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 CDK inhibitor or a selective estrogen receptor degrader (SERB), as described herein. Such methods may comprise the treatment of cancer, such as breast cancer.

Description

PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.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 / 704,467, filed October 7, 2024, which is incorporated herein 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 one or more additional therapeutic agents, such as a CDK inhibitor, a selective Page 1 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 estrogen receptor modulator (SERM), or a combination thereof. The methods may comprise administering a compound (e.g., Compound 1, also known as BBO-11203), or a pharmaceutically acceptable salt thereof (e.g., as described herein), and a CDK inhibitor and / or SERM to a subject in need thereof.

[0006] The present disclosure also 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) in combination with a CDK inhibitor or a selective estrogen receptor degrader (SERD). The methods may comprise administering a compound (e.g., Compound 1), or a pharmaceutically acceptable salt thereof (e.g., as described herein), and a CDK inhibitor to a subject in need thereof. The methods may comprise administering a compound (e.g., Compound 1), or a pharmaceutically acceptable salt thereof (e.g., as described herein), and a SERD to a subject in need thereof.

[0007] 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 CDK inhibitor, or a therapeutically effective amount of a selective estrogen receptor degrader (SERD), wherein the compound of Formula (IF1), the CDK inhibitor, the SERD, the cancer, and the subject are each described herein.

[0008] In some embodiments, the compound of Formula (IF1) is Compound 1: Page 2 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 1), or a

[0009] 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: 1), or aii) a therapeutically effective amount of a CDK inhibitor, wherein the CDK inhibitor, the breast cancer, and the subject are each described herein.

[0010] 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: Page 3 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 (Compound 1), or aii) a therapeutically effective amount of a CDK inhibitor, wherein the CDK inhibitor is palbociclib or ribociclib.

[0011] 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: (Compound 1), or aii) a therapeutically effective amount of a selective estrogen receptor degrader (SERD), wherein the SERD, the breast cancer, and the subject are each described herein.

[0012] In a fifth 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 4 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 (Compound 1), or aii) a therapeutically effective amount of a selective estrogen receptor degrader (SERD), wherein the SERD is fulvestrant or camizestrant. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIGs.1A-1B show that strong anti-proliferative effects are observed with the combination of BBO-10203 and the ER degraders fulvestrant or camizestrant in ER+ HER2- breast cancer cell lines with PIK3CA mutations. FIG.1A shows changes in percent cell confluence in the ER+ HER2- breast cancer MCF7 cell line featuring a PIK3CA E545K mutation. FIG.1B shows changes in percent cell confluence in the ER+ HER2- breast cancer T47D cell line featuring a PIK3CA H1047R mutation.

[0014] FIGs.2A-2C show that strong efficacy is observed with the combination of BBO- 10203 and the ER degrader fulvestrant in the ER+ HER2- breast cancer xenograft models, with PIK3CA mutations. FIG.2A shows changes in tumor volume (mean + / - SEM) in the MCF7 cell line-derived xenograft model (n=10 per group). FIG.2B shows changes in tumor volume (mean + / - SEM) in the T47D cell line-derived xenograft model featuring a PIK3CA H1047R mutation (n=10 per group). FIG.2C shows changes in tumor volume (mean + / - SEM) in the EFM-19 cell line-derived xenograft model featuring a PIK3CA H1047L mutation (n=10 per group).

[0015] FIGs.3A-3B show that strong anti-proliferative effects are observed with the combination of BBO-10203 and the CDK4 / 6 inhibitor palbociclib in ER+ HER2- breast cancer cell lines with PIK3CA mutations. FIG.3A shows changes in percent cell confluence in the ER+ HER2- breast cancer MCF7 cell line featuring a PIK3CA E545K mutation. FIG. Page 5 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 3B shows changes in percent cell confluence in the ER+ HER2- breast cancer T47D cell line featuring a PIK3CA H1047R mutation.

[0016] FIG.4 shows that strong efficacy is observed with the combination of BBO-10203 and the CDK4 / 6 inhibitor palbociclib in the ER+ HER2- breast cancer MCF7 xenograft model, which features a PIK3CA E545K mutation. Changes in tumor volume (mean + / - SEM) in the MCF7 cell line-derived xenograft model (n=10 per group) are shown.

[0017] FIGs.5A-5D show that strong efficacy is observed with the combination of BBO- 10203 and the CDK4 / 6 inhibitor ribociclib in ER+ HER2- breast xenograft cancer models with or without PIK3CA mutations. FIG.5A shows changes in tumor volume (mean + / - SEM) in the MCF7 cell line-derived xenograft model featuring a PIK3CA E545K mutation (n=10 per group). FIG.5B shows changes in tumor volume (mean + / - SEM) in the T47D cell line-derived xenograft model featuring a PIK3CA H1047R mutation (n=10 per group). FIG.5C shows changes in tumor volume (mean + / - SEM) in the EFM-19 cell line-derived xenograft model featuring a PIK3CA H1047L mutation (n=10 per group). FIG.5D shows changes in tumor volume (mean + / - SEM) in the HBCx-34 patient-derived xenograft model featuring wild-type PIK3CA (n=10 per group). DETAILED DESCRIPTION Definitions

[0018] Unless specifically indicated otherwise, the group “ ” as used herein in any oneof formulae of compounds as disclosed herein, refers to methyl.

[0019] 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 themolecule.

[0020] Unless specifically indicated otherwise, a dosage amount (e.g., a total daily dosage of about 1-2000 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 a mono hydrochloric acid (HCl) salt of Compound 1 is dosed, the amount of the mono 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 Page 6 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 conversion when a pharmaceutically acceptable salt of the compound (e.g., Compound 1) is administered in any one of embodiments as described herein.

[0021] When ranges of values are disclosed, and the notation “from n1… to n2” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 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.).

[0022] “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 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.

[0023] 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.

[0024] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropisomeric, or epimeric) forms of the Page 7 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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. 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.

[0025] 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.

[0026] As used herein, the term “aliphatic” or “aliphatic group” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (e.g., multiple bonds, such as double or triplebonds). Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Page 8 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0027] 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- ).

[0028] 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.

[0029] 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.

[0030] 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 Page 9 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 rings, such as indanyl or tetrahydronaphthyl, and the like. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0031] 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, 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.

[0032] As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

[0033] 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 Page 10 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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” 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.

[0034] 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.

[0035] 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, Page 11 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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).

[0036] 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.

[0037] 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 Page 12 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0038] 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 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.

[0039] 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)0–2CH(OR^)2, -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0– 2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2) ^ 0–2NR 2, – Page 13 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 NO ^ ^ ^ 2, –SiR 3, –OSiR 3, -C(O)SR , –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from 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. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0040] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =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, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, 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. *

[0041] 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.

[0042] 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)CH C(O)R†, -S(O) R†, -S(O) NR† , –C(S)NR† , –C(NH)NR† 2 2 2 2 2 2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with Page 14 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0043] 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 C1–4aliphatic, –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.

[0044] “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.

[0045] 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 Page 15 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0046] 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).

[0047] 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.

[0048] 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; Page 16 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 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.

[0049] 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, Page 17 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0050] 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.

[0051] 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.

[0052] 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 quartenary structure of one or both proteins, alteration of the chemical structure of one or both proteins by, for example, chemical modification, or the non-covalent association of a compound at the protein-protein interface. In certain embodiments herein, a compound that is capable of disrupting, inhibiting, and / or preventing an interaction between two proteins Page 18 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 (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 IC50value of 1 µM ≤ IC50value ≤ 3 µM in the assay of Example 3, infra.

[0053] “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.).

[0054] “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.

[0055] “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.

[0056] “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.

[0057] 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 Page 19 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0058] 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.

[0059] 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 Page 20 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0060] 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.

[0061] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

[0062] “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. Page 21 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 PI3K and Small GTPase Proteins

[0063] The aberrant activation of the phosphoinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in treating cancers. PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration. Upon activation, PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2). Signaling proteins such as Ser / Thr kinase AKT (e.g., Protein Kinase B (PKB)) can bind to PIP3 and thereby localize to the cell membrane. Phosphorylated AKT activates or inhibits several signaling proteins through direct phosphorylation including the mammalian target of rapamycin complex 1 (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.

[0064] 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.

[0065] 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 Page 22 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0066] Mutations in RAS proteins are found in over 20% of all human cancers. RAS proteins function as molecular switches that cycle between an active, GTP-bound state and an inactive, GDP-bound state. In the active state, RAS proteins interact with various effector proteins including PI3K, RAF kinase, and RalGDS, leading to activation of multiple downstream signaling pathways. Oncogenic RAS mutations are predominantly found at amino acid positions G12, G13, and Q61, and these mutations impair GTPase activities leading to the accumulation of active RAS proteins. The most common oncogenic RAS mutations are G12C, G12D, G12S, G12V, G12R, G13D, and Q61H.

[0067] 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.

[0068] 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 Page 23 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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).

[0069] 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 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.

[0070] 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 Page 24 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0071] Combinations of PI3Kα “breaker” compounds (e.g., compounds capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein) and CDK inhibitors and selective estrogen receptor degraders have shown efficacy in ER+ / HER2- breast cancer models, suggesting that combinations of these therapeutic agents may be beneficial in treating certain cancers.

[0072] 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM), 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, such as breast cancer).

[0073] 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 or regimen, wherein the additional therapeutic agent or regimen is a CDK inhibitor and / or a selective estrogen receptor modulator (SERM). Compounds

[0074] 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. Page 25 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0075] 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; and / or (ii) pAKT inhibition IC50value of < 0.1 µM, 0.1 µM ≤ IC50value < 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 IC50 value of < 0.1 µM or 0.1 µM ≤ IC50 value < 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 IC50value 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.

[0076] 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.

[0077] 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.

[0078] In some embodiments, the PI3Kα protein is aberrantly activated.

[0079] 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. Page 26 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0080] 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 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.

[0081] 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.

[0082] 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; Page 27 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 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 C1-6aliphatic chain substituted with Ring D′; each –L-W is –CN, or: each L is independently a bivalent straight or branched C1-8 aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from – Page 28 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 C1-6 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 Page 29 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0083] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0084] 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.

[0085] In some embodiments, the compound is a compound according to Formula (I-a-v’): Page 30 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 v’) or a salt (e.g., zwitterionic form,or stereoisomer thereof, 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.

[0086] In some embodiments of Formula (I) or (I-a-v’), Ring A is phenyl.

[0087] 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; Page 31 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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; ,- 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 C1-6alkyl; each R3is independently selected from halogen, -OR, -O(CH2)vCy, and -O-(C1-4 alkylene)-OR; each Cy is independently a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and C1-6 alkyl; Page 32 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 each R is independently hydrogen or C1-6alkyl 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 Page 33 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 is a compound of formula (IF) or a pharmaceutically acceptable salt thereof, as described in classes and subclasses herein, both singly and in combination.

[0089] 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, or stereoisomer 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.

[0091] In some embodiments, the compound is represented by Formula (IF1): Page 34 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , or a pharmaceuticallyRing 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 C1-4 alkyl; each of R5and R5′is independently halogen or C1-4alkyl; each R independently hydrogen or C1-4 alkyl; n is 0 or 1; p is 0 or 1; s is 0 or 1; and y is 0, 1 or 2. Page 35 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0092] In some embodiments of Formula (I-a-v’), (IF), or (IF1), the or.

[0093] In some embodiments of Formula (IF1), the is selected.some of any one of formulae described herein, one R3is –O–(C1-4alkylene)–OR; R is C1-4 alkyl; and the remaining R3are each halogen. Page 36 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0095] In some embodiments of Formula (IF1), the is selectedfrom 4 alkylene)–OR; and R is C1-4 alkyl. In some

[0096] In some embodiments of Formula (IF) or (IF1), the orselected from:Page 37 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 ,some any one n In some embodiments of any one of formulae described herein, n is 1. In some embodiments of any one of formulae described herein, n is 1; and R4is F. Page 38 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0100] 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 ,.Page 39 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , ..

[0105] In some embodiments of a compound of Formula (IF1), -L-W .

[0106] In some embodiments of Formula (IF) or (IF1), the is selected from:Page 40 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , , ,

[0107] In some embodiments of Formula (IF) or (IF1), the is. In some embodiments of Formula (IF1), thePage 41 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1, or a pharmaceutically

[0109] In some embodiments, the compound is Compound 1: (Compound 1), or a

[0110] 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- Page 42 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0111] In some embodiments, the compound is administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977). Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0112] It will be appreciated that compounds described herein may be provided and / or utilized in any available form (e.g., a salt form) and that all such forms are contemplated by the present disclosure. The present disclosure also contemplates forms such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers of the compounds provided herein. Page 43 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0113] 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

[0114] 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 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.

[0115] 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 Page 44 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0116] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0117] 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. Combination agents

[0118] A compound capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein may be administered in combination with a combination agent that is a CDK inhibitor and / or a selective estrogen receptor modulator (SERM). A compound capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein may be administered in combination with a combination agent that is a CDK inhibitor or a selective estrogen receptor degrader (SERD). Page 45 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0119] In some embodiments, the combination agent is a CDK inhibitor. In some embodiments, the CDK inhibitor has inhibitory activity against CDK2, CDK4, CDK6, or a combination thereof. In some embodiments, the CDK inhibitor has inhibitory activity against CDK2. In some embodiments, the CDK inhibitor has inhibitory activity against CDK4. In some embodiments, the CDK inhibitor has inhibitory activity against CDK6. In some embodiments, the combination agent has selectivity for CDK4 over CDK6. In some embodiments, the combination agent has selectivity for CDK6 over CDK4. In some embodiments, the combination agent has beneficial potency against both CDK4 and CDK6.

[0120] In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091. In some embodiments, the CDK inhibitor (e.g., CDK4 / 6 inhibitor) is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, or PF-07220060. In some embodiments, the CDK inhibitor (e.g., CDK4 / 6 inhibitor) is palbociclib, ribociclib, or abemaciclib. In some embodiments, the CDK inhibitor (e.g., CDK4 / 6 inhibitor) is palbociclib or ribociclib.

[0121] In some embodiments, the CDK inhibitor is palbociclib. In some embodiments, the therapeutically effective amount of palbociclib is between about 1 mg and about 1000 mg. In some embodiments, the therapeutically effective amount of palbociclib is between about 25 mg and about 200 mg. In some embodiments, the therapeutically effective amount of palbociclib is between about 75 mg and about 125 mg. In some embodiments, the therapeutically effective amount of palbociclib is about 125 mg, 100 mg, or 75 mg. In some embodiments, the therapeutically effective amount of palbociclib is orally administered.

[0122] In some embodiments, the CDK inhibitor is ribociclib. In some embodiments, the therapeutically effective amount of ribociclib is between about 1 mg and about 1000 mg. In some embodiments, the therapeutically effective amount of ribociclib is between about 100 mg and about 1000 mg. In some embodiments, the therapeutically effective amount of ribociclib is between about 200 mg and about 600 mg. In some embodiments, the therapeutically effective amount of ribociclib is about 200 mg, 400 mg, or 600 mg. In some embodiments, the therapeutically effective amount of ribociclib is orally administered. Page 46 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0123] In some embodiments, the combination agent is a selective estrogen receptor modulator (SERM). In some embodiments, the combination agent is a selective estrogen receptor degrader or downregulator (SERD). In some embodiments, the selective estrogen receptor degrader (SERD) is fulvestrant or camizestrant.

[0124] In some embodiments, the selective estrogen receptor degrader (SERD) is fulvestrant. In some embodiments, the therapeutically effective amount of fulvestrant is between about 1 milligram (mg) and about 1000 mg. In some embodiments, the therapeutically effective amount of fulvestrant is between about 100 mg and about 750 mg. In some embodiments, the therapeutically effective amount of fulvestrant is between about 250 mg and about 500 mg. In some embodiments, the therapeutically effective amount of fulvestrant is about 250 mg or about 500 mg. In some embodiments, the therapeutically effective amount of fulvestrant is administered by intramuscular injection.

[0125] In some embodiments, the selective estrogen receptor degrader (SERD) is camizestrant. In some embodiments, the therapeutically effective amount of camizestrant is between about 1 milligram (mg) and about 500 mg. In some embodiments, the therapeutically effective amount of camizestrant is between about 50 mg and about 200 mg. In some embodiments, the therapeutically effective amount of camizestrant is between about 75 mg and about 150 mg. In some embodiments, the therapeutically effective amount of camizestrant is about 75 mg or about 150 mg. In some embodiments, the therapeutically effective amount of camizestrant is orally administered.

[0126] In some embodiments, both a CDK inhibitor and a selective estrogen receptor modulator are administered. In some embodiments, both a CDK inhibitor and a selective estrogen receptor degrader (SERD) are administered. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, or PF-07220060. In some embodiments, the SERD is fulvestrant or camizestrant. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is palbociclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is ribociclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is abemaciclib. In some embodiments, the SERD is Page 47 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 fulvestrant and the CDK inhibitor is dalpiciciclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is lerociclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is PF-07220060. In some embodiments, the SERD is camizestrant and the CDK inhibitor is palbociclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is ribociclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is abemaciclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is dalpiciciclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is lerociclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is PF-07220060.

[0127] In some embodiments, an aromatase inhibitor is also administered to the subject. In some embodiments, the aromatase inhibitor is anastrozole, exemestane, or letrozole. Uses and Methods of Treatment

[0128] 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (e.g., as described herein). 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (e.g., as described herein). In some embodiments, provided compounds and compositions are useful as medicaments used in combination with a CDK inhibitor and / or selective estrogen receptor modulator (SERM) (e.g., as described herein). 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (e.g., as described herein). Page 48 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0129] 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 CDK inhibitor or a selective estrogen receptor degrader (SERD). 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 CDK inhibitor or selective estrogen receptor degrader (SERD) (e.g., as described herein). In some embodiments, provided compounds and compositions are useful as medicaments used in combination with a CDK inhibitor or selective estrogen receptor degrader (SERD) (e.g., as described herein). 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 CDK inhibitor or selective estrogen receptor degrader (SERD) (e.g., as described herein).

[0130] In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0131] 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.

[0132] 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.

[0133] In some embodiments, administration of the compound, or the pharmaceutically acceptable salt thereof, (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) Page 49 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 occurs according to a treatment cycle. In some embodiments, the treatment cycle is 21 days. In some embodiments, the treatment cycle is 28 days.

[0134] 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.

[0135] 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.

[0136] 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 Page 50 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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, 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 Page 51 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 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. Page 52 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0137] 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.

[0138] In some embodiments, when the subject experiences an adverse event, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered to the subject at a reduced dose comprising 50% of the initial dose level that was administered to the subject. In some embodiments, when the subject experiences a second Page 53 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0139] 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).

[0140] 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) treats a disease, disorder, or condition in the subject. In some embodiments, the disease, disorder, or condition is a cancer.

[0141] 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 CDK inhibitor or selective estrogen receptor degrader (SERD) treats a disease, disorder, or condition in the subject. In some embodiments, the disease, disorder, or condition is a cancer.

[0142] 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 Page 54 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0143] 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.

[0144] In some embodiments, a cancer is selected from pancreatic cancer (e.g., pancreatic ductal carcinoma); 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 Page 55 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinomas, paraganglioma, parathyroid tumors, pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm’s tumor. In some embodiments, the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, melanoma, glioblastoma, sarcomas, and pancreatic cancer. In some embodiments, a cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer. In some embodiments, the cancer is breast cancer.

[0145] 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).

[0146] 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.

[0147] 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 Page 56 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks before administration of the compound.

[0148] 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 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.

[0149] 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, Page 57 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0150] In some embodiments, a cancer is characterized by one or more mutations. In some such embodiments, a subject may be diagnosed with cancer and / or selected for therapy based on the detection of one or more mutations in a biological sample obtained from the subject. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., KRAS, HRAS, or NRAS). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. 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). Page 58 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0151] In some embodiments, the subject has progression on or disease recurrence after, all available standard of care treatments or would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. In some embodiments, the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy. In some embodiments, the cancer is a measurable disease by RECIST v1.1.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] In some embodiments, the subject has not previously been treated with a CDK inhibitor.

[0156] In some embodiments, the subject has previously been treated with a CDK inhibitor. In some embodiments, the subject was previously treated with palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091. In some embodiments, the subject was previously treated with palbociclib or ribociclib.

[0157] In some embodiments, the subject has not previously been treated with a selective estrogen receptor modulator (SERM). In some embodiments, the subject has previously been treated with a selective estrogen receptor modulator (SERM). In some embodiments, the subject has not previously been treated with a selective estrogen receptor degrader (SERD). In some embodiments, the subject has previously been treated with a selective estrogen receptor degrader (SERD). In some embodiments, the subject has previously been treated with fulvestrant or camizestrant. Page 59 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0158] In some embodiments, the subject has not previously been treated with an aromatase inhibitor. In some embodiments, the subject has previously been treated with an aromatase inhibitor. In some embodiments, the subject has previously been treated with anastrozole, exemestane, or letrozole.

[0159] 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 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 Page 60 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.

[0160] 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.

[0161] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are administered concomitantly. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered concomitantly. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor modulator (SERM) are administered concomitantly.

[0162] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor or selective estrogen receptor degrader (SERD) are administered concomitantly. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered concomitantly. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor degrader (SERD) are administered concomitantly.

[0163] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are administered sequentially. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered sequentially. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor modulator (SERM) are administered sequentially.

[0164] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor or selective estrogen receptor degrader (SERD) are administered sequentially. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered sequentially. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor degrader (SERD) are administered sequentially. Page 61 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0165] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor and / or selective estrogen receptor modulator (SERM). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the selective estrogen receptor modulator (SERM).

[0166] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor or selective estrogen receptor degrader (SERD). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the selective estrogen receptor degrader (SERD).

[0167] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor and / or selective estrogen receptor modulator (SERM). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the selective estrogen receptor modulator (SERM).

[0168] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor or selective estrogen receptor degrader (SERD). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the selective estrogen receptor degrader (SERD).

[0169] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are provided in jointly therapeutically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in jointly therapeutically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor modulator (SERM) are provided in jointly therapeutically effective amounts. Page 62 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0170] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor or selective estrogen receptor degrader (SERD) are provided in jointly therapeutically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in jointly therapeutically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor degrader (SERD) are provided in jointly therapeutically effective amounts.

[0171] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are provided in synergistically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in synergistically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor modulator (SERM) are provided in synergistically effective amounts.

[0172] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor or selective estrogen receptor degrader (SERD) are provided in synergistically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in synergistically effective amounts. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and the selective estrogen receptor degrader (SERD) are provided in synergistically effective amounts.

[0173] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and / or the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose or amount 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) 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 CDK inhibitor is used at a dose lower than when it is used alone. In some Page 63 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 selective estrogen receptor modulator (SERM) is used at a dose lower than when it is used alone. In some embodiments, the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose higher than when it is used alone. In some embodiments, the CDK inhibitor is used at a dose higher than when it is used alone. In some embodiments, the selective estrogen receptor modulator (SERM) is used at a dose higher than when it is used alone.

[0174] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, and / or the CDK inhibitor or selective estrogen receptor degrader (SERD) is used at a dose or amount 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 CDK inhibitor or selective estrogen receptor degrader (SERD) 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 CDK inhibitor 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 selective estrogen receptor degrader (SERD) is used at a dose lower than when it is used alone. In some embodiments, the CDK inhibitor or selective estrogen receptor degrader (SERD) is used at a dose higher than when it is used alone. In some embodiments, the CDK inhibitor is used at a dose higher than when it is used alone. In some embodiments, the selective estrogen receptor degrader (SERD) is used at a dose higher than when it is used alone.

[0175] 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (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) CDK inhibitor and / or selective estrogen receptor modulator (SERM) (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 Page 64 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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, 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (e.g., as described herein) are useful in the manufacture of a medicament for treating a cancer or other indication described herein. Page 65 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0176] 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 CDK inhibitor or selective estrogen receptor degrader (SERD) (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) CDK inhibitor / or selective estrogen receptor degrader (SERD) (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, 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 Page 66 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 embodiments, provided compounds or compositions and a CDK inhibitor or selective estrogen receptor degrader (SERD) (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 CDK inhibitor or selective estrogen receptor degrader (SERD) (e.g., as described herein) are useful in the manufacture of a medicament for treating a cancer or other indication described herein.

[0177] 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) (e.g., as described herein) 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM) 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 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, Page 67 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0178] 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 CDK inhibitor or selective estrogen receptor degrader (SERD) (e.g., as described herein) 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 CDK inhibitor or selective estrogen receptor degrader (SERD) 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 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, Page 68 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0179] In an aspect, the present disclosure provides a method of treating 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 CDK inhibitor and / or selective estrogen receptor modulator (SERM).

[0180] In an aspect, the present disclosure provides a method of treating 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 CDK inhibitor or selective estrogen receptor degrader (SERD).

[0181] In an aspect, the present disclosure provides a method of treating 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 CDK inhibitor.

[0182] In an aspect, the present disclosure provides a method of treating 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 selective estrogen receptor modulator (SERM). Page 69 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0183] In an aspect, the present disclosure provides a method of treating 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 CDK inhibitor and a selective estrogen receptor modulator (SERM).

[0184] In some embodiments of any of the preceding aspects, the CDK inhibitor has inhibitory activity against CDK2, CDK4, CDK6, or a combination thereof. In some embodiemnts, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT- 419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, or PF-07220060. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, or abemaciclib.

[0185] In some embodiments of any of the preceding aspects, the CDK inhibitor is palbociclib. In some embodiments, the therapeutically effective amount of palbociclib is between about 1 mg and about 1000 mg. In some embodiments, the therapeutically effective amount of palbociclib is between about 25 mg and about 200 mg. In some embodiments, the therapeutically effective amount of palbociclib is between about 75 mg and about 125 mg. In some embodiments, the therapeutically effective amount of palbociclib is about 125 mg, 100 mg, or 75 mg. In some embodiments, the therapeutically effective amount of palbociclib is orally administered.

[0186] In some embodiments of any of the preceding aspects, the CDK inhibitor is ribociclib. In some embodiments, the therapeutically effective amount of ribociclib is between about 1 mg and about 1000 mg. In some embodiments, the therapeutically effective amount of ribociclib is between about 100 mg and about 1000 mg. In some embodiments, the therapeutically effective amount of ribociclib is between about 200 mg and about 600 mg. In some embodiments, the therapeutically effective amount of ribociclib is about 200 mg, 400 mg, or 600 mg. In some embodiments, the therapeutically effective amount of ribociclib is orally administered.

[0187] In some embodiments of any of the preceding aspects, the selective estrogen receptor modulator is fulvestrant or camizestrant. Page 70 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0188] In some embodiments of any of the preceding aspects, the selective estrogen receptor degrader (SERD) is fulvestrant. In some embodiments, the therapeutically effective amount of fulvestrant is between about 1 milligram (mg) and about 1000 mg. In some embodiments, the therapeutically effective amount of fulvestrant is between about 100 mg and about 750 mg. In some embodiments, the therapeutically effective amount of fulvestrant is between about 250 mg and about 500 mg. In some embodiments, the therapeutically effective amount of fulvestrant is about 250 mg or about 500 mg. In some embodiments, the therapeutically effective amount of fulvestrant is administered by intramuscular injection.

[0189] In some embodiments of any of the preceding aspects, the selective estrogen receptor degrader (SERD) is camizestrant. In some embodiments, the therapeutically effective amount of camizestrant is between about 1 milligram (mg) and about 500 mg. In some embodiments, the therapeutically effective amount of camizestrant is between about 50 mg and about 200 mg. In some embodiments, the therapeutically effective amount of camizestrant is between about 75 mg and about 150 mg. In some embodiments, the therapeutically effective amount of camizestrant is about 75 mg or about 150 mg. In some embodiments, the therapeutically effective amount of camizestrant is orally administered.

[0190] In some embodiments of any of the preceding aspects, both a CDK inhibitor and a selective estrogen receptor modulator are administered. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, or PF-07220060. In some embodiments, the SERD is fulvestrant or camizestrant. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is palbociclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is ribociclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is abemaciclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is dalpiciciclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is lerociclib. In some embodiments, the SERD is fulvestrant and the CDK inhibitor is PF-07220060. In some embodiments, the SERD is camizestrant and the CDK inhibitor is palbociclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is ribociclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is abemaciclib. In some embodiments, the SERD is Page 71 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 camizestrant and the CDK inhibitor is dalpiciciclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is lerociclib. In some embodiments, the SERD is camizestrant and the CDK inhibitor is PF-07220060.

[0191] In some embodiments of any of the preceding aspects, an aromatase inhibitor is also administered to the subject. In some embodiments, the aromatase inhibitor is anastrozole, exemestane, or letrozole.

[0192] In some embodiments of any of the preceding aspects, 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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 Page 72 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0197] 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.

[0198] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is between about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70-1500 mg, about 80-1500 mg, about 90-1500 mg, about 100- 1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, about 300-1500 mg, about 325-1500 mg, about 350-1500 mg, about 375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525-1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about Page 73 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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, 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- Page 74 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0199] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 100 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, or 1200 mg. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the total daily dosage of Page 75 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0200] 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.

[0201] 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.

[0202] In some embodiments, the subject has progression on or disease recurrence after, all available standard of care treatments or would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. In some embodiments, the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy. In some embodiments, the cancer is a measurable disease by RECIST v1.1. Page 76 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0203] 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.

[0204] 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.

[0205] 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.

[0206] In some embodiments, the subject has not previously been treated with a CDK inhibitor.

[0207] In some embodiments, the subject has previously been treated with a CDK inhibitor. In some embodiments, the subject was previously treated with palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, or PF-07220060.

[0208] In some embodiments, the subject has not previously been treated with a selective estrogen receptor modulator (SERM). In some embodiments, the subject has previously been treated with a selective estrogen receptor modulator (SERM). In some embodiments, the subject has previously been treated with fulvestrant or camizestrant.

[0209] In some embodiments, the subject has not previously been treated with an aromatase inhibitor. In some embodiments, the subject has previously been treated with an aromatase inhibitor. In some embodiments, the subject has previously been treated with anastrozole, exemestane, or letrozole.

[0210] 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. Page 77 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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. 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

[0211] 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): Page 78 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , or aii) a therapeutically a therapeutically effective amount of a selective estrogen receptor degrader (SERD), 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–(C1-4 alkylene)–OR; each R4is independently halogen or C1-4alkyl; each of R5and R5′is independently halogen or C1-4 alkyl; each R independently hydrogen or C1-4alkyl; n is 0 or 1; p is 0 or 1; s is 0 or 1; and y is 0, 1 or 2. Page 79 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0212] In some embodiments, the compound of Formula (IF1) is described in International Patent Application No. PCT / US2023 / 012521, which is incorporated in its entirety for all purposes.

[0213] In some embodiments, the compound of Formula (IF1) is described according to any one of embodiments herein in Section – Compounds.

[0214] In some embodiments, the compound of Formula (IF1) is Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IF1) is Compound 1.

[0215] In some embodiments, the cancer is described according to any one of embodiments herein in Section – Uses and Methods of Treatment.

[0216] In some embodiments, the cancer is 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, or pancreatic cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments, the squamous cell carcinoma is heck and neck squamous cell carcinoma.

[0217] In some embodiments, the cancer is resistant to a CDK inhibitor, a SERD, a PI3Kα inhibitor, or a combination thereof. In some embodiments, the cancer is resistant to a CDK inhibitor as described herein. In some embodiments, the cancer is resistant to a SERD 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.

[0218] In some embodiments, the cancer is breast cancer.

[0219] 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: Page 80 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 1), or aii) a

[0220] In some embodiments of the first or second aspect, the CDK inhibitor is described according to any one of embodiments herein in Section – Combination Agents.

[0221] In some embodiments of the first or second aspect, the CDK inhibitor has inhibitory activity against CDK2, CDK4, CDK6, or a combination thereof.

[0222] In some embodiments of the first or second aspect, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU- 222, AZD8421, or PF-07104091.

[0223] In some embodiments of the first or second aspect, the CDK inhibitor is palbociclib or ribociclib.

[0224] 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: Page 81 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 1), or aii) a a the CDK inhibitor is palbociclib or ribociclib.

[0225] In some embodiments of any one of the first, second, and third aspects, the CDK inhibitor is palbociclib. In some embodiments, the CDK inhibitor is ribociclib.

[0226] In some embodiments of any one of the first, second, and third aspects, the CDK inhibitor is administered orally.

[0227] In some embodiments, palbociclib or ribociclib is administered orally. In some embodiments, palbociclib is administered orally. In some embodiments, ribociclib is administered orally.

[0228] 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: 1), or aPage 82 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 ii) a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0229] In some embodiments of the first or fourth aspect, the SERD is described according to any one of embodiments herein in Section – Combination Agents.

[0230] In some embodiments of the first or fourth aspects, the SERD is fulvestrant or camizestrant.

[0231] In a fifth 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 selective estrogen receptor degrader (SERD), wherein the SERD is fulvestrant or camizestrant.

[0232] In some embodiments of any one of the first, fourth, and fifth aspects, the SERD is fulvestrant. In some embodiments, fulvestrant is administered by intramuscular injection.

[0233] In some embodiments of any one of the first, fourth, and fifth aspects, the SERD is camizestrant. In some embodiments, camizestrant is administered orally.

[0234] In some embodiments of any one of the first to fifth aspects, the breast cancer is described according to any one of embodiments herein in Section – Uses and Methods of Treatment.

[0235] In some embodiments, the breast cancer is a hormone receptor (HR) positive breast cancer. In some embodiments, the breast cancer is an estrogen receptor (ER) positive breast cancer. Page 83 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0236] In some embodiments, the breast cancer is a human epidermal growth factor receptor 2 (HER2) negative breast cancer.

[0237] In some embodiments, the breast cancer is a human epidermal growth factor receptor 2 (HER2) positive breast cancer.

[0238] In some embodiments, the breast cancer is estrogen receptor (ER) positive and a human epidermal growth factor receptor 2 (HER2) negative breast cancer.

[0239] In some embodiments, the breast cancer is estrogen receptor (ER) positive and a human epidermal growth factor receptor 2 (HER2) positive breast cancer.

[0240] In some embodiments, the breast cancer is an advanced or metastatic breast cancer.

[0241] In some embodiments, the breast cancer is resistant to a CDK inhibitor, a SERD, a PI3Kα inhibitor, or a combination thereof. In some embodiments, the breast cancer is resistant to a CDK inhibitor as described herein. In some embodiments, the breast cancer is resistant to a SERD as described herein. In some embodiments, the breast cancer is resistant to a PI3Kα inhibitor as described herein. In some embodiments, the breast 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, breast cancer is resistant to Compound 1, or pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the compound of Formula (IF1), 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.

[0243] 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 of Formula (IF1) is described according to any one of embodiments herein in Section – Compounds. In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the small GTPase is Rac1, CDC42, or a RAS protein. Page 84 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0245] In some embodiments, the small GTPase is a RAS protein.

[0246] In some embodiments, the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0247] In some embodiments, the RAS protein is KRAS, NRAS, or HRAS.

[0248] 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.

[0249] In some embodiments, the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0250] In some embodiments, the subject is described according to any one of embodiments herein in Section – Uses and Methods of Treatment.

[0251] In some embodiments, the subject has not previously been treated with a CDK inhibitor, a SERD, a PI3Kα inhibitor, a combination thereof. In some embodiments, the subject has not previously been treated with a CDK inhibitor, a SERD, a PI3Kα inhibitor, a combination thereof, each of which is described herein.

[0252] In some embodiments, the subject has previously been treated with a CDK inhibitor, a SERD, a PI3Kα inhibitor, a combination thereof. In some embodiments, the subject has previously been treated with a CDK inhibitor, a SERD, a PI3Kα inhibitor, a combination thereof, each of which is described herein.

[0253] In some embodiments, the subject has previously been treated with palbociclib or ribociclib.

[0254] In some embodiments, the subject has previously been treated with fulvestrant or camizestrant.

[0255] 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. Page 85 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0256] In some embodiments, the subject has previously been treated with Compound 1, or pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the PI3Kα inhibitor is Compound 1, or pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the subject is a human.

[0259] In some embodiments, the administration of the compound (as described herein), the CDK inhibitor, and the SERD is described according to any one of embodiments herein in Section – Uses and Methods of Treatment.

[0260] In some embodiments, the compound of Formula (IF1), or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0261] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered concomitantly; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are administered concomitantly. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered concomitantly. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the SERD are administered concomitantly.

[0262] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered sequentially; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are administered sequentially. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered sequentially. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the SERD are administered sequentially.

[0263] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor or SERD. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the SERD. Page 86 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0264] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor or SERD. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the SERD.

[0265] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in jointly therapeutically effective amounts; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are provided in jointly therapeutically effective amounts. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in jointly therapeutically effective amounts. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the SERD are provided in jointly therapeutically effective amounts.

[0266] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in synergistically effective amounts; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are provided in synergistically effective amounts. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in synergistically effective amounts. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and the SERD are provided in synergistically effective amounts.

[0267] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and / or the CDK inhibitor are each used at a dose lower than when it is used alone; or the compound, or a pharmaceutically acceptable salt thereof, and / or the SERD are each used at a dose lower than when it is used alone. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and / or the CDK inhibitor are each used at a dose lower than when it is used alone. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, and / or the SERD are each used at a dose lower than when it is used alone. Embodiments

[0268] Embodiment 1. A method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering: Page 87 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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 CDK inhibitor.

[0269] Embodiment 2. 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 selective estrogen receptor modulator (SERM).

[0270] Embodiment 3. 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; ii) a therapeutically effective amount of a CDK inhibitor; and iii) a therapeutically effective amount of a selective estrogen receptor modulator (SERM).

[0271] Embodiment 4. The method of embodiment 2 or embodiment 3, wherein the selective estrogen receptor modulator (SERM) is a selective estrogen receptor degrader or downregulator (SERD).

[0272] Embodiment 5. The method of embodiment 2 or embodiment 3, wherein the selective estrogen receptor modulator (SERM) is fulvestrant.

[0273] Embodiment 6. The method of embodiment 5, wherein the therapeutically effective amount of fulvestrant is between about 1 milligram (mg) and about 1000 mg.

[0274] Embodiment 7. The method of embodiment 6, wherein the therapeutically effective amount of fulvestrant is between about 100 mg and about 750 mg. Page 88 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0275] Embodiment 8. The method of embodiment 7, wherein the therapeutically effective amount of fulvestrant is between about 250 mg and about 500 mg.

[0276] Embodiment 9. The method of embodiment 8, wherein the therapeutically effective amount of fulvestrant is about 250 mg or about 500 mg.

[0277] Embodiment 10. The method of any one of embodiments 6-9, wherein the therapeutically effective amount of fulvestrant is administered by intramuscular injection.

[0278] Embodiment 11. The method of embodiment 2 or embodiment 3, wherein the selective estrogen receptor modulator is camizestrant.

[0279] Embodiment 12. The method of embodiment 11, wherein the therapeutically effective amount of camizestrant is between about 1 milligram (mg) and about 500 mg.

[0280] Embodiment 13. The method of embodiment 12, wherein the therapeutically effective amount of camizestrant is between about 50 mg and about 200 mg.

[0281] Embodiment 14. The method of embodiment 13, wherein the therapeutically effective amount of camizestrant is between about 75 mg and about 150 mg.

[0282] Embodiment 15. The method of embodiment 14, wherein the therapeutically effective amount of camizestrant is about 75 mg or about 150 mg.

[0283] Embodiment 16. The method of any one of embodiments 11-15, wherein the therapeutically effective amount of camizestrant is orally administered.

[0284] Embodiment 17. The method of any one of embodiments 1-16, wherein the CDK inhibitor has inhibitory activity against CDK2, CDK4, CDK6, or a combination thereof.

[0285] Embodiment 18. The method of embodiment 17, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF- 07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO- 021, BLU-222, AZD8421, or PF-07104091.

[0286] Embodiment 19. The method of embodiment 17 or embodiment 18, wherein the CDK inhibitor is palbociclib.

[0287] Embodiment 20. The method of any one of embodiments 17-19, wherein the therapeutically effective amount of palbociclib is between about 1 mg and about 1000 mg. Page 89 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0288] Embodiment 21. The method of embodiment 20, wherein the therapeutically effective amount of palbociclib is between about 25 mg and about 200 mg.

[0289] Embodiment 22. The method of embodiment 21, wherein the therapeutically effective amount of palbociclib is between about 75 mg and about 125 mg.

[0290] Embodiment 23. The method of embodiment 22, wherein the therapeutically effective amount of palbociclib is about 125 mg, 100 mg, or 75 mg.

[0291] Embodiment 24. The method of any one of embodiments 17-23, wherein the therapeutically effective amount of palbociclib is orally administered.

[0292] Embodiment 25. The method of embodiment 17 or embodiment 18, wherein the CDK inhibitor is ribociclib.

[0293] Embodiment 26. The method of embodiment 25, wherein the therapeutically effective amount of ribociclib is between about 1 mg and about 1000 mg.

[0294] Embodiment 27. The method of embodiment 26, wherein the therapeutically effective amount of ribociclib is between about 100 mg and about 1000 mg.

[0295] Embodiment 28. The method of embodiment 27, wherein the therapeutically effective amount of ribociclib is between about 200 mg and about 600 mg.

[0296] Embodiment 29. The method of embodiment 28, wherein the therapeutically effective amount of ribociclib is about 200 mg, 400 mg, or 600 mg.

[0297] Embodiment 30. The method of any one of embodiments 25-29, wherein the therapeutically effective amount of ribociclib is orally administered.

[0298] Embodiment 31. The method of any one of embodiments 1-30, wherein the method further comprises administering a therapeutically effective amount of an aromatase inhibitor to the subject.

[0299] Embodiment 32. The method of embodiment 31, wherein the aromatase inhibitor is anastrozole, exemestane, or letrozole.

[0300] Embodiment 33. The method of any one of embodiments 1-32, 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 Page 90 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of PI3Kα is not significantly inhibited.

[0301] Embodiment 34. The method of embodiment 33, 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.

[0302] Embodiment 35. The method of embodiment 33 or 34, 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.

[0303] Embodiment 36. The method of any one of embodiments 1-35, 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 IC50value of < 0.1 µM or 0.1 µM ≤ IC50 value < 1 µM, or1 µM ≤ IC50 value ≤ 3 µM in the assay of Biological Example 2.

[0304] Embodiment 37. The method of embodiment 36, 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; 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.

[0305] Embodiment 38. The method of embodiment 37, 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.

[0306] Embodiment 39. The method of any one of embodiments 1-38, wherein the compound, or a pharmaceutically acceptable salt thereof, comprises an electrophilic moiety.

[0307] Embodiment 40. The method of embodiment 39, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of interacting with a Cys242 residue in the catalytic subunit of PI3Kα. Page 91 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0308] Embodiment 41. The method of any one of embodiments 1-38, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of irreversibly binding the PI3Kα protein.

[0309] Embodiment 42. The method of any one of embodiments 1-38, wherein the compound, or a pharmaceutically acceptable salt thereof, is capable of reversibly binding the PI3Kα protein.

[0310] Embodiment 43. The method of any one of embodiments 1-42, wherein the PI3Kα protein is aberrantly activated.

[0311] Embodiment 44. The method of any one of embodiments 1-43, 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.

[0312] Embodiment 45. The method of embodiment 44, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0313] Embodiment 46. The method of any one of embodiments 1-45, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

[0314] Embodiment 47. The method of embodiment 46, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0315] Embodiment 48. The method of embodiment 46 or 47, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

[0316] Embodiment 49. The method of embodiment 47 or 48, wherein the RAS protein is KRAS.

[0317] Embodiment 50. The method of embodiment 49, 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.

[0318] Embodiment 51. The method of embodiment 50, wherein the KRAS protein comprises a G12C, G12D, G12V, or G12R mutation. Page 92 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0319] Embodiment 52. The method of embodiment 51, wherein the KRAS protein comprises a G12C or G12D mutation.

[0320] Embodiment 53. The method of embodiment 49, wherein the KRAS protein is a wild-type KRAS protein.

[0321] Embodiment 54. The method of embodiment 47 or 48, wherein the RAS protein is HRAS.

[0322] Embodiment 55. The method of embodiment 54, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H.

[0323] Embodiment 56. The method of embodiment 55, wherein the HRAS protein is a wild-type HRAS protein.

[0324] Embodiment 57. The method of embodiment 47 or 48, wherein the RAS protein is NRAS.

[0325] Embodiment 58. The method of embodiment 57, 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.

[0326] Embodiment 59. The method of embodiment 58, wherein the NRAS protein is a wild-type NRAS protein.

[0327] Embodiment 60. The method of any one of embodiments 1-59, wherein the compound is a compound of Formula (I): , or a salt (e.g.,wherein: Ring A is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Page 93 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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′; 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 C1-6aliphatic chain substituted with Ring D′; each –L-W is –CN, or: each L is independently a bivalent straight or branched C1-8 aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)- Page 94 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , -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; 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 C1-6aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, - SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl Page 95 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0328] Embodiment 61. The method of embodiment 60, wherein the compound is a compound of Formula (I-a-v'): or a salt (e.g.,Page 96 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0329] Embodiment 62. The method of embodiment 60 or 61, wherein the compound is a compound of Formula (IF) or (IF1):

[0330] Embodiment 63. The method of embodiment 60 or 61, wherein Ring A is phenyl.

[0331] Embodiment 64. The method of embodiment 63, wherein Ring A is selected .method of any one of embodiments 60-64, wherein at least one R3is selected from halogen, -OR, -O(CH2)vCy, and -O-(C1-4 alkylene)-OR.

[0333] Embodiment 66. The method of any one of embodiments 60-65, wherein Ring C is phenyl.

[0334] Embodiment 67. The method of any one of embodiments 60-66, wherein Ring C is fused to Ring E.

[0335] Embodiment 68. The method of embodiment 66 or 67, wherein Ring E is selected from a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5′. Page 97 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0336] Embodiment 69. The method of any one of embodiments 60-68, wherein ,R5is independently selected from C1-6aliphatic.

[0338] Embodiment 71. The method of any one of embodiments 60-70, wherein Ring D is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0339] Embodiment 72. The method of any one of embodiments 60-71, wherein Ring D is fused to Ring F.

[0340] Embodiment 73. The method of any one of embodiments 60-72, wherein q is 0.

[0341] Embodiment 74. The method of any one of embodiments 60-73, wherein each R2’is independently selected from C1-6alkyl. Page 98 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0342] Embodiment 75. The method of any one of embodiments 60-74, wherein y is 1 or 2 and r is 0.

[0343] Embodiment 76. The method of any one of embodiments 60-75, 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.

[0344] Embodiment 77. The method of any one of embodiments 60-76, wherein ,Page 99 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 ,any one compound is Compound 1: Page 100 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , or a

[0346] Embodiment 79. The method of embodiment 78, wherein the compound is Compound 1.

[0347] Embodiment 80. The method of any one of embodiments 1-79, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.

[0348] Embodiment 81. The method of embodiment 80, wherein the compound, or a pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0349] Embodiment 82. The method of any one of embodiments 1-81, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily.

[0350] Embodiment 83. The method of embodiment 82, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0351] Embodiment 84. The method of embodiment 82, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0352] Embodiment 85. The method of any one of embodiments 1-84, wherein administration of the compound, or a pharmaceutically acceptable salt thereof, occurs according to a treatment cycle.

[0353] Embodiment 86. The method of embodiment 85, wherein the treatment cycle is 21 days.

[0354] Embodiment 87. The method of embodiment 85, wherein the treatment cycle is 28 days. Page 101 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0355] Embodiment 88. The method of any one of embodiments 1-87, wherein the total daily dosage of the compound, 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.

[0356] Embodiment 89. The method of embodiment 88, wherein the total daily dosage of the compound, or a pharmaceutically acceptable salt thereof, is at least about 50 mg.

[0357] Embodiment 90. The method of embodiment 88, wherein the total daily dosage of the compound, or a pharmaceutically acceptable salt thereof, is at least about 100 mg.

[0358] Embodiment 91. The method of any one of embodiments 1-87, wherein the total daily dosage of the compound, 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.

[0359] Embodiment 92. The method of embodiment 91, wherein the total daily dosage of the compound, or a pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0360] Embodiment 93. The method of any one of embodiments 1-87, wherein the total daily dosage of the compound, 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 Page 102 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550-1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg, Page 103 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0361] Embodiment 94. The method of embodiment 93, 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.

[0362] Embodiment 95. The method of any one of embodiments 1-87, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, Page 104 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0363] Embodiment 96. The method of embodiment 95, 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.

[0364] Embodiment 97. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0365] Embodiment 98. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150 mg.

[0366] Embodiment 99. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg.

[0367] Embodiment 100. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg.

[0368] Embodiment 101. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750 mg.

[0369] Embodiment 102. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1000 mg.

[0370] Embodiment 103. The method of embodiment 96, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1200 mg.

[0371] Embodiment 104. The method of any one of embodiments 1-103, wherein the disease, disorder, or condition is a cancer.

[0372] Embodiment 105. The method of any one of embodiments 1-104, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in a unit dosage form.

[0373] Embodiment 106. The method of embodiment 105, wherein the unit dosage form is a tablet. Page 105 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0374] Embodiment 107. The method of embodiment 106, 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.

[0375] Embodiment 108. The method of embodiment 107, wherein the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0376] Embodiment 109. The method of any one of embodiments 1-108, 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.

[0377] Embodiment 110. The method of embodiment 109, 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.

[0378] Embodiment 111. The method of embodiment 110, wherein the subject is treated with the reduced dose until the adverse event is resolved.

[0379] Embodiment 112. The method of embodiment 111, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0380] Embodiment 113. The method of embodiment 112, 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.

[0381] Embodiment 114. The method of any one of embodiments 1-113, wherein administration of the compound, or the pharmaceutically acceptable salt thereof, treats a disease, disorder, or condition in the subject.

[0382] Embodiment 115. The method of embodiment 114, wherein the disease, disorder, or condition is a cancer.

[0383] Embodiment 116. The method of embodiment 115, 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, Page 106 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 squamous cell carcinoma (e.g., heck and neck squamous cell carcinoma), prostate cancer, melanoma, glioblastoma, sarcomas, biliary cancer, and pancreatic cancer.

[0384] Embodiment 117. The method of embodiment 116, wherein the cancer is lung cancer.

[0385] Embodiment 118. The method of embodiment 117, wherein the cancer is non- small cell lung cancer (NSCLC).

[0386] Embodiment 119. The method of embodiment 118, wherein the NSCLC is KRAS mutant NSCLC.

[0387] Embodiment 120. The method of embodiment 119, wherein the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS.

[0388] Embodiment 121. The method of embodiment 120, wherein the NSCLC is KRAS G12C mutant NSCLC.

[0389] Embodiment 122. The method of embodiment 115 or 116, wherein the cancer is colorectal cancer.

[0390] Embodiment 123. The method of embodiment 115 or 116, wherein the cancer is breast cancer.

[0391] Embodiment 124. The method of embodiment 123, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive breast cancer.

[0392] Embodiment 125. The method of embodiment 124, 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.

[0393] Embodiment 126. The method of embodiment 125, 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.

[0394] Embodiment 127. The method of embodiment 115 or 116, wherein the cancer is gastric cancer. Page 107 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0395] Embodiment 128. The method of any one of embodiments 115-127, 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).

[0396] Embodiment 129. The method of any one of embodiments 115-127, wherein the cancer is a human epidermal growth factor receptor 2 (HER2) positive or HER2 amplified cancer.

[0397] Embodiment 130. The method of any one of embodiments 115-127, wherein the cancer is characterized by a mutant KRAS protein.

[0398] Embodiment 131, The method of embodiment 130, wherein the cancer is resistant to a KRAS G12C, G12D, G12V, G12A, G12S, G12R, or Q61X inhibitor.

[0399] Embodiment 132. The method of any one of embodiments 115-131, wherein the cancer is a KRAS G12C positive cancer resistant to a KRAS G12C inhibitor.

[0400] Embodiment 133. The method of embodiment 132, wherein the cancer is a KRAS G12C positive cancer characterized by acquired and / or intrinsic resistance to a KRAS G12C inhibitor.

[0401] Embodiment 134. The method of embodiment 133, 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.

[0402] Embodiment 135. The method of embodiment 134, wherein the cancer is a KRAS G12C positive cancer resistant to sotorasib, adagrasib, or divarasib.

[0403] Embodiment 136. The method of any one of embodiments 1-135, 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.

[0404] Embodiment 137. The method of embodiment 136, wherein the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy.

[0405] Embodiment 138. The method of embodiment 137, wherein the cancer is a measurable disease by RECIST v1.1. Page 108 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0406] Embodiment 139. The method of embodiment 138, wherein the subject has previously undergone a treatment regimen for cancer.

[0407] Embodiment 140. The method of embodiment 139, wherein the subject has previously entered remission from cancer.

[0408] Embodiment 141. The method of any one of embodiments 1-140, wherein the subject has not previously been treated with a CDK inhibitor.

[0409] Embodiment 142. The method of any one of embodiments 1-140, wherein the subject has previously been treated with a CDK inhibitor.

[0410] Embodiment 143. The method of embodiment 142, wherein the subject was previously treated with palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF- 07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091.

[0411] Embodiment 144. The method of any one of embodiments 1-140, wherein the subject has not previously been treated with a selective estrogen receptor modulator (SERM).

[0412] Embodiment 145. The method of any one of embodiments 1-140, wherein the subject has previously been treated with a selective estrogen receptor modulator (SERM).

[0413] Embodiment 146. The method of embodiment 145, wherein the subject has previously been treated with fulvestrant or camizestrant.

[0414] Embodiment 147. The method of any one of embodiments 1-146, wherein the subject has not previously been treated with an aromatase inhibitor.

[0415] Embodiment 148. The method of any one of embodiments 1-146, wherein the subject has previously been treated with an aromatase inhibitor.

[0416] Embodiment 149. The method of embodiment 148, wherein the subject has previously been treated with anastrozole, exemestane, or letrozole.

[0417] Embodiment 150. The method of any one of embodiments 1-149, 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 109 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0418] Embodiment 151. The method of any one of embodiments 1-149, 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.

[0419] Embodiment 152. The method of any one of embodiments 1-151, wherein the subject is a human.

[0420] Embodiment 153. The method of embodiment 152, wherein the subject is at least 18 years of age.

[0421] Embodiment 154. The method of embodiment 152 or embodiment 153, wherein the subject has been diagnosed with the cancer.

[0422] Embodiment 155. The method of any one of embodiments 1-154, 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; 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.

[0423] Embodiment 156. The method according to any one of embodiments 1-155, wherein the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are administered concomitantly. Page 110 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0424] Embodiment 157. The method according to any one of embodiments 1-155, wherein the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are administered sequentially.

[0425] Embodiment 158. The method according to any one of embodiments 1-155, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor and / or selective estrogen receptor modulator (SERM).

[0426] Embodiment 159. The method according to any one of embodiments 1-155, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor and / or selective estrogen receptor modulator (SERM).

[0427] Embodiment 160. The method according to any one of embodiments 1-155, wherein the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are provided in jointly therapeutically effective amounts.

[0428] Embodiment 161. The method according to any one of embodiments 1-155, wherein the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are provided in synergistically effective amounts.

[0429] Embodiment 162. The method according to any one of embodiments 1-161, wherein the compound, or a pharmaceutically acceptable salt thereof, and / or the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose different than when it is used alone.

[0430] Embodiment 163. The method according to embodiment 162, wherein the compound, or a pharmaceutically acceptable salt thereof, is used at a dose lower than when it is used alone.

[0431] Embodiment 164. The method according to embodiment 162, wherein the compound, or a pharmaceutically acceptable salt thereof, is used at a dose higher than when it is used alone. Page 111 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0432] Embodiment 165. The method according to embodiment 162, wherein the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose lower than when it is used alone.

[0433] Embodiment 166. The method according to embodiment 162, wherein the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose higher than when it is used alone.

[0434] Embodiment 167. A method of treating a cancer in a subject in need thereof, comprising administering to the subject i) a therapeutically effective (Compound 1), or a pharmaceuticallyii) a therapeutically effective amount of a CDK inhibitor.

[0435] Embodiment 168. A method of treating a cancer in a subject in need thereof, comprising administering to the subject i) a therapeutically effective (Compound 1), or a pharmaceuticallyii) a therapeutically effective amount of a selective estrogen receptor modulator (SERM).

[0436] Embodiment 169. A method of treating a cancer in a subject in need thereof, comprising administering to the subject Page 112 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 i) a therapeutically effective (Compound 1), or a pharmaceuticallyii) a therapeutically effective a a therapeutically effective amount of a selective estrogen receptor modulator (SERM).

[0437] Embodiment 170. The method of any one of embodiments 167-169, wherein the selective estrogen receptor modulator is a selective estrogen receptor degrader or downregulator (SERD).

[0438] Embodiment 171. The method of embodiment 170, wherein the selective estrogen receptor modulator is fulvestrant.

[0439] Embodiment 172. The method of embodiment 171, wherein the therapeutically effective amount of fulvestrant is between about 1 milligram (mg) and about 1000 mg.

[0440] Embodiment 173. The method of embodiment 172, wherein the therapeutically effective amount of fulvestrant is between about 100 mg and about 750 mg.

[0441] Embodiment 174. The method of embodiment 173, wherein the therapeutically effective amount of fulvestrant is between about 250 mg and about 500 mg.

[0442] Embodiment 175. The method of embodiment 174, wherein the therapeutically effective amount of fulvestrant is about 250 mg or about 500 mg.

[0443] Embodiment 176. The method of any one of embodiments 171-175, wherein the therapeutically effective amount of fulvestrant is administered by intramuscular injection.

[0444] Embodiment 177. The method of embodiment 170, wherein the selective estrogen receptor modulator is camizestrant.

[0445] Embodiment 178. The method of embodiment 177, wherein the therapeutically effective amount of camizestrant is between about 1 milligram (mg) and about 500 mg. Page 113 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0446] Embodiment 179. The method of embodiment 178, wherein the therapeutically effective amount of camizestrant is between about 50 mg and about 200 mg.

[0447] Embodiment 180. The method of embodiment 179, wherein the therapeutically effective amount of camizestrant is between about 75 mg and about 150 mg.

[0448] Embodiment 181. The method of embodiment 180, wherein the therapeutically effective amount of camizestrant is about 75 mg or about 150 mg.

[0449] Embodiment 182. The method of any one of 177-181, wherein the therapeutically effective amount of camizestrant is orally administered.

[0450] Embodiment 183. The method of any one of embodiments 167-169, wherein the CDK inhibitor has inhibitory activity against CDK2, CDK4, CDK6, or a combination thereof.

[0451] Embodiment 184. The method of embodiment 183, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF- 07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO- 021, BLU-222, AZD8421, or PF-07104091.

[0452] Embodiment 185. The method of embodiment 184, wherein the CDK inhibitor is palbociclib.

[0453] Embodiment 186. The method of embodiment 185, wherein the therapeutically effective amount of palbociclib is between about 1 mg and about 1000 mg.

[0454] Embodiment 187. The method of embodiment 186, wherein the therapeutically effective amount of palbociclib is between about 25 mg and about 200 mg.

[0455] Embodiment 188. The method of embodiment 187, wherein the therapeutically effective amount of palbociclib is between about 75 mg and about 125 mg.

[0456] Embodiment 189. The method of embodiment 188, wherein the therapeutically effective amount of palbociclib is about 125 mg, 100 mg, or 75 mg.

[0457] Embodiment 190. The method of any one of embodiments 185-189, wherein the therapeutically effective amount of palbociclib is orally administered.

[0458] Embodiment 191. The method of embodiment 184, wherein the CDK inhibitor is ribociclib. Page 114 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0459] Embodiment 192. The method of embodiment 191, wherein the therapeutically effective amount of ribociclib is between about 1 mg and about 1000 mg.

[0460] Embodiment 193. The method of embodiment 192, wherein the therapeutically effective amount of ribociclib is between about 100 mg and about 1000 mg.

[0461] Embodiment 194. The method of embodiment 193, wherein the therapeutically effective amount of ribociclib is between about 200 mg and about 600 mg.

[0462] Embodiment 195. The method of embodiment 194, wherein the therapeutically effective amount of ribociclib is about 200 mg, 400 mg, or 600 mg.

[0463] Embodiment 196. The method of any one of embodiments 191-195, wherein the therapeutically effective amount of ribociclib is orally administered.

[0464] Embodiment 197. The method of any one of embodiments 167-196, wherein the method further comprises administering a therapeutically effective amount of an aromatase inhibitor to the subject.

[0465] Embodiment 198. The method of embodiment 197, wherein the aromatase inhibitor is anastrozole, exemestane, or letrozole.

[0466] Embodiment 199. The method of any one of embodiments 167-198, wherein the cancer is breast cancer.

[0467] Embodiment 200. The method of embodiment 199, wherein the breast cancer is HER2+ breast cancer.

[0468] Embodiment 201. The method of embodiment 200, 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.

[0469] Embodiment 202. The method of embodiment 201, 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.

[0470] Embodiment 203. The method of any one of embodiments 167-202, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. Page 115 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0471] Embodiment 204. The method of embodiment 203, wherein the compound, or a pharmaceutically acceptable salt thereof, is formulated as a tablet.

[0472] Embodiment 205. The method of embodiment 204, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered once, twice, thrice, or four times daily.

[0473] Embodiment 206. The method of embodiment 205, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0474] Embodiment 207. The method of embodiment 205, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0475] Embodiment 208. The method of any one of embodiments 167-207, wherein administration of the compound, or a pharmaceutically acceptable salt thereof, occurs according to a treatment cycle.

[0476] Embodiment 209. The method of embodiment 208, wherein the treatment cycle is 21 days.

[0477] Embodiment 210. The method of embodiment 208, wherein the treatment cycle is 28 days.

[0478] Embodiment 211. The method of any one of embodiments 167-210, wherein the total daily dosage of the compound, 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.

[0479] Embodiment 212. The method of embodiment 211, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 mg.

[0480] Embodiment 213. The method of embodiment 212, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 100 mg. Page 116 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0481] Embodiment 214. The method of any one of embodiments 167-210, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1 milligram (mg), 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg.

[0482] Embodiment 215. The method of embodiment 214, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 1200 mg.

[0483] Embodiment 216. The method according any one of embodiments 167-210, 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 Page 117 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475-1200 mg, about 500-1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725-1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, about 875-1200 mg, about 900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000- 1200 mg, about 1025-1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1-1000 mg, about 10-1000 mg, about 20-1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100- 1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550-1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000 mg, about 1-750 mg, about 10-750 mg, about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50- 750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100- 750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200-750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375-750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575- 750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675-750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20-500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70-500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200-500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400- 500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1-300 mg, about 10-300 mg, about 20-300 mg, about 30-300 mg, about 40-300 mg, about 50-300 mg, about Page 118 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0484] Embodiment 217. The method of embodiment 216, 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.

[0485] Embodiment 218. The method of any one of embodiments 167-210, 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.

[0486] Embodiment 219. The method of embodiment 218, 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.

[0487] Embodiment 220. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0488] Embodiment 221. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150 mg. Page 119 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0489] Embodiment 222. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg.

[0490] Embodiment 223. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg.

[0491] Embodiment 224. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750 mg.

[0492] Embodiment 225. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1000 mg.

[0493] Embodiment 226. The method of embodiment 219, wherein the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 1200 mg.

[0494] Embodiment 227. The method of any one of embodiments 167-226, 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.

[0495] Embodiment 228. The method of embodiment 227, 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.

[0496] Embodiment 229. The method of embodiment 228, wherein the subject is treated with the reduced dose until the adverse event is resolved.

[0497] Embodiment 230. The method of embodiment 229, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0498] Embodiment 231. The method of any one of embodiments 227-230, 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.

[0499] Embodiment 232. The method of any one of embodiments 167-231, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in a unit dosage form. Page 120 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0500] Embodiment 233. The method of embodiment 232, wherein the unit dosage form is a tablet.

[0501] Embodiment 234. The method of embodiment 233, 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.

[0502] Embodiment 235. The method of embodiment 234, wherein the tablet comprises about 50 mg or about 150 mg of the compound, or the pharmaceutically acceptable salt thereof.

[0503] Embodiment 236. The method of embodiment 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.

[0504] Embodiment 237. The method of any one of embodiments 167-236, wherein the cancer is advanced unresectable or metastatic cancer and / or lesions that are not amenable to definitive radiotherapy.

[0505] Embodiment 238. The method of any one of embodiments 167-237, wherein the cancer is a measurable disease by RECIST v1.1.

[0506] Embodiment 239. The method of any one of embodiments 167-238, wherein the subject has previously undergone a treatment regimen for cancer.

[0507] Embodiment 240. The method of any one of embodiments 167-239, wherein the subject has previously entered remission from cancer.

[0508] Embodiment 241. The method of any one of embodiments 167-240, wherein the subject has not previously been treated with a CDK inhibitor.

[0509] Embodiment 242. The method of embodiment 241, wherein the subject has previously been treated with a CDK inhibitor.

[0510] Embodiment 243. The method of embodiment 242, wherein the subject was previously treated with palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF- 07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU-222, AZD8421, or PF-07104091. Page 121 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0511] Embodiment 244. The method of any one of embodiments 167-243, wherein the subject has not previously been treated with a selective estrogen receptor modulator (SERM).

[0512] Embodiment 245. The method of any one of embodiments 167-243, wherein the subject has previously been treated with a selective estrogen receptor modulator (SERM).

[0513] Embodiment 246. The method of embodiment 245, wherein the subject has previously been treated with fulvestrant or camizestrant.

[0514] Embodiment 247. The method of any one of embodiments 167-246, wherein the subject has not previously been treated with an aromatase inhibitor.

[0515] Embodiment 248. The method of any one of embodiments 167-246, wherein the subject has previously been treated with an aromatase inhibitor.

[0516] Embodiment 249. The method of embodiment 248, wherein the subject has previously been treated with anastrozole, exemestane, or letrozole.

[0517] Embodiment 250. The method of any one of embodiments 167-249, 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.

[0518] Embodiment 251. The method of any one of embodiments 167-249, 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.

[0519] Embodiment 252. The method of any one of embodiments 167-251, wherein the subject is a human.

[0520] Embodiment 253. The method of embodiment 252, wherein the subject is at least 18 years of age.

[0521] Embodiment 254. The method of any one of embodiments 167-253, wherein the subject has been diagnosed with the cancer.

[0522] Embodiment 255. The method of any one of embodiments 252-254, 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- Page 122 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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; 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.

[0523] Embodiment 256. The method of any one of embodiments 167-255, wherein the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are administered concomitantly.

[0524] Embodiment 257. The method of any one of embodiments 167-255, wherein the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are administered sequentially.

[0525] Embodiment 258. The method of any one of embodiments 167-255, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor and / or selective estrogen receptor modulator (SERM).

[0526] Embodiment 259. The method of any one of embodiments 167-255, wherein the compound, or the pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor and / or selective estrogen receptor modulator (SERM).

[0527] Embodiment 260. The method of any one of embodiments 167-255, wherein the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are provided in jointly therapeutically effective amounts. Page 123 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0528] Embodiment 261. The method of any one of embodiments 167-255, wherein the compound, or the pharmaceutically acceptable salt thereof, and the CDK inhibitor and / or selective estrogen receptor modulator (SERM) are provided in synergistically effective amounts.

[0529] Embodiment 262. The method of any one of embodiments 167-261, wherein the compound, or the pharmaceutically acceptable salt thereof, and / or the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose different than when it is used alone.

[0530] Embodiment 263. The method of any one of embodiments 167-261, wherein the compound, or the pharmaceutically acceptable salt thereof, is used at a dose lower than when it is used alone.

[0531] Embodiment 264. The method of any one of embodiments 167-261, wherein the compound, or the pharmaceutically acceptable salt thereof, is used at a dose higher than when it is used alone.

[0532] Embodiment 265. The method of any one of embodiments 167-261, wherein the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose lower than when it is used alone.

[0533] Embodiment 266. The method of any one of embodiments 167-261, wherein the CDK inhibitor and / or selective estrogen receptor modulator (SERM) is used at a dose higher than when it is used alone. EXAMPLES

[0534] 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.

[0535] Selected abbreviations used in the preceding sections and the Examples are summarized in Table 1. Page 124 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 Table 1. Abbreviations Abbreviation Term MeCN, ACN acetonitrile nPage 125 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 Abbreviation Term g gramPage 126 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 Abbreviation Term mM millimolarPage 127 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 Abbreviation Term UV / Vis ultraviolet / visible Mat

[0536] Preparative thin layer chromatography (PTLC) separations described herein were typically performed on 20 x 20 cm plates (500-µm thick silica gel).

[0537] 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 SiO2 by weight. Normal phase chromatography was performed using elution gradients of various solvents (e.g., hexane, ethyl acetate, methylene chloride, methanol, acetone, chloroform, MTBE, etc.). The columns were SNAP Cartridges containing KP-SIL or SNAP Ultra (25 pm spherical particles) of various sizes (Biotage LLC). Typical loading was between 1:10 to 1:150 crude sample: SiO2 by weight. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0538] 1HNMR analyses of intermediates and exemplified compounds were typically performed on a Bruker Ascend TM 400 spectrometer (operating at 400 MHz), Bruker Ascend 500 MHz Avance Neo Spectrometer (Bruker-Biospin) or Bruker Avance Neo Nanobay (operating at 400 MHz) at 298 °K following standard operating procedure suggested by manufacturer. Reference frequency was set using TMS as an internal standard. 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.

[0539] LCMS analysis was typically performed using one of the following conditions:

[0540] (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%- Page 128 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0541] (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.

[0542] (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.

[0543] (4) LCMS spectra were taken on an alliance Waters 2695 coupled to a Waters 2487 Dual Wavelength Absorbance Detector and a Waters Micromass-ZQ-2000 single quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was from 5-100% A in 10.0 minute using a Kromasil 100-5-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.

[0544] (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). Page 129 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0545] Typically, analytical HPLC spectrometry conditions were as follows:

[0546] 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.

[0547] 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.

[0548] 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.

[0549] 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.

[0550] Preparative HPLC was carried out with one of the following conditions:

[0551] 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% 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.

[0552] 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).

[0553] 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, Page 130 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0554] Chiral supercritical fluid chromatography (SFC) was carried out with one of the following conditions:

[0555] 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.

[0556] 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.

[0557] 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.

[0558] Compound names were generated with ChemDraw Professional.

[0559] 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)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: 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 Page 131 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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).

[0561] 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).

[0562] 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- 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 Na2CO3aqueous 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 Page 132 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 (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

[0563] 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.

[0564] 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.

[0565] 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.

[0566] 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. Page 133 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0567] 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.

[0568] Spectra processing: Spectra were smoothed by SavitzkyGolay algorithm using 7 m / z width and three cycles. Centroid peak detection algorithm was used with signal to noise threshold set to 6, relative intensity threshold 3%, peak width 10 m / z, and median baseline subtraction using flatness of 1 and the median level of 0.1. Peak intensity and area under the peak were evaluated and recorded for all peaks between 16.0 and 19.5 kDa.

[0569] 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.

[0570] 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%. Page 134 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0571] 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

[0572] 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, 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.

[0573] Compounds are characterized based on pAKT inhibition IC50 values 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.

[0574] Compound 1 demonstrates pAKT inhibition IC50 of < 0.1 µM (“A”). Example 4: Compound 1 is efficacious in combination with ER degraders in ER+ HER2- breast cancer cell lines Page 135 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0575] Several in vitro viability studies were conducted to investigate the potential of combining Compound 1 with fulvestrant or camizestrant in the ER+ HER2- breast cancer MCF7 and T47D cell lines, which harbor a PIK3CA mutation at E545K and H1047R, respectively. Fulvestrant is an ER degrader that has been approved by the FDA for patients with HR+ metastatic breast cancer with disease progression following antiestrogen therapy, and camizestrant is a next-generation ER degrader under development for the treatment of metastatic HR+ HER2- ER mutant breast cancer and ER+ HER2- primary breast 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 Compound 1, fulvestrant, or camizestrant. The doses of fulvestrant and camizestrant were picked based on IC50concentrations after conducting a 5- day viability assay in 2D conditions. For MCF7, doses of 1 μM Compound 1, 100 nM fulvestrant, and 10 nM camizestrant were used, and for T47D, doses of 1 μM Compound 1, 10 nM fulvestrant, and 10 nM camizestrant 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.

[0576] In both the MCF7 and T47D cell lines, Compound 1 demonstrated an additive effect when combined with ER degraders that was greater than the effect of the single agent alone (FIGs.1A-1B). Each combination treatment showed statistically significant greater activity than treatment with either test article as a monotherapy. Representative results (mean + / - SEM) from 2 experiments for MCF7 and 2 experiments for T47D are shown. Confluence (+ / - SEM) with two-way repeated measures ANOVA followed by a Tukey multiple comparison test through day 27.5 for MCF7 and day 23 for T47D 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; ER+=estrogen receptor positive; HER2-=Erb-B2 receptor tyrosine kinase 2 negative; μM=micromolar; nM=nanomolar; PIK3CA=phosphotidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SEM=standard error of the mean)

[0577] In MCF7 cells on day 27.5, Compound 1 did not inhibit growth, fulvestrant inhibited growth by 34%, and the camizestrant inhibited growth by 39%. The combination of Compound 1 and fulvestrant inhibited growth by 65% and the combination of Compound 1 and camizestrant inhibited growth by 76% (FIG.1A). The combination of 1 μM BBO-10203 Page 136 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 with 100 nM fulvestrant or 10 nM camizestrant showed greater cell growth inhibition compared to both monotherapy treatments alone. In T47D cells on day 23, Compound 1 did not inhibit growth, fulvestrant inhibited growth by 29%, and camizestrant inhibited growth by 15%. The combinations of Compound 1 and fulvestrant inhibited growth by 70% and the combination of Compound 1 and camizestrant inhibited growth by 62% (FIG.1B). The combination of 1 μM BBO-10203 with 10 nM fulvestrant or 10 nM camizestrant showed greater cell growth inhibition compared to both monotherapy treatments alone.

[0578] These in vitro studies demonstrated that Compound 1 in combination with ER degraders had a statistically significant stronger anti-proliferative effect compared to both monotherapy treatments alone in ER+ HER2- breast cancer cell lines with PIK3CA mutations. Example 5: Compound 1 is efficacious in combination with an ER degrader in an ER+ HER2- breast cancer xenograft model

[0579] Several in vivo study were conducted to assess the anti-tumor activity of Compound 1 (also known as BBO-10203) in combination with fulvestrant in the ER+HER2- breast cancer CDX models, which harbor PIK3CA mutations. Fulvestrant is an ER degrader that has been approved by the FDA for patients with HR+ metastatic breast cancer with disease progression following antiestrogen therapy.

[0580] Female athymic nude mice were implanted subcutaneously with MCF7 human tumor cells. Animals were provided 10 µg / mL 17β-estradiol supplemented water ad libitum to support tumor growth throughout the study. When tumors reached a mean size of 166 mm3, mice were randomized into treatment groups (10 mice per group) and treated with vehicle QD, 100 mg / kg QD Compound 1, 25 mg / kg Q7D fulvestrant, or the combination of 100 mg / kg QD Compound 1 and 25 mg / kg Q7D fulvestrant. Vehicle and Compound 1 were administered once per day (QD) by oral gavage for a period of 28 days. Fulvestrant was administered subcutaneously once every 7 days (Q7D) until day 22. 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 Page 137 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 mixed effects 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.

[0581] In athymic nude mice bearing ER+ HER2- breast cancer MCF7 subcutaneous xenograft tumors, which harbor a PIK3CA E545K mutation, the combination of Compound 1 and fulvestrant showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.2A). Following administration of 100 mg / kg Compound 1 and 25 mg / kg fulvestrant in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 24% 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.

[0582] FIG.2A: *p<0.01 (1: fulvestrant); **p<0.001 (2: BBO-10203) two-way repeated measures or mixed effects ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (QD) or subcutaneously (sc) once every 7 days (Q7D) as indicated.

[0583] In NSG mice bearing ER+ HER2- breast cancer T47D subcutaneous CDX tumors, which harbor a PIK3CA H1047R mutation, the combination of BBO-10203 and fulvestrant showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.2B). Following administration of 100 mg / kg BBO- 10203 and 25 mg / kg fulvestrant in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 35% mean tumor regression observed in the combination group on day 36. There was no impact of treatments on body weight, and all treatments were well tolerated.

[0584] FIG.2B: *p<0.05, **p<0.01 two-way mixed effects ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (quaque die, QD) or subcutaneously (sc) once every 7 days (Q7D) as indicated.

[0585] In NSG mice bearing ER+ HER2- breast cancer EFM-19 subcutaneous CDX tumors, which harbor a PIK3CA H1047L mutation, the combination of BBO-10203 and fulvestrant showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.2C). Following administration of 100 mg / kg BBO-10203 and 25 mg / kg fulvestrant in combination, a statistically significant tumor volume Page 138 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 reduction was observed in the combination group compared to both monotherapy groups, with 55% mean tumor regression observed in the combination group on day 29. There was no impact of treatments on body weight and all treatments were well tolerated.

[0586] FIG.2C: *p<0.0001 two-way repeated measures or mixed effects ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (quaque die, QD) or subcutaneously (sc) once every 7 days (Q7D) as indicated.

[0587] Abbreviations: ANOVA=analysis of variance; ER=estrogen receptor; ER+=estrogen receptor positive; HER2-=Erb-B2 receptor tyrosine kinase 2 negative; mm3=cubic millimeters; mg / kg=milligrams per kilogram; n=number

[0588] These in vivo efficacy studies demonstrated that Compound 1 and fulvestrant administered in combination had a statistically significant anti-tumor efficacy benefit compared to both monotherapy treatments alone in three ER+ HER2- breast cancer subcutaneous CDX models, which harbored PIK3CA mutations (at E545K, H1047R, and H1047L for MCF7, T47D, and EFM-19, respectively), at well-tolerated doses. This demonstrated that treatment with Compound 1 led to a combination benefit with an ER degrader. Example 6: Compound 1 is efficacious in combination with a CDK 4 / 6 inhibitor in ER+ HER2- breast cancer cell lines

[0589] Several in vitro viability studies were conducted to investigate the potential of combining Compound 1 with palbociclib in the ER+ HER2- breast cancer MCF7 and T47D cell lines, which harbor a PIK3CA mutation at E545K and H1047R, respectively. Palbociclib is a CDK 4 / 6 inhibitor that has been approved by the FDA for patients in combination with an aromatase inhibitor or fulvestrant for the treatment of HR+ HER2- advanced or metastatic breast 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 Compound 1 or palbociclib. The doses of palbociclib were picked based on IC50 concentrations after conducting a 5-day viability assay in 2D conditions. For MCF7 and T47D, doses of 1 μM of Compound 1 and 100 nM palbociclib 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. Page 139 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1

[0590] In both the MCF7 and T47D cell lines, Compound 1 demonstrated an additive effect when combined with CDK 4 / 6 inhibitors that was greater than the effect of the single agent alone (FIGs.3A-3B). Each combination treatment showed statistically significant greater activity than treatment with either test article as a monotherapy. Representative results (mean + / - SEM) from 2 experiments for MCF7 and 2 experiments for T47D are shown. Confluence (+ / - SEM) with two-way repeated measures ANOVA followed by a Tukey multiple comparison test day 17 for MCF7 and T47D 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; CDK4 / 6=cyclin-dependent kinase 4 / 6; ER+=estrogen receptor positive; HER2-=Erb-B2 receptor tyrosine kinase 2 negative; μM=micromolar; nM=nanomolar; PIK3CA=phosphotidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SEM=standard error of the mean)

[0591] In MCF7 cells on day 17, Compound 1 inhibited growth by 4%, palbociclib inhibited growth by 33%, and the combination of Compound 1 and palbociclib significantly inhibited growth by 61%. (FIG.3A). The combination of 1 μM BBO-10203 with 100 nM palbociclib showed greater cell growth inhibition compared to both monotherapy treatments alone. In T47D cells on day 17, Compound 1 did not inhibit growth, palbociclib inhibited growth by 25%, and the combination of Compound 1 and palbociclib significantly inhibited growth by 52% (FIG.3B). The combination of 1 μM BBO-10203 with 100 nM palbociclib showed greater cell growth inhibition compared to both monotherapy treatments alone.

[0592] These in vitro studies demonstrated that Compound 1 in combination with a CDK 4 / 6 inhibitor had a statistically significant stronger anti-proliferative effect compared to both monotherapy treatments alone in ER+ HER2- breast cancer cell lines with PI3KCA mutations. Example 7: Compound 1 is efficacious in combination with a CDK4 / 6 inhibitor in an ER+ HER2- breast cancer xenograft model

[0593] An in vivo study was conducted to assess the anti-tumor activity of BBO-1020 Compound 13 in combination with palbociclib in the ER+HER2- breast cancer MCF7 CDX model, which harbors a PIK3CA E545K mutation. Palbociclib is a CDK 4 / 6 inhibitor that has been approved by the FDA for patients in combination with an aromatase inhibitor or fulvestrant for the treatment of HR+ HER2- advanced or metastatic breast cancer. Female Page 140 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 athymic nude mice were implanted subcutaneously with MCF7 human tumor cells. Animals were provided 10 µg / mL 17β-estradiol supplemented water ad libitum to support tumor growth throughout the study. When tumors reached a mean size of 166 mm3, mice were randomized into treatment groups (10 mice per group) and orally administered vehicle QD, 100 mg / kg QD Compound 1, 10 mg / kg BID palbociclib, or the combination of 100 mg / kg QD Compound 1 and 10 mg / kg BID palbociclib for a period of 28 days. Mouse tumor volumes and body weights were measured twice weekly until day 28. TGI, an indicator of anti-tumor effectiveness, was calculated for each treatment (T) versus control (C) group using the first day of dosing (0) and day 28 (i) mean tumor volume measurements with the formula: TGI (%) = (1 - (Ti-T0) / (Ci-C0)) × 100. For statistical analyses comparing each monotherapy group to the combination group, two-way mixed effects 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.

[0594] In athymic nude mice bearing ER+ HER2- breast cancer MCF7 subcutaneous xenograft tumors, which harbor a PIK3CA E545K mutation, the combination of Compound 1 and palbociclib 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 Compound 1 and 10 mg / kg palbociclib in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 99% TGI observed in the combination group on day 28. There was no impact of treatments on body weight, and all treatments were well tolerated.

[0595] FIG.4: *p<0.01, **p<0.001 two-way mixed effects ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (QD) or twice daily (bis in die, BID) as indicated. (ANOVA=analysis of variance; CDK4 / 6=cyclin-dependent kinase 4 / 6; ER+=estrogen receptor positive; HER2-=Erb-B2 receptor tyrosine kinase 2 negative; mm3=cubic millimeters; mg / kg=milligrams per kilogram; n=number; SEM=standard error of the mean)

[0596] This in vivo efficacy study demonstrated that Compound 1 and palbociclib administered in combination had a statistically significant anti-tumor efficacy benefit compared to both monotherapy treatments alone in the ER+ HER2- breast cancer MCF7 Page 141 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 subcutaneous xenograft model, which harbors a PIK3CA E545K mutation, at well-tolerated doses. This demonstrated that treatment with Compound 1 led to a combination benefit with a CDK inhibitor such as a CDK4 / 6 inhibitor.

[0597] Several in vivo studies were conducted to assess the anti-tumor activity of BBO- 10203 in combination with ribociclib in ER+ HER2+ breast cancer CDX and PDX models with or without PIK3CA mutations. Ribociclib is a CDK 4 / 6 inhibitor that has been approved by the FDA for patients in combination with an aromatase inhibitor or fulvestrant for the treatment of HR+ HER2- advanced or metastatic breast cancer. Female immunocompromised mice were implanted subcutaneously with MCF7 human tumor cells, ~125 mm3T47D CDX tumor fragments harvested from stock mice, EFM-19 human tumor cells, or HBCx-34 PDX tumor fragments harvested from stock mice. Animals were provided 10 µg / mL 17β-estradiol supplemented water ad libitum (MCF7), implanted subcutaneously with 17β-estradiol pellets (0.72 mg / pellet 90-day release pellets; T47D), or provided 8.5 µg / mL 17β-estradiol supplemented water ad libitum (EFM-19 and HBCx-34) to support tumor growth throughout the study. When tumors reached a mean size of 171 mm3(MCF7) and 185 mm3(HBCx-34), mice were randomized into treatment groups (10 mice per group) and treated with vehicle QD, 100 mg / kg QD BBO-10203, 60 mg / kg QD ribociclib, or the combination of 100 mg / kg QD BBO-10203 and 60 mg / kg QD ribociclib. When tumors reached a mean size of 263 mm3(T47D) and 209 mm3(EFM-19), mice were randomized into treatment groups (10 mice per group) and treated with vehicle QD, 100 mg / kg QD BBO-10203, 75 mg / kg QD ribociclib, or the combination of 100 mg / kg QD BBO-10203 and 75 mg / kg QD ribociclib. Vehicle, BBO- 10203, and ribociclib were administered once per day (QD) by oral gavage for a period of 28 days (MCF7 and HBCx-34), 36 days (T47D), or 29 days (EFM-19). Mouse tumor volumes and body weights were measured twice weekly until day 28 (MCF7 and HBCx-34), day 36 (T47D), or day 29 (EFM-19). TGI, an indicator of anti-tumor effectiveness, was calculated for each treatment (T) versus control (C) group using the first day of dosing (0) and day 28 (i) mean tumor volume measurements with the formula: TGI (%) = (1 - (Ti-T0) / (Ci-C0)) × 100. TGI was only reported if <100%. Tumor regression was also 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 Page 142 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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.

[0598] In athymic nude mice bearing ER+ HER2- breast cancer MCF7 subcutaneous CDX tumors, which harbor a PIK3CA E545K mutation, the combination of BBO-10203 and ribociclib showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.5A). Following administration of 100 mg / kg BBO-10203 and 60 mg / kg ribociclib in combination, a statistically significant tumor volume reduction was observed in the combination group compared to both monotherapy groups, with 97% TGI observed in the combination group on day 28. There was no impact of treatments on body weight, and all treatments were well tolerated.

[0599] FIG.5A: *p<0.01, **p<0.001 two-way repeated measures ANOVA vs. monotherapy groups; all groups dosed per os (po, orally) once daily (QD)).

[0600] In NSG mice bearing ER+ HER2- breast cancer T47D subcutaneous CDX tumors, which harbor a PIK3CA H1047R mutation, the combination of BBO-10203 and ribociclib showed statistically significantly greater anti-tumor activity than treatment with either test article alone as a monotherapy (FIG.5B). Following administration of 100 mg / kg BBO- 10203 and 75 mg / kg ribociclib in combination, a statistically significant tumor volume reduction was observed in the combi...

Claims

PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.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 a or a therapeutically effective amount of a selective estrogen receptor degrader (SERD), 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–(C1-4 alkylene)–OR; each R4is independently halogen or C1-4 alkyl; each of R5and R5′is independently halogen or C1-4alkyl; each R independently hydrogen or C1-4 alkyl; n is 0 or 1; Page 145 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 p is 0 or 1; s is 0 or 1; and y is 0, 1 or 2.

3. The method of any one of claims 1 and 2, is selected, .

4. or 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.

7. The method of any one of claims 1 to 6,Page 146 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , , ,8. The method of any one of claims 1 to 7, wherein the compound is represented by: Page 147 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 , or a9. The method of any one of claims 1 to 8, wherein the compound is Compound 1: 1), or a10. The method of any one of claims 1 to 9, wherein the compound is Compound 1: (Compound 1).

11. The method of any one of claims 1 to 10, wherein the cancer is breast cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), endometrial cancer, Page 148 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 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, or pancreatic cancer.

12. The method of any one of claims 1 to 11, wherein the cancer is resistant to a CDK inhibitor, a SERD, a PI3Kα inhibitor, or a combination thereof.

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

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

15. The method of any one of claims 1 to 14, wherein the CDK inhibitor has inhibitory activity against CDK2, CDK4, CDK6, or a combination thereof.

16. The method of any one of claims 1 to 15, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, PF-07220060, atirmociclib, PF-07248144, BTX-9341, AU2-94, IpY.20, RGT-419B, ebvaciclib, TY-0540, FN-1501, AVZO-021, BLU- 222, AZD8421, or PF-07104091.

17. The method of any one of claims 1 to 16, wherein the CDK inhibitor is palbociclib or ribociclib. Page 149 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 18. 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: 1), or aii) a a CDK inhibitor is palbociclib or ribociclib.

19. The method of any one of claims 1 to 18, wherein the CDK inhibitor is palbociclib.

20. The method of any one of claims 1 to 18, wherein the CDK inhibitor is ribociclib.

21. The method of any one of claims 18 to 20, wherein the CDK inhibitor is administered orally.

22. 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: 1), or aPage 150 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 ii) a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

23. The method of any one of claims 1 to 13 and 22, wherein the SERD is fulvestrant or camizestrant.

24. 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: 1), or aii) a therapeutically effective amount of a selective estrogen receptor degrader (SERD), wherein the SERD is fulvestrant or camizestrant.

25. The method of any one of claims 1 to 13 and 22 to 24, wherein the SERD is fulvestrant.

26. The method of claim 25, wherein fulvestrant is administered by intramuscular injection.

27. The method of any one of claims 1 to 13 and 22 to 24, wherein the SERD is camizestrant.

28. The method of claim 27, wherein camizestrant is administered orally.

29. The method of any one of claims 13 to 28, wherein the breast cancer is a hormone receptor (HR) positive breast cancer.

30. The method of any one of claims 13 to 29, wherein the breast cancer is an estrogen receptor (ER) positive breast cancer. Page 151 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 31. The method of any one of claims 13 to 30, wherein the breast cancer is a human epidermal growth factor receptor 2 (HER2) negative breast cancer.

32. The method of any one of claim 13 to 30, wherein the breast cancer is a human epidermal growth factor receptor 2 (HER2) positive breast cancer.

33. The method of any one of claims 13 to 28, wherein the breast cancer is an estrogen receptor (ER) positive and a human epidermal growth factor receptor 2 (HER2) negative breast cancer.

34. The method of any one of claims 13 to 33, wherein the breast cancer is an advanced breast cancer or metastatic breast cancer.

35. The method of any one of claims 13 to 34, wherein the breast cancer is resistant to a CDK inhibitor, a SERD, a PI3Kα inhibitor, or a combination thereof.

36. The method of any one of claims 1 to 35, 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.

37. The method of claim 36, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

38. The method of claim 36 or 37, wherein the small GTPase is a RAS protein.

39. The method of claim 38, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

40. The method of claim 38 or 39, wherein the RAS protein is KRAS, NRAS, or HRAS.

41. The method of any one of claims 36 to 40, 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. Page 152 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 42. The method of any one of claims 36 to 41, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

43. The method of any one of claims 1 to 42, wherein the subject has not previously been treated with a CDK inhibitor, a SERD, a PI3Kα inhibitor, a combination thereof.

44. The method of any one of claims 1 to 42, wherein the subject has previously been treated with a CDK inhibitor, a SERD, a PI3Kα inhibitor, a combination thereof.

45. The method of claim 44, wherein the subject has previously been treated with palbociclib or ribociclib.

46. The method of claim 44 or 45, wherein the subject has previously been treated with fulvestrant or camizestrant.

47. The method of any one of claims 12, 35, 43, and 44, wherein the PI3Kα inhibitor is a compound of Formula (IF1) according to any one of claims 1 to 10, or pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the PI3Kα inhibitor is Compound 1, or pharmaceutically acceptable salt thereof.

49. The method of any one of claims 1 to 48, wherein the subject is a human.

50. The method of any one of claims 1 to 49, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.

51. The method of any one of claims 1 to 50, wherein the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered concomitantly; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are administered concomitantly.

52. The method of any one of claims 1 to 50, wherein the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are administered sequentially; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are administered sequentially. Page 153 of 155 13020314v1PATENT Attorney Docket No.: 2014229-0165 Client Ref. No.: Thera-27.WO1 53. The method of claim 52, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the CDK inhibitor or SERD.

54. The method of claim 52, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of the CDK inhibitor or SERD.

55. The method of any one of claims 1 to 54, wherein the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in jointly therapeutically effective amounts; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are provided in jointly therapeutically effective amounts.

56. The method of any one of claims 1 to 54, wherein the compound, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor are provided in synergistically effective amounts; or the compound, or a pharmaceutically acceptable salt thereof, and the SERD are provided in synergistically effective amounts.

57. The method of any one of claims 1 to 54, wherein the compound, or a pharmaceutically acceptable salt thereof, and / or the CDK inhibitor are each used at a dose lower than when it is used alone; or the compound, or a pharmaceutically acceptable salt thereof, and / or the SERD are each used at a dose lower than when it is used alone. Page 154 of 155 13020314v1

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