embodiment 263: The method of any one of embodiments 211-262, 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.

[0515] Embodiment 264: The method of any one of embodiments 211-263, wherein the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy.

[0516] Embodiment 265: The method of any one of embodiments 211-264, wherein the cancer is a measurable disease by RECIST v1.1.

[0517] Embodiment 266: The method of any one of embodiments 211-265, wherein the subject has previously undergone a treatment regimen for cancer.

[0518] Embodiment 267: The method of any one of embodiments 211-266, wherein the subject has previously entered remission from cancer.

[0519] Embodiment 268: The method of any one of embodiments 211-267, 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 PI3Kα protein. Page 120 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0520] Embodiment 269: The method of any one of embodiments 211-267, 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 PI3Kα protein.

[0521] Embodiment 270: The method of any one of embodiments 211-269, wherein the subject is a human.

[0522] Embodiment 271: The method of any one of embodiments 211-270, wherein the subject is at least 18 years of age.

[0523] Embodiment 272: The method of any one of embodiments 211-271, wherein the subject has been diagnosed with the cancer.

[0524] Embodiment 273: The method of any one of embodiments 211-272, wherein the subject has adequate organ function as follows: a) Hematological: Absolute neutrophil count (ANC) ≥1500 / microliter (µL); Platelets ≥100000 / µL; Hemoglobin ≥9 grams per deciliter (g / dL) without transfusion for at least 2 weeks before enrollment or without erythropoiesis- stimulating agents (e.g., 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) × (weight in kilogram ((kg) × (0.85 if female) / 72 × (serum creatinine in milligrams per deciliter (mg / dL))] or measured using 24-hour urine collection; c) Hepatic: Serum total bilirubin ≤1.5 × institutional upper limit of normal (ULN) or ≤2.0 × ULN if the subject has a diagnosis of Gilbert syndrome or ≤3.0 × ULN for subjects with liver metastases; Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and / or alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) ≤3.0×ULN or AST and / or ALT ≤3.0×ULN with documented liver metastases; and d) Coagulation: International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × 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 × 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. Page 121 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 EXAMPLES

[0525] 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.

[0526] Selected abbreviations used in the preceding sections and the Examples are summarized in Table 1. Table 1. Abbreviations. Abbreviation Term M N A N t it il nPage 122 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Abbreviation Term DCM dichloromethanePage 123 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Abbreviation Term MeOH methanolPage 124 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Abbreviation Term THF tetrahydrofuran Mate

[0527] Preparative thin layer chromatography (PTLC) separations described herein were typically performed on 20 x 20 cm plates (500-µm thick silica gel).

[0528] 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+ columns (Biotage LLC) of various sizes. Typical loading was between 1:50 and 1:1000 crude sample: RP SiO2by 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: SiO2by weight. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0529] 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 Page 125 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 manufacturer. Reference frequency was set using TMS as an internal standard. Chemical shift values (δ) 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.

[0530] LCMS analysis was typically performed using one of the following conditions:

[0531] (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-C1850 mm x 3.0 mm x 2.7 μM 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.

[0532] (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-C1850 mm x 2.1 mm x 1.8 μM 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.

[0533] (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-C184.6 mm x 150 mm x 3.5 μM RapidResol column with a mobile phase of water (0.1 % formic acid) / 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.

[0534] (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 Page 126 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 100-5-C18150 mm x 4.6 mm x 5 µm column. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius unless otherwise noted.

[0535] (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 μm); Flow Rate: 0.5 mL / min. Mass spectra (MS) were measured by Electrospray Ion-Mass spectroscopy (ESI).

[0536] Typically, analytical HPLC spectrometry conditions were as follows:

[0537] LC1: Agilent Technologies 1260 Infinity coupled, Column: poroshell 120 EC-C18 150 mm x 4.6 mm x 4 μm; 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.

[0538] LC2: Shimadzu 2010 CHT, Column Waters X-select CSH C18 (150 x 4.6) mm x 3.5 µm, 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.

[0539] LC3: Shimadzu LC-2010A HT, Column: XBRIDGE-C183.5 µm 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.

[0540] LC4: Shimadzu LC-2050c, Column: XBRIDGE-C183.5 µm 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.

[0541] Preparative HPLC was carried out with one of the following conditions:

[0542] Condition 1: GILSON Preparative HPLC System; Column: Ultimate XB-C18, 21.2 mm x 250 mm, 5 μm; Mobile phase: Water with 0.1% trifluoroacetic acid; MeCN with 0.1% Page 127 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0543] Condition 2: C18-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 v1.6. The preparative HPLC column used was a Waters XBridge® Prep C185uM OBDTM19 x 250 mm column with a mobile phase of water / MeCN or water (0.1% TFA) / MeCN (0.1% TFA).

[0544] Condition 3: Shimadzu Preparative HPLC System; Column: Phenomenex Luna C18, 21.1 mm × 250 mm, 10 μm; 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.

[0545] Chiral supercritical fluid chromatography (SFC) was carried out with one of the following conditions:

[0546] Condition 1: SFC Thar prep 80; Column: CHIRALPAK® AD-H 250 mm x 20 mm, 5 μm; Mobile phase: 40% EtOH / CO2 (contining 0.2% NH4OH); 40 g / min.

[0547] Condition 2: SFC Thar prep 80; Column: CHIRALPAK® OD-H 250 mm x 20 mm, 5 μm; Mobile phase: 40% MeOH / CO2(contining 0.2% NH4OH); 40 g / min.

[0548] Condition 3: SFC Thar prep 80; Column: CHIRALPAK® IC 250 mm x 20 mm, 5 μm; Mobile phase: 40% IPA / CO2 (containing 0.2% DEA); 40 g / min.

[0549] Compound names were generated with ChemDraw Professional.

[0550] 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 1-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(1- methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)prop-2-en-1-one (Compound 1). Page 128 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1methoxyethoxy)phenyl)-4-(1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl- 6,7-dihydropyrazolo[1,5-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[1,5-a]pyrazine-5(4H)-carboxylate (5.00 g, 7.10 mmol) and (1-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-(1-methyl- 1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (4.0 g, 82% yield). LCMS ESI (+) m / z 687.3 (M+H).

[0552] Step B: Preparation of (S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4-(1- methyl-1H-indazol-5-yl)-6-((R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-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-(1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6- yl)-4-methyl-6,7-dihydropyrazolo[1,5-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-(1-methyl-1H-indazol-5-yl)-6-((R)-4-methyl-4,5,6,7- tetrahydropyrazolo[1,5-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).

[0553] Step C: Preparation 1-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4- (1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)prop-2-en-1-one: To a solution of (S)-7-(2,4-difluoro-6-(2- Page 129 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 methoxyethoxy)phenyl)-4-(1-methyl-1H-indazol-5-yl)-6-((R)-4-methyl-4,5,6,7- tetrahydropyrazolo[1,5-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 Na2CO3 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) 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 Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM:MeOH= 20:1) to give 1-((R)-2-((S)-7-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-4- (1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)prop-2-en-1-one (42 mg, 86% yield) as a white solid1H NMR (400 MHz, CD3OD) δ 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

[0554] 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 µM protein target and 1:7.5 protein to compound ratio were used; later the target protein concentration was adjusted to 1 µM with 1:5 protein to compound ratio for more potent compounds.

[0555] Reaction: 3.33 µM or 1 µM 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 MgCl2, pH 7.3 was prepared freshly before assay. Twelve-µL 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 µL 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. Page 130 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1

[0556] Target pretreatment: Before each assay MALDI target (Bruker MPT 384 ground steel BC) was pre-treated by pipetting on each spot 0.75 µL of saturated sinapinic acid in acetonitrile (ACN). This step significantly improves the uniformity of sample crystallization across the plate resulting in enhanced sensitivity.

[0557] Sample preparation: At collection time point, 2 µL of reaction mixtures were pipetted out into 20 µL 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 µL 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.

[0558] 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 0.64× (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 µm 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.

[0559] 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 Page 131 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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.

[0560] 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 were observed each was calculated as a ratio of peak height for given modification versus the sum of peak heights for all observed protein species.

[0561] Data are reported from a 4 h reaction time point. Compounds are characterized basedon 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%.

[0562] Data for Compound 1 is collected using 3.33 µM 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

[0563] 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 μM, with a 3-fold dilution between concentrations.20 μL was transferred onto the cell plates (final volume in wells was 100 μL). Plates were harvested after 4 hr incubation by aspirating media and adding kit-supplied 1x supplemented lysis buffer to all wells (75 µL 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 μL 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 μL 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, Page 132 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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 µs.

[0564] Compounds are characterized based on pAKT inhibition IC50values as follows: “A” means IC50 < 0.1 µM; “B” means IC50 ≥ 0.1 µM and < 1 µM; “C” means IC50 ≥ 1 µM and ≤ 3 µM; “D” means IC50 > 3 µM.

[0565] Compound 1 demonstrates pAKT inhibition IC50 of < 0.1 µM (“A”). Example 4: A Phase 1a / 1b Study of the PI3Kα:RAS Breaker BBO-10203 in Subjects with Advanced Solid Tumors

[0566] The present example describes a Dose Escalation and Dose Expansion Study of Compound 1 (BBO-10203) in subjects with advanced solid tumors.

[0567] 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 (ER- positive 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.

[0568] 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 PI3Kα inhibitor, alpelisib and more recently that of an AKT specific inhibitor, capivasertib, both in combination with standard of care (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 Page 133 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 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).

[0569] 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.

[0570] Compound 1 covalently modifies p110α, the catalytic subunit of PI3K, thereby inhibiting its interaction with RAS. Inhibition of the PI3Kα: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 PI3Kα:RAS interactions. Thus, in addition to testing the activity of Compound 1 in HR- positive aBC as described above, this trial will also enroll patients with HER2-positive aBC 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).

[0571] Compound 1 will be studied in combination with an anti-HER2 monoclonal antibody in subjects with HER2-positive aBC and as monotherapy in subjects with HER2- Page 134 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 positive aBC, HR-positive, HER-2 negative aBC, KRAS mutant aNSCLC, and KRAS mutant aCRC. Synopsis

[0572] The study will include a Phase 1a dose escalation / cohort expansion and a Phase 1b dose expansion. Phase 1a objectives and endpoints are summarized in Table 2. Phase 1b objectives and endpoints are summarized in Table 3. Table 2. Overview of Phase 1a objectives and endpoints. Objectives Endpoints Phase 1a Dose Escalation / Cohort Expansion Compound 1 Monotherapy se d est der g orPage 135 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 Objectives Endpoints To characterize metabolites of Compound 1 in • Plasma Compound 1 metabolite identity and l d g .Table 3. Overview of Phase 1b objectives and endpoints. Objectives Endpoints Ph 1b D E i d 1 T t b i b t ith HER2P iti BPage 136 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 To evaluate additional measures of antitumor • ORR in CNS metastases per Response activity of Compound 1 in combination with Assessment in Neuro-Oncology-Brain trastuzumab on central nervous s stem (CNS) M t t (RANO BM) ( bj t with CNS to

[0573] FIG.1 schematically illustrates the overall study design of the Phase 1a / 1b Study. 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 a 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.cDL A will be the dose below the highest BBO-10203 dose determined to be safe in the monotherapy dose escalation part of the study. The DLT assessment period for combination therapy cohorts is 21 days after first dose of study drug for HER2-positive aBC cohorts.dBBO-10203 dose levels for evaluation in the Phase 1b expansion cohort will be based on SRC review of the totality of safety, preliminary efficacy, Page 137 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 PK, and PD data for BBO-10203 at different doses in the Phase 1a dose escalation monotherapy and combination therapy cohorts. Example 5: BBO-10203 is efficacious in combination with a HER2-targeted antibody in ER+ HER2+ breast cancer cell lines

[0574] Several in vitro viability studies were conducted to investigate the potential of combining BBO-10203 with trastuzumab in the ER+ HER2+ breast cancer BT-474 and ZR- 75-30 cell lines, which harbor HER2 amplification. The BT-474 cell line also bears a PIK3CA K111N mutation. Trastuzumab is a HER2-targeted monoclonal antibody that has been approved by the FDA for patients with HER2+ breast and metastatic stomach cancer. For the clonogenic viability studies, the cell lines were plated at a low density in 12-well plates and the next day treated with either BBO-10203 or trastuzumab. The dose of BBO- 10203 and trastuzumab were picked based on IC50concentrations after conducting a 5-day viability assay in 2D conditions. For BT-474, doses of 60 nM of BBO-10203 and 0.1 µg / mL of trastuzumab were used, and for ZR-75-30, doses of 30 nM of BBO-10203 and 0.1 µg / mL of trastuzumab were used. For the clonogenic assay, compounds were refreshed every 3-4 days and cell confluence was read 1-2 times per day on an Incucyte S3. For the statistical analyses, two-way repeated measures ANOVA followed by a Tukey multiple comparison test was performed to compare all group means.

[0575] In both the BT-474 and ZR-75-30 cell lines, BBO-10203 demonstrated an additive effect when combined with trastuzumab that was greater than the effect of the single agent alone (FIGs.2A-2B). Representative results (mean + / - SEM) from 2 experiments for BT- 474 and 2 experiments for ZR-75-30 are shown. Confluence (+ / - SEM) with two-way repeated measures ANOVA followed by a Tukey multiple comparison test day 16.5 for BT- 474 and day 27.5 for ZR-75-30 showed that the indicated treatment groups had statistically significant activity of the combination compared to each respective monotherapy (*p<0.001). (ANOVA=analysis of variance; ER+=estrogen receptor positive; HER2=erb-b2 receptor tyrosine kinase 2, HER2+=erb-b2 receptor tyrosine kinase 2 positive; μg=microgram; mL=milliliter; nM=nanomolar; PIK3CA=phosphotidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SEM=standard error of the mean)

[0576] In BT-474 cells on day 16.5, BBO-10203 inhibited growth by 41%, trastuzumab inhibited growth by 8%, and the combination of BBO-10203 with trastuzumab significantly Page 138 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 inhibited growth by 65% (FIG.2A). The combination of 60 nM BBO-10203 with 0.1 µg / mL trastuzumab showed greater cell growth inhibition compared to both monotherapy treatments alone. In ZR-75-30 cells on day 27.5, BBO-10203 did not inhibit growth, trastuzumab inhibited growth by 35%, and the combination of BBO-10203 with trastuzumab significantly inhibited growth by 96% (FIG.2B). The combination of 30 nM BBO-10203 with 0.1 µg / mL trastuzumab showed greater cell growth inhibition compared to both monotherapy treatments alone.

[0577] These in vitro studies demonstrate that BBO-10203 and trastuzumab had a statistically significant stronger anti-proliferative effect compared to both monotherapy treatments alone in ER+ HER2+ breast cancer cell lines. Example 6: BBO-10203 is efficacious in combination with a HER2-targeted antibody in HER2+ breast cancer xenograft models

[0578] Several in vivo studies were conducted to assess the anti-tumor activity of BBO- 10203 in combination with trastuzumab in HER2+ breast cancer CDX models. Trastuzumab is a HER2-targeted monoclonal antibody that has been approved by the FDA for patients with HER2+ breast and metastatic stomach cancer. Female immunocompromised mice were implanted subcutaneously with BT-474 or MDA-MB-453 human tumor cells. Animals were implanted subcutaneously with 17β-estradiol pellets to support tumor growth 3 days prior to inoculations for the BT-474 CDX model. When tumors reached a mean size of 168 mm3(BT- 474) or 203 mm3(MDA-MB-453), mice were randomized into treatment groups (10 mice per group for BT-474 and 9 mice per group for MDA-MB-453) and dosed with vehicle or the indicated levels of BBO-10203, trastuzumab, or the combination of BBO-10203 and trastuzumab. Vehicle and BBO-10203 were administered orally once per day (QD) for a period of 28 days. Trastuzumab was administered intraperitoneally once every 7 days (Q7D) until day 22; mice were given one additional dose on day 28 for the BT-474 CDX model. Mouse tumor volumes and body weights were measured twice weekly until day 28. Tumor regression was assessed and defined as a tumor with a smaller tumor volume on the indicated day of the study compared to the first day of dosing. The mean percentage of tumor regression on the day after the last dose compared to the first dose on day 1 was calculated. For statistical analyses comparing each monotherapy group to the combination group, two- way repeated-measures or mixed effects ANOVA was performed between each monotherapy Page 139 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 group mean and combination group mean. Treatments were not considered tolerated if >20% of the mice in the group had >20% body weight loss or >20% of the mice in the group spontaneously died or had any clinical signs of distress that required euthanasia.

[0579] In NSG mice bearing ER+HER2+breast cancer BT-474 CDX subcutaneous xenograft tumors, which harbors HER2 amplification and a PIK3CA K111N mutation, the combination of BBO-10203 and trastuzumab showed statistically significantly greater anti- tumor activity than treatment with either test article alone as a monotherapy (FIG.3A). Following administration of 100 mg / kg BBO-10203 and 20 mg / kg trastuzumab in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 68% mean tumor regression observed in the combination group on day 28. There was no impact of treatments on body weight, and all treatments were well tolerated.

[0580] FIG.3A: *p<0.05, **p<0.0001 two-way repeated measures ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (QD) or intraperitoneally (ip) once every 7 days (Q7D) as indicated. (ANOVA=analysis of variance; ER-=estrogen receptor negative; ER+=estrogen receptor positive; HER2+=Erb-B2 receptor tyrosine kinase 2 positive; mm3=cubic millimeters; mg / kg=milligrams per kilogram; n=number; SEM=standard error of the mean).

[0581] In NCG mice bearing ER- HER2+breast cancer MDA-MB-453 CDX subcutaneous xenograft tumors, which harbor a PIK3CA H1047R mutation, the combination of BBO- 10203 and trastuzumab showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.3B). Following administration of 30 mg / kg BBO-10203 and 4 mg / kg trastuzumab in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 85% mean tumor regression observed in the combination group on day 28. Both BBO-10203 and trastuzumab were well tolerated as monotherapies, but the combination of BBO-10203 and trastuzumab was less well tolerated. Three mice in the combination group were either found dead or had to be euthanized before the end of the study due to body weight loss >20%. The reason for the body weight loss of these mice is unknown but is most likely specific to this model since mice in the vehicle group of this study did not gain weight and BBO-10203 has been well tolerated in combination with a wide range of Page 140 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 compounds across other many studies, including BT-474 tumor-bearing NSG mice which were dosed with higher levels of BBO-10203 and trastuzumab (100 mg / kg QD BBO-10203 and 20 mg / kg Q7D trastuzumab in combination).

[0582] FIG.3B: *p<0.01, *p<0.001 two-way mixed effects ANOVA vs. monotherapy groups; all groups dosed po QD or ip Q7D as indicated. (ANOVA=analysis of variance; ER- =estrogen receptor negative; ER+=estrogen receptor positive; HER2+=Erb-B2 receptor tyrosine kinase 2 positive; mm3=cubic millimeters; mg / kg=milligrams per kilogram; n=number; SEM=standard error of the mean).

[0583] These in vivo efficacy studies demonstrated that BBO-10203 and trastuzumab administered in combination had a statistically significant anti-tumor efficacy benefit compared to both monotherapy treatments alone in two HER2+ breast cancer subcutaneous xenograft models which were either ER+ (BT-474) or ER- (MDA-MB-453) and harbored PIK3CA mutations (at K111N for BT-474 and at H1047R for MDA-MB-453) at well- tolerated doses. This demonstrated that treatment with BBO-10203 led to a combination benefit with a HER2-targeted antibody. Example 7: BBO-10203 is efficacious in combination with a HER2 inhibitor in a HER2+ breast cancer xenograft model

[0584] An in vivo study was conducted to assess the anti-tumor activity of BBO-10203 in combination with tucatinib in the ER+HER2+breast cancer BT-474 CDX model, with harbors HER2 amplification and a PIK3CA K111N mutation. Tucatinib is small molecule which inhibits the tyrosine kinase domain of HER2 that has been approved by the FDA in combination with trastuzumab and capecitabine for treatment of patients with advanced or metastatic HER2+ breast cancer who have received one or more prior HER2-targeted therapies. Female NSG mice were implanted subcutaneously with BT-474 human tumor cells. Animals were implanted subcutaneously with 17β-estradiol pellets to support tumor growth 3 days prior to inoculations. When tumors reached a mean size of 168 mm3, mice were randomized into treatment groups (10 mice per group) and orally administered vehicle QD, 100 mg / kg QD BBO-10203, 50 mg / kg QD tucatinib, or the combination of 100 mg / kg QD BBO-10203 and 50 mg / kg QD tucatinib for a period of 28 days. Mouse tumor volumes and body weights were measured twice weekly until day 28. Tumor regression was assessed and defined as a tumor with a smaller tumor volume on the indicated day of the study Page 141 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 compared to the first day of dosing. The mean percentage of tumor regression on the day after the last dose compared to the first dose on day 1 was calculated. For statistical analyses comparing each monotherapy group to the combination group, two-way repeated-measures ANOVA was performed between each monotherapy group mean and combination group mean. Treatments were not considered tolerated if >20% of the mice in the group had >20% body weight loss or >20% of the mice in the group spontaneously died or had any clinical signs of distress that required euthanasia.

[0585] In NSG mice bearing ER+ HER2+ breast cancer BT-474 subcutaneous xenograft tumors, which harbor HER2 amplification and a PIK3CA K111N mutation, the combination of BBO-10203 and tucatinib showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.4). Following administration of 100 mg / kg BBO-10203 and 50 mg / kg tucatinib in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 51% mean tumor regression observed in the combination group on day 28. There was no impact of treatments on body weight, and all treatments were well tolerated.

[0586] FIG.4: *p<0.0001 two-way repeated measures ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (QD). (ANOVA=analysis of variance; ER+=estrogen receptor positive; HER2+=Erb-B2 receptor tyrosine kinase 2 positive; mm3=cubic millimeters; mg / kg=milligrams per kilogram; n=number; SEM=standard error of the mean).

[0587] This in vivo efficacy study demonstrated that BBO-10203 and tucatinib administered in combination had a statistically significant anti-tumor efficacy benefit compared to both monotherapy treatments alone in the ER+ HER2+ breast cancer BT-474 subcutaneous xenograft model, which harbors HER2 amplification and a PIK3CA K111N mutation, at well-tolerated doses. This demonstrated that treatment with BBO-10203 led to a combination benefit with a HER2 inhibitor. Example 8: BBO-10203 is efficacious in combination with a HER2-targeted antibody- drug conjugate in a HER2+ breast cancer xenograft model

[0588] An in vivo study was conducted to assess the anti-tumor activity of BBO-10203 in combination with the antibody-drug conjugate trastuzumab deruxtecan in the ER- HER2+Page 142 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 breast cancer JIMT-1 CDX model, with harbors HER2 amplification and a PIK3CA C420R mutation. Trastuzumab deruxtecan is a HER2-targeted antibody and topoisomerase inhibitor conjugate that was approved by the FDA for previously treated unresectable or metastatic HER2+ or HER2 low breast cancer, HER2-mutant NSCLC, HER2+ gastric cancer, and HER2+ solid tumors of all types for which there are no other alternative treatment options. Female NOD / SCID mice were implanted subcutaneously with JIMT-1 human tumor cells. When tumors reached a mean size of 170 mm3, mice were randomized into treatment groups (10 mice per group) and treated with vehicle QD, 30 mg / kg QD BBO-10203, 10 mg / kg QDx1 trastuzumab deruxtecan, or the combination of 30 mg / kg QD BBO-10203 and 10 mg / kg QDx1 trastuzumab deruxtecan. Vehicle and BBO-10203 were administered orally once per day (QD) for a period of 28 days. Trastuzumab deruxtecan was administered intravenously once on day 1 of the study (QDx1). Mouse tumor volumes and body weights were measured twice weekly until day 28. Tumor regression was assessed and defined as a tumor with a smaller tumor volume on the indicated day of the study compared to the first day of dosing. The mean percentage of tumor regression on the day after the last dose compared to the first dose on day 1 was calculated. For statistical analyses comparing each monotherapy group to the combination group, two-way repeated-measures ANOVA was performed between each monotherapy group mean and combination group mean. Treatments were not considered tolerated if >20% of the mice in the group had >20% body weight loss or >20% of the mice in the group spontaneously died or had any clinical signs of distress that required euthanasia.

[0589] In NOD / SCID mice bearing ER- HER2+ breast cancer JIMT-1 subcutaneous xenograft tumors, which harbor HER2 amplification and a PIK3CA C420R mutation, the combination of BBO-10203 and trastuzumab deruxtecan showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.5). Following administration of 30 mg / kg BBO-10203 and 10 mg / kg trastuzumab deruxtecan in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 15% mean tumor regression observed in the combination group on day 28. There was no impact of treatments on body weight, and all treatments were well tolerated.

[0590] FIG.5: *p<0.05, *p<0.0001 two-way repeated measures ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (QD) or intravenously (iv) once on day Page 143 of 155 13009881v1PATENT Attorney Docket No.2014229-0164 Client Ref. No. Thera-26.WO1 1 (QDx1) as indicated. (ANOVA=analysis of variance; ER-=estrogen receptor negative; HER2+=Erb-B2 receptor tyrosine kinase 2 positive; mm3=cubic millimeters; mg / kg=milligrams per kilogram; n=number; SEM=standard error of the mean).

[0591] This in vivo efficacy study demonstrates that BBO-10203 and trastuzumab deruxtecan administered in combination had a statistically significant anti-tumor efficacy benefit compared to both monotherapy treatments alone in the ER- HER2+ breast cancer JIMT-1 subcutaneous xenograft model, which harbors HER2 amplification and a PIK3CA C420R mutation, at well-tolerated doses. This demonstrated that treatment with BBO-10203 led to a combination benefit with a HER2-targeted antibody-drug conjugate.

[0592] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. Page 144 of 155 13009881v1

Claims

PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of a compound represented by Formula (IF1): , or aii) a therapeutically effective amount of a HER2 receptor antagonist, 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 R3is independently halogen or –O–(C1-4alkylene)–OR; each R4is independently halogen or C1-4alkyl; each of R5and R5′is independently halogen or C1-4 alkyl; each R independently hydrogen or C1-4 alkyl; Page 145 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 n is 0 or 1; p is 0 or 1; s is 0 or 1; and y is 0, 1 or 2. (R3)0-2,4. The method of claim 2 or 3, wherein is –OCH2CH2OCH3.

5. The method of any one of claims 1 to 4, wherein n is 0.

6. The method of any one of claims 1 to 4, wherein n is 1; and R4is F. Page 146 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 ,8. The method of any one of claims 1 to 7, wherein the compound is represented by: Page 147 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 , or a9. The method of any one of claims 1 to 8, wherein the compound is Compound 1: (Compound 1), or a10. The method of any one of claims 1 to 9, wherein the compound is Compound 1: . 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 11. The method of any one of claims 1 to 10, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified cancer.

12. The method of any one of claims 1 to 11, wherein the cancer is breast cancer, stomach cancer, esophageal cancer, or lung cancer.

13. The method of any one of claims 1 to 12, wherein the cancer is resistant to a HER2 receptor antagonist and / or a PI3Kα inhibitor.

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

15. A method of treating breast cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of a compound, which is Compound 1: , or aii) a therapeutically effective amount of a HER2 receptor antagonist.

16. The method of any one of claims 1 to 15, wherein the HER2 receptor antagonist comprises a monoclonal antibody.

17. The method of any one of claims 1 to 16, wherein the HER2 receptor antagonist comprises or is trastuzumab, pertuzumab, or margetuximab, or a biosimilar thereto.

18. The method of any one of claims 1 to 17, wherein the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto.

19. A method of treating breast cancer in a subject in need thereof, comprising administering: Page 149 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 i) a therapeutically effective amount of a compound, which is Compound 1: (Compound 1), or aii) a therapeutically effective amount of a HER2 receptor antagonist, wherein the HER2 receptor antagonist comprises or is trastuzumab or a biosimilar thereto.

20. The method of any one of claims 1 to 19, wherein the HER2 receptor antagonist is trastuzumab (Herceptin), trastuzumab-strf (Hercessi), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant), or trastuzumab-qyyb (Trazimera).

21. The method of any one of claims 1 to 20, wherein the HER2 receptor antagonist is trastuzumab (Herceptin).

22. The method of claim 20 or 21, wherein the HER2 receptor antagonist is administered by intravenous infusion.

23. The method of any one of claims 1 to 19, wherein the HER2 receptor antagonist is administered in combination with an endoglycosidase.

24. The method of any one of claims 1 to 19 and 23, wherein the HER2 receptor antagonist is (i) trastuzumab and hyaluronidase-oysk (Herceptin Hylecta); or (ii) pertusumab / trastuzumab / hyaluronidase-zzxf (Phesgo).

25. The method of claim 24, wherein the HER2 receptor antagonist is trastuzumab and hyaluronidase-oysk (Herceptin Hylecta). Page 150 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 26. The method of any one of claims 23 to 25, wherein the HER2 receptor antagonist is administered subcutaneously.

27. The method of any one of claims 1 to 19, wherein the HER2 receptor antagonist is trastuzumab, or a biosimilar thereto, conjugated to another entity.

28. The method of any one of claims 1 to 19 and 27, wherein the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu) or ado-trastuzumab emtansine (Kadcyla).

29. The method of claim 28, wherein the HER2 receptor antagonist is fam-trastuzumab deruxtecan-nxki (Enhertu).

30. The method of any one of claims 27 to 29, wherein the HER2 receptor antagonist is administered by intravenous infusion.

31. The method of any one of claims 1 to 15, wherein the HER2 receptor antagonist is a small molecule inhibitor.

32. The method of any one of claims 1 to 15 and 31, wherein the HER2 receptor antagonist is neratinib, dacomitinib, lapatinib, or tucatinib.

33. The method of claim 32, wherein the HER2 receptor antagonist is tucatinib.

34. A method of treating breast cancer in a subject in need thereof, comprising administering: i) a therapeutically effective amount of a compound, which is Compound 1: , or aPage 151 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 ii) a therapeutically effective amount of a HER2 receptor antagonist, wherein the HER2 receptor antagonist is tucatinib.

35. The method of any one of claims 31 to 34, wherein the HER2 receptor antagonist is administered orally.

36. The method of any one of claims 14 to 35, wherein the breast cancer is a human epidermal growth factor receptor 2 (HER2) positive breast cancer or HER2 amplified cancer.

37. The method of any one of claims 14 to 36, wherein the breast cancer is an estrogen receptor (ER) positive and HER2 positive breast cancer.

38. The method of any one of claims 14 to 36, wherein the breast cancer is an estrogen receptor (ER) negative and HER2 positive breast cancer.

39. The method of any one of claims 14 to 38, wherein the breast cancer is an advanced or metastatic breast cancer.

40. The method of any one of claims 14 to 39, wherein the breast cancer is resistant to a HER2 receptor antagonist and / or a PI3Kα inhibitor.

41. The method of any one of claims 1 to 40, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of: 1) disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein; 2) interacting with a Cys242 residue in the catalytic subunit of PI3Kα; and / or 3) irreversibly binding to the PI3Kα protein.

42. The method of claim 41, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

43. The method of claim 41 or 42, wherein the small GTPase is a RAS protein.

44. The method of claim 43, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

45. The method of claim 43 or 44, wherein the RAS protein is KRAS, NRAS, or HRAS. Page 152 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 46. The method of any one of claims 41 to 45, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

47. The method of any one of claims 41 to 46, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

48. The method of any one of claims 1 to 47, wherein the subject has not previously been treated with a HER2 receptor antagonist; and / or a PI3Kα inhibitor.

49. The method of any one of claims 1 to 47, 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.

50. The method of any one of claims 1 to 47, wherein the subject has previously been treated with a HER2 receptor antagonist; and / or a PI3Kα inhibitor.

51. The method of claim 50, wherein the subject has previously been treated with trastuzumab or a biosimilar thereto.

52. The method of claim 50 or 51, wherein the subject has previously been treated with tucatinib.

53. The method of any one of claims 13, 40, 48, and 50, wherein the PI3Kα inhibitor is a compound of Formula (IF1) according to any one of claims 1 to 10, or pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein the PI3Kα inhibitor is Compound 1, or pharmaceutically acceptable salt thereof.

55. The method of any one of claims 1 to 54, wherein the subject is a human.

56. The method of any one of claims 1 to 55, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. Page 153 of 155 13009881v1PATENT Attorney Docket No. 2014229-0164 Client Ref. No. Thera-26.WO1 57. The method of any one of claims 1 to 55, wherein the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered concomitantly.

58. The method of any one of claims 1 to 55, wherein the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are administered sequentially.

59. The method of claim 58, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the HER2 receptor antagonist.

60. The method of claim 58, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the HER2 receptor antagonist.

61. The method of any one of claims 1 to 60, wherein the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in jointly therapeutically effective amounts.

62. The method of any one of claims 1 to 60, wherein the compound, or a pharmaceutically acceptable salt thereof, and the HER2 receptor antagonist are provided in synergistically effective amounts.

63. The method of any one of claims 1 to 60, wherein the compound, or a pharmaceutically acceptable salt thereof, and / or the HER2 receptor antagonist are each used at a dose lower than when it is used alone. Page 154 of 155 13009881v1

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