Compounds having a T-structure formed by at least four cycles for use in the treatment of cancer and other indications

Abstract

Provided herein are compounds and compositions thereof that may be capable of disrupting, interrupting, and / or preventing an interaction between a small GTPase protein and a PI3K protein (e.g., PI3Ka). The present disclosure also provides methods of treating cancers and other indications with such compounds or compositions thereof.

Description

COMPOUNDS HAVING A T-STRUCTURE FORMED BY AT LEAST FOUR CYCLES FOR USE IN THE TREATMENT OF CANCER AND OTHER INDICATIONSGOVERNMENT SUPPORT

[0001] This invention was made with government support under Contract No. DE-AC52-07NA27344 awarded by the United States Department of Energy. The government has certain rights in the invention.RELATED APPLICATIONS

[0002] This application claims priority to and benefit of U.S. Application No. 63 / 307,882, filed February 8, 2022, and U.S. Application No. 63 / 416,772, filed October 17, 2022, the entire contents of each of which are hereby incorporated by reference.BACKGROUND

[0003] 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%.

[0004] 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.

[0005] 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.SUMMARY

[0006] The present disclosure provides new therapeutic modalities for treating cancers and other indications (e.g., cancers and other indications associated with and / or characterized by aberrant activation of PI3K). The present disclosure encompasses the recognition that a therapeutic agent (e.g., a therapeutic agent comprising a small molecule, e.g., a compound provided herein) that disrupts, inhibits, and / or prevents an interaction between a PI3K protein (e.g., PI3Ka) and a small GTPase (e.g., Rael, CDC42, or aRAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) may be particularly useful for treating, ameliorating, delaying the progress of, ameliorating or eliminating a symptom of, and / or inhibiting a cancer and / or other indication (e.g., an indication associated with and / or characterized by aberrant activation of PI3K). Without wishing to be bound by theory, therapeutic agents provided herein (e.g., therapeutic agents comprising small molecules, e.g., compounds provided herein) may be capable of binding to a PI3K protein (e.g., PI3Ka) while displaying (i) no or minimal binding to a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and / or (ii) no substantial effect on the kinase activity of the PI3K protein (e.g., PI3Ka). In some embodiments, such therapeutic agents may provide advantages such as improved efficacy or reduced side effects as compared to, e.g., ATP -competitive PI3K kinase inhibitors, as described herein. For example, in some embodiments, such therapeutic agents may provide reduced instances of hyperglycemia and / or hyperinsulinemia relative to PI3K kinase inhibitors.

[0007] The present disclosure provides compounds (including in any available forms, such as salt forms) useful in disrupting, inhibiting, and / or preventing an interaction between a PI3K protein (e.g., PI3Ka) and a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). In some embodiments, the present disclosure provides compounds capable of binding a PI3Ka protein, such that (i) the interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3Ka protein is disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of the PI3Ka protein is not inhibited. In some embodiments, such compounds are useful for treating a cancer or other indication, as described herein.

[0008] In an aspect, the present disclosure provides a compound of Formula I:I or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein each of Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, q, and r is as defined herein. In some embodiments, a compound of Formula I is capable of binding a PI3Ka protein, such that (i) the interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3Kaprotein is disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of the PI3Ka protein is not inhibited.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula I), or a salt (e.g., a pharmaceutically acceptable salt) thereof, together with a pharmaceutically acceptable carrier.

[0010] In another aspect, the present disclosure provides a method of inhibiting, disrupting, and / or preventing an interaction between a PI3Ka protein and a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) such that the kinase activity of the PI3Ka protein is not inhibited. In some embodiments, the PI3Ka protein is in a cell, such as in a cell of a human or animal subject (e.g., as described herein).

[0011] In a further aspect, the present disclosure provides a method of treating, ameliorating, delaying the progress of, ameliorating or eliminating a symptom of, and / or inhibiting a cancer and / or other indication (e.g., an indication associated with and / or characterized by aberrant activation of PI3K) comprising administering a compound provided herein (e.g., a compound of Formula I), or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0012] In a related aspect, the present disclosure provides a use of a compound provided herein (e.g., a compound of Formula I), or a salt (e.g., a pharmaceutically acceptable salt) thereof, in the manufacture of a medicament for the treatment, amelioration, or inhibition of a cancer or other indication (e.g., an indication associated with and / or characterized by aberrant activation of PI3K). The present disclosure also provides a compound (e.g., a compound of Formula I), or a salt (e.g., a pharmaceutically acceptable salt) thereof, for use as a medicament, which medicament may be used in the treatment, amelioration, or inhibition of a cancer or other indication (e.g., an indication associated with and / or characterized by aberrant activation of PI3K).BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows the effect of inhibiting PI3Ka with a PI3Ka kinase inhibitor such as alpelisib in normal cells (left panel) and tumor cells (right panel). In normal cells, inhibiting PI3Ka blocks normal cell signaling resulting in dose-limiting hyperglycemia and insulin-driven resistance. The right panel shows an alternative scheme of using a PI3Ka breaker to inhibit the PI3Ka:RAS proteimprotein interaction in tumor cells. This mechanism should avoid hyperglycemia and insulin-driven resistance by selectively targeting tumor cells and may provide multiple therapeutic advantages. The observation that mutations in the RAS binding domain that impair the PI3Ka:RAS interaction blocks oncogene-driven non-small cell lung cancer (NSCLC) tumor growth in vivo and have no effect on glucose metabolism support the potential of this mechanism.

[0014] FIGs. 2A and 2B show that a PI3Ka breaker can have broad in vitro activity. FIG. 2A shows one third of human tumor cell lines tested have a pAKT IC50 < 100 nanomolar (nM) and depend on the RAS:PI3Ka interaction for activation of Akt signaling. In particular, 29 of 50 (58%) G12X cell lines have a pAKT IC50 < 100 nM. Bioinformatic analyses in FIG. 2B show that cell lines with PIK3CA helical mutations are particularly sensitive to the PI3Ka breaker without inducing hyperglycemia; in addition, 78% of HER2 amplified lines are sensitive to the PI3Ka breaker.

[0015] FIGs. 3A-3D shows that PI3Ka breakers are orally bioavailable and can achieve near complete inhibition of signaling in tumors without risk of hyperglycemia or hyperinsulinemia. FIG. 3A shows the pharmacokinetics of a PI3Ka breaker compound in mouse. FIG. 3B shows dose response pharmacodynamics for a PI3Ka breaker (“BBO”) and the PI3Ka kinase domain inhibitor alpelisib in a BT474 cell line-derived xenograft model. The dose response pharmacodynamics demonstrate that near complete target inhibition is achieved at 100 mg / kg of PI3Ka breaker. (One-way ANOVA with Dunnett’s test vs. vehicle; *=p<0.01; **=p<0.0001). From left to right along x-axis in FIG. 3B: vehicle, 30 mg / kg BBO, 100 mg / kg BBO, 300 mg / kg BBO, 50 mg / kg alpelisib. FIG. 3C and 3D demonstrate that unlike PI3Ka kinase domain inhibitors, PI3Ka breaker compounds do not affect glucose metabolism. FIG. 3C shows blood glucose levels at the time of and after administration of a single dose of vehicle, the PI3Ka kinase domain inhibitor alpelisib, and a PI3Ka breaker (Compound 58, “BBO”) in fasted male mice after an oral glucose tolerance test. Hyperglycemia is observed in alpelisib but not in PI3Ka breaker treated mice. (One-way ANOVA with Dunnett’s test vs vehicle, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001) FIG. 3D shows insulin levels at the time of and 240 minutes after administration of a single oral dose of vehicle, 50 mg / kg alpelisib, or 300 mg / kg Compound 58 (“BBO”) in fed male mice. Hyperinsulinemia is observed in alpelisib but not PI3Ka breaker treated mice. (One-way ANOVA with Tukey's multiple comparisons test vs all other groups : *p<0.0001) (IV=intravenous administration; PO=per os or oral administration; ng / mL=nanograms per milliliters; mg / kg=milligrams per kilogram; mg / dL=milligrams per deciliter; min=minutes; CDX=cell line derived xenograft; QD=quaque die or once daily, PK=pharmacokinetics)

[0016] FIGs. 4A-4D show that strong efficacy is observed in xenograft models with KRAS G12X mutations, with or without PIK3CA mutations. FIG. 4A shows changes in tumor volume in a KYSE-410 cell line-derived xenograft model featuring a KRAS G12C mutation and HER2 amplification. Dose dependent, significant efficacy was observed and there was tumor regression with 100 mg / kg of PI3Ka breaker (“BBO”). FIG. 4B shows changes in tumor volume in a GP2d cell line-derived xenograft model featuring a KRAS G12D mutation and a PIK3CA H1047L mutation. Significant tumor volume reduction is observed with 10 mg / kg and higher amounts of PI3Ka breaker (“BBO”). FIG. 4C shows changes in tumor volume in a SNU-601 cell line-derived xenograft model featuring a KRAS G12D mutation and aPIK3CA E542K mutation. Significant tumor volume reduction is observed with 10 mg / kg and higher amounts of PI3Ka breaker (“BBO”). FIG. 4D shows changes in tumor volume in a SNU-16 cell Ime- denved xenograft model that features a KRAS G12D mutation. Significant tumor volume reduction is observed with 10 mg / kg and higher amounts of PI3Ka breaker (“BBO”). (p<0.0005 two-way repeated measures ANOVA vs. vehicle; all groups dosed per os (PO, orally), once daily (QD) (mm3=cubic millimeters; mg / kg=milligrams per kilogram)DETAILED DESCRIPTIONCompounds and Definitions

[0017] 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.

[0018] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropisomeric, or epimeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure; and the D- and L-isomers of each compound are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Table 1 and Table 2 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from 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.

[0019] 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.

[0020] Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein, means a straight-cham (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.

[0021] Alkyl: 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, Ci-s, C1-6, CM, CM, 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-).

[0022] Alkenyl: 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.

[0023] Alkynyl: 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.

[0024] Aryl. 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 shareone or more atoms. The term “aryl” may be used interchangeably with the term “aryl ring(s).” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system. Examples of aryl groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents as defined herein. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl or tetrahydronaphthyl, and the like. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0025] Carbocyclyl: The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, 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, norbomyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted Cg-C 10 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.

[0026] Halogen. The term “halogen” or “halo” means F, Cl, Br, or I.

[0027] Heteroaryl. 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 7i electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Examples of bicyclic heteroaromatic groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, indazolyl, indolizinyl, benzimidazolyl, benzthiazolyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiadiazolyl, tetrazolopyndazinyl, 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(177)-one.

[0028] Heteroatom. 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 quatemized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2 / f-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)). In some embodiments, a heteroatom is selected from oxygen, sulfur, and nitrogen.

[0029] Heterocycle. 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, oxazepmyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more ary l, heteroaryl, or cycloaliphatic rings, such as indolinyl, H- 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).

[0030] Partially Unsaturated'. 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. Theterm “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.

[0031] Patient or Subject: 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. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, hamsters, guinea pigs, cats, dogs, goats, pigs, sheep, cows, deer, horses, non-human primates, and / or humans). In some embodiments, a patient or subject is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0032] Prevent or prevention: 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.

[0033] Substituted or Optionally Substituted: 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| r hydrogens that are either explicit or implicit from the structure (e.g.,R1refers to at leastR1). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CChjo—iR0: -(dUfniOR0: -0(CH2)o-4R°, -O-fCFbjo-iCfOjOR0: -(CH2)O-4CH(OR°)2; (C H2)O^S R°; -(CH3)o-4Ph, which may be substituted with R°; (C H2)o 40(C H2)O I Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(Ctbjo-iOfClUjo-i- pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CIUlo-iNfR0^: -(CH2)O-4N(R°)C(0)R°; - N(R°)C(S)R°; -(CH2)O-4N(R0)C(0)NR°2; -N(R°)C(S)NRO2; -(CH2)O^N(R°)C(0)OR0;N(R°)N(R°)C(O)R°; -N(Ro)N(Ro)C(0)NRo2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; -C(S)R°; - (CH2)O-4C(0)OR°; -(CH2)O^C(0)SR°; -(CH2)O^C(0)OSIR°3; -(CH2)O-40C(0)R°; -OC(0)(CH2)O^SR°; - (CH2)O-4SC(0)R°; -(CH2)O^C(0)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)O-4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O-4SSR0; -(CH2)O-4S(0)2RO; -(CH2)O^S(0)20R°; -(CH2)O-OS(0)2R0; -S(0)2NRO2; -(CH2)O^S(0)R°; -N(RO)S(O)2NR°2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SIR°3; -(CI-4 straight or branched alkylene)O-N(R°)2; or -(CH straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH3Ph, - 0(CH2)o-iPh, -CH3-(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.

[0035] 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)O-2OH, -(CH2)O-2OR*, -(CH2)O-2CH(OR*)2, -O(haloR’), -CN, -N3, -(CH2)0-2C(O)R*, - (CH2)O-2C(0)OH, -(CH2)O-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*, - (CH2)O-2NR*2, -NO2, -SiR*3, -OSiR’s, -C(O)SR*, -(CM 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 CM aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0036] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*,wherein each independent occurrence of R* is selected from hydrogen, CM aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] 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 CM aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -C(NH)NR:2. or N( R )S(O)2R I wherein each R:is independently hydrogen, CM aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R’ , taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] 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* isunsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy (e.g., therapeutic agent) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. Treatment may also refer to any other indicia of success in the treatment or amelioration of an injury, pathology, disease, disorder, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, disease, disorder, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; and / or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.

[0041] Composition 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. For example, a “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject.PI3K and Small GTPase Proteins

[0042] The aberrant activation of the phosphoinositide 3 -kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in treating cancers. PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism,proliferation, and migration. Upon activation, PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5- bisphosphate (PIP2). Signaling proteins such as Ser / Thr kinase AKT (e.g., Protein Kinase B (PKB)) can bind to PIP3 and thereby localize to the cell membrane. Phosphorylated AKT activates or inhibits several signaling proteins through direct phosphorylation including the mammalian target of rapamycin complex 1 (mTORCl), which acts as a regulator of cell growth and survival pathways, cyclin DI, GSK3(B), BAD, MDM2, FOXO, TSC1 / 2, and PRAS40. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulates this pathway by dephosphorylating PIP3 to PIP2 and thus prevents activation of downstream kinases.

[0043] Based on the sequence homology and substrate preference, PI3Ks have been grouped into three separate classes (e.g., classes I, II, and III). Class I PI3Ks are further divided into two subclasses, IA and IB depending on their modes of regulation. Class IA PI3Ks are heterodimers comprising pl 10 catalytic and p85 regulatory subunits, and are most clearly implicated in human cancer. Class IA PI3K contains pl 10a, pHOp, and pl 108 catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while pl 10y produced by PIK3CG represents the only catalytic subunit in class IB PI3K. The expression of PI3K isoforms (e.g., PI3Ka, PI3K0, PI3K8, and PI3Ky) is specific to cell types. The pl 10a and P isoforms are expressed in all cell types, whereas pl 108 expression is mainly confined to leukocytes. The pl 10y isoform is expressed primarily in the myeloid cell lineage.

[0044] PIK3CA gene encodes the 1068 amino acid pl 10a protein that contains five domains: an N- terminal adaptor binding domain (ABD) that binds to regulatory subunit p85a, a RAS-binding domain (RBD), a C2 domain, a helical domain, and a kinase catalytic domain. RAS contributes directly to the activation of the PI3K pathway through direct binding of RAS proteins (e.g., HRAS, NRAS, and KRAS) to a RAS-binding domain (RBD) in the pl 10a catalytic subunit of PI3Ka. Activating mutations in the KRAS and PIK3CA genes are frequently detected in cancer, making these two proteins important targets for drug discovery. Somatic missense mutations in the PIK3CA gene have been reported in many human cancer types including breast, colon, liver, stomach, endometrial, bladder, and lung cancers. The most frequent hotspot mutations in PIK3CA are E542K, E545K, H1047R, and H1047L, and they account for 80-90% of all PIK3CA mutations detected in human malignancies. These PIK3CA mutations lead to increased catalytic activity of pl 10a, which causes downstream effects such as unregulated cell growth, proliferation, and survival.

[0045] 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 arepredominantly 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.

[0046] RAS signaling through PI3K is necessary for normal lymphatic development and RAS-mduced transformation, especially in lung cancer, where the interaction between mutant RAS and pl lOa-RBD is essential for tumor initiation and maintenance. RAS interactions with pl lOa-RBD have been shown to be crucial for epidermal growth factor (EGF) signaling to 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 pl 10a to endogenous RAS proteins in EGFR-driven lung adenocarcinoma is critical in tumors driven by upstream activators of the RAS pathways and not just those in which RAS is mutationally activated.

[0047] Small GTPases (e.g., other than RAS) are also expected to bind the RBD of PI3Ka resulting in activation of signaling. The small GTPases Rael and CDC42 have been shown to bind the RBD of PI3K0 and are hypothesized to also be capable of binding the RBD of PI3Ka. Accordingly, in some embodiments, the present disclosure encompasses the recognition that disrupting an interaction between PI3Ka and any small GTPase that binds the RBD of PI3Ka may be a useful therapeutic strategy for treating cancers and other indications. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins (including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).

[0048] The frequency of oncogenic PIK3CA hotspot mutations across cancers has fueled the development and testing of numerous PI3K (e.g., PI3Ka) inhibitors. Most PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance. In 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (BYL719; Novartis Pharma AG), an inhibitor specific to the PI3Ka isoform, combined with fulvestrant for the treatment of patients diagnosed with HR+ / HER2- PIK3CA-mutation. The therapeutic window of PI3K inhibitors is mainly limited by isoform selectivity and off-tumor toxicity. Moreover, hyperglycemia and hypermsulinemia have been observed as major dose-limiting toxicities for pl 10a inhibitors, which prevent the use of sufficiently high doses to fully suppress PI3Ka signaling in the tumor. Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3Ka inhibition, as inhibition of the PI3K / AKT pathway reduces glucose uptake, which in turn leads to increased secretion of insulin and subsequent activation of insulin / insulin-like growth factor I receptor in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of the PI3Ka inhibitor. Indeed,hyperglycemia was observed in 65% of patients in a Phase III clinical trial of al pel i sib. leading to significant dose interruptions.

[0049] To overcome the limitations of current PI3Ka inhibitors, novel strategies to target PI3Ka need to be explored. Previous studies have suggested that inhibiting the RAS-pl lOa(RBD) interaction has minimal toxicity in adult animals while effectively causing tumor regression. The present disclosure encompasses the recognition that 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). The present disclosure also appreciates that this therapeutic modality may provide certain advantages over known PI3Ka inhibitors (e.g., those that target the ATP binding pocket of PI3Ka). For example, provided technologies may avoid hyperglycemia and insulin-driven resistance common to PI3Ka inhibitors, e.g., because such technologies target activation of PI3Ka by RAS, which is mostly present in transformed cells.Provided Compounds

[0050] In some embodiments, the present disclosure provides compounds useful for disrupting, inhibiting, and / or preventing the interaction between small GTPases (e.g., RAS proteins, as described herein) and PI3Ka proteins. In some embodiments, the present disclosure provides compounds capable of binding PI3Ka, such that (i) the interaction between the small GTPase (e.g., RAS protein, as described herein) and PI3Ka is disrupted, inhibited, or prevented; and / or (ii) the kinase activity of PI3Ka is not significantly inhibited. In some embodiments, such compounds bind PI3Ka reversibly. As used herein, a compound that binds “reversibly” refers to a compound that is able to bind to and become dissociated from a target protein kinase (e.g., PI3Ka). Often, but not always, reversible inhibitors are not able to form a covalent bond with a target protein kinase. In some embodiments, such compounds bind PI3Ka irreversibly. As used herein, a compound that binds “irreversibly” refers to a compound that is able to interact (e.g., to form a covalent bond) with a target protein kinase (e.g., PI3Ka) in a substantially non- reversible manner. In some embodiments, a reversible or irreversible inhibitor may be capable of interacting covalently with PI3Ka. For example, in some embodiments the present disclosure provides compounds comprising an electrophilic moiety (e.g., a Michael acceptor or the like) capable of binding (e.g., reversibly or irreversibly) to, e.g., a cysteine residue in the catalytic subunit of PI3Ka (e.g., C242). In some embodiments, provided compounds that interact with PI3Ka covalently are compounds of Formula I wherein -L-W comprises an electrophilic moiety (e.g., a Michael acceptor or the like) capable of binding (e.g., reversibly or irreversibly) to, e.g., a cysteine residue of PI3Ka (e.g., C242).

[0051] In some embodiments, the present disclosure provides a compound of formula I:I or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein:Ring A is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is selected from phenyl, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 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 independentlyselected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W and y instances of R2;R1is selected from -L-W, Ring D', or a bivalent Ci-6 aliphatic chain substituted with Ring D'; each -L-W is -CN, or: each L is independently a bivalent straight or branched Cus aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, - C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2- each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN; each Ring D' is independently a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D' is substituted with t instances of -L-W; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and C1-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted C1-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 - to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R 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 C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 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.

[0052] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the present disclosure provides a compound of formula I, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein:Ring A is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is selected from phenyl, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 - to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur; and a 9- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl, hctcroaryl. 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 hctcroaryl 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; 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 6-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;R1is selected from -L-W, Ring D', or a bivalent Ci-6 aliphatic chain substituted with Ring D’; each L is independently a bivalent straight or branched Ci-s aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -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 -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 R2is independently selected from oxo, halogen, -CN, -OR, and C1-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted C1-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 - to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatomsindependently 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 Ci-6 aliphatic; each of R5and R is independently selected from oxo, =NH, -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, -(CH2)xCy, and optionally substituted Ci-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, - N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, and an optionally substituted group selected from Ci-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered hctcroar l 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, or 2; q is 0 or 1; r is 0, 1, or 2; s is 0, 1, or 2; t is 0, 1, or 2; u is 0 or 1; each v is independently 0, 1, or 2; and each x is independently 0, 1, or 2.

[0054] In some embodiments, the present disclosure provides a compound of formula I, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein:Ring A is phenyl;Ring B is selected from a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6- membered heteroaryl ring;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered bicyclic carbocyclic ring; a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl, heteroaryl, and heterocyclic rings is optionally fused to Ring E;Ring D is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl and heteroaryl rings is optionally fused to Ring F;Ring E is selected from a 5- to 6-membered carbocyclic ring; a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7- to 10- membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5;Ring F is selected from phenyl; a 5- to 6-membered carbocyclic ring; a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W and y instances of R2;R1is selected from -L-W, Ring D', or a bivalent Ci-6 aliphatic chain substituted with Ring D'; each -L-W is -CN, or: each L is independently a bivalent straight or branched Cus aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, - C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN;each Ring D' is independently a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D' is substituted with t instances of-L-W; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and Ci-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted C1-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, - C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -C(O)N(R)2, -C(O)N(R)(CH2)sCy, - (CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, - P(O)R2, -(CH2)xCy, -O(CH2)xCy, and optionally substituted C1-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, - N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Cue 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 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.

[0055] In some embodiments, the present disclosure provides a compound of formula I, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein:Ring A is phenyl;Ring B is selected from 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 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; each -L-W is -CN, or:each L is independently a bivalent straight or branched Cus aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, - C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and C1-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted C1-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, - C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -C(O)N(R)2, -C(O)N(R)(CH2)xCy, - (CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, - P(O)R2, -(CH2)xCy, -O(CH2)xCy, and optionally substituted C1-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, - N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from 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 2 or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0; r is 0, 1, or 2; s is 0, 1, 2, or 3; 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.

[0056] In some embodiments, the present disclosure provides a compound of formula I, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein:Ring A is phenyl;Ring B is selected from 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 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 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; each -L-W is -CN, or: each L is independently a bivalent straight or branched Cus aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, - C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and C1-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted Ci-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, - C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -C(O)N(R)2, -C(O)N(R)(CH2)xCy, - (CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, - P(O)R2, -(CH2)xCy, -O(CH2)xCy, and optionally substituted C1-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, - N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having1-3 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 2 or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0; r is 0, 1, or 2; s is 0, 1, 2, or 3; 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.

[0057] In some embodiments, the present disclosure provides a compound selected from formulae I- a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, and I-k:or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, q, and r are as defined above forFormula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-d or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the present disclosure provides a compound selected from formulae I- a-z, I-b-Z, I— c— z, I-d-z, I-e-z, I-f-z, I-g-z. I-h-z, I-i-z, I-j-z, and I-k-z :I-a-z I-b-zI-k-z or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring E, R1, R2, R3, R4, R5, R5, m, n, p, q, r, and s are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a-z or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b- i or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I -c-i or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-d-i or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e-z or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f-z or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-z or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-Z or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i-z or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j-z or apharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k-z or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the present disclosure provides a compound selected from formulae I- a-zz, I-b-zz, I-c-zz, I-d-zz, I-e-zz, I-f-zz, I-g-zz, I-h-zz, I-i-zz, I-j-zz, and I-k-zz:or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring F, R2, R3, R4, R5, L, W, m, n, p, r, and u are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b- / ' / or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c-ii or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-d-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i-zz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j- ii or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I -k- / z or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the present disclosure provides a compound selected from formulae I- a-zz ’, I-b-zz ’, I-c-zz ’, I-d-zz ’, I-e-zz ’, I-f-zz ’, I-g-zz I-h-zz ’, I-i-zz I-j-zz ’, and I-k- / / I-c-ii’ I-d-zz’or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring F, R2, R2, R3, R4, R5, L, W, m, n, p, r, u, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b- ii ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-d-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f- zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i-zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j- zz ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k-zz ’ or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the present disclosure provides a compound selected from formulae I- a-zzz, I-b-zzz, I-c-zzz, I-d-zzz, I-e-zzz, I-f-zzz, I-g-zzz, I-h-zzz, I-i-zzz, I-j-zzz, and I-k-zzz:I-a-iiiI-b-znI-k-iii or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring D’, L, R2, R3, R4, R5, W, m, n, p, r, and t are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a-zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b- iii or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c-iii or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-d-zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e-zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f- zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i-zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j- zzz or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k-iii or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the present disclosure provides a compound selected from formulae I- a-zv, I-b-zv, I-c-zv, I-d-zv, I-e-zv, I-f-zv, I-g-zv, I-h-zv, I-i-zv, I-j-zv, and I-k-zv:or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D’, L, R2, R3, R4, R5, W, m, n, p, r, and t are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a- / v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b- iv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c-zv or a pharmaceutically acceptable salt thereof. In some embodiments, thepresent disclosure provides a compound of formula I-d-zv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e-zv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f- iv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-zv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-zv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i-zv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j- iv or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k-zv or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the present disclosure provides a compound selected from formulae I- a-v, I-b-v, I-c-v, I-d-v, I-e-v, I-f-v, I-g-v, I-h-v, I-i-v, I-j-v, and I-k-v:I-c-v I-d-vI-k-v or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring E, Ring F, R2, R3, R4, R5, R5, L, W, m, n, p, r, s, and u are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-d-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e- v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i- v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j -v or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k-v or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the present disclosure provides a compound selected from formulae I- a-v', I-b-v ’, I-c-v ’, I-d-v ’, I-e-v ’, I-f-v ’, I-g-v ’, I-h-v ’, I-i-v ’, I-j-v ’, and I-k-vor a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, Ring D, Ring E, Ring F, R2, R2, R3, R4, R5, R5, L, W, m, n, p, r, s, u, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula I-a-v’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-b-v ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-c-v ' or a pharmaceutically acceptable salt thereof. Insome embodiments, the present disclosure provides a compound of formula I-d-v ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-e- v’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-f-v ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-g-v ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-h-v ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-i- v’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-j-v ’ or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-k-v ’ or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the present disclosure provides a compound selected from formulae I- 1, 1-m, I-n, I-p, I-q, and I-r:I-q I-r or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D’, L, R3, R4, R5, W, m, n, p, and t are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula 1-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-m or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-n or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-p or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-q or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-r or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the present disclosure provides a compound of formula IA:IA or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, q, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IA or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the present disclosure provides a compound of formula IA1:IA1 or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, n, p, q, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IA1 or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the present disclosure provides a compound of formula IB:IB or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, q, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IB or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the present disclosure provides a compound of formula IB 1 :IB1or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, Ring D, R1, R2, R3, R4, R5, n, p, q, and r are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IB 1 or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the present disclosure provides a compound of formula IC:IC or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, L, R2, R3, R4, R5, W, m, n, p, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IC or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the present disclosure provides a compound of formula IC 1 :IC1 or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, L, R2, R3, R4, R5, W, n, p, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IC1 or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the present disclosure provides a compound of formula ID:ID or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, L, R2, R3, R4, R5, W, m, n, p, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula ID or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the present disclosure provides a compound of formula ID 1 :ID1 or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, L, R2, R3, R4, R5, W, n, p, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula ID 1 or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the present disclosure provides a compound of formula IE:IEor a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, Ring E, L, R2, R3, R4, R\ R5, W, m, n, p, s, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IE or a pharmaceutically acceptable salt thereof

[0075] In some embodiments, the present disclosure provides a compound of formula IE 1 :IE1 or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, Ring E, L, R2, R3, R4, R5, R5, W, n, p, s, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IE 1 or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the present disclosure provides a compound of formula IF :IF or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, Ring E, L, R2, R3, R4, R5, R5, W, m, n, p, s, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IF or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the present disclosure provides a compound of formula IF 1 :IF1 or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring C, Ring E, L, R2, R3, R4, R5, R5, W, n, p, s, and y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of formula IF 1 or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments in any formulae described herein, Ring A is phenyl or a 5- to 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is phenyl or a 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments of any formulae described herein, Ring A is phenyl. In some embodiments, RingIn some embodiments, RingIn some embodiments, Ringsome embodiments, Ring A is selected fromIn some embodiments, Ring A is selected fromIn some embodiments, Ring

[0080] In some embodiments of any formulae described herein, Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5 -membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a pyrazole. In some embodiments, Ring A is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, Ring A is a pyridine or pyridone.

[0081] In some embodiments of any formulae described herein, Ring A, substituted with m instances

[0082] In some embodiments of any formulae described herein, each R3is independently selected from oxo, halogen (e.g., F or Cl), -CN, -OR, -O(CH2)vCy, -0-(Ci-4 alkylene)-OR (e.g., -OCH2CH2OR), - CH2CH2OR, C1-6 aliphatic, and C1-6 haloaliphatic. In some embodiments, each R3is independently selected from oxo, halogen (e.g., F or Cl), -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, -CH2CH2OR, C1-6 aliphatic, and C1-6 haloaliphatic. In some embodiments, each R3is independently selected from halogen, -CN, -OR, - O(CH2)vCy, -OCH2CH2OR, and optionally substituted C1-6 aliphatic. In some embodiments, each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted C1-6 alkyl. In some embodiments, each R3is independently selected from oxo, halogen, -CN, - OR, -O(CH2)vCy, -OCH2CH2OR, and C1-6 aliphatic optionally substituted with one or more halogen or -OR0. In some such embodiments, R° is C1-4 alkyl. Accordingly, in some embodiments, each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and C1-6 aliphatic optionally substituted with one or more halogen or -O(Ci-4 alkyl). In some embodiments, each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and C1-6 alkyl optionally substituted with one or more halogen or -O(Ci-4 alkyl). In some embodiments, at least one R3is selected from halogen, -OR, -O(CH2)vCy, and -OCH2CH2OR. In some embodiments, at least one R3is selected from -OR, -O(CH2)vCy, and -OCH2CH2OR. In some embodiments, RingR3R3'C^R3 j™' , wherein each R3is independently selected from halogen, -OR, -O(CH2)vCy, and -OCH2CH2OR. In some embodiments, Ring, wherein each R3is independently selected from halogen, -OR, -O(CH2)vCy, and -O-(Ci-4 alkylene)-OR. In some embodiments, Ring, wherein R is selected from -OR, -O(CH2)vCy, and -F FR36. R3dOCH2CH2OR. In some embodiments, Ring A is or , wherein R3is selected from -OR, -O(CH2)vCy, and -O-(Ci-4 alkylene)-OR.

[0083] In some embodiments of any formulae described herein, each R3is independently selected from halogen, -OR, -OCH2CH2OR, and C1-6 alkyl optionally substituted with one or more halogen or -O(Ci-4 alkyl). In some embodiments, at least one RJis selected from halogen (e.g., F). In some embodiments, at least one R is selected from -OCH2CH2OR, and C1-6 alkyl optionally substituted with one or more halogen or-O(Ci-4 alkyl). In some embodiments, at least one is R3selected from -OCH3, -OCH2CH3, -OCH(CH3)2,-OCHF2, -OCH2CHF2. -OCH(CH2F)2, -OCH2CH2OH. -OCH2CH2OCH3. -OCH2CH(CH3)OH, - OCH2C(CH3)2OH, -OCH(CH3)CH2OH, and -O(cyclopropyl).

[0084] In some embodiments of any formulae described herein, R3is oxo (e.g., when Ring A is not phenyl). In some embodiments, R3is halogen (e.g., fluoro or chloro). In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is -CN. In some embodiments, R3is -OR. In some embodiments, R3is -O(Ci-4 alkyl optionally substituted with -OH) or -O(Ci-4 haloalkyl). In some embodiments, R3is -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH(CH3)CH2OH, -OCH2CH(CH3)OH, - OCH2C(CH3)2OH, -OCHF2, -OCH2CHF2, or -OCH(CH2F)2. In some embodiments, R3is -O(Ci-4 alkyl) or -O(Ci-4 haloalkyl). In some embodiments, R3is -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, or - OCH2CHF2. In some embodiments, R3is -O(CH2)vCy. In some embodiments, R3is -OCH2Cy. In some embodiments, R3is -O(CH2)vCy, wherein Cy is a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 0-2 instances of R6(e.g., Cy is a pyridine substituted with fluoro). In some embodiments, R3is -O(CH2)vCy, wherein Cy is a 3- to 6- membered carbocyclic ring substituted with 0-2 instances of R6(e.g., Cy is a cyclopropane or cyclobutane substituted with one or more halogens). In some embodiments, R3is -O(CH2)vCy, wherein Cy is a 3 - to 6- membered carbocyclic ring (e.g., Cy is a cyclopropane). In some embodiments, R3is -O(CH2)vCy, wherein Cy is a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., Cy is a pyrrolidone or piperidinone optionally substituted with C1-6 alkyl). In some embodiments, R3is -O-(Ci-4 alkylene)-OR. In some embodiments, R3is -O-(Ci-4 alkylene)-OR. In some embodiments, R3is -OCH2CH2OH, -OCH(CH3)CH2OH, -OCH2CH(CH3)OH, -OCH2C(CH3)2OH, - OCH2CH2O(CI-4 alkyl), or -OCH2CH2O(CI-4 haloalkyl). In some embodiments, R3is -OCH2CH2OR. In some embodiments, R3is -OCH2CH2OH or -OCH2CH2O(CI-4 alkyl). In some embodiments, R3is - CH2CH2OR. In some embodiments, R3is -CH2CH2O(CI-4 alkyl). In some embodiments, RJis optionally substituted C1-6 aliphatic. In some embodiments, R3is optionally substituted C1-6 alkyl. In some embodiments, R3is C1-6 aliphatic optionally substituted with one or more halogen (e.g., fluoro) or -OR0(e.g., -O(Ci-4alkyl)). In some embodiments, R3is C1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro) or -OR0(e.g., -O(Ci-4 alkyl)). In some embodiments, R3is C1-6 haloaliphatic. In some embodiments, R3is C1-6 haloalkyl.

[0085] In some embodiments of any formulae described herein, each R3is independently selected from oxo, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCH2CHF2, -OCH(CH2F)2, - OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCD3, -OCH(CH3)CH2OH, -OCH2CH(CH3)OH, -

[0086] In some embodiments of any formulae described herein, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0087] In some embodiments of any formulae described herein, Ring B is selected from a 6-membered heteroaryl ring having 1-3 nitrogen atoms and a 9- to 10-membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, Ring B is selected from a 6-membered heteroaryl ring having 1-2 nitrogen atoms and a 9- to 10-membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, Ring B is selected from a 6-membered heteroaryl ring having 1-2 nitrogen atoms and a 9- membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom.

[0088] In some embodiments of any formulae described herein, Ring B is phenyl.

[0089] In some embodiments of any formulae described herein, Ring B is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Ring B is a pyridine. In some embodiments, Ring B is a pyrazine. In some embodiments, Ring B is a pyrimidine. In some embodiments, Ring B is a pyridazine.

[0090] In some embodiments of any formulae described herein, Ring B is a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring comprising at least one nitrogen atom. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises one 5- or 6-membered heteroaryl ring comprising at least one nitrogen atom. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises at least one 6-membered heteroaryl ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises at least one 6-membered heteroaryl ring comprising at leastone nitrogen atom. In some embodiments. Ring B is a 9- to 10-membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bicyclic ring comprises at least one 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, Ring B is a 9-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring. In some embodiments, Ring B is a 9-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring comprising at least one nitrogen atom. In some embodiments, Ring B is a 9-membered bicyclic heteroaryl ring that comprises at least one 5- or 6-membered heteroaryl ring comprising at least one nitrogen atom. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a pyridine ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a pyrazine ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a pyrazole ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a thiazole ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a thiophene ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a furan ring. In some embodiments, Ring B is a 9- to 10-membered bicyclic ring that comprises a cyclopentane or cyclopentene ring. In some embodiments, Ring B is a thieno[3,2-c]pyridine, thieno[2,3-c]pyridine, thiazolo[4,5- c]pyridine, pyrazolo[l,5-a]pyrazine, furo[3,2-c]pyridine, or 6,7-dihydro-5H-cyclopenta[c]pyridine. In some embodiments, Ring B is a 10-membered bicyclic ring that comprises at least one 6-membered heteroaryl ring. In some embodiments, Ring B is a 10-membered bicyclic ring that comprises at least one 6-membered heteroaryl ring comprising at least one nitrogen atom.

[0091] In some embodiments of any formulae described herein, Ring B, substituted with n instances

[0092] In some embodiments of any formulae described herein, Ring B, substituted with n instancesembodiments, Ring B, substituted with n instances

[0093] In some embodiments of any formulae described herein, each R4is independently selected from halogen, C1-6 aliphatic, and C1-6 haloaliphatic. In some embodiments, each R4is independently selected from halogen and C1-6 aliphatic. In some embodiments, each R4is independently selected from halogen and optionally substituted C1-6 alkyl. In some embodiments, R4is halogen (e.g., fluoro or chloro). In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is optionally substituted C1-6 aliphatic. In some embodiments, R4is C1-6 aliphatic. In some embodiments, R4is C1-6 haloaliphatic. In some embodiments, R4is optionally substituted Ci-6 alkyl. In some embodiments, R4is Ci-6 haloalkyl. In some embodiments, R4is -CF3. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is methyl.

[0094] In some embodiments of any formulae described herein, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0095] In some embodiments of any formulae described herein, 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 saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 10-membered saturated or partially unsaturated 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. In some embodiments, Ring C is selected from phenyl; a5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 - to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9- to 10-membered saturated or partially unsaturated 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. In some embodiments, Ring C is 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. In some embodiments, Ring C is phenyl; a 5 - to6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 - to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is phenyl; a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 Ring C is fused to Ring E. In some embodiments, Ring C is phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C is fused to Ring E.

[0096] In some embodiments of any formulae described herein, Ring C is not fused to Ring E. In some embodiments, Ring C is fused to Ring E. In some embodiments, when Ring C is fused to Ring E, only one of Ring C and Ring E is aromatic.

[0097] It will be appreciated that, throughout the present disclosure, when a ring is described as being fused to another ring, one of skill in the art will understand that such fusion may or may not result in additional unsaturation in one or both of the rings that is not accounted for in the name of each ring alone.For example, a cyclopentane ring fused to a phenyl ring has the following structure:, and aphenyl ring fused to a pyrrole ring has the following structure: H

[0098] In some embodiments of any formulae described herein, Ring C is phenyl. In some embodiments, Ring C is phenyl that is not fused to Ring E. In some embodiments, Ring C is phenyl fused to Ring E.

[0099] In some embodiments of any formulae described herein, Ring C is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C is not fused to Ring E. In some embodiments, Ring C is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C is fused to Ring E. In some embodiments, Ring C is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a pyrazole, imidazole, or tnazole. In some embodiments, Ring C is a pyrazole, imidazole, triazole, oxazole, thiazole, or oxadiazole. In some embodiments, Ring C is 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, Ring C is a pyridine, pyridone, pyrimidine, or pyridazinone. In some embodiments, Ring C is a pyridine, pyridone, pyrazine, pyrimidine, pyridazine, or pyridazinone.

[0100] In some embodiments of any formulae described herein, Ring C is a 5- to 8-membered bicyclic carbocyclic ring. In some embodiments, Ring C is a 5- to 8-membered bridged bicyclic carbocyclic ring. In some embodiments, Ring C is a bridged cyclobutane (e.g., bicyclo[l. l.l]pentane).

[0101] In some embodiments of any formulae described herein, Ring C is a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 4- to 8-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C is not fused to Ring E. In some embodiments, Ring C is a 4- to 8- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C is fused to Ring E. In some embodiments, Ring C is a 4- to 8-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is an azetidine. In some embodiments, Ring C is a 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a pyrrolidine. In some embodiments, Ring C is a 6-membered heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a piperidine, tetrahydropyridine, piperazine, piperazmone, or thiomorpholine- 1,1 -dioxide. In some embodiments, Ring C is a 7- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a bridged ring system. In some embodiments, Ring C is a 7- to 8-membered bridged heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a bridged piperazine (e.g., 3,8- diazabicyclo[3.2.1]octane). In some embodiments, Ring C is a bridged piperidine (e.g., 3- azabicyclo [3.1.1 ]heptane) .

[0102] In some embodiments of any formulae described herein, Ring C is a 7- to 10-membered spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 7- to 10-membered saturated or partially unsaturated spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfor, wherein Ring C is not fused to Ring E. In some embodiments, Ring C is a 7- to 10-membered saturated or partially unsaturated spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C is fused to Ring E. In some embodiments, Ring C is a 7- to 10-membered saturated or partially unsaturated spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfor. In some embodiments, Ring C is a 9- to 10-membered saturated or partially unsaturated spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfor. In some embodiments, Ring C is a 7-membered spirofosed heterocyclic ring having two 4-membered rings. In some embodiments, Ring C is a 2-azaspiro[3.3]heptane or 2,6-diazaspiro[3.3]heptane. In some embodiments, Ring C is an 8-membered spirofosed heterocyclic ring having a 4-membered ring and a 5- membered ring. In some embodiments, Ring C is a2,6-diazaspiro[3.4]octane. In some embodiments, Ring C is a 9-membered spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfor. In some embodiments, Ring C is a 9-membered spirofosed heterocyclic ring having a 4-membered ring and a 6-membered ring. In some embodiments, Ring C is 2-azaspiro[3 ,5]nonane, 2-azaspiro[3.5]non-6-ene, 2,7-diazaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane, or 2-thia-7- azaspiro[3.5]nonane-2,2-dioxide. In some embodiments, Ring C is a 10-membered spirofosed heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfor. In some embodiments, Ring C is a 2,8-diazaspiro[4.5]decan-3-one or 2,8-diazaspiro[4.5]decane.

[0103] In some embodiments of any formulae described herein, Ring C is not fused to Ring E, andRing C, substituted with p instances of R5, is selected from

[0104] In some embodiments of any formulae described herein, Ring E is selected from a 5- to 6- membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 7- to 10-membered saturated or partially unsaturated 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. In some embodiments, Ring E is selected from a 5- to 6-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated 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.

[0105] In some embodiments of any formulae described herein, Ring E is a 5- to 6-membered carbocyclic ring substituted by s instances of R5. In some embodiments, Ring E is a 5- to 6-membered saturated or partially unsaturated carbocyclic ring substituted by s instances of R5. In some embodiments, Ring E is a 5-membered carbocyclic ring substituted by s instances of R5. In some embodiments, Ring E is a cyclopentane substituted by s instances of R5. In some embodiments, Ring E is a 6-membered carbocyclic ring substituted by s instances of R5. In some embodiments, Ring E is a cyclohexane substituted by s instances of R5.

[0106] In some embodiments of any formulae described herein, Ring E is a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a 5 -membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a pyrrolidine, pyrrolidinone, I -iminotetrahydro- 1 H- 1 / / '-thiophene- 1 -oxide, or tetrahydrothiophene- 1,1 -dioxide, each substituted by s instances of R5. In some embodiments, Ring E is a pyrrolidine, pyrrolidinone, imidazolidin-2-one, 1 -iminotetrahydro- 1H- ll6-thiophene- 1 -oxide, or tetrahydrothiophene- 1 , 1 -dioxide, each substituted by s instances of R5. In some embodiments, Ring E is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a piperidine, piperidinone, hexahydropyrimidine, piperazine, or piperazinone, each substituted by s instances of R5. In some embodiments, Ring E is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is an azepane substituted by s instances of R5. In some embodiments, Ring E is an azepane or l,4-diazepan-2-one, each substituted by s instances of R5.

[0107] In some embodiments of any formulae described herein, Ring E is a 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a 8-membered spirofused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a 5- azaspiro[2.5]octane or a 5-azaspiro[2.5]octan-4-one, each substituted by s instances of R

[0108] In some embodiments of any formulae described herein, Ring E is 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. In some embodiments, Ring E is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. In some embodiments, Ring E is a pyrazole or triazole, each substituted by s instances of R5. In some embodiments, Ring E is a pyrazole, imidazole, oxazole, or triazole, each substituted by s instances of R5. In some embodiments, Ring E is a 6-membered heteroaryl ring having 1- 3 nitrogen atoms substituted by s instances of R5. In some embodiments, Ring E is a pyridazinone substituted by s instances of R5. In some embodiments, Ring E is a pyridone, pyrazine, pyrimidine, pyridazine, pyrazinone, pyrimidinone, or pyridazinone substituted by s instances of R5.

[0109] In some embodiments of any formulae described herein, Ring C is fused to Ring E, and

[0110] In some embodiments of any formulae described herein, Ring C is fused to Ring E, and Ring

[0112] In some embodiments of any formulae described herein, each R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(0)R, -(CH2)XC(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)(R)2, -(CH2)xCy, -O(CH2)xCy, and Ci-6 aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, -CN, -N(R)C(0)R, -N(R)2, or -OR. In some embodiments, each R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(O)R, - (CH2)XC(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, -(CH2)xCy, and Ci6aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, or -OR. In some embodiments, each R5is independently selected from -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, -(CH2)xCy, and optionally substituted Ci-6 aliphatic (e.g., Ci-6 aliphatic substituted with one or more substituents selected from halogen, -OR, -C(O)NR2, and -N(R)2). In some embodiments, each R5is independently selected from oxo, =NH, -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)2J-(CH2)xCy, and optionally substituted Ci-6 alkyl (e.g., Ci-6 alkyl substituted with one or more substituents selected from halogen -OR, -C(O)NR2, and -N(R)2). In some embodiments, each R5is independently selected from oxo, -CN, halogen, -N(R)2, -C(O)R, -C(O)N(R)2, -SO2R, -SO2N(R)2, - (CH2)xCy, and optionally substituted Ci-6 aliphatic (e.g., Ci-6 aliphatic substituted with one or more substituents selected from halogen, -OR, -C(O)NR2, and -N(R)2). In some embodiments, each R5is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -C(O)R, -(CH2)XC(O)N(R)2, - C(O)N(R)(CH2)xCy, -(CH2)xC(O)Cy, -SO2R, -N=S(O)(R)2, -SO2N(R)2, -P(O)(R)2, -(CH2)xCy, - O(CH2)xCy, and Ci-e aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, -CN, -N(R)C(O)R, -N(R)2, or -OR. In some embodiments, each R5is independently selected from oxo, -CN, halogen, -NH2, -N(CI-4 alkyl)2, -C(0)(Ci-4 alkyl), -C(O)NH2, -SO2(Ci-4 alkyl), -SO2NH2, -SO2N(H)(CI-4 alkyl), -CH2(3- to 6-membered carbocyclic ring optionally substituted with one or more halogen), 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ci-6 alkyl optionally substituted with one or more halogen, -OR0, and -C(O)NR°2. In some such embodiments R° is hydrogen. Accordingly, in some embodiments, each R5is independently selected from oxo, -CN, halogen, -NH2, -N(CI-4 alkyl)2, -C(O)(Ci-4 alkyl), -C(O)NH2, -SO2(Ci-4 alkyl), - SO2NH2, -SO2N(H)(CI-4 alkyl), -CH2(3- to 6-membered carbocyclic ring optionally substituted with one or more halogen), 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ci-6 alkyl optionally substituted with one or more halogen, -OH, and - CO2NH2.

[0113] In some embodiments of any formulae described herein, R5is oxo. In some embodiments, R5is =NH. In some embodiments, R5is -CN. In some embodiments, R5is halogen (e.g., fluoro or chloro). In some embodiments, R5is fluoro. In some embodiments, R5is chloro. In some embodiments, R5is -OR. In some embodiments, R5is -O(Ci-4 alkyl optionally substituted with one or more -N(CM alkyl)2). In some embodiments, R5is -N(R)2. In some embodiments, R5is -NH2. In some embodiments, R5is -N(CM alkyl)2. In some embodiments, R5is -SR. In some embodiments, R5is -C(O)R. In some embodiments, R5is -C(O)(Ci-4 alkyl). In some embodiments, R5is -N(R)C(O)R. In some embodiments, R5is - (CH2)XC(O)N(R)2. In some embodiments, R5is -(CH2)XC(O)NH2, -(CH2)XC(O)NH(CI-4alkyl), - (CH2)XC(O)NH(CI-4haloalkyl), -(CH2)XC(O)N(CI-4alkyl)2, or -(CH2)XC(O)N(CI-4haloalkyl)2. In some embodiments, R5is -C(O)N(R)2. In some embodiments, R5is -C(O)NH2, -C(O)NH(CI-4 alkyl), - C(O)NH(CI-4 haloalkyl), -C(O)N(CI-4 alkyl)2, or -C(0)N(CM haloalkyl)2. In some embodiments, R5is - C(O)N(R)(CH2)xCy (e.g., -C(O)NH(CH2)xCy). In some embodiments, R5is -(CH2)xC(O)Cy. In some embodiments, R5is -OC(O)R. In some embodiments, R5is -C(O)OR. In some embodiments, R5is - SO2R. In some embodiments, R5is -SO2(Ci-4 alkyl). In some embodiments, R5is -N(R)SO2R. In some embodiments, R5is -N=S(O)(R)2. In some embodiments, R5is -SO2N(R)2. In some embodiments, R5is - SO2NH2or -SO2NH(CI-4 alkyl). In some embodiments, R5is -P(O)R2. In some embodiments, R5is - (CH2)xCy. In some embodiments, R5is -(CH2)xCy, wherein Cy is 3- to 6-membered carbocyclic ring optionally substituted with one or more halogen. In some embodiments, R5is -(CH2)xCy, wherein Cy is 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is -(CH2)xCy, and x is 0. In some embodiments, R5is -(CH2)xCy, wherein x is 0 and Cy is 3- to 6-membered carbocyclic ring optionally substituted with one or more halogen. In some embodiments, R5is -(CH2)xCy, wherein x is 0 and Cy is 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 instances of R6. In some embodiments, R5is -O(CH2)xCy. In some embodiments, R5is optionally substituted Ci-6 aliphatic (e.g., Ci-6 aliphatic substituted with one or more substituents selected from halogen, -OR, -CN, -N(R)C(O)R, -C(O)NR3, and -N(R)2). In some embodiments, R5is Ci-6 aliphatic optionally substituted with one or more halogen, -OR0(e.g., -OH), and -C(O)NR°2 (e.g., -CO2NH2). In some embodiments, R5is optionally substituted C1-6 alkyl (e.g., C1-6 alkyl substituted with one or more substituents selected from halogen, -OR, -CN, -N(R)C(O)R, -C(0)NR2, and -N(R)2). In some embodiments, R5is C1-6 alkyl optionally substituted with one or more halogen, -OH, and -CO2NH2.

[0114] In some embodiments of any formulae described herein, each R5is independently selected from oxo, -CN, fluoro, chloro, -NH2, -N(CH3)2, -OCH3, -C(O)CH3, -C(O)N(CH3)2, -C(O)N(H)CH3, - CH2C(O)N(H)CH3, -CH2C(O)N(CH3)2, -C(O)N(H)CH2CH2N(CH3)2, -CO2NH2, -SO2CH3, -SO2NH2, - SO2N(H)CH3, -N=S(O)(CH3)2, -P(O)(CH3)2, -CH3, -CH2F, -CHF2, -CH2CHF2, -CH2OH, -CH2CH2OH, - CH2CH2OCH3, -CH2C(CH3)2OH, -C(CH3)2CH2OH, -C(CH3)2OH, -C(CH3)2NH2, -C(CH3)2CN, - CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2C(CH3)2NH2, -CH2N(H)C(O)CH3, -OCH2CH2N(CH3)2, - CH2CH2N(CH3)2, -C(O)N(CH3)2, -CH2C(O)NH2, -CH2C(O)N(H)(CH3), -CH2C(O)N(CH3)2, -CH(CH3)2, - CH(CF3)N(H)CH3, -CH(CF3)N(CH3)2, -C(O)N(H)CH3, -C(O)N(H)CH2CHF2, -OCH2CH2N(CH3)2, -some embodiments, each R5is independently selected from oxo, -CN, fluoro, chloro,-NH2, -N(CH3)2, -OCH3, -C(O)CH3, -C(O)N(CH3)2, -C(O)N(H)CH3, -CH2C(O)N(H)CH3, - CH2C(O)N(CH3)2, -C(O)N(H)CH2CH2N(CH3)2, -CO2NH2, -SO2CH3, -SO2NH2, -SO2N(H)CH3, - N=S(O)(CH3)2, -P(O)(CH3)2, -CH3, -CH2F, -CHF2, -CH2CHF2, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, - CH2C(CH3)2OH, -C(CH3)2CH2OH, -C(CH3)2OH, -C(CH3)2NH2, -C(CH3)2CN, -CH2N(CH3)2, - CH2CH2N(CH3)2, -CH2C(CH3)2NH2, -OCH2CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2C(O)NH2, -CH(CH3)2, - CH(CF3)N(H)CH3, and -CH(CF3)N(CH3)2.

[0115] In some embodiments of any formulae described herein, each R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(0)R, -(CH2)XC(O)N(R)2, - (CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, -P(O)(R)2, -(CH2)xCy, -O(CH2)xCy, and Ci-6 aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, -CN, -N(R)C(O)R, -N(R)2, or -OR. In some embodiments, each R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(0)R, -(CH2)XC(O)N(R)2, -OC(O)R, - C(O)OR, -SO2R, -N(R)S02R, -SO2N(R)2, -(CH2)xCy, and Ci-6 aliphatic, wherein Ci-e aliphatic is unsubstituted or substituted with one or more halogen and -OR. In some embodiments, each R5is independently selected from -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(0)R, -C(O)N(R)2, - OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, -(CH2)xCy, and optionally substituted Ci-6 aliphatic (e.g., Ci-6 aliphatic substituted with one or more substituents selected from halogen, -OR, -C(0)NR2, and - N(R)2). In some embodiments, each R5is independently selected from oxo, =NH, -CN, halogen, -OR, - N(R)2, -SR, -C(O)R, -N(R)C(0)R, -C(0)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, - (CH2)xCy, and optionally substituted Ci-6 alkyl (e.g., Ci-6 alkyl substituted with one or more substituents selected from halogen -OR, -C(0)NR2, and -N(R)2). In some embodiments, each R5is independently selected from oxo, =NH, -OR, -N(R)2, and optionally substituted Ci-6 aliphatic (e.g., Ci-6 aliphatic substituted with one or more substituents selected from halogen, -OR, -C(0)NR2, and -N(R)2). In some embodiments, each R5is independently selected from oxo, =NH, halogen, -OR, -N(R)2, and Ci-6 aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, -N(R)2, or -OR. In some embodiments, each R5is independently selected from oxo, =NH, -OH, -NH2, -N(CI-4 alkyl)2, and Ci-6 alkyl optionally substituted with one or more -OR0(e.g., -OH).

[0116] In some embodiments of any formulae described herein, R5is oxo. In some embodiments, R5is =NH. In some embodiments, R5is -CN. In some embodiments, R5is halogen (e.g., fluoro or chloro). In some embodiments, R5is fluoro. In some embodiments, R5is -OR (e.g., -OH or -OCH3). In some embodiments, R5is -N(R)2. In some embodiments, R5is -NH2. In some embodiments, R5is -N(CI-4 alkyl)2. In some embodiments, R5is -SR. In some embodiments, R5is -C(O)R. In some embodiments, R5is -N(R)C(0)R. In some embodiments, R5is -(CH2)XC(O)N(R)2. In some embodiments, R5is - C(0)N(R)2. In some embodiments, R5is -C(O)N(R)(CH2)xCy. In some embodiments, R5is -(CH2)xC(0)Cy. In some embodiments, R5is -OC(O)R. In some embodiments, R5is -C(O)OR. In some embodiments, R5is -SO2R. In some embodiments, R5is -N(R)SC>2R. In some embodiments, R5is - N=S(O)(R)2. In some embodiments, R5is -SChbhKh. In some embodiments, R5is -P(O)R2. In some embodiments, R5is -(CH2)xCy. In some embodiments, R5is -(CIDxCy, wherein Cy is 3- to 6-membered carbocyclic ring optionally substituted with one or more halogen. In some embodiments, R5is -(CFfhCy. wherein Cy is 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is -(CIDxCy, and x is 0. In some embodiments, R5is -(CH2)xCy, wherein x is 0 and Cy is 3- to 6-membered carbocyclic ring optionally substituted with one or more halogen. In some embodiments, R5is -(CH3)xCy, wherein x is 0 and Cy is 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is -O(CH2)xCy. In some embodiments, R5is optionally substituted C1-6 aliphatic. In some embodiments, R5is C1-6 aliphatic optionally substituted with one or more -OR° (e.g., -OH). In some embodiments, R5is C1-6 aliphatic optionally substituted with one or halogens (e g., F), -OH, or - O(Ci-4 alkyl). In some embodiments, R5is optionally substituted C1-6 alkyl. In some embodiments, R5is C 1-6 alkyl optionally substituted with one or more -OH, such as -CH2CH2OH. In some embodiments, R5is C1-6 alkyl optionally substituted with one or more halogens (e.g., F) , -OH, or -O(Ci-4 alkyl). In some embodiments, R5is unsubstituted C1-6 aliphatic. In some embodiments, R5is unsubstituted C1-6 alkyl. In some embodiments, R5is methyl, ethyl, or isopropyl.

[0117] In some embodiments of any formulae described herein, each R5is independently selected from oxo, =NH, -OH, -OCH3, -NH2, -N(CH3)2, fluoro, cyclopropyl, -CH3, -CD3, -CH2CHF2, -CH2CF3, - CH2CH2CH2F, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, and -CH(CH3)2. In some embodiments, each R5is independently selected from oxo, =NH, -OH, -NH2, -N(CH3)3, -CH3, -CH2CH2OH, and - CH(CH3)2.

[0118] In some embodiments of any formulae described herein, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0119] In some embodiments of any formulae described herein, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.

[0120] In some embodiments of any formulae described herein, 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. In some embodiments, 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 Ring D is fused to Ring F.

[0121] In some embodiments of any formulae described herein, Ring D is not fused to Ring F. In some embodiments, Ring D is fused to Ring F. In some embodiments, when Ring D is fused to Ring F, q is 0.

[0122] In some embodiments of any formulae described herein, Ring D is phenyl.

[0123] In some embodiments of any formulae described herein, Ring D is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is apyrazole, imidazole, triazole, oxazole, or thiazole. In some embodiments, Ring D is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, Ring D is a pyridine, pyridone, pyridazinone, or pyrazinone.

[0124] In some embodiments of any formulae described herein, Ring D is not fused to Ring F, andNRing D, substituted with r instances of R2and q instances of R1, is selected from

[0125] In some embodiments of any formulae described herein. Ring F is selected from phenyl, a 5- to 6-membered saturated or partially unsaturated carbocyclic ring, a 5 - to 7-membered saturated or partially unsaturated 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. In some embodiments, Ring F is selected from phenyl, a 5- to 6-membered saturated or partially unsaturated carbocyclic ring, a 5- to 6-membered saturated or partially unsaturated 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.

[0126] In some embodiments of any formulae described herein, Ring F is phenyl substituted by u instances of-L-W and y instances of R2. In some embodiments, Ring F is phenyl substituted by u instances of-L-W.

[0127] In some embodiments of any formulae described herein, Ring F is a 5- to 6-membered carbocyclic ring substituted by u instances of-L-W and y instances of R2. In some embodiments, Ring F is a 5- to 6-membered carbocyclic ring substituted by u instances of-L-W. In some embodiments, Ring F is a 5- to 6-membered saturated or partially unsaturated carbocyclic ring substituted by u instances of-L- W. In some embodiments, Ring F is a 5-membered carbocyclic ring substituted by u instances of -L-W. In some embodiments, Ring F is a cyclopentane substituted by u instances of-L-W. In some embodiments, Ring F is a 6-membered carbocyclic ring substituted by u instances of-L-W.

[0128] In some embodiments of any formulae described herein, Ring F is a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of-L-W and y instances of R2. In some embodiments, Ring F is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of-L-W. In some embodiments, Ring F is a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W and y instances of R2. In some embodiments, Ring F is a 5- to 6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W. In some embodiments, Ring F is 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W. In some embodiments, Ring F is a pyrrolidine substituted by u instances of -L-W. In some embodiments, Ring F is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W and y instances of R2. In some embodiments, Ring F is 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of -L-W. In some embodiments, Ring F is a piperidine or piperazine, each substituted by u instances of -L-W and y instances of R2. In some embodiments, Ring F is a piperidine or piperazine, each substituted by u instances of -L-W.

[0129] In some embodiments of any formulae described herein, Ring F is 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. In some embodiments, Ring F is 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. In some embodiments, Ring F is a 5- 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. In some embodiments, Ring F is a pyrrole substituted by u instances of -L-W. In some embodiments, Ring F is a 6-membered heteroaryl ring having 1-3 nitrogen atoms substituted by u instances of -L-W.

[0130] In some embodiments of any formulae described herein, u is 0. In some embodiments, u is 1. In some embodiments, when u is 1, then q is 0.

[0131] In some embodiments of any formulae described herein, Ring D is fused to Ring F, q is 0, and

[0132] In some embodiments of any formulae described herein, Ring D is fused to Ring F, q is 0, and

[0133] In some embodiments of any formulae described herein, Ring D is fused to Ring F, and RingF, substituted with u instances of -L-W and y instances of R2, is selected from

[0135] In some embodiments of any formulae described herein, R1is -L-W or Ring D’. In some embodiments, R1is Ring D’ or a bivalent Ci-6 aliphatic chain substituted with Ring D’. In some embodiments, R1is Ring D’ or -CIL-Ring D’. In some embodiments, R1is -L-W. In some embodiments, R1is Ring D’. In some embodiments, R1is a bivalent Ci-6 aliphatic chain substituted with Ring D’. In some embodiments, R1is -CFL-Ring D’.

[0136] In some embodiments of any formulae described herein, R1is selected from -CH3, -CH(CH3)2,

[0137] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched Ci-6 aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SC>2N(R)-, and -N(R)SC>2-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -0- , -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(0)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and - N(R)SO2-.

[0138] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched CM aliphatic chain, wherein one or two methylene units of the aliphatic chain are independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, - C(O)N(R)-, -N(R)C(0)-, -C(O)O-, -OC(O)-, -SC>2N(R)-, and -N(R)SC>2-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain, wherein one or two methylene units of the aliphatic chain are independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, - CH(X)-, -C(X)2-, -C(0)N(R)-, -N(R)C(0)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. In some embodiments, each L is independently a bivalent straight or branched C aliphatic chain, wherein one or two methylene units of the aliphatic chain are independently replaced by a group selected from -N(R)-, - O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(0)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and - N(R)SO2-.

[0139] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched C aliphatic chain, wherein one or two methylene units of the aliphatic chain are independently replaced by a group selected from -N(R)-, -O-, C(O)-, -C(O)N(R)-, and -N(R)C(O)-. Insome embodiments, each L is independently a bivalent straight or branched CM aliphatic chain, wherein one or tw o methylene units of the aliphatic chain are independently replaced by a group selected from - N(R)-, -O-, C(O)-, -C(O)N(R)-, and -N(R)C(O)-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain, wherein one or two methylene units of the aliphatic chain are independently replaced by a group selected from -N(R)-, -O-, C(O)-, -C(O)N(R)-, and -N(R)C(O)-.

[0140] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched C alkyl chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. In some embodiments, each L is independently a bivalent straight or branched CM alkyl chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -0- , -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-. In some embodiments, each L is independently a bivalent straight or branched C alkyl chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O- , -OC(O)-, -SO2N(R)-, and -N(R)SO2-.

[0141] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched C aliphatic chain having one or more units of unsaturation, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)- , and -N(R)SO2-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain having one or more units of unsaturation, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)- , -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain having one or more units of unsaturation, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, - C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-.

[0142] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched C aliphatic chain having one double bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, - C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2- . In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain having one double bond, wherein one or more methylene units of the aliphatic chain are optionally andindependently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)3-, - C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SC>2-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain having one double bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, - SO2N(R)-, and -N(R)SO2-.

[0143] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched C aliphatic chain having one triple bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, - C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2- . In some embodiments, each L is independently a bivalent straight or branched C1-6 aliphatic chain having one triple bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, - N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain having one triple bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -0- , -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(0)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and - N(R)SO2-.

[0144] In some embodiments of any formulae described herein, each L is independently a bivalent straight or branched Ci-s aliphatic chain having one double or triple bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -0- , C(O)-, -C(0)N(R)-, and -N(R)C(0)-. In some embodiments, each L is independently a bivalent straight or branched CM aliphatic chain having one double or triple bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, C(O)- , -C(0)N(R)-, and -N(R)C(0)-. In some embodiments, each L is independently a bivalent straight or branched C aliphatic chain having one double or triple bond, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, C(O)-, - C(0)N(R)-, and -N(R)C(0)-.

[0145] In some embodiments of any formulae described herein, each L is independently selected from -N(R)C(O)CH2CH2-, -N(R)C(O)CH(CH3)CH2-, -OCH(CH3)CH2-, -C(O)-, -C(O)CC1H-, -C(O)CC1F-, - C(O)CH2CH2-, -C(0)CH(0H)CH(0H)-, -C(O)N(R)CH(CH3)CH2-, -C(O)N(R)CH2CH(CH3)CH2-, -CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(O)-, -CH2C(O)N(R)C(CH3)2CH2-,CH2CH2C(O)N(R)C(CH3)2CH2-, -CH2N(R)-, -CH2N(R)C(0)-, -CH2N(R)C(O)CH2CH2-, -CH2N(R)C(O)CH(CH3)CH2-, -CH2N(R)C(O)C(CH3)2CH2-, -CH2N(R)C(O)CH2C(CH3)2CH2-, -CH2CH2N(R)C(O)CH(CH3)CH2-, and -CH2O-. In some embodiments, each L is independently selected from -N(H)C(O)CH2CH2-, -N(H)C(O)CH(CH3)CH2-, -OCH(CH3)CH2-, -C(O)-, -C(O)CC1H-, - C(O)CC1F- -C(O)CH2CH2-, -C(O)CH(OH)CH(OH)-, -C(O)N(H)CH(CH3)CH2-, C(O)N(H)CH2CH(CH3)CH2-, -CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(O)-, -CH2C(O)N(H)C(CH3)2CH2-, -CH2CH2C(O)N(H)C(CH3)2CH2-, -CH2N(H)-, -CH2N(H)C(O)-, - CH2N(H)C(O)CH2CH2-, -CH2N(H)C(O)CH(CH3)CH2-, -CH2N(H)C(O)C(CH3)2CH2-, CH2N(H)C(O)CH2C(CH3)2CH2-, -CH2CH2N(H)C(O)CH(CH3)CH2-, and -CH2O-.

[0146] In some embodiments of any formulae described herein, each L is independently selected from-N(R)C(O)CH2CH2-, -N(R)C(O)CH(CH3)CH2-, -OCH(CH3)CH2-, -C(O)-, -C(O)CH2CH2-, - C(O)CH(OH)CH(OH)-, -C(O)N(R)CH(CH3)CH2-, -C(O)N(R)CH2CH(CH3)CH2-, -CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(O)-, -CH2C(O)N(R)C(CH3)2CH2-, -CH2CH2C(O)N(R)C(CH3)2CH2-, - CH2N(R)-, -CH2N(R)C(O)-, -CH2N(R)C(O)CH2CH2-, -CH2N(R)C(O)CH(CH3)CH2-,CH2N(R)C(O)C(CH3)2CH2-, -CH2N(R)C(O)CH2C(CH3)2CH2-, -CH2CH2N(R)C(O)CH(CH3)CH2-, and - CH2O-. In some embodiments, each L is independently selected from -N(H)C(O)CH2CH2-, - N(H)C(O)CH(CH3)CH2-, -OCH(CH3)CH2-, -C(O)-, -C(O)CH2CH2-, -C(O)CH(OH)CH(OH)-, - C(O)N(H)CH(CH3)CH2-, -C(O)N(H)CH2CH(CH3)CH2-, -CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, - CH2C(O)-, -CH2C(O)N(H)C(CH3)2CH2-, -CH2CH2C(O)N(H)C(CH3)2CH2-, -CH2N(H)-, -CH2N(H)C(O)-, -CH2N(H)C(O)CH2CH2-, -CH2N(H)C(O)CH(CH3)CH2-, -CH2N(H)C(O)C(CH3)2CH2-, CH2N(H)C(O)CH2C(CH3)2CH2-, -CH2CH2N(H)C(O)CH(CH3)CH2-, and -CH2O-.

[0147] In some embodiments of any formulae described herein, each L is independently selected from-C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH2)-, -C(O)C(=CHCH3)-, -C(O)CH=CH-CH2-, - C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(R)-, -CH2N(R)C(O)CH=CH-, -CH2CH2N(R)C(O)CH=CH- , -C(O)C=C-, -C(O)C=CCH2-, and -SO2CH=CH-. In some embodiments, each L is independently selected from -C(O)CH=CH-, -NHC(O)CH=CH-, -C(O)C(=CH2)-, -C(O)C(=CHCH3)-, -C(O)CH=CH-CH2-, - C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(CH3)-, -CH2NHC(O)CH=CH-, -CH2CH2NHC(O)CH=CH-, -C(O)C=C-, -C(O)C=CCH2-, and -SO2CH=CH-. In some embodiments, each L is independently -C(O)CH=CH-, -C(O)CF=CH-, -NHC(O)CF=CH-, or -NHC(O)CH=CH-. In some embodiments, each L is independently -C(O)CH=CH- or -NHC(O)CH=CH-.

[0148] In some embodiments of any formulae described herein, each L is independently selected from-C(O)CC1H-, -C(O)CC1F-, -C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH2)-, -C(O)C(=CHCH3)-, - C(O)CH=CH-CH2-, -C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(R)-, -CH2N(R)C(O)CH=CH-, - CH2CH2N(R)C(O)CH=CH-, and -SO2CH=CH-. In some embodiments, each L is independently selected from -C(O)CC1F-, -C(O)CH=CH-, -NHC(O)CH=CH-, -C(O)C(=CH2)-, -C(O)C(=CHCH3)-, - C(O)CH=CH-CH2-, -C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(CH3)-, -CH2NHC(O)CH=CH-, -CH2CH2NHC(O)CH=CH-, -C(O)C=C-, -C(O)C=CCH2-, and -SO2CH=CH-. In some embodiments, each L is independently -C(O)CH=CH- or -NHC(O)CH=CH-.

[0149] In some embodiments of any formulae described herein, each W is independently hydrogen, halogen, -CN, or 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each W is independently hydrogen, halogen, 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. In some embodiments, each W is independently hydrogen, halogen, or -CN. In some embodiments, W is hydrogen. In some embodiments, W is halogen (e.g., fluoro or chloro). In some embodiments, W is fluoro. In some embodiments, W is chloro. In some embodiments, W is -CN. In some embodiments, W is 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. In some embodiments, W is an optionally substituted group selected from phenyl, 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, and a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, W is an optionally substituted 3- to 6-membered carbocyclic ring. In some embodiments, W is a cyclopentane. In some embodiments, W is an optionally substituted 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, W is a pyrrolidine.

[0150] In some embodiments of any formulae described herein, each X is independently halogen or - CN. In some embodiment, each X is independently halogen (e.g., chloro or fluoro). In some embodiments, each X is independently chloro. In some embodiments, each X is independently fluoro. In some embodiments, each X is independently -CN. In some embodiments, each X is independently -OR (e.g., - OH).

[0151] In some embodiments of any formulae described herein, each -L-W is independently selected from

[0152] In some embodiments of any formulae described herein, each -L-W is independently selected from -CH3, -CH(CH3)2, -CH2C(CH3)3, -CH2OH, -CH2NH2, -OCH(CH3)2,CN, -C(O)CH=CH2, -C(O)CF=CH2, -NHC(O)CF=CH2, and -NHC(O)CH=CH2.

[0153] In some embodiments of any formulae described herein, each -L-W is independently selected from -C(O)CH=CH2and -NHC(O)CH=CH2. In some embodiments, -L-W is independently selected from -C(O)CH=CH2, -C(O)CF=CH2, -NHC(O)CF=CH2, and -NHC(O)CH=CH2. In some embodiments, each -L-W is -C(O)CH=CH2. In some embodiments, each -L-W is -CN.

[0154] In some embodiments of any formulae described herein, each Ring D’ is independently a 4- to 6-membered saturated or partially unsaturated carbocyclic ring or a 4- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D' is substituted with t instances of -L-W.

[0155] In some embodiments of any formulae described herein, Ring D’ is a 4- to 6-membered carbocyclic ring substituted with t instances of -L-W. In some embodiments, Ring D’ is a 4- to 6-membered saturated or partially unsaturated carbocyclic ring substituted with t instances of -L-W. In some embodiments, Ring D’ is a 4- to 6-membered cycloalkyl ring substituted with t instances of -L-W. In some embodiments, Ring D’ is a 4-membered carbocyclic ring substituted with t instances of -L-W. In some embodiments, Ring D’ is a cyclobutane substituted with t instances of -L-W. In some embodiments, RingD’ is a 5-membered carbocyclic ring substituted with t instances of-L-W. In some embodiments, Ring D’ is a 6-membered carbocyclic ring substituted with t instances of-L-W.

[0156] In some embodiments of any formulae described herein, Ring D’ is 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. In some embodiments, Ring D’ is a 4- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D’ is substituted with t instances of -L-W. In some embodiments, Ring D’ is a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D’ is substituted with t instances of -L-W. In some embodiments, Ring D’ is a 4-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. In some embodiments, Ring D’ is an azetidine substituted with t instances of -L-W. In some embodiments, Ring D’ is a 5-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. In some embodiments, Ring D’ is a pyrrolidine substituted with t instances of-L-W. In some embodiments, Ring D’ is a 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. In some embodiments, Ring D’ is a piperidine substituted with t instances of-L-W.

[0157] In some embodiments of any formulae described herein, Ring D’, substituted with t instances

[0158] In some embodiments of any formulae described herein, when R1is Ring D’ or a bivalent Ci-6 aliphatic chain substituted with Ring D’, then Ring D, substituted with r instances of R2, is selected from

[0159] In some embodiments of any formulae described herein, Ring D is substituted with 1 instance

[0160] In some embodiments of any formulae described herein, q is 0. In some embodiments, q is 1.

[0161] In some embodiments of any formulae described herein, t is 0 or 1. In some embodiments, t is1 or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0162] In some embodiments of any formulae described herein, each R2is independently selected from halogen, -CN, -OR, and Ci-6 alkyl. In some embodiments, each R2is independently selected from oxo, halogen, -CN, -O(Ci-4 alkyl), and Ci-6 alkyl. In some embodiments, R2is oxo. In some embodiments, R2is halogen (e.g., fluoro or chloro). In some embodiments, R2is -CN. In some embodiments, R2is -OR. In some embodiments, R2is -O(Ci-4 alkyl). In some embodiments, R2is Ci-6 alkyl. In some embodiments, each R2is independently selected from oxo, fluoro, chloro, -CN, -OCH3, -OCH(CH3)2, -CH3, -CH(CH3)2, and -CH2C(CH3)3.

[0163] In some embodiments of any formulae described herein, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, when q is 1, r is 0 or 1. In some embodiments, when q is 0, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.

[0164] In some embodiments of any formulae described herein, each R2is independently selected from halogen, -CN, -OR, and Ci-6 alkyl. In some embodiments, R2is oxo. In some embodiments, R2is halogen (e.g., fluoro or chloro). In some embodiments, R2is -CN. In some embodiments, R2is -OR. In some embodiments, R2is Ci-6 alkyl (e.g., methyl).

[0165] In some embodiments of any formulae described herein, y is 0 or 1. In some embodiments, y is 1 or 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0166] In some embodiments of any formulae described herein, 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 saturated or partially unsaturated carbocyclic ring, or a 4- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6. In some embodiments, Cy is substituted with 0-1 instances of R6. In some embodiments, Cy is substituted with 1-2 instances of R6. In some embodiments, Cy is not substituted with R6. In some embodiments, Cy is substituted with 1 instance of R6. In some embodiments, Cy is substituted with 2 instances of R6.

[0167] In some embodiments of any formulae described herein, Cy is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6. In some embodiments, Cy is a 5-membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0- 2 instances of R6. In some embodiments, Cy is a 6-membered heteroaryl ring having 1-3 nitrogen atoms, wherein Cy is substituted with 0-2 instances of R6. In some embodiments, Cy is a pyridine substituted with 0-2 instances of R6.

[0168] In some embodiments of any formulae described herein, Cy is a 3- to 6-membered carbocyclic ring substituted with 0-2 instances of R6. In some embodiments, Cy is a 3- to 6-membered saturated or partially unsaturated carbocyclic ring substituted with 0-2 instances of R6. In some embodiments, Cy is a 3- to 6-membered cycloalkyl ring substituted with 0-2 instances of R6. In some embodiments, Cy is a 3- membered carbocyclic ring (e.g., a cyclopropyl ring) substituted with 0-2 instances of R6. In some embodiments, Cy is a 4-membered carbocyclic ring substituted with 0-2 instances of R6. In some embodiments, Cy is a 5-membered carbocyclic ring substituted with 0-2 instances of R6. In some embodiments, Cy is a 6-membered carbocyclic ring substituted with 0-2 instances of R6.

[0169] In some embodiments of any formulae described herein, Cy is a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an azetidine. In some embodiments, Cy is a 5 -membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a pyrrolidone. In some embodiments, Cy is a 6-membered heterocyclic ring having 1- 2 nitrogen atoms. In some embodiments, Cy is a piperidinone or a piperazine.

[0170] In some embodiments of any formulae described herein, Cy, substituted with 0-2 instances ofR6, is selected from

[0171] In some embodiments of any formulae described herein, each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(0)R, -N(R)C(0)R, -C(0)N(R)2, -OC(O)R, -C(O)OR, -SO2R, - N(R)S02R, -SO2N(R)2, and a group selected from Ci-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(0)R, -N(R)C(0)R, -C(0)N(R)2, - 0C(0)R, -C(0)0R, -SO2R, -N(R)S02R, -SO2N(R)2, and an optionally substituted group selected from Ci- 6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6- membered saturated or partially unsaturated 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. In some embodiments, each R6is independently selected from -CN, halogen, -OR, -N(R)2, -SR, - C(0)R, -N(R)C(0)R, -C(0)N(R)2, -0C(0)R, -C(O)OR, -SO2R, -N(R)S02R, -SO2N(R)2, and an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered carbocyclic ring, phenyl, a 3- to 6- membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10-membered aryl ring, and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R6is independently selected from oxo, halogen, -OR, -N(R)2, -C(0)N(R)2, and optionally substituted Ci-6 aliphatic. In some embodiments, each R6is independently selected from oxo, halogen, and optionally substituted Ci-6 aliphatic. In some embodiments, each R6is independently selected from oxo, halogen, andoptionally substituted Ci-6 alkyl. In some embodiments, each R6is independently selected from halogen and optionally substituted Ci-6 aliphatic. In some embodiments, each R6is independently selected from halogen and optionally substituted Ci-6 alkyl. In some embodiments, R6is oxo. In some embodiments, R6is halogen (e.g., fluoro or chloro). In some embodiments, R6is fluoro. In some embodiments, R6is -OR (e.g., -OH). In some embodiments, R6is -N(R)i (e.g., -N(CI-4 alkyl)? or -NH2). In some embodiments, R6is -C(O)N(R)2. In some embodiments, R6is optionally substituted C1-6 aliphatic. In some embodiments, R6is optionally substituted C1-6 alkyl. In some embodiments, R6is C1-6 alkyl (e.g., methyl).

[0172] In some embodiments of any formulae described herein, each v is independently 0 or 1. In some embodiments, each v is independently 1 or 2. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2.

[0173] In some embodiments of any formulae described herein, each x is independently 0 or 1. In some embodiments, each x is independently 1 or 2. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0174] In some embodiments of any formulae described herein, each R is independently hydrogen, C 1- 6 aliphatic, C1-6 haloaliphatic, 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. In some embodiments, each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 6-membered saturated or partially unsaturated 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. In some embodiments, each R is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted 4- to 6-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen, C1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro), or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with C1-6 alkyl. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each R is independently hydrogen or C1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is C1-6 haloaliphatic.In some embodiments, R is optionally substituted Ci-6 alkyl. In some embodiments, R is Ci-6 alkyl optionally substituted with one or more halogen (e.g., fluoro).

[0175] Also provided herein are embodiments wherein any embodiment described herein may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive. As used herein, two embodiments are “mutually exclusive” when one is defined to be something which is different than the other. For example, an embodiment wherein two groups combined to form a ring is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment wherein one group is CH2is mutually exclusive with an embodiment wherein the same group is NH.

[0176] In some embodiments of any of the preceding aspects, the compound is a compound included in Table 1 or 2 or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 1, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 1, or a salt (e.g., pharmaceutically acceptable salt) thereof. In some embodiments, the compound is a compound included in Table 2, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrag, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 2, or a salt (e.g., pharmaceutically acceptable salt) thereof.

[0177] Also provided herein is a compound selected from Table 1 or 2 or any of the Examples provided herein, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrag, zwitterionic form, or stereoisomer thereof. In some embodiments, the present disclosure provides a compound selected from Table 1 or 2 or any of the Examples provided herein, or a salt (e.g., pharmaceutically acceptable salt) thereof.

[0178] A compound of the present disclosure, such as a compound of a formula included in Table 1 or 2, may be synthesized according to one of the general routes outlined in Synthetic Examples 1-88 or by various other methods generally known in the art.

[0179] Table 1 includes selected compounds of the present disclosure.Table 1. Selected compounds of the present disclosure.25677249018

[0180] In some embodiments, the present disclosure provides compounds selected from those included in Table 2, or pharmaceutically acceptable salts thereof.Table 2. Selected compounds of the present disclosure.L‘ 1 6 2 ( 3 2 =L’ 1 1 6 2 ( 6aL18 ( J 1 1 2 6L11 1 2 6 4 - 2LX1 3L’ 7 ( 1 5 2 3 3L17 ( = ( - 1 1 3L‘ 2 5 1 4 (L' 2 1 1 ( 4 4 2L‘ 1 1 1 1 5 (L J = 6 ( ( 3 1L17 J 2 4 4 2 0L‘ 1 = 2 1 ( 4 3 3L’ 7 - 6 1 ( (L’ 2 1 6 1 1 1 ( 1

[0181] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherw ise indicated. 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, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-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.

[0182] 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.

[0183] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of formula I is intended to also include formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-a-z, I-b-z, I-c-z, I-d-z, I-e-z, I-f-z, I-g-z, I-h-z, I-i-z, I-j-7, 1-k-z, I-a-zz, I-b-zz, I-c-zz, I-d-zz, I-e-zz, I- f-zz. I-e-zz I-h-zz, I-i-zz, I-i-zz, I-k-zz, I-a-zz I-b-zz I-c-zz I-d-zz I-e-zz I-f-zz I-e-zz I-h-zz I-i-zz I-i-zz I- k-zz ’, I-a-zzz, I-b-zzz, I-c-zzz, I-d-zzz, I-e-zzz, I-f-zzz, I-g-zzz, I-h-zzz, I-i-zzz, I-j-zzz, I-k-zzz, I-a-zv, I-b-zv, I-c-zv, I-d- zv, I-e-zv, I-f-zv, I-g-zv, I-h-zv, I-i-zv, I-j-zv, I-k-zv, I-a-v, I-b-v, I-c-v, I-d-v, I-e-v, I-f-v, I-g-v, I-h-v, I-i-v, I-j- v, I-k-v, I-a-v', I-b-v ’, I-c- ', I-d-v ’, I-e-v ’, I-f-v ’, I-g-v ’, I-h-v ’, I-i-v ’, I-j-v ’, I-k-v ’, 1-1, 1-m, I-n, I-p, I-q, I-r, IA, IA1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, and IF1, and compound species of such formulae disclosed herein.

[0184] In some embodiments, provided compounds are prepared as described herein, such as according to any one of Synthetic Examples 1-88.Compositions

[0185] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-a-z, I-b- / , I-c- / , I-d- / , I-e- / , I-f- / , I-g- / , I-h- / , I-i- / , I-j- / , I-k- / , I-a- / / , I-b- / / , I-c- / / , I-d- / / , I-e- / / , I-f- / / , I-g-zz, I- h-zz, I-i- / / , I-j - / / , I-k- / / , I-a- / / ’, I-b- / / ’, I-c- / / ’, I-d- / / ’, I-e- / / ’, I-f- / / ’, I-g-zz ’, I-h- / / ’, I-i- / / ', I-j- / / ’, I-k- / / ’, I-a- / / / , I-b-zzz, I-c-zzz, I-d-zz / , I-e- / / / , I-f-zzz, I-g-zzz, I-h-zzz, I-i-zzz, I-j-zzz, I-k- / / / , I-a-zv, I-b-zv, I-c-zv, I-d-zv, I-e-zv, I-f- zv, I-g-zv, I-h-zv, I-i-zv, I-j-zv, I-k-zv, I-a-v, I-b-v, I-c-v, I-d-v, I-e-v, I-f-v, I-g-v, I-h-v, I-i-v, I-j-v, I-k-v, I-a- v ’, I-b-v ’, I-c-v ’, I-d-v ’, I-e-v I-f-v ’, I-g-v ’, I-h-v ’, I-i-v ’, I-j-v ’, I-k-v 1-1, 1-m, I-n, I-p, I-q, I-r, IA, IA1, IB, IB 1, IC, IC1, ID, ID1, IE, IE1, IF, or IF1, or compounds selected from Table 1 or Table 2).

[0186] 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, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-a-z, I-b-z, I-c-z, I-d-z, I-e-z, I-f-z, I-g-z, I-h- / , I-i-z, I-j -7, 1-k-z, I-a-zz, I-b-zz, I-c-zz, I-d-zz, I-e- / / , I-f- / / , I-g-zz, I-h- / / , I-i- / / , I-j - / / , I-k- / / , I-a-zz ’, I-b-zz ’, I-c-zz ’, I-d-zz ’, I-e- / / ’, I-f- / / ’, I-g-zz ’, I-h- / / ’, I-i- / / ’, I-j- / / ’, I-k- / / ’, I-a- / / / , I-b-zz / , I-c-zzz, I-d- / / / , I-e- / / / , I-f-zzz, I-g-zzz, I-h-zzz, I-i-z / / , I-j-zzz, I-k-zzz, I-a-zv, I-b- / v, I-c-zv, I-d- / v, I-e-zv, I-f-zv, I-g-zv, I-h-zv, I-i-zv, I-j-zv, I-k-zv, I-a-v, I-b-v, I-c-v, I-d-v, I-e-v, I-f-v, I-g-v, I-h-v, I-i-v, I-j-v, I-k-v, I-a-v ’, I-b-v ’, I-c-v ’, I-d-v ’, I-e-v ’, I-f-v ’, I-g-v ’, I-h-v ’, I-i-v ’, I-j-v ’, I-k-v ’, I-L I-m, I-n, I-p, I-q, I-r, IA, IA1, IB, IB 1, IC, IC1, ID, ID1, IE, IE1, IF, or IF1, or compounds selected from Table 1 or Table 2) and further comprises a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, ghdants, 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.

[0187] 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 unitdosage 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.

[0188] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein.Uses

[0189] The present disclosure provides uses for compounds and compositions described herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-a-z, I-b-z, I-c-z, I-d-z, I-e-z, I-f-z, I- g-z, I-h-z, I-i-z, I-j- / , I-k-z, I-a-zz, I-b-zz, I-c-zz, I-d-zz, I-e-zz, I-f-zz, I-g-zz, I-h-zz, I-i-zz, I-j-zz, I-k-zz, I-a-zz ’, I-b- zz ’, I-c-zz I-d-zz I-e-zz I-f-zz ’, I-g-zz I-h-zz ’, I-i-zz ’, I-j-zz I-k-zz ’, I-a-zzz, I-b-zzz, I-c-zzz, I-d-zzz, I-e-zzz, I-f- zzz, I-g-zzz, I-h-zzz, I-i-zzz, I-j-zzz, I-k-zzz, I-a-zv, I-b-zv, I-c-zv, I-d-zv, I-e-zv, I-f-zv, I-g-zv, I-h-zv, I-i-zv, I-j-zv, I- k-zv, I-a-v, I-b-v, I-c-v, I-d-v, I-e-v, I-f-v, I-g-v, I-h-v, I-i-v, I-j-v, I-k-v, I-a-v ’, I-b-v ’, I-c-v’, I-d-v ’, I-e-v’, I- f-v’, I-g-v ’, I-h-v ’, I-i-v’, I-j-v ’, I-k-v ’, 1-1, 1-m, I-n, I-p, I-q, I-r, IA, IA1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, or IF 1 , or compounds selected from Table 1 or Table 2). 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 some embodiments, provided compounds and compositions are useful as medicaments. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0190] In some embodiments, provided compounds are useful for disrupting (e.g., inhibiting and / or preventing and / or modulating) an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, the present disclosure provides methods of disrupting, interrupting, and / or preventing an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein in a subject, comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of disrupting, interrupting, and / or preventing an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein in a biological sample, comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods comprising contacting a cell containing a small GTPase (e.g., Rael,CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein with a provided compound or composition. In some such embodiments, a small GTPase is capable of binding a RAS-binding domain (RBD) of a PI3Ka protein. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wildtype RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Ka protein is a wild-type PI3Ka protein. In some embodiments, a PI3Ka protein is a mutant PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, EHOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0191] In some embodiments, the present disclosure provides methods comprising administering a provided compound or composition to a subject in need thereof. In some such embodiments, a subject has a disease, disorder, or condition associated with an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, a subject has a disease, disorder, or condition ameliorated by disruption of an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Ka protein. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RITE In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises aGUC, G12D, G12S, GUV, 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 Q61Rmutation. 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 GUV, GBR, and / or Q61R mutation. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a PI3Ka protein is a wild-type PI3Ka protein. In some embodiments, a PI3Ka protein is a mutant PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, EHOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a subject has a cancer or other indication described herein. 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.

[0192] In some embodiments, provided methods comprise administering a provided compound or composition to a subject in need thereof, according to a regimen such that the subject does not experience hyperglycemia or insulin-driven resistance.

[0193] In some embodiments, the present disclosure provides methods of treating a cancer, comprising administering to a subject a provided compound or composition. In some embodiments, a cancer is associated with and / or characterized by aberrant activation of PI3Ka. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, GUV, 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, GUV, 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 GUC, G12D, G12S, GUV, 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, GUV, 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 GUC, G12D, G12S, GUV, G12R, G12A, G13D, G13C, GBR, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a GUV, GBR, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in a PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R,G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0194] As used herein, “cancer” (and also, “malignancy”, “neoplasm”, “tumor”, and “carcinoma”), refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, a tumor may be or comprise cells that are precancerous (e.g., benign), malignant, pre- metastatic, metastatic, and / or non-metastatic. In some embodiments, a cancer may be characterized by a solid tumor. In some embodiments, a cancer may be characterized by a hematologic tumor. Numerous different types of cancers are known.

[0195] In some embodiments, a cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; nonHodgkin’s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. Additional exemplary types of cancer include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphatic system cancer, lymphomas, lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myelomas, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinomas, paraganglioma, parathyroid tumors, pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm’s tumor. In some embodiments, a canceris 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.

[0196] 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, GBR, 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 Q61Rmutation. In some embodiments, a cancer is characterized by a mutation in a PI3Ka protein. In some embodiments, the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family (e.g., HER2 and / or HER3), Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). In some embodiments, a cancer is characterized by a mutation in or a deletion of a PTEN protein. In some embodiments, a cancer has demonstrable sensitivity to Avastin. For example, a cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, a cancer is ER positive (e.g., having estrogen receptors). In some embodiments, a cancer is PR positive (e.g., having progesterone receptors).

[0197] In some embodiments, the present disclosure provides methods of treating a metabolic syndrome, comprising administering to a subject a provided compound or composition. In some embodiments, a metabolic syndrome is selected from hyperinsulinemia and type 2 diabetes.

[0198] In some embodiments, the present disclosure provides methods of treating a RASopathy (e.g., a genetic syndrome caused by a germline mutation in a gene that encodes a component or regulator of the RAS / MAPK pathway), comprising administering to a subject a provided compound or composition. Insome embodiments, a RASopathy is selected from the group consisting of capillary malformation- arteriovenous malformation syndrome and Legius syndrome. In some embodiments, a RASopathy is neurofibromatosis type 1 (NFl).

[0199] In some embodiments, the present disclosure provides methods of treating a vascular disorder, comprising administering to a subject a provided compound or composition. In some embodiments, a vascular disorder is selected from / WJ / 'd -related overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibro-adipose vascular anomaly (FAVA)).

[0200] In some embodiments, the present disclosure provides methods of treating pulmonary hypertension, such as pulmonary arterial hypertension, comprising administering to a subject a provided compound or composition.

[0201] In some embodiments, the present disclosure provides methods of treating age-related macular degeneration or diabetic macular edema, comprising administering to a subject a provided compound or composition

[0202] In some embodiments, the present disclosure provides compounds or compositions for use in the manufacture of a medicament. In some embodiments, provided compounds or compositions are useful in the manufacture of a medicament for treating a disease, disorder, or condition associated with or ameliorated by an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, a small GTPase (e g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Ka protein. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and 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, G 13D. 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 Q61Hmutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Ka protein is a wild-type PI3Ka protein. In some embodiments, a PI3Ka protein is a mutant PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions are useful in the manufacture of a medicament for treating a disease, disorder, or condition described herein. In some embodiments, provided compounds or compositions are useful in the manufacture of a medicament for treating a cancer or other indication described herein.

[0203] In some embodiments, the present disclosure provides compounds or compositions for use in treating a disease, disorder, or condition in a subject in need thereof. In some embodiments, provided compounds or compositions are useful in treating a disease, disorder, or condition associated with or ameliorated by an interaction between a small GTPase (e.g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In some embodiments, a small GTPase (e g., Rael, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Ka protein. In some embodiments, a small GTPase is selected from Rael, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RITE In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, 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, G 13D. and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Ka protein is a wild-type PI3Ka protein. In some embodiments, a PI3Ka protein is a mutant PI3Ka protein. In some embodiments, a PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, providedcompounds 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.

[0204] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agents or modalities to a subject receiving the other agent or modality in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although, in some embodiments, two or more agents may be administered together in a combination composition.

[0205] In some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapeutic agents (e.g., an anti-cancer agent and / or a therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care). Exemplary anti -cancer agents include, but are not limited to, an alkylating agent, an antimitotic, a checkpoint inhibitor, an anti-metabolite, a plant alkaloid, a terpenoid, a cytotoxic agent, an antibiotic, a topoisomerase inhibitor, an aromatase inhibitor, an angiogenesis inhibitor, an anti-steroid, an anti-androgen, an mTOR inhibitor, monoclonal antibodies, a kinase inhibitor, a HIF2a inhibitor, or a tyrosine kinase inhibitor. An alkylating agent may be, for example, armustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, or cyclophosphamide (ENDOXAN). An antimetabolite maybe, for example, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate (RHEUMATREX), or raltitrexed. An antimitotic may be, for example, a taxane such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL), or a vinca alkaloid such as vincristine (ONCOVIN), vinblastine, vmdesine, or vinorelbine (NAVELBINE). A checkpoint inhibitor may be an anti-PD-1 or anti-PD-Ll antibody such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, or MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); or an agent that targets LAG3 (lymphocyte activation gene 3 protein),KIR (killer cell immunoglobulin-like receptor), 4- IBB (tumor necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3), or 0X40 (tumor necrosis factor receptor superfamily member 4). A topoisomerase inhibitor may be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), temposide (VUMON), or etoposide (EPOSIN). A cytotoxic antibiotic may be, for example, actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or plicamycin. An aromatase inhibitor may be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN). An angiogenesis inhibitor may be, for example, genistein, sunitimb (SUTENT), or bevacizumab (AYASTIN). An anti-steroid or antiandrogen may be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON). A tyrosine kinase inhibitor may be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA). An mTOR inhibitor may be, for example, everolimus, temsirolimus (TORISEL), or sirolimus. Monoclonal antibody may be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). A kinase inhibitor may be, for example, a BRAF inhibitor, MEK inhibitor, or a KRAS inhibitor (e.g., KRAS G12C inhibitor, such as sotorasib, adagrasib, or BBO- 8520). Additional examples of agents that may be useful in combination with a compound provided herein include, but are not limited to, amsacrine; Bacillus Calmette-Guerin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamme; mesna; metformin; mitotane (o,r'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone.Exemplary Embodiments

[0206] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure:1. A compound of formula I :I or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:Ring A is selected from phenyl and a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is selected from 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 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9- to 10- membered spirofased 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 heteroary l 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; 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 6-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;R1is selected from -L-W, Ring D', or a bivalent Ci-6 aliphatic chain substituted with Ring D'; each L is independently a bivalent straight or branched Ci-s aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a groupselected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, - C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or a 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 -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 R2is independently selected from oxo, halogen, -CN, -OR, and C1-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, - CH2CH2OR, C1-6 aliphatic, and C1-6 haloaliphatic; each Cy is independently a 5- to 6-membered hctcroaryl 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 C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, - N(R)C(O)R, -(CH2)XC(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, - (CH2)xCy, and C1-6 aliphatic, wherein C1-6 aliphatic is unsubstituted or substituted with one or more halogen and -OR; 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 a group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 - to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen; C1-6 aliphatic; C1-6 haloaliphatic; 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, or 2; q is 0 or 1; r is 0. 1, or 2; s is 0, 1, or 2; t is 0, 1, or 2; u is O or 1; each v is independently 0, 1, or 2; and each x is independently 0, 1, or 2.2. The compound according to embodiment 1, wherein L is a bivalent straight or branched Ci-s aliphatic chain, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2- , -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-.3. The compound according to embodiment 1 or 2, wherein L is a bivalent straight or branched C aliphatic chain, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, C(O)-, -C(O)N(R)-, and -N(R)C(O)-4. The compound according to any one of embodiments 1-3, wherein L is a bivalent straight or branched Ci-s aliphatic chain having one or more units of unsaturation, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, - OC(O)-, -SO2N(R)-, and -N(R)SO2-.5. The compound according to embodiment 4, wherein L is a bivalent straight or branched CM aliphatic chain having one or more units of unsaturation, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O- , -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-.6. The compound according to embodiment 5, wherein L is a bivalent straight or branched C aliphatic chain having one double bond, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -C(O)-, -SO2-, - C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-.7. The compound according to embodiment 6, wherein L is a bivalent straight or branched CM aliphatic chain having one double bond, wherein one or two methylene units of the aliphatic chainare optionally and independently replaced by a group selected from -N(R)-, -C(O)-, and -N(R)C(O)-. The compound according to embodiment 1, wherein L is selected from -C(O)CC1F--C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH2)-, -C(O)CH=CH-CH2- -C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(R)-, -CH2N(R)C(O)CH=CH-, and -CH2CH2N(R)C(O)CH=CH-. The compound according to embodiment 8, wherein L is selected from -C(O)CC1F--C(O)CH=CH-, -NHC(O)CH=CH-, -C(O)C(=CH2)-, -C(O)CH=CH-CH2- , -C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(CH3)-, -CH2NHC(O)CH=CH-, and -CH2CH2NHC(O)CH=CH-. The compound according to embodiment 1 or 2, wherein L is a bivalent straight or branched Ci-s alkyl chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2- , -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. The compound according to embodiment 1, wherein L is selected from -N(R)C(O)CH2CH2-, -N(R)C(O)CH(CH3)CH2-, -OCH(CH3)CH2-, -C(O)-, -C(O)CH2CH2-, -C(O)N(R)CH(CH3)CH2-, -C(O)N(R)CH2CH(CH3)CH2-, -CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(O)-, -CH2C(O)N(R)C(CH3)2CH2-, -CH2CH2C(O)N(R)C(CH3)2CH2-, -CH2N(R)-, -CH2N(R)C(O)- , -CH2N(R)C(O)CH2CH2-, -CH2N(R)C(O)CH(CH3)CH2-, -CH2N(R)C(O)C(CH3)2CH2-, -CH2N(R)C(O)CH2C(CH3)2CH2-, -CH2CH2N(R)C(O)CH(CH3)CH2-, and -CH2O-. The compound according to embodiment 11, wherein L is selected from -N(H)C(O)CH2CH2- , -N(H)C(O)CH(CH3)CH2-, -OCH(CH3)CH2-, -C(O)-, -C(O)CH2CH2-, -C(O)N(H)CH(CH3)CH2-, -C(O)N(H)CH2CH(CH3)CH2-, -CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(O)-, - CH2C(O)N(H)C(CH3)2CH2-, -CH2CH2C(O)N(H)C(CH3)2CH2-, -CH2N(H)-, -CH2N(H)C(O)- , -CH2N(H)C(O)CH2CH2-, -CH2N(H)C(O)CH(CH3)CH2-, -CH2N(H)C(O)C(CH3)2CH2- , -CH2N(H)C(O)CH2C(CH3)2CH2-, -CH2CH2N(H)C(O)CH(CH3)CH2-, and -CH2O-. The compound according to any one of embodiments 1-12, wherein W is hydrogen. The compound according to any one of embodiments 1-12, wherein W is a halogen. The compound according to embodiment 1, wherein -L-W is selected from -CH3, -CH(CH3)2, -CH2C(CH3)3, -CH2OH, -CH2NH2, -OCH(CH3)2,The compound according to any one of embodiments 1-17, wherein Ring B is a 9- to 10-membered bicyclic ring which comprises at least one 5- or 6-membered heteroaryl ring comprising at least one nitrogen atom. The compound according to any one of embodiments 1-18, wherein Ring B, substituted with n instances of R4, is selected fromThe compound according to any one of embodiments 1-19, wherein the compound is selected from Formulae I-a, I-b, I-c, I-d, I-e, I-f I-g, and I-h:or a pharmaceutically acceptable salt thereof.The compound according to any one of embodiments 1-20, wherein each R4is halogen.The compound according to any one of embodiments 1-20, wherein n is 0. The compound according to any one of embodiments 1-22, wherein Ring A is phenyl.The compound according to any one of embodiments 1-23, wherein RingThe compound according to embodiment 24, wherein Ring A is selected fromThe compound according to embodiment 25, wherein Ring A is selected fromThe compound according to embodiment 26, wherein R3is selected from halogen, -OR, - O(CH2)vCy, and -OCH2CH2OR. The compound according to any one of embodiments 1-27, wherein Ring A, substituted with m instances of R3, is selected fromThe compound according to any one of embodiments 1-22. wherein Ring A is a 5- to 6-membered heteroary l ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound according to embodiment 29, wherein Ring A substituted with m instances of R3is selected fromThe compound according to any one of embodiments 1-30, wherein m is 1, 2, or 3. The compound according to any one of embodiments 1-31, wherein at least one R3is selected from halogen, -OR, -O(CH2)vCy, and -OCH2CH2OR. The compound according to any one of embodiments 1-32, wherein Ring C is phenyl. The compound according to any one of embodiments 1-32, wherein Ring C is a 5- to 6-membered heteroary l ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound according to any one of embodiments 1-32, wherein Ring C is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound according to any one of embodiments 1-32, wherein Ring C is a 9- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound according to any one of embodiments 1-32, wherein Ring C, substituted with p instances of R5, is selected fromThe compound according to any one of embodiments 1-36, wherein Ring C is fused to Ring E. The compound according to embodiment 38, wherein the compound is selected from Formulae I- a-z, I-b-z, I-c-z, I-d-z, I-e-z, I-f-z, I-g-z, and I-h-z :I-g- I-h-i or a pharmaceutically acceptable salt thereof.The compound according to any one of embodiments 38-40, wherein Ring E is a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. The compound according to embodiment 41, wherein Ring E, substituted with s instances of R5, is selected fromThe compound according to any one of embodiments 38-40, wherein Ring E is 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. The compound according to embodiment 19, wherein Ring E, substituted with s instances of R5, is selected fromThe compound according to any one of embodiments 38-40, wherein Ring E is a 5- to 6-membered carbocyclic ring substituted by s instances of R5. The compound according to embodiment 45, wherein Ring E, substituted with s instances of R5, is selected fromThe compound according to any one of embodiments 38-40, whereinselected fromThe compound according to any one of embodiments 1-47, wherein p is 1 or 2. The compound according to any one of embodiments 1-48, wherein each R5is independently selected from oxo, -CN, halogen, -N(R)2, -(CH2)XC(O)N(R)2, -SO2R, -SC>2N(R)2, -(CH2)xCy, and C1-6 aliphatic, wherein C1-6 aliphatic is unsubstituted or substituted with one or more halogen and - OR. The compound according to any one of embodiments 1-49, wherein each R5is independently selected from oxo, =NH, -OR, -N(R)2, and Ci-e aliphatic, wherein C1-6 aliphatic is unsubstituted or substituted with one or more halogen and -OR. The compound according to any one of embodiments 1-50, wherein Ring D is phenyl. The compound according to any one of embodiments 1-50, wherein Ring D is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound according to any one of embodiments 1-52, wherein Ring D, substituted with r instances of R2and q instances of R1, is selected from4. The compound according to any one of embodiments 1-52, wherein Ring D is fused to Ring F. 5. The compound according to embodiment 54, wherein q is 0. 6. The compound according to any one of embodiments 1-52, 54, and 55, wherein the compound is selected from Formulae I-a-zz, I-b-zz, I-c-zz, I-d-zz, I-e-zz, I-f-zz, I-g-z'z, and I-h-zz:or a pharmaceutically acceptable salt thereof.The compound according to embodiment 56, whereinselected fromThe compound according to any one of embodiments 1-52 and 54-57, wherein Ring F is phenyl substituted by u instances of-L-W. The compound according to embodiment 58, wherein Ring F, substituted with u instances of-L- W, is selected fromThe compound according to embodiment 56, whereinselected fromThe compound according to any one of embodiments 1-52, 54-57, and 60, wherein Ring F is a 5- to 6-membered carbocyclic ring substituted by u instances of-L-W. The compound according to embodiment 61, wherein Ring F, substituted by u instances of-L-W,The compound according to any one of embodiments 1-52, 54-57, and 60, wherein Ring F is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring F is substituted by u instances of-L-W.The compound according to embodiment 63, wherein Ring F, substituted by u instances of-L-W, is selected fromThe compound according to any one of embodiments 1-52, 54-57, and 60, wherein Ring F is 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. The compound according to embodiment 65, wherein Ring F, substituted by u instances of-L-W,The compound according to any one of embodiments 1-52, wherein R1is Ring D’. The compound according to embodiment 68, wherein Ring D is not fused to Ring F. The compound according to any one of embodiments 1-52, wherein the compound is selected from Formulae I-a-zzz, I-b-zzz, I-c-iii, I-d-zzz, I-e-iii, I-f-iii, I-g-iii, and I-h-zzz:or a pharmaceutically acceptable salt thereof.71. The compound according to embodiment 70, wherein Ring D, substituted with r instances of R2, is selected fromThe compound according to any one of embodiments 1-52 and 68-71, wherein Ring D’ is a 4- to 6-membered carbocyclic ring substituted with t instances of-L-W. The compound according to any one of embodiments 1-52 and 68-71, wherein Ring D’ is 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. The compound according to any one of embodiments 1-52 and 68-71, wherein Ring D', substituted with t instances of-L-W, is selected fromThe compound according to any one of embodiments 1-52 and 68-75, wherein the compound is selected from Formulae I-a-zv, I-b-zv, I-c-zv, I-d- / 'v, I-e-zv, I-f- / 'v, I-g-z'v, and I-h- / 'v:The compound according to any one of embodiments 1-36, 38-52, and 54-67, wherein the compound is selected from Formulae I-a-v, I-b-v, I-c-v, I-d-v, I-e-v, I-f-v, I-g-v, and I-h-v:I-e-v I-f-Vor a pharmaceutically acceptable salt thereof.The compound according to any one of embodiments 1-52 and 68-76, wherein the compound isor a pharmaceutically acceptable salt thereof. The compound according to any one of embodiments 1-78, wherein t is 1. The compound according to any one of embodiments 1-79, wherein q is 1. The compound according to any one of embodiments 1-80, wherein v is 0 or 1. The compound according to any one of embodiments 1-81, wherein x is 0 or 1. The compound according to any one of embodiments 1-82, wherein each R is independently hydrogen, Ci-6 aliphatic, or Ci-6 haloaliphatic. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of embodiments 1- 84, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof to a subject in need thereof. The method according to embodiment 86, wherein the subject has a disease, disorder, or condition ameliorated by disruption, inhibition, and / or prevention of an interaction between a small GTPase and a PI3Ka protein. The method of embodiment 87, wherein the small GTPase is Rael, CDC42, or a RAS protein. The method of embodiment 88, wherein the small GTPase is a RAS protein. The method of embodiment 89, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITl. The method according to any one of embodiments 86-90, wherein the subject has a cancer. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof. The method according to embodiment 91 or 92, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in PI3Ka.The method according to embodiment 93. wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, EllOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. The method according to any one of embodiments 91-94, wherein the cancer is characterized by a mutation in a RAS protein. The method according to embodiment 95, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The method according to embodiment 95 or 96, wherein the RAS protein is KRAS. The method according to embodiment 97, wherein the KRAS protein comprisesa G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to embodiment 95 or 96, wherein the RAS protein is HRAS. The method according to embodiment 99, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, GBR, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to embodiment 95 or 96, wherein the RAS protein is NRAS. The method according to embodiment 101, wherein the 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. The method according to any one of embodiments 91-102, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non-Hodgkin’s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. The method according to embodiment 103, wherein the 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.The method according to any one of embodiments 91-104, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kmases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases) The method according to any one of embodiments 91-105, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. The method according to any one of embodiments 86-106, wherein the subject has previously undergone a treatment regimen for cancer. The method according to any one of embodiments 86-107, wherein the subject has previously entered remission from cancer. A method of treating a metabolic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof. The method according to embodiment 109, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes. A method of treating a RASopathy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof. The method according to embodiment 111, wherein the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome. A method of treating a vascular disorder or condition, comprising administering to a subj ect in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1- 84 or a pharmaceutically acceptable salt thereof. The method according to embodiment 113, wherein the vascular disorder or condition is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibro-adipose vascular anomaly (FAVA)). A method of disrupting an interaction between a small GTPase and a PI3Ka protein in a subject, comprising administering to the subject a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof. A method of disrupting an interaction between a small GTPase and a PI3Ka protein, comprising contacting a cell containing the small GTPase and the PI3Ka protein with a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof.A method comprising contacting a cell containing a small GTPase and a PI3Ka protein with a compound according to any one of embodiments 1 -84 or a pharmaceutically acceptable salt thereof. The method of embodiment 116 or 117, wherein the cell is included in a subject. The method according to any one of embodiments 115-118, wherein the small GTPase is selected from Rael, CDC42, and a RAS protein. The method according to embodiment 119, wherein the small GTPase is a RAS protein. The method according to embodiment 120, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. The method according to embodiment 121, wherein the RAS protein is KRAS. The method according to embodiment 122, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to embodiment 121, wherein the RAS protein is HRAS. The method according to embodiment 124, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to embodiment 121, wherein the RAS protein is NRAS. The method according to embodiment 126, wherein the 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. A compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof for use as a medicament. Use of a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. The compound or use according to embodiment 128 or 129, wherein the medicament is for treating a cancer. The compound or use according to embodiment 130, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in PI3Ka. The compound or use according to embodiment 131, wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. The compound or use according to any one of embodiments 130-132, wherein the cancer is characterized by a mutation in a RAS protein.The compound or use according to embodiment 133, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The compound or use according to embodiment 133 or 134, wherein the RAS protein is KRAS. The compound oruse according to embodiment 135, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound or use according to embodiment 133 or 134, wherein the RAS protein is HRAS. The compound according to embodiment 137, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound or use according to embodiment 133 or 134, wherein the RAS protein is NRAS. The compound or use according to embodiment 139, wherein the 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. The compound or use according to any one of embodiments 130-140, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non-Hodgkin’s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. The compound or use according to embodiment 141, wherein the 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. The compound or use according to any one of embodiments 130-142, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases).The compound or use according to any one of embodiments 130-143, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. The compound or use according to embodiment 128 or 129, wherein the medicament is for treating a metabolic disorder, a RASopathy, or a vascular disorder. The compound or use according to embodiment 145, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome; or (lii) the vascular disorder or condition is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); or fibro-adipose vascular anomaly (FAVA)). A compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition. The compound for use according to embodiment 147 for use in treating a cancer. The compound for use according to embodiment 148, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in PI3Ka. The compound for use according to embodiment 149, wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. The compound for use according to any one of embodiments 148-150, wherein the cancer is characterized by a mutation in a RAS protein. The compound for use according to embodiment 151, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The compound for use according to embodiment 151 or 152, wherein the RAS protein is KRAS. The compound for use according to embodiment 153, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound for use according to embodiment 151 or 152, wherein the RAS protein is HRAS. The compound for use according to embodiment 155, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound for use according to embodiment 151 or 152, wherein the RAS protein is NRAS.The compound for use according to embodiment 157, wherein the 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. The compound for use according to any one of embodiments 148-158, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non-Hodgkin’s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. The compound for use according to embodiment 159, wherein the 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. The compound for use according to any one of embodiments 148-160, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). The compound for use according to any one of embodiments 148-161, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. The compound for use according to embodiment 147 for use in treating a metabolic disorder, a RASopathy, or a vascular disorder. The compound for use according to embodiment 163, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome; or (lii) the vascular disorder or condition is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibro-adipose vascular anomaly (FAVA)).A compound capable of disrupting an interaction between a small GTPase and a PI3Ka protein. The compound according to embodiment 165, wherein the compound is capable of binding to PI3Ka, such that (i) the interaction between the small GTPase and PI3Ka is at least partially disrupted, prevented, or inhibited; and / or (ii) the kinase activity of PI3Ka is not significantly inhibited. The compound according to embodiment 165 or 166, wherein the compound has an activity of:(i) < 5 pM or > 5 pM and < 25 pM in the assay of Biological Example 1 (e.g., a surface plasmon resonance (SPR) binding assay assessing inhibition of the KRAS-PI3Ka interaction);(ii) > 75%, <75% and > 50%, or <50% and > 25% in the assay of Biological Example 2 (e.g., a Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis of covalent modification of Cys242 in human PIK3CA (157- 299);(iii) < 1 pM or > 1 pM and < 10 pM in the assay of Biological Example 3 (e.g., a matrix- assisted cell-based pAKT homogenous time-resolved fluorescence (HTRF) assay in Teton KRAS G12D HeLa cells); and / or(iv) < 0.1 pM, > 0.1 pM and < 1 pM, or > 1 pM and < 3 pM in the assay of Biological Example 4 (e.g., a matrix-assisted cell-based pAKT HTRF assay in BT474 cells). The compound according to any one of embodiments 165-167, wherein the compound comprises an electrophilic moiety. The compound according to any one of embodiments 165-168, wherein the compound is capable of interacting with a Cys242 residue in the catalytic subunit of PI3Ka. The compound according to any one of embodiments 165-169, wherein the compound is capable of irreversibly binding the PI3Ka protein. The compound according to any one of embodiments 165-169, wherein the compound is capable of reversibly binding the PI3Ka protein. The compound according to any one of embodiments 165-171, wherein the small GTPase is Rael, CDC42, or a RAS protein. The compound according to embodiment 172, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITE The compound according to embodiment 173, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The compound according to embodiment 173 or 174, wherein the RAS protein is KRAS.The compound according to embodiment 175, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound according to embodiment 173 or 174, wherein the RAS protein is HRAS. The compound according to embodiment 177, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound according to embodiment 173 or 174, wherein the RAS protein is NRAS. The compound according to embodiment 179, wherein the 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. The compound of any one of embodiments 165-180, wherein the compound is a compound according to any one of embodiments 1-84. A method of disrupting, inhibiting, or preventing an interaction between a small GTPase and a PI3Ka protein, comprising contacting a cell containing the small GTPase and the PI3Ka protein with a compound according to any one of embodiments 165-181 or a pharmaceutically acceptable salt thereof. The method according to embodiment 182, wherein the cell is within a subject. The method according to embodiment 182 or 183, wherein the small GTPase is Rael, CDC42, or a RAS protein. The method according to embodiment 184, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITE The method according to embodiment 185, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The method according to embodiment 185 or 186, wherein the RAS protein is KRAS. The method according to embodiment 187, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to embodiment 185 or 186, wherein the RAS protein is HRAS. The method according to embodiment 189, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to embodiment 185 or 186, wherein the RAS protein is NRAS.192. The method according to embodiment 191, wherein the 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.EXAMPLES

[0207] 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.

[0208] Selected abbreviations used in the preceding sections and the Examples are summarized in Table 3.Table 3. Abbreviations.Materials and Methods

[0209] Preparative thin layer chromatography (PTLC) separations described herein were typically performed on 20 x 20 cm plates (500-pm thick silica gel).

[0210] 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: SiCL by weight. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0211] 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 (5) are reported in parts per million (ppm) with splitting patterns abbreviated to: s (singlet), br. s (broad singlet), d (doublet), dd (double doublet), t (triplet), and m (multiplet). The coupling constant (J) is given in Hz. Typical deuterated solvents were utilized as indicated in the individual examples.

[0212] LCMS analysis was typically performed using one of the following conditions:

[0213] (1) LCMS spectra were taken on an Agilent Technologies 6120B Quadrupole spectrometer.The mobile phase for the LC was acetonitrile (A) with 0.1% formic acid, and water (B) with 0.1% formic acid, and the eluent gradient was from 5-95% A in 6.0 min, 5 %-40% A in 6.0 min, 80-100% A in 6.0 min. using a poroshell 120 EC-C18 50 mm x 3.0 mm x 2.7 pM 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.

[0214] (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 mm, using a ZORBAX SB-C18 50 mm x 2.1 mm x 1.8 pM capillary column; Flow Rate: 0.3 mL / min. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius unless otherwise noted.

[0215] (3) LC-MS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C18 4.6 mm x 150 mm x 3.5 pM RapidResol column with amobile 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.

[0216] (4) LCMS spectra were taken on an alliance Waters 2695 coupled to a Waters 2487 DualWavelength 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-C 18 150 mm x 4.6 mm x 5 pm column. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius unless otherwise noted.

[0217] (5) LCMS spectra were taken on Waters Micromass-ZQ 2000 Quadrupole spectrometer. The mobile phase for the LC was (A) 0.1% formic acid in water; (B) Acetonitrile 100% and the eluent gradient was from 10-90% B in 10.0 min, 90% up to 12 min B, 12-13 min 90-10% B, 13-15 min 90-10% B using Phenomenex Gemini-C18 (50 mm x 4.6 mm x 5 pm); Flow Rate: 0.5 mL / min. Mass spectra (MS) were measured by Electrospray Ion-Mass spectroscopy (ESI).

[0218] Typically, analytical HPLC spectrometry' conditions were as follows:

[0219] LC1: Agilent Technologies 1260 Infinity coupled, Column: poroshell 120 EC-C18 150 mm x 4.6 mm x 4 pm; Temperature: 40 °C; Eluent: 5:95 v / v acetonitrile / water + 0.02% trifluoroacetic acid in 20 min; Flow Rate: 1.2 mL / min; Detection: VWD. 190-600 nm.

[0220] LC2: Shimadzu 2010 CHT, Column Waters X-select CSH C18 (150 x 4.6) mm x 3.5 pm, Temperature: 30 °C; MP-A 10mm ammonium acetate Buffer, MP-B: Acetonitrile (100%), Flow Rate: 1.0 mL / min; Detection: VWD, 270 nm. Gradient elevation: time / B con: 0 / 5, 2 / 5, 20 / 50, 25 / 50, 30 / 90, 35 / 90, 37 / 05, 40 / 05.

[0221] LC3: Shimadzu LC-2010A HT, Column: XBRIDGE-C18 3.5 pm 2.1 x 50 mm; Temperature: 45 °C; Mobile phase: water (0.05%TFA)-ACN (0.05%TFA), ACN from 0 to 60% over 7 minutes, 7-8 min, ACN from 60% to 100%; Flow Rate: 0.8 mL / min; Detection: PDA, 214 nm, 254 nm.

[0222] LC4: Shimadzu LC-2050c, Column: XBRIDGE-C18 3.5 pm 2.1 x 50 mm; Temperature: 45 °C; Mobile phase: water (0.05%TFA)-ACN (0.05%TFA), ACN from 0 to 60% over 7 minutes, 7-8 min, ACN from 60% to 100%; Flow Rate: 0.8 mL / min; Detection: VWD, PDA, 214 nm, 254 nm.PDA, 214 nm, 254 nm.

[0223] Preparative HPLC was carried out with one of the following conditions:

[0224] Condition 1: GILSON Preparative HPLC System; Column: Ultimate XB-C18, 21.2 mm x 250 mm, 5 pm; Mobile phase: Water with 0.1% trifluoroacetic acid; MeCN with 0.1% trifluoroacetic acid; Method: 15 minutes gradient elution; Initial organic: 10% to 30%; Final organic: 60% to 80%; UV1: 240; UV2: 230; Flow: 15 mL / min.

[0225] 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 vl.6. The preparative HPLC column used was a Waters XBridge® Prep C18 5uM OBD™ 19 x 250 mm column with a mobile phase of water / MeCN or water (0.1% TFA) / MeCN (0. 1% TFA).

[0226] Condition 3: Shimadzu Preparative HPLC System; Column: Phenomenex Luna C18, 21.1 mm X 250 mm, 10 pm; Mobile phase; MP-A 10mm ammonium acetate Buffer, MP-B: Methanol (100%), 35 minutes gradient elution UV: 254; Flow: 10 mL / min. Gradient elevation: time / B con: 0 / 50, 25 / 90, 30 / 90, 32 / 50, 35 / 50.

[0227] Chiral supercritical fluid chromatography (SFC) was carried out with one of the following conditions:

[0228] Condition 1: SFC Thar prep 80; Column: CHIRALPAK® AD-H 250 mm x 20 mm, 5 pm; Mobile phase: 40% EtOH / CCL (contining 0.2% NH4OH); 40 g / min.

[0229] Condition 2: SFC Thar prep 80; Column: CHIRALPAK® OD-H 250 mm x 20 mm, 5 pm; Mobile phase: 40% McOH / CCL (contining 0.2%NH4OH); 40 g / min.

[0230] Condition 3: SFC Thar prep 80; Column: CHIRALPAK® IC 250 mm x 20 mm, 5 pm; Mobile phase: 40% IPA / CCL (containing 0.2% DEA); 40 g / min.

[0231] Compound names were generated with ChemDraw Professional.

[0232] 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.Synthesis of Provided CompoundsSynthetic Example 1: Synthesis of A-(3-(4-(2-(2-methoxyethoxy)phenyl)-l-(l,2,3,4- tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)benzyl)acrylamide (Compound 1)

[0233] Step A: Preparation of N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)acrylamide: To a stirred solution of [3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] methanamine hydrochloride (100 mg, 0.371 mmol) and triethylamine (0.16 mL, 1.1 mmol) in DCM (5 mL) was added acrylic anhydride (70 mg, 0.56 mmol). The solution was stirred at 25 °C for 1 h. The mixture was concentrated and purified by preparative -TLC (petroleum ether / EtOAc: 3 / 1) to give N-(3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)acrylamide (100 mg, 94% yield) as a colorless oil. LCMS ESI(+) m / z 288.2 (M+H).

[0234] Step B: Preparation of l-benzyloxy-4-bromo-3-methoxy-6,7-dihydro-5H- cyclopenta[c]pyridine: To a solution of benzyl alcohol (3.80 mL, 36.3 mmol) stirred in DMF (50 mL) at 0 °C was added sodium hydride (0.870 g, 36.3 mmol) by portions. The mixture was stirred at 0 °C for 30 min. 4-Bromo-3 -methoxy- l-methylsulfonyl-6,7-dihydro-5H-cyclopenta[c]pyndme (3.70 g, 12.1 mmol) was added, and the resulting mixture was stirred at 0 °C to 25 °C for additional 4 hours. The mixture was diluted with water and extracted with EtOAc. The organic layers were dried over Na2SC>4 and concentrated. The residue was purified by silica gel column (EtOAc / petroleum ether: 0 to 10%) to give l-benzyloxy-4- bromo-3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine (3.90 g, 97% yield). LCMS ESI (+) m / z 334.0 (M+H).

[0235] Step C: Preparation of l-(benzyloxy)-3-methoxy-4-(2-(2-methoxyethoxy)phenyl)-6,7- dihydro-5H-cyclopenta[c]pyridine: A mixture of l-benzyloxy-4-bromo-3-methoxy-6,7-dihydro-5H- cyclopenta[c]pyridine (1.00 g, 2.99 mmol), [2-(2 -methoxyethoxy )phenyl]boronic acid (0.65 g, 3.29 mmol), l,l'-bis(diphenylphosphino)ferrocenedichloro palladium (II) (219 mg, 0.299 mmol) and sodium carbonate (634 mg, 5.98 mmol) in 1,4-dioxane (30 mL) / water (3 mL) was stirred at 85 °C for 6 hours. The mixture was concentrated and purified by silica gel column (petroleum ether:EtOAc =10:1) to give l-benzyloxy-3- methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (1.10 g, 91% yield). LCMS ESI (+) m / z 406.2 (M+H).

[0236] Step D: Preparation of 3-methoxy-4-[2-(2-methoxyethoxy)phenyl]- 6,7-dihydro-5H- cyclopenta [c]pyridin-l-ol: A mixture of l-benzyloxy-3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7- dihydro-5H-cyclopenta[c]pyridine (1.10 g, 2.71 mmol) and Pd / C (100 mg) in methanol (10 mL) / THF (10 mL) was stirred at 12 °C for 12 hours. The mixture was filtered and concentrated. The residue was purified by silica gel column (petroleum ether: EtOAc= 1 : 1) to give 3-methoxy-4-[2-(2-methoxyethoxy)phenyl]- 6,7- dihydro-5H-cyclopenta [c]pyridin-l-ol (870 mg, 100% yield). LCMS ESI (+) m / z 316.2 (M+H).

[0237] Step E: Preparation of [3-methoxy-4-[2-(2-methoxyethoxy)phenyl] -6,7-dihydro-5H- cyclopenta[c]pyridin-l-yl] trifluoromethanesulfonate: To a stirred solution of 3-methoxy-4-[2-(2- methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c] pyridin-l-ol (870 mg, 2.76 mmol) and N,N- diisopropylethylamine (1.40 mL, 8.28 mmol) in DCM (lOmL) was added trifluoromethanesulfonic anhydride (0.560 mL, 3.31 mmol) at 0 °C. The mixture was stirred at 10 °C for 1 hour. The mixture was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column (petroleum ether:EtOAc=20: l to 10: 1) to give [3-methoxy-4-[2-(2-methoxyethoxy)phenyl]- 6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl] trifluoromethanesulfonate (690 mg, 56% yield). LCMS ESI (+) m / z 448.2 (M+H).

[0238] Step F: Preparation of tert-butyl 6-[3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro- 5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate: To a stirred solution of [3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c] pyridin-l-yl] trifluoromethanesulfonate (300 mg, 0.670 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-3,4-dihydro-lH-isoquinoline-2-carboxylate (289 mg, 0.805 mmol) and potassium carbonate (185 mg, 1.34 mmol) in MeCN (10 mL) / Water (1.2 mL) was added palladium (II) acetate (15 mg, 0.067 mmol) and X-PHOS (64 mg, 0.13 mmol). The mixture was stirred at 100 °C for 12 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column (petroleum ether:EtOAc=10: l to 4: 1) to give tert-butyl 6-[3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4- dihydro- lH-isoquinoline-2 -carboxylate (312 mg, 88% yield). LCMS ESI (+) m / z 531.4 (M+H).

[0239] Step G: Preparation of 4-(2-(2-methoxyethoxy)phenyl)-l-(l,2,3,4- tetrahydroisoquinolin-6- yl)-6,7-dihydro-5H-cyclopenta[c]pyndin-3-ol: To a stirred solution of tert-butyl 6-[3-methoxy-4-[2-(2- methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2- carboxylate (280 mg, 0.528 mmol) in MeCN (4 mL) was added sodium iodide (237 mg, 1.58 mmol) and trimethylchlorosilane (0.67 mL, 5.3 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was cooled to ambient temperature and quenched with water. The product was extracted with DCM, dried over NajSCE and concentrated to dryness to give crude product 4-(2-(2 -methoxyethoxy )phenyl)-l-( 1,2, 3,4- tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (208 mg) which was used in next step directly. LCMS ESI (+) m / z 417.2 (M+H).

[0240] Step H: Preparation of tert-butyl 6-[3-hydroxy-4-[2-(2-methoxyethoxy) phenyl]-6,7-dihydro- 5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate: To a solution of 4-(2-(2- methoxyethoxy)phenyl)-l-(l,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (208 mg, 0.600 mmol) and potassium carbonate (219 mg, 1.58 mmol) in ethanol (4 mL) and H2O (2 mL) was added di-tert-butyl dicarbonate (0.25 mL, 1.1 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with water and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column (EtOAc) to give tert-butyl 6-[3-hydroxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H- cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (280 mg, 90%). LCMS ESI (+) m / z 517.3.

[0241] Step I: Preparation of tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3- (trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2- carboxylate: To a solution of tert-butyl 6-[3-hydroxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H- cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (260 mg, 0.503 mmol) and N,N- diisopropylethylamine (0.260 mL, 1.51 mmol) in DCM (5 mL) was added trifluoromethanesulfonic anhydride (0.100 mL, 0.604 mmol). The mixture was stirred at 7 °C for 1 hour. The mixture was pouredinto NaHCOs aqueous solution. The product was extracted with EtOAc, washed with brine, dried over NajSCh and concentrated. The residue was purified by silica gel column (petroleum ether:EtOAc=4: l) to give tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H- cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (180 mg, 55% yield). LCMS ESI (+) m / z 649.3 (M+H).

[0242] Step J: Preparation of tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-[3-[(prop-2- enoylamino)methyl]phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinolme-2- carboxylate: To a solution of tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-(trifluoromethylsulfonyloxy)- 6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (40 mg, 0.062 mmol) and N-[[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl] prop-2-enamide (35 mg, 0.12 mmol) in acetonitrile (2 mL) and water (0.2 mL) was added X-Phos (5.9 mg, 0.012 mmol), K2CO3 (17 mg, 0.12 mmol) and palladium (II) acetate (1.4 mg, 0.0062 mmol). The solution was stirred for 2 hours at 100 °C under N2. The mixture was concentrated and purified by preparative -TLC (petroleum ether:EtOAc=l: l) to give tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-[3-[(prop-2- enoylamino)methyl]phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2- carboxylate (30 mg, 70% yield) as a light yellow oil. LCMS ESI (+) m / z 660.2 (M+H).

[0243] Step K: Preparation of N-[[3-[4-[2-(2-methoxyethoxy)phenyl]-l-(l,2,3,4- tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl]phenyl]methyl]prop-2-enamide: To a solution of tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-[3-[(prop-2-enoylamino)methyl]phenyl]-6,7- dihydro-5H-cyclopenta[c]pyridin-l-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (30 mg, 0.043 mmol) in DCM (2 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The solution was stirred for 1 h at ambient temperature. The solution was concentrated and purified by reverse phase preparative -HPLC to give N-[[3-[4-[2-(2 -methoxyethoxy )phenyl]-l-(l, 2,3, 4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H- cyclopenta[c]pyridin-3-yl]phenyl]methyl]prop-2-enamide (11 mg, 044% yield) as a tnfluoroacetic acid salt. LCMS ESI (+) m / z 560.2 (M+H).1H NMR (400 MHz, CD3OD) 5:7.74-7.76 (m, 2H), 7.48-7.50 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.26-7.35 (m, 4H), 7.02-7.04 (d, J = 8.4 Hz, 1H), 6.96-6.98 (d, J = 7.6 Hz, 1H), 6.86-6.90 (t, J = 7.2Hz, 1H), 6.24-6.25 (d, J = 7.2Hz, 2H), 5.69-5.72 (t, J = 5.2Hz, 1H), 4.50 (s,2H), 4.33- 4.61 (m, 2H), 4.12-4.15 (m, 1H), 3.95-3.98 (m, 1H), 3.57-3.61 (m, 4H), 3.06-3.28 (m, 8H), 2.85-2.93 (m, 1H), 2. 18-2.24 (m, 2H).Synthetic Example 2: Synthesis of 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridine (Compound 4)

[0244] Step A: Preparation of l-(2-methoxyethoxy)-2-(phenylethynyl)benzene: To a solution of 1- iodo-2-(2-methoxyethoxy)benzene (300 mg, 1.08 mmol), phenylacetylene (0.120 mL, 1.13 mmol), triethylamine (0.75 mL, 5.4 mmol) and Cui (41 mg, 0,22 mmol) in THF (7.5 mL) was added Pd(PPh3)2C12 (76 mg, 0.11 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was then heated to 50 °C and stirred for 4 hours under nitrogen. The reaction was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and the filtrate was concentrated by rotary evaporation. The product was purified by column chromatography on silica gel (EtOAc / petroleum ether: 1 / 15) to afford l-(2-methoxyethoxy)-2-(2- phenylethynyl) benzene (237 mg, 87% yield).XHNMR (400 MHz, CDC13): 57.47-7.50 (m, 3H), 7.25-7.36 (m, 4H), 6.90-6.97(m, 2H), 4.22(t, J = 4.8 Hz, 2H), 3.84 (t, J = 4.8 Hz, 2H), 3.51 (s, 3H).

[0245] Step B: Preparation of 6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-5H-thieno[3,2-c]pyridin-4- one and 7- [2-(2 -methoxyethoxy )phenyl]-6-phenyl-5H-thieno [3, 2-c]pyridin-4-one: To a solution of l-(2- methoxyethoxy)-2-(2-phenylethynyl)benzene (230 mg, 0.912 mmol), thiophene -3 -carbonitrile (99 mg, 0.91 mmol), potassium hexafluorophosphate (34 mg, 0.18 mmol) and cupric acetate monohydrate (50 mg, 0.27 mmol) in acetic acid (10 mL) was added [{RuCl2(p-cymene)}2] (28 mg, 0.046 mmol). The reaction was stirred at 120 °C for 10 hours. The reaction was concentrated to dryness and the residue was taken upin EtOAc. The organic layers were washed with water and brine, dried and concentrated. The crude was purified by column chromatography (5% MeOH in DCM) to afford a mixture of 6-[2-(2- methoxyethoxy)phenyl]-7-phenyl-5H-thieno[3,2-c]pyndin-4-one and 7-[2-(2-methoxyethoxy)phenyl]-6- phenyl-5H-thieno [3,2-c]pyridin-4-one (201 mg, 58% yield). LCMS ESI (+) m / z 378.1 (M+H).

[0246] Step C: Preparation of 4-chloro-6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-thieno[3,2- c]pyridine and 4-chloro-7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridine: A solution of 6- [2-(2-methoxyethoxy)phenyl] -7 -phenyl-5H-thieno [3 ,2-c]pyridin-4-one and 7-[2-(2- methoxyethoxy)phenyl]-6-phenyl-5H-thieno[3,2-c]pyndin-4-one (201 mg, 0.533 mmol) in POCL (5.0 mL) was stirred at 100 °C for 3 hours. The reaction was concentrated to dryness and the residue was taken up in EtOAc. The organic layers were washed with saturated sodium bicarbonate solution and saturated brine solution, dried and concentrated. The crude was then purified by column chromatography (20% EtOAc in hexanes) to afford a mixture of two isomers, which was further purified by reverse phase HPLC to give 4- chloro-6-[2-(2 -methoxyethoxy) phenyl] -7-phenyl-thieno [3, 2-c] pyridine (41 mg, 19% yield) and 4-chloro- 7-[2-(2 -methoxyethoxy )phenyl]-6-phenyl- thieno[3,2-c]pyridine (64 mg, 30% yield). LCMS ESI (+) m / z 396.1 (M+H).

[0247] Step D: Preparation of tert-butyl 6-[7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2- c]pyridin-4-yl]-3,4-dihydro- lH-isoquinoline-2 -carboxylate: To a suspension of a mixture of 4-chloro-6-[2- (2 -methoxyethoxy )phenyl] -7 -phenyl -thieno [3 ,2-c]pyridine and 4-chloro-7-[2-(2-methoxyethoxy)phenyl] - 6-phenyl-thieno[3,2-c]pyridine (18 mg, 0.046 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-3,4-dihydro-lH-isoquinoline-2-carboxylate (20 mg, 0.056 mmol) and sodium carbonate (14 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (4.0 mg, 0.0055 mmol). The mixture was stirred at 85 °C for 4 hours under Ar. The mixture was concentrated and purified by preparative TLC (EtOAc / petroleum ether: 1 / 4) to give tert-butyl 6-[7-[2-(2-methoxyethoxy)phenyl]-6- phenyl-thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (22 mg, 82%) as a lightyellow solid.

[0248] Step E: Preparation of 7-[2-(2-methoxyethoxy) phenyl]-6-phenyl-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridine: To a solution of tert-butyl 6-[7-[2-(2- methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridm-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate (22 mg, 0.037 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 10 °C for 2 hours. The mixture was concentrated and purified by reverse phase preparative-HPLC to give 7-[2-(2- methoxyethoxy)phenyl]-6-phenyl-4-(l,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridine (15 mg, 83% yield) as a trifluoroacetic acid salt. LCMS ESI (+) m / z 493.2 (M+H).rH NMR (400 MHz, CD3OD) 5: 7.95 (d, J = 4.8 Hz, 1H), 7.85-7.88 (m, 2H),7.72 (d, J = 5.6 Hz, 1H), 7.47-7.55 (m, 3H), 7.42 (t, J = 8.0Hz, 1H), 7.24-7.38 (m, 4H), 7.08 (d, J =8.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.52 (s, 2H), 4.00-4.08 (m, 1H), 3.84-3.88 (m, 1H), 3.60 (t, J = 6.2 Hz, 2H), 3.42-3.53 (m, 2H), 3.15 (s, 3H).Synthetic Example 3: Synthesis of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]benzonitrile (Compound 8)

[0249] Step A: Preparation of 6-(3-iodophenyl)-5H-thieno[3,2-c]pyridin-4-one: To a solution of 2- methylthiophene-3-carboxylic acid (2.00 g, 14.1 mmol) in THF (20 mL) was added n-butyllithium (12.0 mL, 2.5M in hexanes, 30.0 mmol) dropwise under Ar at -78 °C. The mixture was stirred at -60 °C for 0.5 h under Ar. 3 -iodobenzonitrile (3.50 g, 15.3 mmol) was then added at -60 °C. The temperature was allowed to warm to 0 °C, and the resulting mixture was stirred at 0 °C for additional 1 hour. The mixture was poured into water and the pH was adjusted to 5 with IN HC1. The mixture was concentrated to remove THF anddiluted with water. The solid was filtered, washed with water (20 mL) and EtOAc (20 mL), then dried in vacuo to give the crude product 6-(3-iodophenyl)-5H-thieno[3,2-c]pyridin-4-one (2.30 g, 46% yield) as a yellow solid.1H NMR (400 MHz, CDCh): 5 8.14 (s, 1H), 7.77-7.83(m, 2H), 7.64 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.27-7.31 (m, 2H).

[0250] Step B: Preparation of 3-(4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile: A suspension of copper(I) cyanide (76 mg, 0.85 mmol) and 6-(3-iodophenyl)-5H-thieno[3,2-c]pyridin-4-one (200 mg, 0.566 mmol) in DMF (5 mL) was stirred at 130 °C for 16 hours. The mixture was allowed to cool to ambient temperature. Ammonia (1 mL) was added, and the mixture was stirred for additional 2 hours. The pH was adjusted to 6 with 3 N HC1. The solid was collected by filtration, and then washed with water and EtOAc / petroleum ether (1 / 1). The solid was dried in vacuo to give 3-(4-oxo-5H-thieno[3,2-c]pyridin-6- yljbenzonitrile (110 mg, 77% yield) as a yellow solid. LCMS ESI (+) m / z 253.0 (M+H).

[0251] Step C: Preparation of 3-(7-bromo-4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzomtrile: To a solution of crude 3-(4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (1.27 g, 5.03 mmol) in DMF (15 mL) was added N-bromosuccinimide (941 mg, 5.29 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was poured into water and the solid was filtered, washed with water and EtOAc / petroleum ether (1 / 1), then dried in vacuo to give 3-(7-bromo-4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (870 mg, 52% yield) as a yellow solid. LCMS ESI (+) m / z 331, 333 (M+H).

[0252] Step D: Preparation of 3-(7-bromo-4-methoxy-thieno[3,2-c]pyridin-6-yl)benzonitrile: To a suspension of 3-(7-bromo-4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (870 mg, 2.63 mmol) and silver carbonate (761 mg, 2.76 mmol) in toluene (20 mL) was added methyl iodide (0.41 mL, 6.6 mmol). The mixture was stirred at 90 °C for 16 hours in a sealed tube. The mixture was filtered through Celite® and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc / petroleum ether: 1 / 5) to give 3-(7-bromo-4-methoxy-thieno[3,2-c]pyridin-6-yl)benzonitrile (592 mg, 65% yield) as a light-yellow solid.

[0253] Step E: Preparation of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methoxy-thieno[3,2- c]pyridin-6-yl] benzonitrile: To a solution of 3-(7-bromo-4-methoxy-thieno[3,2-c]pyridin-6-yl)benzonitrile (290 mg, 0.840 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added [4-fhioro-2-(2- methoxyethyl)phenyl]boronic acid (216 mg, 1.09 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (61 mg, 0.084 mmol) and sodium carbonate (178 mg, 1.68 mmol). The mixture was stirred at 100 °C for 4 hours. After cooling, the mixture was poured into water (20 mL) and the product was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether:EtOAc=3:l) to give 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methoxy-thieno[3,2-c]pyndin-6-yl]benzonitrile (280 mg. 77% yield). LCMS ESI (+) m / z 435 (M+H).

[0254] Step F: Preparation of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2- c]pyridin-6-yl]benzonitrile: To a solution of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methoxy- thieno[3,2-c]pyridin-6-yl]benzonitrile (205 mg, 0.472 mmol) in acetonitrile (20 mL) were added sodium iodide (212 mg, 1.42 mmol) and trimethylchlorosilane (0.180 mL, 1.42 mmol). The mixture was stirred at 0 °C for 2 hours. The mixture was poured into water (20 mL), and the solid was filtered to give 3-[7-[4- fhioro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridin-6-yl]benzonitrile (150 mg, 76% yield). LCMS ESI (+) m / z 421 (M+H).

[0255] Step G: Preparation of 3-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy) phenyl]thieno[3,2- c]pyridin-6-yl]benzonitrile: A solution of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H- thieno[3,2-c]pyridin-6-yl] benzonitrile (150 mg, 0.357 mmol) in phosphorus oxychloride (3.00 mL, 32.2 mmol) was stirred at 90 °C for 1 hour. After cooling, the mixture was poured into ice-water (20 mL). NaHCOa was carefully added to adjust pH to 8. The product was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether:EA=5: l) to give 3-[4-chloro-7-[4-fhioro-2-(2- methoxyethoxy) phenyl]thieno[3,2-c]pyridin-6-yl]benzonitrile (130 mg, 83% yield). LCMS ESI (+) m / z 439.0 (M+H).

[0256] Step H: Preparation of tert-butyl 6-[6-(3-cyanophenyl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate: To a solution of 3-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]benzonitrile (130 mg, 0.296 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added tert-butyl 6-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro-lH-isoquinoline-2-carboxylate (138 mg, 0.385 mmol), sodium carbonate (63 mg, 0.59 mmol) and l,l'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (22 mg, 0.030 mmol). The mixture was stirred at 95 °C for 2 hours under Ar. After cooling, the mixture was poured into water (20 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine, dried overNa2SC>4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether:EA=3: l) to give tert-butyl 6-[6-(3-cyanophenyl)-7-[4- fluoro-2-(2 -methoxyethoxy )phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoqumoline-2-carboxylate (160 mg, 85% yield). LCMS ESI (+) m / z 636 (M+H).

[0257] Step I: Preparation of 3-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]benzonitrile: To a solution of tert-butyl 6-[6-(3- cyanophenyl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno [3 ,2-c]pyridin-4-yl] -3 ,4-dihydro- 1H- isoquinoline-2 -carboxylate (17 mg, 0.027 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.0 mL,13 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated and the residue was purified by reverse phase preparative-HPLC to give 3-[7-[4-fluoro-2-(2 -methoxyethoxy )phenyl-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]benzonitrile (4.5 mg, 31% yield) as a trifluoroacetic acid salt. LCMS ESI (+) m / z 536 (M+H). 1H NMR (400 MHz, CD3OD) 5 7.89 (s, 1H), 7.81-7.86 (m, 3H),7.68-7.72 (m, 2H), 7.63 (d, J = 8 Hz, 1H), 7.39-7.47 (m, 2H), 7.32-7.35 (m, 1H), 6.90 (dd, J = 11.1, 2.2Hz, 1H), 6.79-6.83 (m, 1H), 4.49 (s, 2H), 3.98-4.01 (m, 1H), 3.83-3.86 (m, 1H), 3.60 (t, J = 6.4 Hz, 2H),3.44 (t, J = 4.8, 2H), 3.26-3.30 (m, 2H), 3.15 (s, 3H).Synthetic Example 4: Synthesis of A-[[3-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]phenyl]methyl]prop-2-enamide (Compound 11)

[0258] Step A: Preparation of tert-butyl 6-[6-[3-(aminomethyl)phenyl]-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate: To a solution of tert-butyl 6-[6-(3-cyanophenyl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin- 4-yl] -3 ,4-dihydro- lH-isoquinoline-2 -carboxylate (178 mg, 0.280 mmol) in methanol (5 mL) were added cobaltous chloride (73 mg, 0.56 mmol) and sodium borohydride (106 mg, 2.80 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate(40 mL). The combined organic layers were washed with brine, dried over NazSCL and concentrated. The residue was purified by preparative TLC (DCM:MeOH=20: l) to give tert -butyl 6-[6-[3- (aminomethyl)phenyl]-7-[4-fluoro-2-(2 -methoxyethoxy )phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro- lH-isoquinoline-2 -carboxylate (135 mg, 75% yield). LCMS ESI (+) m / z 640.3 (M+H).

[0259] Step B: Preparation of tert-butyl 6-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-6-[3-[(prop-2- enoylamino)methyl]phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoqumoline-2-carboxylate: To the solution of tert-butyl 6-[6- [3 -(ammomethyl)phenyl] -7- [4-fluoro-2-(2 -methoxy ethoxy )phenyl]thieno [3,2- c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (12 mg, 0.019 mmol) in DCM (2 mL) was added triethylamme (0.0078 mL, 0.056 mmol). The mixture was cooled to -20 °C. To this was added a solution of prop-2 -enoyl prop-2-enoate (2.8 mg, 0.023 mmol) in DCM. The mixture was stirred for 15 mm at -20 °C. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were concentrated and the residue was purified by preparative TLC (EtOAc / petroleum ether: 50 to 100% EtOAc) to give tert-butyl 6-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-6-[3-[(prop-2- enoylamino)methyl]phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoqumoline-2-carboxylate (12 mg, 92% yield). LCMS ESI (+) m / z 694.3 (M+H).

[0260] Step C: Preparation of N-[[3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]phenyl]methyl]prop-2-enamide: To a solution of tertbutyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-[(prop-2-enoylamino)methyl]phenyl]thieno[3,2- c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (14 mg, 0.020 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred for 1 hour. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase preparative-HPLC to afford N-[[3-[7-[4-fluoro-2-(2 -methoxyethoxy )phenyl]-4-(l, 2, 3, 4-tetrahydroisoquinolin-6-yl)thieno[3, 2- c]pyridin-6-yl]phenyl]methyl]prop-2-enamide (2.3 mg, 1 % yield) as a trifluoroacetic acid salt. LCMS ESI (+) m / z 593.2 (M+H). ^NMR (400 MHz, CD3OD) 5 7.91 (d, J = 5.6 Hz, 1H), 7.84-7.87 (m, 2H), 7.70 (d, J = 5.6 Hz, 1H), 7.45-7.51 (m, 2H), 7.36-7.40 (m, 1H), 7.22 -7.32 (m, 3H), 6.88 (dd, J = 11.1, 2.2 Hz, 1H), 6.75 (td, J = 8.3, 2.3 Hz, 1H), 6.25 (d, J = 6.0 Hz, 2H), 5.70 (t, J = 6.0 Hz, 1H), 4.51 (s, 2H), 4.40 (s, 2H), 3.96 - 4.08 (m, 1H), 3.78 - 3.91 (m, 1H), 3.60 (t, J = 6.3 Hz, 1H), 3.44-3.47 (m, 2H), 3.13 (s, 3H).Synthetic Example 5: Synthesis of A-[3-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]phenyl]prop-2-enamide (Compound 12)

[0261] Step A: Preparation of 3-[4-(2-tert-butoxycarbonyl-3,4-dihydro-lH-isoquinolin-6-yl)-7-[4- fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]benzoic acid: A solution of tert-butyl 6-[6- (3-cyanophenyl)-7-[4-fluoro-2-(2 -methoxyethoxy )phenyl]thieno[3,2-c]pyndin-4-yl]-3,4-dihydro-lH- isoquinoline-2-carboxylate (350 mg, 0.551 mmol) in ethanol (3 mL) and NaOH (2 N, 3 mL) was stirred at 95 °C for 12 h. The mixture was diluted with water (20 mL), and IN HC1 was added to adjust pH to 2. The product was extracted with EtOAc, washed with brine, dried over Na2SC>4, filtered and concentrated to dryness to give 3-[4-(2-tert-butoxycarbonyl-3,4-dihydro-lH-isoquinolin-6-yl)-7-[4-fluoro-2-(2- methoxy ethoxy )phenyl]thieno [3, 2-c]pyridin-6-yl]benzoic acid (310 mg, 86% yield) as a white solid. LCMS ESI (+) m / z 655.3 (M+H).

[0262] Step B: Preparation of tert-butyl 6-[6-[3-(benzyloxycarbonylamino)phenyl]-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate: To a solution of 3-[4-(2 -tert-butoxycarbonyl-3 ,4-dihydro-lH-isoquinolin-6-yl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]benzoic acid (42 mg, 0.064 mmol), triethylamine (0.090 mL, 0.64 mmol) and benzyl alcohol (0.033 mL, 0.32 mmol) in dry toluene (3 mL) was added [azido(phenoxy)phosphoryl]oxybenzene (89 mg, 0.32 mmol). The mixture was stirred at 90 °C for 2 hours. The mixture was concentrated and purified by preparative TLC (EtOAc / petroleum ether: 1 / 2) to give tertbutyl 6-[6- [3 -(benzyloxy carbonylamino)phenyl] -7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno [3 ,2- c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate (36 mg, 74% yield). LCMS ESI (+) m / z 760.2 (M+H).

[0263] Step C: Preparation of tert-butyl 6-[6-(3-aminophenyl)-7-[4-fhioro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate: A solution of tert-butyl 6-[6-[3-(benzyloxycarbonylamino)phenyl]-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate (36 mg, 0.047 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) in 1,4-dioxane (1 mL) and water (1 mL) was stirred at 95 °C for 16 hours under Ar. The mixture was poured into water. The mixture was extracted with EtOAc, dried over anhydrous NajSCL, filtered and concentrated. The residue was purified by preparative TLC (EtOAc / petroleum ether: 1 / 2) to give tert-butyl 6-[6-(3-aminophenyl)-7-[4-fluoro-2- (2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2-carboxylate (24 mg, 81% yield) as a white solid. LCMS ESI (+) m / z 626.3 (M+H).

[0264] Step D: Preparation of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6- [3-(prop-2- enoylamino)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro- lH-isoquinoline-2 -carboxylate: To a solution of tert-butyl 6-[6-(3-aminophenyl)-7-[4-fluoro-2-(2 -methoxyethoxy )phenyl]thieno[3,2-c]pyridin-4-yl]- 3,4-dihydro-lH-isoquinoline-2-carboxylate (12 mg, 0.019 mmol) and N,N-diisopropylethylamine (0.015 mL, 0.085 mmol) in DCM (2mL) was added acryloyl chloride (0.0045 mL, 0.055 mmol) at -30 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was poured into NaHCOa aqueous solution and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSO^ concentrated and purified by preparative TLC (EtOAc / petroleum ether: 1 / 2) to give tert-butyl 6-[7-[4-fluoro-2-(2- methoxy ethoxy )phenyl] -6- [3 -(prop-2-enoylamino)phenyl]thieno [3 ,2-c]pyridin-4-yl] -3 ,4-dihydro- 1H- isoquinoline-2 -carboxylate (12 mg, 92% yield).

[0265] Step E: Preparation of N-[3-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]phenyl]prop-2-enamide: To a solution of tert-butyl 6- [7-[4-fluoro-2-(2-methoxyethoxy)phenyl] -6- [3 -(prop-2-enoylamino)phenyl]thieno [3 ,2-c]pyndm-4-yl] - 3,4-dihydro-lH-isoquinoline-2-carboxylate (12 mg, 0.018 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated and purified by reverse phase preparative-HPLC to give N-[3-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]phenyl] prop-2-enamide (7.4 mg, 72% yield) as a trifluoroacetic acid salt. LCMS ESI (+) m / z 580.2 (M+H). ‘H NMR (400 MHz, CD3OD) 5 8.06 (s, 1H), 7.83-7.87 (m, 3H), 7.68 (d, J = 5.6 Hz, 1H), 7.45-7.49 (m, 2H), 7.29 (dd, J = 8.4, 6.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.10-7.14 (m, 1H), 6.88 (dd, J = 11.0, 1.0 Hz, 1H), 6.74-6.80 (m, 1H), 6.32-6.46 (m, 2H), 5.76 (dd, J =9.6, 2.1 Hz, 1H), 4.50 (s, 2H), 3.99-4.50 (m, 1H), 3.82-3.87 (m, 1H), 3.60 (t, J = 6.4 Hz, 2H), 3.45- 3.49 (m, 2H), 3.12 (s, 2H).Synthetic Example 6: Synthesis of A-[2-[7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]-3H-benzimidazol-5-yl]prop-2-enamide (Compound23)

[0266] Step A: Preparation of tert-butyl 6-(6-((2 -ammo-5 -nitrophenyl)carbamoyl)-7-(4-fluoro-2-(2- methoxyethoxy)phenyl)thieno[3,2-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate: To a solution of 4-(2-tert-butoxycarbonyl-3,4-dihydro-lH-isoquinolin-6-yl)-7-[4-fluoro-2-(2- methoxy ethoxy )phenyl]thieno [3, 2-c]pyridine-6-carboxylic acid (100 mg, 0.173 mmol) in DMF (2 mL) were added HATU (99 mg, 0.26 mmol) and TEA (0.072 mL, 0.52 mmol). After the mixture was stirred at ambient temperature for 15 min, 4-nitrobenzene-l,2-diamine (32 mg, 0.21 mmol) was added. The resulting mixture was stirred at 30 °C for 2 hours. The reaction was quenched with water and extracted with EtOAc twice. The combined organic phases were washed with saturated NH4CI and brine, dried and concentrated. The residue was purified by preparative TLC (EtOAc / petroleum ether: 1 / 2) to afford tert-butyl 6-(6-((2- amino-5-nitrophenyl)carbamoyl)-7-(4-fluoro-2-(2 -methoxyethoxy )phenyl)thieno[3,2-c]pyridin-4-yl)-3, 4- dihydroisoquinoline-2(lH)-carboxylate (80 mg, 65% yield). LCMS ESI (+) m / z 714.2 (M+H).

[0267] Step B: Preparation of 2-(7-(4-fhioro-2-(2-methoxyethoxy)phenyl)-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl)-lH-benzo[d]imidazol-6-amine: To a solution of tertbutyl 6-[6-[(2-amino-5-nitro-phenyl)carbamoyl]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate (73 mg, 0.10 mmol) in ethanol (1 mL) was added stannous chloride dihydrate (162 mg, 0.716 mmol). Concentrated hydrochloric acid (0.5 mL) was added to the reaction mixture. The reaction mixture was refluxed for 4 hours. Upon completion, the reactionmixture was basified with 30% sodium hydroxide solution. The mixture was extracted with dichloromethane (20 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by preparative TLC (DCM / MeOH (containing 0.2% EtsN): 20 / 1) to afford 2-(7-(4-fluoro-2-(2 -methoxyethoxy )phenyl)-4-(l, 2, 3, 4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6- yl)-lH-benzo[d]imidazol-6-amine (60 mg, 93% yield). LCMS ESI (+) m / z 566.2 (M+H).

[0268] Step C: Preparation of tert-butyl 6-(6-(6-amino-lH-benzo[d] imidazol-2-yl)-7-(4-£hioro-2-(2- methoxyethoxy)phenyl)thieno[3,2-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate: To a solution of 2-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(l,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2- c]pyridin-6-yl]-3H-benzimidazol-5 -amine (60 mg, 0.096 mmol) in 1,4-dioxane (4 mL) and water (2 mL) was added NaOH (19 mg, 0.48 mmol) and di-tert-butyl dicarbonate (21 mg, 0.096 mmol). The reaction was stirred at 30 °C for 1 hour. The reaction was quenched with water and extracted with DCM twice. The organic layers were washed with brine, dried and concentrated. The residue was purified by preparative TLC (EtOAc) to afford tert-butyl 6-(6-(6-amino-lH-benzo[d]imidazol-2-yl)-7-(4-fluoro-2-(2- methoxyethoxy)phenyl)thieno[3,2-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (65 mg, 82% yield). LCMS ESI (+) m / z 666.2 (M+H).

[0269] Step D: Preparation of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6- [6-(prop-2- enoylamino)-lH-benzimidazol-2-yl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2- carboxylate: To a solution of tert-butyl 6-[6-(6-amino-lH-benzimidazol-2-yl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-lH-isoquinoline-2 -carboxylate (65 mg, 0.078 mmol) in DCM (3 mL) was added triethylamine (0.033 mL, 0.23 mmol). Solution of acryloyl chloride (0.0063 mL, 0.078 mmol) in DCM was added at -30 °C. The mixture was stirred at 30 °C for 1 hour and then quenched with water and extracted with DCM twice. The organic layers were washed with brine, dried and concentrated. The residue was purified by preparative TLC (EtOAc) to afford tert-butyl 6-[7-[4-fluoro- 2-(2-methoxyethoxy )phenyl]-6-[6-(prop-2 -enoylamino)- lH-benzimidazol-2-yl]thieno[3,2-c]pyridin-4- yl] -3 ,4-dihydro-lH-isoquinoline-2 -carboxylate (40 mg, 71% yield). LCMS ESI (+) m / z 720.3 (M+H).

[0270] Step E: Preparation of N-[2-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(l, 2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]-3H-benzimidazol-5-yl]prop-2-enamide: To a solution of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[6-(prop-2-enoylamino)-lH- benzimidazol-2-yl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro- lH-isoquinoline-2-carboxylate (40 mg, 0.056 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The mixture was stirred at 30 °C for 1 h. The mixture was concentrated and purified by reverse phase preparative-HPLC to afford N-[2- [7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(l,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6- yl]-3H-benzimidazol-5-yl]prop-2-enamide (18 mg, 52% yield). LCMS ESI (+) m / z 620.2 (M+H).rHNMR (400 MHz, CD3OD) 5 8.48 (s, 1H), 8.06 (d, J = 5.6 Hz, 1H), 7.99-8.01 (m, 2H), 7.85 (d, J = 5.4 Hz, 1H),7.77 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.49-7.53 (m, 2H), 6.97-7.04 (m, 2H), 6.38-6.52 (m, 2H), 5.83 (dd, J = 9.3, 2.3 Hz, 1H), 4.53 (s, 2H), 3.88-3.95 (m, 1H), 3.72-3.80 (m, 1H), 3.61 (t, J = 6.3 Hz 2H), 3.20-3.30 (m, 4H), 2.96 (s, 3H).Synthetic Example 7: Synthesis of l-[3-[4-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4- (1,2, 3, 4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]pyrazol-l-yl]azetidin-l-yl]prop-2-en-l-one (Compound 44)

[0271] Step A: Preparation of N,N-diethyl-2-[[4-fluoro-2-(2-methoxyethoxy)phenyl]-hydroxy- methyl]thiophene-3-carboxamide: A solution of N,N-diethylthiophene-3-carboxamide (7.00 g, 38.2 mmol) in THF (50 mL) was cooled to -78 °C. n-Butyllithium (15.0 mL, 2.5 M in THF, 36.3 mmol) was added dropwise. The mixture was stirred at -60 °C for 0.5 h, and a solution of 4-fluoro-2-(2- methoxyethoxy)benzaldehyde (7.12 g, 35.9 mmol) in THF (20 mL) was added dropwise. The resultingmixture was stirred at 0 °C for 1 hour. Aqueous NH4CI solution was added slowly to quench the reaction. The product was extracted with EtOAc. The combined organic phases were washed with brine, dried over NajSCE and concentrated. The residue was then purified by column chromatography (petroleum ether / EtOAc 2: 1) to give N, N-diethyl-2-[[4-fluoro-2-(2 -methoxyethoxy )phenyl]-hydroxy- methyl]thiophene-3 -carboxamide (9.60 g, 66% yield). LCMS ESI (+) m / z 714.2 (M+H).

[0272] Step B: Preparation of N,N-diethyl-2-[[4-fluoro-2-(2- methoxyethoxy)phenyl]methyl]thiophene-3-carboxamide: To a solution of N,N-diethyl-2-[[4-fhroro-2-(2- methoxyethoxy)phenyl]-hydroxy-methyl]thiophene-3-carboxamide (9.60 g, 25.2 mmol) in methanol (80 mL) was treated with 10% Pd / C (9.6 g) under hydrogen atmosphere at 50 °C for 2 days. The mixture was filtered through Celite® with methanol rinse (2 x 50 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc 5: 1) to give N,N-diethyl-2-[[4- fluoro-2-(2-methoxyethoxy)phenyl]methyl]thiophene-3-carboxamide (7.20 g, 78% yield) as a yellow oil. 1HNMR (400 MHz, CD3OD) 5: 7.13 (t, J = 7.6 Hz, 1H), 7,70 (d, J = 5.2 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6,56-6.60 (m, 2H), 4.08-4.12 (m, 4H), 3.77 (t, J = 4.8 Hz, 2 H), 3.51 (q, J = 6.8 Hz, 2H), 3.14 (q, J = 6.8 Hz, 2H), 1.21 (t, J = 6.8 Hz, 3H), 1.02 (t, J = 6.8 Hz, 3H).

[0273] Step C: Preparation of 7-(4-fluoro-2-(2-methoxyethoxy)phenyl)-6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol: To a solution N,N-diethyl-2- [[4-fhioro-2-(2-methoxyethoxy)phenyl]methyl]thiophene-3-carboxamide (3.50 g, 9.58 mmol) in THF (40 mL) was added n-BuLi (2.5 M solution in hexanes, 8.40 mL, 21.1 mmol) dropwise at -78 °C. The mixture was stirred at -65 °C for 1 hour. A solution of l-(2-trimethylsilylethoxymethyl)pyrazole-4-carbonitrile (2.14 g, 9.58 mmol) in THF (10 mL) was then added, and the resulting mixture was stirred at ambient temperature for additional 2 hours. The reaction was quenched by the addition of water. 1 M aqueous HC1 was added to adjust pH to 5. The mixture was diluted with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / DCM = 1: 100 to 1:60) to give 7-(4-fluoro-2-(2 -methoxyethoxy )phenyl)-6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4- yl)thieno[3,2-c]pyndm-4-ol (3.1 g, 63% yield) as a yellow solid. LCMS ESI (+) m / z 516.2 (M+H).

[0274] Step D: Preparation of 7-(4-fluoro-2-(2 -methoxyethoxy )phenyl)-6-(lH-pyrazol-4- yl)thieno[3,2-c]pyndm-4-ol: To a solution of 7-[4-fhioro-2-(2-methoxyethoxy)phenyl]-6-[l-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-4-ol (3.10 g, 6.02 mmol) in DCM (27 mL) was added TFA (9 mL). The mixture was stirred at ambient temperature for 2 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL). Saturated sodium bicarbonate solution was added to adjust pH to 9 and the mixture was stirred for addition 0.5 h. The mixture was filtered and the filter cake was collected and dried in vacuo to give 7-(4-fluoro-2-(2-methoxyethoxy)phenyl)-6-(lH-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol (1.8 g, 78% yield) as an off-white solid which was used in the next step without further purification. LCMS ESI (+) m / z 386.1 (M+H).

[0275] Step E: Preparation of 4-chloro-7-(4-fluoro-2-(2-methoxyethoxy)phenyl)-6-(lH-pyrazol-4- yl)thieno[3,2-c]pyndme: To a solution of 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-(lH-pyrazol-4- yl)thieno[3,2-c]pyndm-4-ol (1.80 g, 4.67 mmol) in phosphorus oxychloride (25 mL) was added DMF (0.2 mL). The mixture stirred for 14 hours at 100 °C. The mixture was concentrated under vacuum. The residue was diluted with DCM (15 mL) and poured into ice water (80 mL). Saturated sodium bicarbonate solution was added to adjust pH to 9. The product was extracted EtOAc (70 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (MeOH / DCM = 1: 100 to 1:70) to give 4-chloro-7-(4-fluoro-2-(2-methoxyethoxy)phenyl)-6-(lH-pyrazol- 4-yl)thieno[3,2-c]pyridine (1.2 g, 64% yield) as a yellow solid. LCMS ESI (+) m / z 404.1 (M+H).

[0276] Step F: Preparation of tert-butyl 3-[4-[4-chloro-7-[4-fluoro-2- (2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]pyrazol-l-yl]azetidine-l-carboxylate: A suspension of 4- chloro-7-[4-fluoro-2-(2-methoxy ethoxy )phenyl]-6-(lH-pyrazol-4-yl)thieno [3, 2-c]pyridine (70 mg, 0.17 mmol), tert-butyl 3 -iodoazetidine -1 -carboxylate (147 mg, 0.520 mmol) and cesium carbonate (282 mg, 0.867 mmol) in DMF (2 mL) was stirred at 80 °C for 2 hours. The mixture was diluted with water (30 mL), and the product was extracted with EtOAc (40 mL x 3). The organic layers were washed with saturated brine solution, dried over Na2SO4 and concentrated. The crude was then purified by preparative TLC (MeOH / DCM = 1 / 20) to give tert-butyl 3-[4-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridin-6-yl]pyrazol-l-yl]azetidine-l -carboxylate (80 mg, 83% yield) as colorless oil. LCMS ESI (+) m / z 559.1 (M+H).

[0277] Step G: Preparation of 6-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4-chloro-7-(4-fluoro-2-(2- methoxyethoxy)phenyl)thieno[3,2-c]pyridine: To a solution of tert-butyl 3-[4-[4-chloro-7-[4-fluoro-2-(2- methoxy ethoxy )phenyl]thieno [3, 2-c]pyridin-6-yl]pyrazol-l-yl]azetidine-l -carboxylate (80 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated to dryness to give crude 6-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4-chloro-7- (4-fluoro-2-(2-methoxyethoxy)phenyl)thieno[3,2-c]pyridine (100 mg), which was used in the next step without further purification. LCMS ESI (+) m / z 459.1 (M+H).

[0278] Step H: Preparation of l-[3-[4-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridin-6-yl]pyrazol-l-yl]azetidin-l-yl]prop-2-en-l-one: To a solution of 6-[l-(azetidin-3-yl)pyrazol-4- yl]-4-chloro-7-[4-fluoro-2-(2 -methoxyethoxy )phenyl]thieno[3,2-c]pyridine (62 mg, 0.14 mmol) and triethylamine (0.056 mL, 0.41 mmol) in DCM (3 mL) was added prop-2-enoyl prop-2-enoate (20 mg, 0.16 mmol). The mixture was stirred at -60 °C for 1 hour. The mixture was quenched with saturated sodium bicarbonate solution (2 mL) and diluted with water (10 mL). The product was extracted with EtOAc (20mL x 3). The combined organic layers were washed with brine (10 mL), dried over NaiSCL, fdtered and concentrated. The residue was purified by preparative TLC (MeOH / DCM: 1 / 20) to give l-[3-[4-[4-chloro- 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]pyrazol-l-yl]azetidin-l-yl]prop-2-en- l-one (60 mg, 87% yield). LCMS ESI (+) m / z 513.1 (M+H).

[0279] Step I: Preparation of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[l-(l-prop-2- enoylazetidin-3-yl)pyra...

Claims

CLAIMS A compound of formula I:or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:Ring A is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is selected from a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6- membered heteroaryl ring, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and phenyl;Ring C is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 8-membered bicyclic carbocyclic ring; a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, 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 Ci-6 aliphatic chain substituted with Ring D'; each -L-W is -CN, or: each L is independently a bivalent straight or branched Cus aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)- , -C(X)2-, -C(0)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-; each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen, -OR, or -CN; each Ring D' is independently a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D' is substituted with t instances of -L-W; each R2and R2is independently selected from oxo, halogen, -CN, -OR, and C1-6 alkyl; each R3is independently selected from oxo, halogen, -CN, -OR, -O(CH2)vCy, -OCH2CH2OR, and optionally substituted Ci-6 aliphatic; each Cy is independently a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 6-membered carbocyclic ring; or a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-2 instances of R6; each R4is independently selected from halogen and optionally substituted C1-6 aliphatic; each of R5and R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, - C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -C(O)N(R)2, -C(O)N(R)(CH2)xCy, - (CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, - P(O)R2, -(CH2)xCy, -O(CH2)xCy, and optionally substituted C1-6 aliphatic; each R6is independently selected from oxo, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, - N(R)C(O)R, -C(O)N(R)2, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -SO2N(R)2, and an optionally substituted group selected from C1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1; r is 0, 1, or 2; s is 0, 1, 2, or 3; t is 0, 1, or 2; u is 0 or 1; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; and y is 0, 1, or 2. The compound of claim 1, wherein the compound is a compound according to Formula IA:IA or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 2, wherein the compound is a compound according to Formula IA1 :IA1 or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to Formula IB:or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 4, wherein the compound is a compound according to Formula IB 1 :IB1 or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to Formula IC:or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 6. wherein the compound is a compound according to Formula IC1 :IC1 or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to Formula ID:ID or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 8, wherein the compound is a compound according to Formula ID1 :ID1 or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to Formula IE:IE or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 10, wherein the compound is a compound according to Formula IE 1 :IE1 or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to Formula IF:or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 12, wherein the compound is a compound according to Formula IF 1 :IF1 or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, or I-k:I-k or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- a-z, I-b-z, I-c-z, I-d-z, I-e-z, I-f-z, I-g-z, I-h-z, I-i-z, I-j-z, or I-k-z:I-k-z or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- a-zz I-b-zz I-c-ii I-d-zz I-e-zz I-f-zz I-g-zz I-h-zz I-i-zz I-j-zz or I-k-zzI-k-H’ or a salt (e.g., pharmaceutically acceptable salt) thereof.

17. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- a-zzz, I-b-izz, I-c-iii, I-d-zzz, I-e-zzz, I-f-iii, I-g-iii, I-h-zzz, I-i-zzz, I-j-zzz, or I-k-iii:or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- a-zv, I-b-zv, I-c-zv, I-d-zv, I-e-zv, I-f-zv, I-g-zv, I-h-zv, I-i-zv, I-j-zv, or l-k-zv:I-k- / v or a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- a-v', I-b-v I-c-v I-d-v I-e-v I-f-v I-g-v I-h-v I-i-v I-j-v or I-k-vor a salt (e.g., pharmaceutically acceptable salt) thereof. The compound of claim 1, wherein the compound is a compound according to one of Formulae I- 1, 1-m, I-n, I-p, I-q, or I-r:The compound of claim 22, wherein Ring A is selected fromThe compound of claim 23, wherein Ring A is selected fromThe compound of any one of claims 21-24, wherein Ring A, substituted with m instances of R3, is selected fromThe compound of any one of claims 1-20, wherein Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of claim 26, wherein Ring A substituted with m instances of R3is selected fromThe compound of any one of claims 1-27, wherein m is 1, 2, or 3. The compound of any one of claims 1-28, wherein at least one R3is selected from halogen, -OR, - O(CH2)vCy, and -O-(Ci-4 alkylene)-OR. The compound of any one of claims 1-29, wherein Ring B is selected from a 9- to 10-membered bicyclic ring that comprises at least one 5- or 6-membered heteroaryl ring comprising at least one nitrogen atom. The compound of claim 30, wherein Ring B, substituted with n instances of R4, is selected fromThe compound of any one of claims 1-29, wherein Ring B is selected from a 6-membered heteroaryl ring having 1-2 nitrogen atoms. The compound of claim 32, wherein Ring B, substituted with n instances of R4, is selected from:The compound of any one of claims 1-29, wherein Ring B is phenyl. The compound of any one of claims 1-34, wherein each R4is halogen. The compound of any one of claims 1-3 , wherein n is 0. The compound of any one of claims 1-36, wherein Ring C is phenyl. The compound of any one of claims 1-36, wherein Ring C is selected from a 5- to 6-membered heteroary l ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of any one of claims 1-36, wherein Ring C is selected from a 5- to 8-membered bicyclic carbocyclic ring. The compound of any one of claims 1-36, wherein Ring C is selected from a 4- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of any one of claims 1-36, wherein Ring C is selected from a 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of any one of claims 1-41, wherein Ring C is not fused to Ring E, and Ring C, substituted with p instances of R5, is selected from:I£643. The compound of any one of claims 1-41, wherein Ring C is fused to Ring E.The compound of claim 43 or 44, wherein Ring E is selected from a 5- to 6-membered carbocyclic ring, wherein Ring E is substituted by s instances of R5. The compound of claim 43 or 44, wherein Ring E is selected from a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. The compound of claim 43 or 44, wherein Ring E is selected from a 7- to 10-membered spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E is substituted by s instances of R5. The compound of claim 43 or 44, wherein Ring E is selected from 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. The compound of any one of claims 43-48, wherein Ring C is fused to Ring E, and Ring E, substituted with s instances of R5, is selected from:8£66£6The compound of any one of claims 1-50, wherein each R5is independently selected from oxo,=NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, - C(O)N(R)(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)(R)2, -(CH2)xCy, -O(CH2)xCy, and Ci-6 aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, -CN, -N(R)C(O)R, -N(R)2, or -OR. The compound of any one of claims 1-51, wherein p is 0. The compound of any one of claims 1-51, wherein p is 1 or 2. The compound of any one of claims 1-53, wherein each R5is independently selected from oxo, =NH, -CN, halogen, -OR, -N(R)2, -SR, -C(O)R, -N(R)C(O)R, -(CH2)XC(O)N(R)2, -(CH2)xC(O)Cy, -OC(O)R, -C(O)OR, -SO2R, -N(R)SO2R, -N=S(O)(R)2, -SO2N(R)2, -P(O)(R)2, -(CH2)XCY, - O(CH2)xCy, and Ci-6 aliphatic, wherein Ci-6 aliphatic is unsubstituted or substituted with one or more halogen, -CN, -N(R)C(O)R, -N(R)2, or -OR. The compound of any one of claims 1-54, wherein s is 0. The compound of any one of claims 1-54, wherein s is 1 or 2. The compound of any one of claims 1-56, wherein Ring D is phenyl. The compound of any one of claims 1-56, wherein Ring D is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of any one of claims 1-58, wherein Ring D is fused to Ring F. The compound of claim 59, wherein q is 0. The compound of claim 60, whereinselected from:The compound of any one of claims 59-63, wherein u is 1. The compound of any one of claims 59-64, wherein each R2is independently selected from Ci-6 alkyl.The compound of any one of claims 59-65. wherein y is 0. The compound of any one of claims 59-65, wherein y is 1 or 2. The compound of any one of claims 1-58, wherein Ring D is not fused to Ring F. The compound of claim 68, wherein Ring D, substituted with r instances of R2and q instances ofR1, is selected from:The compound of claim 68, wherein R1is -L-W.The compound of claim 68, wherein R1is Ring D' or a bivalent Ci-6 aliphatic chain substituted with Ring D'.The compound of claim 71, wherein Ring D' is selected from a 4- to 6-membered carbocyclic ring, wherein Ring D' is substituted with t instances of-L-W.The compound of claim 71, wherein Ring D' is selected from 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.The compound of any one of claims 71-73, wherein Ring D', substituted with t instances of-L-W,The compound of any one of claims 71-74, wherein Ring D, substituted with r instances of R2, is76. The compound of any one of claims 71-73, wherein Ring D is substituted with 1 instance of R1, R1The compound of any one of claims 68-76, wherein q is 1. The compound of any one of claims 1-77, wherein r is 0. The compound of any one of claims 1-77, wherein r is 1 or 2. The compound of any one of claims 1-79, wherein t is 0. The compound of any one of claims 1-79, wherein t is 1. The compound of any one of claims 1-81, wherein each L is independently selected from a bivalent straight or branched Ci-s aliphatic chain, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2- , -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(0)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. The compound of claim 1-82, wherein each L is independently selected from a bivalent straight or branched Ci-s aliphatic chain having one or more units of unsaturation, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, -S-, -C(O)-, -SO2-, -CH(X)-, -C(X)2-, -C(O)N(R)-, -N(R)C(0)-, -C(O)O-, - OC(O)-, -SO2N(R)-, and -N(R)SO2-. The compound of claim 83, wherein each L is independently selected from a bivalent straight or branched Ci-s aliphatic chain having one double bond, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, - C(O)-, -SO2-, -C(0)N(R)-, -N(R)C(0)-, -C(O)O-, -OC(O)-, -SO2N(R)-, and -N(R)SO2-. The compound of any one of claims 1-84 , wherein each L is independently selected from a bivalent straight or branched Ci-s aliphatic chain, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -O-, C(O)-, -C(0)N(R)- , and -N(R)C(0)-. The compound of any one of claims 1-85, wherein each L is independently selected from a bivalent straight or branched C1-4 aliphatic chain.The compound of any one of claims 1-86, wherein each L is independently selected from a bivalent straight or branched CM aliphatic chain having one double bond, wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from -N(R)-, -C(O)-, and -N(R)C(O)-.The compound of any one of claims 1-87, wherein each L is independently selected from - C(O)CC1F-, -C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH2)-, -C(O)CH=CH-CH2- -C(O)CH=CHCH2OCH2-, -C(O)CH=CHCH2N(R)-, -CH2N(R)C(O)CH=CH-, and -CH2CH2N(R)C(O)CH=CH-.The compound of any one of claims 1-88, wherein each W is hydrogen.The compound of any one of claims 1-88, wherein each W is a halogen.The compound of any one of claims 1-90, wherein each -L-W is independently selected from -The compound of any one of claims 1-91, 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.

93. The compound of any one of claims 1-92, wherein R1is selected from -CH3, -CH(CH3)2, -The compound according to any one of claims 1-93, wherein each R is independently hydrogen, Ci-6 aliphatic, or Ci-6 haloaliphatic. A compound selected from Table 1, or a salt (e.g., pharmaceutically acceptable salt) thereof. A compound selected from Table 2, or a salt (e.g., pharmaceutically acceptable salt) thereof. A pharmaceutical composition comprising a compound according to any one of claims 1-96, or a salt (e.g., pharmaceutically acceptable salt) thereof, and a pharmaceutically acceptable carrier or excipient. A method comprising administering a therapeutically effective amount of a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof to a subject in need thereof. The method of claim 98, wherein the subject has a disease, disorder, or condition ameliorated by disruption, inhibition, and / or prevention of an interaction between a small GTPase and a PI3Ka protein. The method of claim 99, wherein the small GTPase is Rael, CDC42, or a RAS protein. The method of claim 100, wherein the small GTPase is a RAS protein. The method of claim 101, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITE The method of any one of claims 98-102, wherein the subject has a cancer. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof. The method of claim 103 or 104, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in PI3Ka. The method of claim 105, wherein the PI3Ka protein comprises aN345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El 1 Odel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. The method of claim 106, wherein the PI3Ka protein comprises a E542K, E545K, H1047R, and / or Hl 047L mutation. The method of any one of claims 103-107, wherein the cancer is characterized by a mutation in a RAS protein. The method of claim 108, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The method of claim 108 or 109, wherein the RAS protein is KRAS. The method of claim 110, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.The method of claim 111, wherein the KRAS protein comprises a G12C or G12D mutation. The method according to claim 108 or 109, wherein the RAS protein is HRAS. The method according to claim 113, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to claim 108 or 109, wherein the RAS protein is NRAS. The method according to claim 115, wherein the 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. The method according to any one of claims 103-116, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel 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. The method according to claim 117, wherein the 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. The method according to any one of claims 103-118, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kmases (e.g., HER family, Met, EGER, Aik, PDGF, EGFR, or ROS kinases) The method according to any one of claims 103-119, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. The method according to any one of claims 98-120, wherein the subject has previously undergone a treatment regimen for cancer. The method according to any one of claims 98-121, wherein the subject has previously entered remission from cancer.A method of treating a metabolic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof. The method according to claim 123, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes. A method of treating a RASopathy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof. The method according to claim 125, wherein the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome. A method of treating a vascular disorder or condition, comprising administering to a subj ect in need thereof a therapeutically effective amount of a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof. The method according to claim 127, wherein the vascular disorder or condition is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibro-adipose vascular anomaly (FAVA)). A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein in a subject, comprising administering to the subject a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein, comprising contacting a cell containing the small GTPase and the PI3Ka protein with a compound according to any one of claims 1 -96 or a pharmaceutically acceptable salt thereof. A method comprising contacting a cell containing a small GTPase and a PI3Ka protein with a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof. The method of claim 130 or 131, wherein the cell is included in a subject. The method of any one of claims 129-132, wherein the small GTPase is selected from Rael,CDC42, and a RAS protein. The method of claim 133, wherein the small GTPase is a RAS protein. The method of claim 134, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. The method of claim 135, wherein the RAS protein is KRAS.The method of claim 136, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method of claim 137, wherein the KRAS protein comprises a G12C or G12D mutation. The method according to claim 135, wherein the RAS protein is HRAS. The method according to claim 139, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method according to claim 135, wherein the RAS protein is NRAS. The method according to claim 141, wherein the 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. A compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof for use as a medicament. Use of a compound according to any one of claims 1-96 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. The compound or use according to claim 143 or 144, wherein the medicament is for treating a cancer. The compound or use according to claim 145, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in PI3Ka. The compound or use according to claim 146, wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. The compound or use according to claim 147, wherein the PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. The compound or use according to any one of claims 145-148, wherein the cancer is characterized by a mutation in a RAS protein. The compound or use according to claim 149, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The compound or use according to claim 149 or 150, wherein the RAS protein is KRAS. The compound or use according to claim 151, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, GBR, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.The compound or use according to claim 152, wherein the KRAS protein comprises a G12C or G12D mutation. The compound or use according to claim 149 or 150, wherein the RAS protein is HRAS. The compound according to claim 154, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound or use according to claim 149 or 150, wherein the RAS protein is NRAS. The compound or use according to claim 156, wherein the 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. The compound or use according to any one of claims 145-157, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel 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. The compound or use according to claim 158, wherein the 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. The compound or use according to any one of claims 145-159, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). The compound or use according to any one of claims 145-159, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. The compound or use according to claim 143 or 144, wherein the medicament is for treating a metabolic disorder, a RASopathy, or a vascular disorder.The compound or use according to claim 162, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NFl), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome; and / or (iii) the vascular disorder or condition is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); or fibro-adipose vascular anomaly (FAVA)). A compound according to any one of claim 1-96 or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition. The compound for use according to claim 164 for use in treating a cancer. The compound for use according to claim 165, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in PI3Ka. The compound for use according to claim 166, wherein the PI3Ka protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. The compound for use according to claim 167, wherein the PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. The compound for use according to any one of claims 165-168, wherein the cancer is characterized by a mutation in a RAS protein. The compound for use according to claim 169, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The compound for use according to claim 169 or 170, wherein the RAS protein is KRAS. The compound for use according to claim 171, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound for use according to claim 172, wherein the KRAS protein comprises a G12C or G12D mutation. The compound for use according to claim 169 or 170, wherein the RAS protein is HRAS. The compound for use according to claim 174, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound for use according to claim 169 or 170, wherein the RAS protein is NRAS.The compound for use according to claim 176, wherein the 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. The compound for use according to any one of claims 165-177, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel 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. The compound for use according to claim 178, wherein the 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. The compound for use according to any one of claims 165-179, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). The compound for use according to any one of claims 165-180, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. The compound for use according to claim 164 for use in treating a metabolic disorder, a RASopathy, or a vascular disorder. The compound for use according to claim 182, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NFl), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome; and / or (iii) the vascular disorder or condition is selected from PIK3CA-related overgrowth syndrome (PROS) and vascular malformations (e g., venous malformations; lymphatic malformations; congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibro-adipose vascular anomaly (FAVA)).A compound capable of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein. The compound of claim 184, wherein the compound is capable of binding to PI3Ka, such that (i) the interaction between the small GTPase and PI3Ka is at least partially disrupted, prevented, or inhibited; and / or (ii) the kinase activity of PI3Ka is not significantly inhibited. The compound of claim 184 or 185, wherein the compound has an activity of:(i) < 5 pM or > 5 pM and < 25 pM in the assay of Biological Example 1 (e.g., a surface plasmon resonance (SPR) binding assay assessing inhibition of the KRAS-PI3Ka interaction);(ii) > 75%, <75% and > 50%, or <50% and > 25% in the assay of Biological Example 2 (e.g., a Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis of covalent modification of Cys242 in human PIK3CA (157- 299);(iii) < 1 pM or > 1 pM and < 10 pM in the assay of Biological Example 3 (e.g., a matrix- assisted cell-based pAKT homogenous time-resolved fluorescence (HTRF) assay in Teton KRAS G12D HeLa cells); and / or(iv) < 0.1 pM, > 0.1 pM and < 1 pM, or > 1 pM and < 3 pM in the assay of Biological Example 4 (e.g., a matrix-assisted cell-based pAKT HTRF assay in BT474 cells). The compound of any one of claims 184-186, wherein the compound comprises an electrophilic moiety. The compound of any one of claims 184-187, wherein the compound is capable of interacting with a Cys242 residue in the catalytic subunit of PI3Ka. The compound of any one of claims 184-188, wherein the compound is capable of irreversibly binding the PI3Ka protein. The compound of any one of claims 184-189, wherein the compound is capable of reversibly binding the PI3Ka protein. The compound of any one of claims 184-190, wherein the small GTPase is Rael, CDC42, or a RAS protein. The compound of claim 191, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITl. The compound of claim 191 or 192, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. The compound of claim 192 or 193, wherein the RAS protein is KRAS.The compound of claim 194, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound of claim 195, wherein the KRAS protein comprises a G12C or G12D mutation. The compound of claim 192 or 193, wherein the RAS protein is HRAS. The compound of claim 197, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound of claim 192 or 193, wherein the RAS protein is NRAS. The compound of claim 199, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The compound of any one of claims 184-200, wherein the compound is a compound according to any one of claims 1-96. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Ka protein, comprising contacting a cell containing the small GTPase and the PI3Ka protein with a compound according to any one of claims 184-201 or a pharmaceutically acceptable salt thereof. The method of claim 202, wherein the cell is within a subject. The method of claim 202 or 203, wherein the small GTPase is Rael, CDC42, or a RAS protein. The method of claim 204, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RITE The method of claim 205, wherein the RAS protein comprises a mutation in codon 12, B, or 6E The method of claim 205 or 206, wherein the RAS protein is KRAS. The method of claim 207, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, GBR, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method of claim 208, wherein the KRAS protein comprises a G12C or G12D mutation. The method of claim 205 or 206, wherein the RAS protein is HRAS. The method of claim 210, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, GBR, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. The method of claim 205 or 206, wherein the RAS protein is NRAS.The method of claim 212, wherein the 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.