Fused pyridines for the treatment of cancer and other indications

Abstract

Provided herein are compounds of Formula I" and Formula II and compositions thereof that are 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

FUSED PYRIDINES FOR THE TREATMENT OF CANCER AND OTHER INDICATIONS GOVERNMENT SUPPORT

[0001] This invention was made with government support under 75N91019D00024 awarded by the National Institutes of Health and under DE-AC52-07NA27344 awarded by the United States Department of Energy. The government has certain rights in the invention. CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and benefit of U.S. Application No.63 / 518,242, filed August 8, 2023, and U.S. Application No. 63 / 666,479, filed July 1, 2024, 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., PI3Kα) and a small GTPase (e.g., Rac1, 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., PI3Kα) while displaying (i) no or minimal binding to a small GTPase (e.g., Rac1, 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., PI3Kα). 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 form, such as salt forms) useful in disrupting, inhibiting, and / or preventing an interaction between a PI3K protein (e.g., PI3Kα) and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). In some embodiments, the present disclosure provides compounds capable of binding a PI3Kα protein, such that (i) the interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3Kα protein is disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of the PI3Kα protein is not inhibited. In some embodiments, such compounds are useful for treating a cancer or other indication, as described herein.

[0008] In some embodiments, the present disclosure provides a compound of Formula I’’: or a salt (e.g., a pharmaceutically, ach of Ring A, Ring B, Ring C, Ring D, L, R1, R2, R3, R4, R5, R6, R6’, m, n, p, q, and r is as defined herein.

[0009] In some embodiments, the present disclosure provides a compound of Formula I’:or a salt (e.g., a pharmaceutically ach of Ring A, Ring B, Ring C, Ring 1D, L, R , R2, R3, R4, R5, R6, R6’, m, n, p, q, and r is as defined herein.

[0010] In some embodiments, the present disclosure provides a compound of Formula I: or a salt (e.g., a pharmaceuticallyach of Ring A, Ring B, Ring C, Ring D, L, R1, R2, R3, R4, R5, R6, R6’, m, n, p, q, and r is as defined herein.

[0011] In some embodiments, the present disclosure provides a compound of Formula II: or a salt (e.g., a pharmaceutically ap , each of Ring A, Ring B, Ring D, J, R1, R2, R4, R5, X, m, n, and q is as defined herein.

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula I’’, I’, I, or II), or a salt (e.g., a pharmaceutically acceptable salt) thereof, together with a pharmaceutically acceptable carrier.

[0013] In some embodiments, the present disclosure provides a method of inhibiting, disrupting, and / or preventing an interaction between a PI3Kα protein and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) such that the kinase activity of the PI3Kα protein is not inhibited. In some embodiments, the PI3Kα protein is in a cell, such as in a cell of a human or animal subject (e.g., as described herein).

[0014] In some embodiments, 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’’, I’, I, or II), or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0015] In some embodiments, the present disclosure provides a use of a compound provided herein (e.g., a compound of Formula I’’, I’, I, or II), 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’’, I’, I, or II), 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). DETAILED DESCRIPTION Compounds and Definitions

[0016] 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.

[0017] 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 eachstereocenter 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, Table 2, or Table 3 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 a 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.

[0018] 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.

[0019] Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (e.g., multiple bonds, such as double or triple bonds). Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.

[0020] 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, C1-8, C1-6, C1-4, C1-3, or C1-2). Examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl), isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, isoamyl, hexyl, heptyl, octyl, and nonyl. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH2-).

[0021] 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.

[0022] 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.

[0023] 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. The term “aryl” may be used interchangeably with the term “aryl ring(s).” Examples of aryl groups include phenyl, 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.

[0024] 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, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8hydrocarbon, or an optionally substituted C5-C10bicyclic 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 3 to 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 3 to 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0025] 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.

[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 optionally substituted groups having 5 to 14 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. “Heteroaryl”, as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings. Examples of bicyclic heteroaromatic groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, indazolyl, indolizinyl, benzimidazolyl, benzthiazolyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiadiazolyl, tetrazolopyridazinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, chromonyl, coumarinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and 4H–quinolizinyl. Examples of tricyclic heterocyclic groups include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenazinyl, phenanthridinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. It will be appreciated that certain tautomeric forms of a heteroaryl ring can exist and are encompassed by the term “heteroaryl.” Such tautomeric forms include, for example, pyridin- 2(1H)-one.

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

[0029] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a 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 heterocycle 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). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be unsubstituted or substituted with one or more substituents (e.g., as described herein). Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. “Heterocycle,” as used herein, also includes groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.

[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. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0031] Patient or Subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided compound or 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 diseaseprogression (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 hydrogens that are either explicit or implicit from the structure (e.g., refers to at least or ble venstructure 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; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; – (CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1- pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; – N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; – (CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°; – (CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0– 4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; – N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; –SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, – O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[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)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2, -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, – CH C O OH CH C O OR^CH SR^CH SH CH NH CH NHR^, –r – SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0036] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include – R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with 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^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] 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.PI3K and Small GTPase Proteins

[0041] The aberrant activation of the phosphoinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in treating cancers. PI3Ks signal downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a large number of cellular activities, including metabolism, proliferation, and migration. Upon activation, PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5- bisphosphate (PIP2). Signaling proteins such as Ser / Thr kinase AKT (e.g., Protein Kinase B (PKB)) can bind to PIP3 and thereby localize to the cell membrane. Phosphorylated AKT activates or inhibits several signaling proteins through direct phosphorylation including the mammalian target of rapamycin complex 1 (mTORC1), which acts as a regulator of cell growth and survival pathways, cyclin D1, GSK3(B), BAD, MDM2, FOXO, TSC1 / 2, and PRAS40. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulates this pathway by dephosphorylating PIP3 to PIP2 and thus prevents activation of downstream kinases.

[0042] Based on the sequence homology and substrate preference, PI3Ks have been grouped into three separate classes (e.g., classes I, II, and III). Class I PI3Ks are further divided into two subclasses, IA and IB depending on their modes of regulation. Class IA PI3Ks are heterodimers comprising p110 catalytic and p85 regulatory subunits, and are most clearly implicated in human cancer. Class IA PI3K contains p110α, p110β, and p110δ catalytic subunits produced from different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3K. The expression of PI3K isoforms (e.g., PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) is specific to cell types. The p110α and β isoforms are expressed in all cell types, whereas p110δ expression is mainly confined to leukocytes. The p110γ isoform is expressed primarily in the myeloid cell lineage.

[0043] PIK3CA gene encodes the 1068 amino acid p110α protein that contains five domains: an N- terminal adaptor binding domain (ABD) that binds to regulatory subunit p85α, a RAS-binding domain (RBD), a C2 domain, a helical domain, and a kinase catalytic domain. RAS contributes directly to the activation of the PI3K pathway through direct binding of RAS proteins (e.g., HRAS, NRAS, and KRAS) to a RAS-binding domain (RBD) in the p110α catalytic subunit of PI3Kα. Activating mutations in the KRAS and PIK3CA genes are frequently detected in cancer, making these two proteins important targets for drug discovery. Somatic missense mutations in the PIK3CA gene have been reported in many human cancer types including breast, colon, liver, stomach, endometrial, bladder, and lung cancers. The most frequent hotspot mutations in PIK3CA are E542K, E545K, H1047R, and H1047L, and they account for 80–90% of all PIK3CA mutations detected in human malignancies. These PIK3CA mutations lead toincreased catalytic activity of p110α, which causes downstream effects such as unregulated cell growth, proliferation, and survival.

[0044] Mutations in RAS proteins are found in over 20% of all human cancers. RAS proteins function as molecular switches that cycle between an active, GTP-bound state and an inactive, GDP-bound state. In the active state, RAS proteins interact with various effector proteins including PI3K, RAF kinase, and RalGDS, leading to activation of multiple downstream signaling pathways. Oncogenic RAS mutations are predominantly found at amino acid positions G12, G13, and Q61, and these mutations impair GTPase activities leading to the accumulation of active RAS proteins. The most common oncogenic RAS mutations are G12C, G12D, G12S, G12V, G12R, G13D, and Q61H.

[0045] RAS signaling through PI3K is necessary for normal lymphatic development and RAS-induced transformation, especially in lung cancer, where the interaction between mutant RAS and p110a-RBD is essential for tumor initiation and maintenance. RAS interactions with p110α-RBD have been shown to be crucial for epidermal growth factor (EGF) signaling to PI3K. Recent studies have shown that disrupting the RAS-PI3K interaction inhibits AKT and RAC1 activation in EGFR-mutant lung cancer cells, leading to reduced growth and survival and inhibiting EGFR-mutant-induced tumor onset. These results suggest that the binding of p110α to endogenous RAS proteins in EGFR-driven lung adenocarcinoma is critical in tumors driven by upstream activators of the RAS pathways and not just those in which RAS is mutationally activated.

[0046] Small GTPases (e.g., other than RAS) are also expected to bind the RBD of PI3Kα resulting in activation of signaling. The small GTPases Rac1 and CDC42 have been shown to bind the RBD of PI3Kβ and are hypothesized to also be capable of binding the RBD of PI3Kα. Accordingly, in some embodiments, the present disclosure encompasses the recognition that disrupting an interaction between PI3Kα and any small GTPase that binds the RBD of PI3Kα may be a useful therapeutic strategy for treating cancers and other indications. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins (including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).

[0047] The frequency of oncogenic PIK3CA hotspot mutations across cancers has fueled the development and testing of numerous PI3K (e.g., PI3Kα) inhibitors. Most PI3K inhibitors that have entered clinical development thus far are reversible, ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcome of PI3K inhibitor-based treatments for solid tumors has been disappointing, mainly due to intolerable toxicity and drug resistance. In 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (BYL719; Novartis Pharma AG), an inhibitor specific to the PI3Kα isoform, combined with fulvestrant for the treatment of patients diagnosed with HR+ / HER2- PIK3CA-mutation. The therapeutic window of PI3K inhibitors is mainly limited by isoform selectivity and off-tumor toxicity. Moreover, hyperglycemia and hyperinsulinemia have been observed as major dose-limiting toxicities forp110α inhibitors, which prevent the use of sufficiently high doses to fully suppress PI3Kα signaling in the tumor. Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3Kα inhibition, as inhibition of the PI3K / AKT pathway reduces glucose uptake, which in turn leads to increased secretion of insulin and subsequent activation of insulin / insulin-like growth factor I receptor in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of the PI3Kα inhibitor. Indeed, hyperglycemia was observed in 65% of patients in a Phase III clinical trial of alpelisib, leading to significant dose interruptions.

[0048] To overcome the limitations of current PI3Kα inhibitors, novel strategies to target PI3Kα need to be explored. Previous studies have suggested that inhibiting the RAS-p110α(RBD) interaction has minimal toxicity in adult animals while effectively causing tumor regression. 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 PI3Kα inhibitors (e.g., those that target the ATP binding pocket of PI3Kα). For example, provided technologies may avoid hyperglycemia and insulin-driven resistance common to PI3Kα inhibitors, e.g., because such technologies target activation of PI3Kα by RAS, which is mostly present in transformed cells. Provided Compounds

[0049] 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 PI3Kα proteins. In some embodiments, the present disclosure provides compounds capable of binding PI3Kα, such that (i) the interaction between the small GTPase (e.g., RAS protein, as described herein) and PI3Kα is disrupted, inhibited, or prevented; and / or (ii) the kinase activity of PI3Kα is not significantly inhibited. In some embodiments, such compounds bind PI3Kα 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., PI3Kα). 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 PI3Kα 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., PI3Kα) in a substantially non- reversible manner. In some embodiments, a reversible or irreversible inhibitor may be capable of interacting covalently with PI3Kα. 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 PI3Kα (e.g., C242).In some embodiments, provided compounds that interact with PI3Kα covalently are compounds of Formula I or II wherein –R5comprises 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 PI3Kα (e.g., C242).

[0050] In some embodiments, the present disclosure provides a compound of Formula I’’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl, pyridinyl, or a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 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 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered carbocyclic ring; and phenyl; Ring C is selected from phenyl; 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is absent or selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7- membered carbocyclic ring; 5- to 10-membered bicyclic or polycyclic carbocyclic ring; 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur; and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent straight or branched C1-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-; and when Ring D is absent, then L is also absent; each R1is independently selected from halogen, optionally substituted C1-6alkyl, cycloalkyl, –CN, – C(O)OR, –C(O)NR2, –CH2NR2, –N(R7)2, -N=S(R7)2, –SR7, –(C1-4 alkylene)OR, and –OR7, wherein a sulfur atom in R1can be oxidized; each R7is independently selected from hydrogen, optionally substituted C1-6 aliphatic, –(C1-4 alkylene)OR, –(C1-4 alkylene)NR2, optionally substituted 3- to 6-membered carbocyclic ring, optionally substituted 4- to 7-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R7groups, together with the atom(s) to which they are attached, form a 4- to 6-membered heterocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic, and -OR; each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, optionally substituted carbocyclic ring, and optionally substituted C1-6 aliphatic; each R4is independently optionally substituted C1-6 aliphatic; R5is absent, optionally substituted C1-6 aliphatic, -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with an optionally substituted C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; each x is independently 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6aliphatic;each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; and each R8is independently selected from oxo, halogen, and optionally substituted C1-6 aliphatic.

[0051] In some embodiments, the present disclosure provides a compound of Formula I’’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0052] In some embodiments, the present disclosure provides a compound of Formula I’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl, pyridinyl, or a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered carbocyclic ring; and phenyl; Ring C is selected from phenyl; 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7- membered carbocyclic ring; 5- to 10-membered bicyclic or polycyclic carbocyclic ring; 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and when L is C2-5alkynyl, then Ring D may be absent; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-; each R1is independently selected from halogen, optionally substituted C1-6 alkyl, cycloalkyl, –CN, – C(O)OR, –C(O)NR2, –CH2NR2, –SR7, –(C1-4 alkylene)OR, and –OR7; each R7is independently selected from optionally substituted C1-6 aliphatic, –(C1-4 alkylene)OR, –(C1-4 alkylene)NR2, optionally substituted 3- to 6-membered carbocyclic ring, optionally substituted 4- to 7-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic; each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, optionally substituted carbocyclic ring, and optionally substituted C1-6 aliphatic; each R4is independently optionally substituted C1-6 aliphatic; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with an optionally substituted C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; each x is independently 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6aliphatic; each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; and each R8is independently selected from oxo, halogen, and optionally substituted C1-6aliphatic.

[0053] In some embodiments, the present disclosure provides a compound of Formula I’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0054] In some embodiments, the present disclosure provides a compound of Formula I:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,and when L is C2-5alkynyl, then Ring D may be absent; L is a covalent bond or a bivalent straight or branched C1-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-; each R1is independently selected from halogen and –OR7; each R7is independently selected from optionally substituted C1-6aliphatic and –(C1-4alkylene)OR; each R2is independently selected from halogen and optionally substituted C1-6aliphatic; each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2)xC(O)OR, - (CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, and optionally substituted C1-6 aliphatic; each R4is independently optionally substituted C1-6 aliphatic; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with an optionally substituted C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; each x is independently 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6 aliphatic; each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; and each R8is independently selected from oxo, halogen, and optionally substituted C1-6aliphatic.

[0055] In some embodiments, the present disclosure provides a compound of Formula I or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0056] In some embodiments, the present disclosure provides a compound of Formula I, I’, or I’’, wherein: Ring A is phenyl;Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and when L is C2-5 alkynyl, then Ring D may be absent; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-; each R1is independently selected from halogen and –OR7; each R7is independently selected from C1-6 aliphatic and –(C1-4 alkylene)OR; each R2is independently selected from halogen and C1-6 aliphatic; each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2)xC(O)OR, - (CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, and C1-6 aliphatic optionally substituted with one or more R10; each R4is independently selected from C1-6aliphatic optionally substituted with one or more R10; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is C2-6alkenyl optionally substituted with one or more R10, C2-6alkynyl optionally substituted with one or more R10, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with a C4-8hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3;n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; each x is independently 0, 1, or 2; each R is independently hydrogen or C1-6aliphatic optionally substituted with one or more R10; each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; each R8is independently selected from oxo, halogen, and C1-6 aliphatic; and each R10is independently selected from halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2.

[0057] In some embodiments, the present disclosure provides a compound of Formula I’, wherein: Ring A is phenyl; Ring B is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond; each R1is independently selected from halogen and –OR7; each R7is independently selected from optionally substituted C1-6aliphatic, –(C1-4alkylene)OR, and optionally substituted 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R2is independently selected from halogen and C1-6aliphatic;each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, a carbocyclic ring, and C1-6aliphatic optionally substituted with one or more R10; each R4is independently selected from C1-6aliphatic optionally substituted with one or more R10; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is C2-6alkenyl optionally substituted with one or more R10, C2-6alkynyl optionally substituted with one or more R10, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with a C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0; each x is independently 0, 1, or 2; each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more R10; each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; each R8is independently selected from oxo, halogen, and C1-6 aliphatic; and each R10is independently selected from halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2.

[0058] In some embodiments, the present disclosure provides a compound of Formula IA: or a salt (e.g., a pharmaceuticay p , , mer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring D, L, R1, R2, R3, R4, R5, R6, R6’, m, n, p, q, and r areas defined above for Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: Ring C1 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C1 is fused to Ring C2; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0059] In some embodiments, the present disclosure provides a compound of Formula IA’: or a salt (e.g., a pharmaceuticmer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring D, L, R1, R2, R3, R4, R5, R6, R6’, 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, and wherein: Ring C1 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C1 is fused to Ring C2; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some embodiments, the present disclosure provides a compound of Formula IB:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, L, R1, R2, R3, R4, R5, R6, R6’, 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, and wherein: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D1 is fused to Ring D2; and Ring D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0061] In some embodiments, the present disclosure provides a compound of Formula IB1:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, L, R1, R2, R3, R4, R5, R6, R6’, 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; Ring C1 and Ring C2 are as defined above for Formula IA and described in classes and subclasses herein, bothsingly and in combination; and Ring D1 and Ring D2 are as defined above for Formula IB and described in classes and subclasses herein, both singly and in combination.

[0062] In some embodiments, the present disclosure provides a compound of Formula IB’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, L, R1, R2, R3, R4, R5, R6, R6’, 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, and wherein: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D1 is fused to Ring D2; and Ring D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0063] In some embodiments, the present disclosure provides a compound of Formula IB1’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, L, R1, R2, R3, R4, R5, R6, R6’, 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; Ring C1 and Ring C2 are as defined above for Formula IA’ and described in classes and subclasses herein, both singly and in combination; and Ring D1 and Ring D2 are as defined above for Formula IB’ and described in classes and subclasses herein, both singly and in combination.

[0064] It will be appreciated that for a compound of Formula IA, IA’, IB1, or IB1’, any R3group may be attached to either Ring C1 or Ring C2. It will also be appreciated that for a compound of Formula IB, IB’, IB1, or IB1’, any R4, R5, or R6’group may be attached to either Ring D1 or Ring D2.

[0065] In some embodiments, the present disclosure provides a compound of Formula IA or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IA’ or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IB or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IB’ or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IB1 or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IB1’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0066] In some embodiments, the present disclosure provides a compound of Formula IC: or a salt (e.g., a pharmaceuticalomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, and q 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 salt (e.g., a pharmaceutically acceptable salt) thereof.

[0067] In some embodiments, the present disclosure provides a compound of Formula IC1:or a salt (e.g., a pharmaceuticall omer, prodrug, zwitterionic form, orstereoisomer thereof, wherein Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, R7, n, p, and q 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 salt (e.g., a pharmaceutically acceptable salt) thereof.

[0068] In some embodiments, the present disclosure provides a compound selected from Formulae IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, and IC1-g:or a salt nic form, orstereoisomer thereof, wherein Ring C, Ring D, R1, R2, R3, R4, R5, R7, n, p, and q 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-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0069] In some embodiments, the present disclosure provides a compound of Formula IC2:or a salt (e.g., a pharmaceutic mer, prodrug, zwitterionic form, orstereoisomer thereof, wherein Ring A, Ring B, Ring C, R1, R2, R3, R4, R5, m, n, p, and q 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 IC2 or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0070] In some embodiments, the present disclosure provides a compound selected from Formulae IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, and IC2-g:or a s ic form, orstereoisomer thereof, wherein Ring A, Ring C, R1, R2, R3, R4, R5, m, n, p, and q 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 IC2-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0071] In some embodiments, the present disclosure provides a compound selected from Formulae IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, or IC3-m:(R1)mAor a salt (e.g., a 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, and q 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 IC3-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In someembodiments, the present disclosure provides a compound of Formula IC3-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-h, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-i, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-j, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-k, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-l, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3-m, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0072] In some embodiments, the present disclosure provides a compound of Formula IC4: or a salt (e.g., a pharmaceuticmer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R5, R7, n, p, and q 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 IC4 or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0073] In some embodiments, the present disclosure provides a compound of Formula IC’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, and q 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 salt (e.g., a pharmaceutically acceptable salt) thereof.

[0074] In some embodiments, the present disclosure provides a compound of Formula IC1’: or a salt (e.g., a pharmaceuticall omer, prodrug, zwitterionic form, orstereoisomer thereof, wherein Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, R7, n, p, and q 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 salt (e.g., a pharmaceutically acceptable salt) thereof.

[0075] In some embodiments, the present disclosure provides a compound selected from Formulae IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, and IC1’-g:or a saltnic form, or stereoisomer thereof, wherein Ring C, Ring D, R1, R2, R3, R4, R5, R7, n, p, and q 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’-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1’-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1’-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1’-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1’-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides acompound of Formula IC1’-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC1’-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0076] In some embodiments, the present disclosure provides a compound of Formula IC2’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, R1, R2, R3, R4, R5, m, n, p, and q 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 IC2’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0077] In some embodiments, the present disclosure provides a compound selected from Formulae IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, and IC2’-g:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring C, R1, R2, R3, R4, R5, m, n, p, and q 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 IC2’-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2’-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2’-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2’-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2’-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2’-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC2’-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0078] In some embodiments, the present disclosure provides a compound selected from Formulae IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, or IC3’-m:(R1)mAor a salt (e.g., a 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, and q 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 IC3’-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In someembodiments, the present disclosure provides a compound of Formula IC3’-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-h, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-i, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-j, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-k, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-l, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IC3’-m, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0079] In some embodiments, the present disclosure provides a compound of Formula IC4’: or a salt (e.g., a pharmaceuticmer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R5, R7, n, p, and q 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 IC4’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0080] In some embodiments, the present disclosure provides a compound of Formula ID:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, and q are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein: L is a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-.

[0081] In some embodiments, the present disclosure provides a compound of Formula ID or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0082] In some embodiments, the present disclosure provides a compound of Formula ID’: or a salt (e.g., a pharmaceuticmer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, m, n, p, and q are as defined above for Formula I’ and described in classes and subclasses herein, both singly and in combination; and wherein: L is a bivalent straight or branched C1-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-.

[0083] In some embodiments, the present disclosure provides a compound of Formula ID’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0084] In some embodiments, the present disclosure provides a compound of Formula IE:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, R6, R6’, m, n, p, and q 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 salt (e.g., a pharmaceutically acceptable salt) thereof.

[0085] In some embodiments, the present disclosure provides a compound of Formula IE1: R66'1R (R )mR5or a salt (e.g., a pharmaceuticmer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R5, R6, R6’, m, n, p, and q 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 IE1 or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0086] In some embodiments, the present disclosure provides a compound selected from Formulae IE1-a and IE1-b: or a s, , , , , c form, or stereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R5, R6, R6’, m, n, p, and q 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 IE1-a, or a salt (e.g., apharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IE1-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0087] In some embodiments, the present disclosure provides a compound of Formula IE’: or a salt (e.g., a pharmaceuticall omer, prodrug, zwitterionic form, orstereoisomer thereof, wherein Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, R5, R6, R6’, m, n, p, and q 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 salt (e.g., a pharmaceutically acceptable salt) thereof.

[0088] In some embodiments, the present disclosure provides a compound of Formula IE1’: R6R6'R1R5or a salt (e.g., a pharmaceuticmer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R5, R6, R6’, m, n, p, and q 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 IE1’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0089] In some embodiments, the present disclosure provides a compound selected from Formulae IE1’-a and IE1’-b:or a sa c form, orstereoisomer thereof, wherein Ring B, Ring C, R1, R2, R3, R4, R5, R6, R6’, m, n, p, and q 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 IE1’-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IE1’-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0090] In some embodiments, the present disclosure provides a compound of Formula IF’: F (R4)qR5 or a salt (e.g., a pharmaceuticamer, prodrug, zwitterionic form, or stereoisomer thereof, wherein R1, R2, R3, R4, R5, n, p, and q are as defined above for Formula I’ and described in classes and subclasses herein, both singly and in combination; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present disclosure provides a compound of Formula IF’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0091] In some embodiments, the present disclosure provides a compound of Formula IF1’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein R1, R2, R3, R4, n, p, and q are as defined above for Formula I’ and described in classes and subclasses herein, both singly and in combination; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present disclosure provides a compound of Formula IF1’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0092] In some embodiments, the present disclosure provides a compound of Formula IF2’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein R1, R3, R4, p, and q are as defined above for Formula I’ and described in classes and subclasses herein, both singly and in combination; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present disclosure provides a compound of Formula IF2’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0093] In some embodiments, the present disclosure provides a compound of Formula IF3’: or a salt (e.g., a pharmaceutica mer, prodrug, zwitterionic form, orstereoisomer thereof, wherein R3, R4, R7, p, and q are as defined above for Formula I’ and described in classes and subclasses herein, both singly and in combination; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present disclosure provides a compound of Formula IF3’ or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0094] In some embodiments, the present disclosure provides a compound of Formula II: or a salt (e.g., a pharmaceutically aprodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; J is a covalent bond or a bivalent straight or branched C1-4hydrocarbon chain; X is –OR, -N(R)2, -C(O)N(R)2, or an optionally substituted group selected from phenyl, 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen and –OR7; each R7is independently selected from optionally substituted C1-6 aliphatic and –(C1-4 alkylene)OR; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic; each R4is independently selected from optionally substituted C1-6 aliphatic; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6 aliphatic.

[0095] In some embodiments, the present disclosure provides a compound of Formula II, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0096] In some embodiments, the present disclosure provides a compound of Formula II, wherein: Ring A is phenyl and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; J is a covalent bond or a bivalent straight or branched C1-4hydrocarbon chain; X is –OR, -N(R)2, -C(O)N(R)2, or a group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C1-6 alkyl; each R1is independently selected from halogen and –OR7; each R7is independently selected from C1-6 aliphatic and –(C1-4 alkylene)OR; each R2is independently selected from halogen and C1-6 aliphatic; each R4is independently selected from C1-6 aliphatic optionally substituted with one or more R10; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is C2-6 alkenyl optionally substituted with one or more R10, C2-6 alkynyl optionally substituted with one or more R10, or a 4-membered bicyclic carbocyclic ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more R10; and each R10is independently selected from halogen, -CN, -OH, -O(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), and -N(C1-6alkyl)2.

[0097] In some embodiments, the present disclosure provides a compound of Formula IIA:or a salt (e.g., a pharmaceutic mer, prodrug, zwitterionic form, orstereoisomer thereof, wherein Ring A, Ring B, J, R1, R2, R4, R5, X, m, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination, and wherein: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D1 is fused to Ring D2; and Ring D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, the present disclosure provides a compound of Formula IIA or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0099] It will also be appreciated that for a compound of Formula IIA, any R4or R5group may be attached to either Ring D1 or Ring D2. [000100] In some embodiments, the present disclosure provides a compound of Formula IIB:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, Ring D, J, R1, R2, R4, R5, R7, X, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIB or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000101] In some embodiments, the present disclosure provides a compound selected from Formulae IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, or IIB7:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring D, J, R1, R2, R4, R5, R7, X, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIB1, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB2, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB3, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB4, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB5, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB6, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIB7, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000102] In some embodiments, the present disclosure provides a compound of Formula IIC: or a salt (e.g., a pharmaceutic, , mer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring B, J, R1, R2, R4, R5, X, m, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In someembodiments, the present disclosure provides a compound of Formula IIC or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000103] In some embodiments, the present disclosure provides a compound selected from Formulae IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, and IIC7:1(R4)q(R )mAN N 5or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, J, R1, R2, R4, R5, X, m, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIC1, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIC2, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIC3, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIC4, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIC5, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIC6, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IIC7, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000104] In some embodiments, the present disclosure provides a compound selected from Formulae IID1, IID2, IID3, IID4, IID5, IID6, and IID7:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring A, Ring D, J, R1, R2, R4, R5, X, m, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IID1, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IID2, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IID3, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IID4, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IID5, or a salt (e.g., apharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IID6, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound of Formula IID7, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000105] In some embodiments, the present disclosure provides a compound of Formula IIE:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein Ring B, J, R1, R2, R4, R5, R7, X, n, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIE or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000106] In some embodiments, the present disclosure provides a compound of Formula IIF:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: X is -C(O)N(R)2 or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000107] In some embodiments, the present disclosure provides a compound of Formula IIF or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000108] In some embodiments, the present disclosure provides a compound of Formula IIG:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: J is a bivalent straight or branched C1-4 hydrocarbon chain; and X is –OR or -N(R)2. [000109] In some embodiments, the present disclosure provides a compound of Formula IIG or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000110] In some embodiments of any one of Formulae I, I’, I’’, IA, IA’, IB, IB’, IC, IC’, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3- a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’- c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, and IE’, Ring A is phenyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is a 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000111] In some embodiments of Formulae II, IIA, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring A is phenyl. In some embodiments, Ring A is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000112] In some embodiments of any Formulae described herein, a R1is halogen (e.g., fluoro). In some embodiments, R1is selected from optionally substituted C1-6alkyl, cycloalkyl (e.g., 3-6 memberedcycloalkyl, such as cyclopropyl), –CN, –C(O)OR, –C(O)NR2, –CH2NR2, –SR7, and –(C1-4alkylene)OR. In some embodiments, R1is optionally substituted C1-6alkyl. In some such embodiments, R1is optionally substituted C1-2alkyl. In some embodiments, R1is -CH3. In some embodiments, R1is cycloalkyl (e.g., 3- 6 membered cycloalkyl, such as cyclopropyl). In some embodiments, R1is cyclopropyl. In some embodiments, R1is –CN. In some embodiments, R1is –C(O)OR. In some such embodiments, R1is – C(O)OH. In some embodiments, R1is –C(O)NR2. In some embodiments, R1is –C(O)N(CH3)2. In some embodiments, R1is –CH2NR2. In some embodiments, R1is –CH2N(CH3)2. In some embodiments, R1is – SR7. In some embodiments, R1is –SCH3. In some embodiments, R1is –(C1-4 alkylene)OR. In some embodiments, R1is –CH2OR. In some embodiments, R1is –CH2OH. In some embodiments, R1is – CH2OCH3. In some embodiments, a R1is –OR7. In some embodiments, at least one R1is –OR7. In some embodiments, one R1is –OR7and any other R1groups are halogen (e.g., fluoro). In some embodiments, one R1is –OR7and one other R1group is halogen (e.g., fluoro). In some embodiments, one R1is –OR7and two other R1groups are halogen (e.g., fluoro). [000113] In some embodiments of any Formulae described herein, each R7is independently selected from C1-6 aliphatic and –(C1-4 alkylene)OR. In some embodiments, each R7is independently selected from C1-6 alkyl and –(C1-4 alkylene)OR. In some embodiments, each R7is optionally substituted C1-6 aliphatic. In some embodiments, each R7is C1-6 aliphatic. In some embodiments, each R7is C1-6 aliphatic substituted with a group selected from –(CH2)0-4R°, –(CH2)0-4OR°, –(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)R°, -(CH2)0- 4NHC(O)R°, –(CH2)0-4C(O)NHR°, and –(CH2)0-4C(O)N(R°)2. In some embodiments, each R7is C1-6 aliphatic substituted with –R°, –OR°, –N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, –C(O)NHR°, and – C(O)N(R°)2. In some such embodiments, R° is an optionally substituted group selected from C1-6 aliphatic, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 6-membered carbocyclic ring. In some embodiments, R° is substituted with halogen, oxo,–(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, and –(CH2)0–2OR^. In some embodiments, R° is substituted with halogen, oxo,–R^, –(haloR^), –OH, and –OR^. In some embodiments, R^is C1-4 aliphatic. In some embodiments, R^is -CH3 or -CH2CH3. In some embodiments, R° is substituted with halogen, oxo, -CH3, -CH2CF3, -OH, and -OCH3. [000114] In some embodiments, each R7is optionally substituted C1-6alkyl. In some embodiments, each R7is C1-6alkyl substituted with a group selected from –(CH2)0-4R°, –(CH2)0-4OR°,–(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)R°, -(CH2)0-4NHC(O)R°, –(CH2)0-4C(O)NHR°, –(CH2)0-4C(O)N(R°)2, . In some embodiments, each R7is C1-6alkyl substituted with –R°, –OR°, –N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, –C(O)NHR°, and –C(O)N(R°)2. In some embodiments, each R7is C1-2alkyl substituted with –R°, –OR°, –N(R°)2, - N(R°)C(O)R°, -NHC(O)R°, –C(O)NHR°, and –C(O)N(R°)2. In some embodiments, R° is an optionallysubstituted group selected from C1-6aliphatic, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 6-membered carbocyclic ring. In some embodiments, each R7is C1-6alkyl. In some embodiments, each R7is –(C1-4alkylene)OR. In some embodiments, each R7is –(C1-4 alkylene)NR2. In some embodiments, each R7is independently selected from C1-6aliphatic substituted with an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C1-6aliphatic substituted with an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring. In some embodiments, each R7is independently selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R7is independently selected from C1-6 aliphatic substituted with an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7is an optionally substituted 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R7is independently selected from C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring. In some , , , ,o 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 4- to 7-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and optionally substituted 3- to 6-membered carbocyclic ring. In some embodiments, each R7is independently selected from optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R7is independently selected from optionally substituted pyrrolidinyl and piperidinyl. In some embodiments, each R7is independently selected from optionally substituted 4- to 7- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R7is independently selected from optionally substituted 3- to 6- membered carbocyclic ring. In some embodiments, each R7is independently selected fro, andHO O , , and 7is selected from: -OCH3, -OCH(CH3)2, -O(CH2)2OH, -O(CH2)CH(CH3)OH, -O(CH2)2OCH3, and - O(CH2)2OCHF2. [000119] In some embodiments, R1is -N=S(R7)2, wherein the two R7groups, together with the atom(s) to which they are attached, form a 4- to 6-membered heterocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R1. [000120] In some embodiments of any Formulae described herein, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. (R1)mA[000121] In some embodiments of any Formulae described herein, a moiet is1or . In, , , , , ,, , , , , , ,, , ted , , ,, , , , , , , ,, ted , , , , , ,, , , , , , , ty, , , s, a , , , ,[000122] In some embodiments, for a compound of any one of Formulae IF , IF1 , and IF2 , R1is –OR7. [000123] In some embodiments, for a compound of any one of Formulae IF’, IF1’, IF2’, and IF3’, R7is selected from optionally substituted C1-6 aliphatic and –(C1-4 alkylene)OR. In some embodiments, R7is selected from C1-6 alkyl and –(C1-4 alkylene)OR. In some embodiments, R7is optionally substituted C1-6 aliphatic. In some embodiments, R7is C1-6 aliphatic. In some embodiments, R7is optionally substituted C1-6alkyl. In some embodiments, each R7is C1-6aliphatic substituted with a group selected from –(CH2)0-4R°, –(CH2)0-4OR°, –(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)R°, -(CH2)0-4NHC(O)R°, –(CH2)0-4C(O)NHR°, and –(CH2)0-4C(O)N(R°)2. In some embodiments, each R7is C1-6 aliphatic substituted with –R°, –OR°, – N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, –C(O)NHR°, and –C(O)N(R°)2. In some such embodiments, R° is an optionally substituted group selected from C1-6aliphatic, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 6- membered carbocyclic ring. In some embodiments, R° is substituted with halogen, oxo,–(CH2)0–2R^, – (haloR^), –(CH2)0–2OH, and –(CH2)0–2OR^. In some embodiments, R° is substituted with halogen, oxo,– R^, –(haloR^), –OH, and –OR^. In some embodiments, R^is C1-4aliphatic. In some embodiments, R^is -CH3or -CH2CH3. In some embodiments, R° is substituted with halogen, oxo, -CH3, -CH2CF3, -OH, and - OCH3. [000124] In some embodiments, for a compound of any one of Formulae IF’, IF1’, IF2’, and IF3’, each R7is optionally substituted C1-6alkyl. In some embodiments, each R7is C1-6alkyl substituted with a group selected from –(CH2)0-4R°, –(CH2)0-4OR°,–(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)R°, -(CH2)0-4NHC(O)R°, – (CH2)0-4C(O)NHR°, –(CH2)0-4C(O)N(R°)2, . In some embodiments, each R7is C1-6alkyl substituted with – R°, –OR°, –N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, –C(O)NHR°, and –C(O)N(R°)2. In some embodiments, each R7is C1-2 alkyl substituted with –R°, –OR°, –N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, –C(O)NHR°, and –C(O)N(R°)2. In some embodiments, R° is an optionally substituted group selected from C1-6 aliphatic, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 6-membered carbocyclic ring. In some embodiments, R7is C1-6 alkyl. In some embodiments, R7is –(C1-4 alkylene)OR. In some embodiments, R7is –(C1-4 alkylene)NR2. In some embodiments, R7is independently selected from C1-6 aliphatic substituted with an optionallysubstituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C1-6aliphatic substituted with an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and C1-6aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring. In some embodiments, R7is selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7is selected from C1-6aliphatic substituted with an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7is an optionally substituted 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7is selected from C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring. In some embodiments, , andach , , ,, , , , ,7is selected from optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and optionally substituted 3- to 6-membered carbocyclic ring. In some embodiments, R7is selected from optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7is selected from optionally substituted pyrrolidinyl and piperidinyl. In some embodiments, R7is selected from optionally substituted 3- to 6-membered carbocyclic ring. In some embodiments, for a compound of any one of Formulae IF’, IF1’, IF2’, and IF3’, R7is selected from andach ,iety F .F [000129] In some embodiments, for a compound of Formula IF3’, a moiet is. mbodiments of any Formulae described herein, Ring B is selected from 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 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered carbocyclic ring; and phenyl. In some embodiments of any Formulae described herein, Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5- to 6-membered carbocyclic ring. In some embodiments, Ring B is selected from a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered carbocyclic ring, and a phenyl ring. In some embodiments, Ring B is selected from a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-membered carbocyclic ring. In some embodiments, Ring B is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is selected from a thiophene, a furan, or an isothiazole. In some embodiments, Ring B is a thiophene. In some embodiments, Ring B is a furan. In some embodiments, Ring B is an isothiazole. In some embodiments, Ring B is 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5- to 6-membered carbocyclic ring. In some embodiments, Ring B is a 5- to 6-membered cycloalkyl ring. In some embodiments, Ring B is a 5-membered carbocyclic ring (e.g., cyclopentyl). In some embodiments, Ring B is a 6-membered carbocyclic ring. In some embodiments, Ring B is a phenyl ring. [000131] In some embodiments of any Formulae described herein, each R2is independently selected from halogen and optionally substituted C1-6 alkyl. In some embodiments, each R2is independently selected from halogen and C1-6aliphatic. In some embodiments, each R2is independently selected from halogen andC1-6alkyl. In some embodiments, R2is halogen (e.g., fluoro or chloro). In some embodiments, R2is optionally substituted C1-6aliphatic. In some embodiments, R2is C1-6aliphatic. In some embodiments, R2is optionally substituted C1-6alkyl. In some embodiments, R2is C1-6alkyl (e.g., methyl). [000132] In some embodiments of any Formulae described herein, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. is , , , bed , ,, iety , meembodiments of any Formulae described herein, a moiet om:, iety , ,n some embodiments of any Formulae described herein, a moietyand me or and .g., is .g., is.g., is me In me , , ety, ted , ,-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from 9- to 10-membered bicyclic aryl ring, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, and 3- to 7- membered carbocyclic ring. In some embodiments, Ring C is selected from 5- to 6-membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000135] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is phenyl. [000136] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 9- to 10-membered bicyclic aryl ring. In some embodiments, Ring C is a 9-membered bicyclic aryl ring (e.g., an indane). In some embodiments, Ring C is a 10-membered bicyclic aryl ring. [000137] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5- to 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a pyrazolyl.In some embodiments, Ring C is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a pyridinyl. [000138] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is an indolyl, indazolyl, benzimidazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyridinyl, or imidazo[4,5-b]pyridinyl. In some embodiments, Ring C is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000139] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring C is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring C is a 3- to 5- membered carbocyclic ring. In some embodiments, Ring C is a 3- to 5-membered cycloalkyl ring. In some embodiments, Ring C is a cyclopropyl. [000140] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 4- to 7-membered 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 azetidinyl ring. In some embodiments, Ring C is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a piperazinyl ring. In some embodiments, Ring C is a 1,2,3,6-tetrahydropyridinyl ring. In some embodiments, Ring C is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. , , and

[0000] n some emo ments o any o ormuae , , , , , C, C, C, C , C-a, C1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 6- to 11-membered bicyclic heterocyclic ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a fused 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocyclic ring fused to an aryl, heteroaryl, cycloalkyl, or heterocyclic ring, wherein the point of attachment to the rest of the molecule is on either ring). In some embodiments, Ring C is a spirocyclic 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocyclic ring spirofused to a cycloalkyl or heterocyclic ring, wherein the point of attachment to the result of the molecule is on either ring). In some embodiments, Ring C is a 6-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 7-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is an 8-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 10-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from: mently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3-b, IC3-c, IC3- d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C is a 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, comprising two or more fused and / or bridged rings. In some embodiments, Ring C is a 12-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000143] In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’- d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, and IE1’-b, Ring C substituted with p R3groups , wherein: Ring C1 is fused to Ring C2;Ring C1 is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Ring C2 is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000144] In some such embodiments, Ring C1 is a phenyl, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, or 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000145] In some embodiments of any of Formulae IA, IA’, IB1, and IB1’, Ring C1 is selected from phenyl and 3- to 7-membered carbocyclic ring. In some embodiments, Ring C1 is selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is selected from phenyl and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is selected from 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is phenyl. In some embodiments, Ring C1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolyl or imidazolyl). In some embodiments, Ring C1 is a 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridinyl). In some embodiments, Ring C1 is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring C1 is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring C1 is a 3- to 5- membered carbocyclic ring. In some embodiments, Ring C1 is a 3- to 5-membered cycloalkyl ring (e.g., a cyclopropyl). In some embodiments, Ring C1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidinyl). In some embodiments, Ring C1 is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidinyl or a piperazinyl). [000146] In some embodiments of any of Formulae IA, IA’, IB1, IB1’, IF’, IF1’, IF2’, and IF3’, Ring C2 is selected from phenyl and 3- to 7-membered carbocyclic ring. In some embodiments, Ring C2 is selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is selected from phenyl and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is selected from 3- to 7-membered carbocyclic ring and 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is phenyl. In some embodiments, Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolyl, pyrazolyl, or imidazolyl). In some embodiments, Ring C2 is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur (e.g., a pyridinyl, or pyridonyl). In some embodiments, Ring C2 is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring C2 is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring C2 is a 3- to 5-membered carbocyclic ring. In some embodiments, Ring C2 is a 3- to 5-membered cycloalkyl ring (e.g., a cyclopropyl or cyclopentyl). In some embodiments, Ring C2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidinyl). In some embodiments, Ring C2 is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidinyl or a piperazinyl). In some embodiments, Ring C2 is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an azepanyl). [000147] In some embodiments of any of Formulae IA, IA’, IB1, and IB1’, Ring C1 is a phenyl, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000148] In some embodiments of any of Formulae IF’, IF1’, IF2’, and IF3’, Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C2 is a 3- to 7- membered carbocyclic ring.[000149] In some embodiments of any of Formulae IF’, IF1’, IF2’, and IF3’, a moietyis selected from: ,, , , ,, , , ted , andN , N , and1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3- a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’- c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, IE1’-b, IF’, IF1’, IF2’, and IF3’, each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, - (CH2)xCy, -O(CH2)xCy, -C(O)Cy, optionally substituted carbocyclic ring, and optionally substituted C1-6 alkyl. In some embodiments, each R3is independently selected from halogen, -CN, -OR, -C(O)R, - (CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, and optionally substituted C1-6 aliphatic. In some embodiments, each R3is independently selected from oxo, halogen, - CN, -OR, -C(O)R, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, - C(O)Cy, and C1-6 aliphatic optionally substituted with one or more R10. In some embodiments, each R3is independently selected from halogen, -C(O)N(R)2, and optionally substituted C1-6alkyl (e.g., C1-6alkyl optionally substituted with one or more R10). In some embodiments, each R3is independently selected from halogen, -C(O)N(R)2, and C1-6alkyl. In some embodiments, an R3is oxo. In some embodiments, an R3ishalogen (e.g., fluoro). In some embodiments, an R3is –CN. In some embodiments, an R3is –OR (e.g., - OH). In some embodiments, an R3is -C(O)R. In some embodiments, an R3is –C(O)(C1-6alkyl) (e.g., - C(O)CH3). In some embodiments, an R3is -(CH2)xC(O)OR, such as –CH2C(O)OR. In some embodiments, an R3is -(CH2)xC(O)OH (e.g., -CH2C(O)OH). In some embodiments, an R3is -(CH2)xC(O)N(R)2(e.g., - CH2C(O)N(R)2 or –C(O)N(R)2). In some embodiments, an R3is –(CH2)xC(O)NH(C1-6 alkyl) (e.g., - CH2C(O)NHCH3or –C(O)NHCH3). In some embodiments, an R3is –(CH2)xC(O)N(C1-6alkyl)2(e.g., – CH2C(O)N(CH3)2or –C(O)N(CH3)2). In some embodiments, an R3is -(CH2)xN(R)C(O)R, such as - CH2N(R)C(O)R. In some embodiments, an R3is -(CH2)xN(H)C(O)(C1-6 alkyl) (e.g., -N(H)C(O)CH3 or - CH2N(H)C(O)CH3). In some embodiments, an R3is –(CH2)xCy (e.g., phenyl, -(CH2)xazetidinyl, - (CH2)xpyrolidinyl, -(CH2)xpiperidinyl, oxetanyl, or pyrazolyl, any of which are substituted with 0-3 instances of R8). In some embodiments, an R3is -O(CH2)xCy, such as –O(CH2)2Cy. In some embodiments, an R3is –O(CH2)2Cy, wherein Cy is an azetidinyl substituted with 0-3 instances of R8. In some embodiments, an R3is -C(O)Cy (e.g., -C(O)Cy, wherein Cy is a cyclobutyl or azetidinyl, either of which is substituted with 0-3 instances of R8). In some embodiments, an R3is optionally substituted C1-6 aliphatic (e.g., C1-6 aliphatic optionally substituted with one or more R10). In some embodiments, an R3is optionally substituted C1-6 alkyl (e.g., C1-6 alkyl optionally substituted with one or more R10). In some embodiments, an R3is C1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro), -OH, -O(C1-6 alkyl) (e.g., -OCH3), or -N(C1-6 alkyl)2 (e.g., -N(CH3)2). In some embodiments, an R3is selected from –CH3, -CH2F, - CF3, -CH2OH, –CH2N(CH3)2, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2OCH3, -CH(CH3)2, – CH2CH(OH)CH2OH, and –CH2CH(OH)CH2OCH3. [000151] In some embodiments of any of Formulae I, I’, I’’, IA, IA’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3- a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’- c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a, IE1-b, IE1’-a, IE1’-b, IF’, IF1’, IF2’, and IF3’, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments of any of Formulae I, I’, I’’, IB, IB’, IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC2, IC2’, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2’-a, IC2’-b, IC2’-c, IC2’-d, IC2’-e, IC2’-f, IC2’-g, IC3-a, IC3-b, IC3-c, IC3- d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, IC4, IC4’, ID, ID’, IE, IE’, IE1, IE1’, IE1-a,, , , , ,, , , , ,, , , , ,, , , is ,, , , ,, , , ,, , , , , ,,. In some embodiments, a moiety is selected from: ,, , ,, , , ,, , , is ,, , , , ,, 1-b,IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, and 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is selected from phenyl, 3- to 7-membered carbocyclic ring, and 5- to 10-membered bicyclic or polycyclic carbocyclic ring. In some embodiments, Ring D is selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000153] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c IC3-d IC3-e IC3-f IC3-g IC3-h IC3-i IC3-j IC3-k IC3-l IC3-m IC3’-a IC3’-b IC3’-c IC3’-d IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is phenyl. [000154] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000155] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a pyrazolo[1,5- a]pyrimidinyl. In some embodiments, Ring D is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000156] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring D is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring D is a 3- to 5-membered carbocyclic ring. In some embodiments, Ring D is a 3- to 5- membered cycloalkyl ring. [000157] In some embodiments of any of Formulae Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1- a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c,IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is a 5- to 10-membered bicyclic or polycyclic carbocyclic ring. In some embodiments, Ring D is a 5- to 10- membered bicyclic carbocyclic ring. In some embodiments, Ring D is a bridged 5- to 10-membered bicyclic carbocyclic ring. In some embodiments, Ring D is a bridged 5- to 7-membered bicyclic carbocyclic ring (e.g., a bicyclo[1.1.1]pentane). In some embodiments, Ring D is a 8- to 10-membered polycyclic carbocyclic ring (e.g., a cubane). [000158] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an azetidinyl. In some embodiments, Ring D is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a pyrrolidinyl. In some embodiments, Ring D is a 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a piperidinyl or piperazinyl. In some embodiments, Ring D is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000159] In some embodiments of any of Formulae Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1- a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, IE, IE’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, Ring D is a 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a fused 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocyclic ring fused to an aryl, heteroaryl, cycloalkyl, or heterocyclic ring, wherein the point of attachment to the rest of the molecule is on either ring). In some embodiments, Ring D is a spirocyclic 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocyclic ring spirofused to a cycloalkyl or heterocyclic ring, wherein the point of attachment to the result of the molecule is on either ring). In some embodiments, Ring D is a 6-membered bicyclicheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 7-membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an 8-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 9-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 10-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is absent. [000160] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, II, IIB, IIB1, IIB2, IIB3, IIB4, ted , , , , ,ety , , , , ,C1- a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, L is C2-5alkynyl, and Ring D is absent. [000162] In some embodiments of any of Formulae Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1- a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, II, IIB, IIB1, IIB2,IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, a moiety n:Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;and Ring D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, Ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000163] In some embodiments of any of Formulae IB, IB’, IB1, and IB1’, Ring D1 is selected from phenyl and 3- to 7-membered carbocyclic ring. In some embodiments, Ring D1 is selected from 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is selected from phenyl and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is selected from 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is phenyl. In some embodiments, Ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrazolyl). In some embodiments, Ring D1 is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridinyl). In some embodiments, Ring D1 is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring D1 is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring D1 is a 3- to 5-memberedcarbocyclic ring. In some embodiments, Ring D1 is a 3- to 5-membered cycloalkyl ring (e.g., a cyclopropyl). In some embodiments, Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidinyl). In some embodiments, Ring D1 is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidinyl). [000164] In some embodiments of any of Formulae IB, IB’, IB1, and IB1’, Ring D2 is selected from phenyl and 3- to 7-membered carbocyclic ring. In some embodiments, Ring D2 is selected from 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is selected from phenyl and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is selected from 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is phenyl. In some embodiments, Ring D2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrimidinyl). In some embodiments, Ring D2 is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring D2 is a 3- to 7-membered cycloalkyl ring. In some embodiments, Ring D2 is a 3- to 5-membered carbocyclic ring. In some embodiments, Ring D2 is a 3- to 5-membered cycloalkyl ring (e.g., a cyclopropyl). In some embodiments, Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D2 is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidinyl). In some embodiments, Ring D2 is a 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidinyl or a piperazinyl). In some embodiments, Ring D2 is a 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000165] In some embodiments of any of Formulae IB, IB’, IB1, and IB1’, Ring D1 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000166] In some embodiments of any of Formulae I, I’, I’’, IA, IA’ IC, IC’, IC1, IC1’, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1’-a, IC1’-b, IC1’-c, IC1’-d, IC1’-e, IC1’-f, IC1’-g, IC3-a, IC3-b, IC3- c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’- e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, IC3’-m, ID, ID’, II, IIB, IIB1, IIB2, IIB3, IIB4, ted , , , ,, , , , , , , In ,O N , , , , , , , ,, , and -b, C3- 3’- B4, is ach om: ,, , is , nd m: ,, is ,ally substituted C1-6alkyl. In some embodiments, each R4is independently selected from C1-6aliphatic optionally substituted with one or more R10. In some embodiments, each R4is independently selected from C1-6alkyl optionally substituted with one or more R10. In some embodiments, each R4is independently C1-6aliphatic (e.g., C1-6alkyl). In some embodiments, each R4is independently C1-6alkyl optionally substituted with one or more –OH. In some embodiments, each R4is independently selected from –CH3, -CH2OH, - CH2CH3, and -CH(CH3)2. [000171] In some embodiments of any Formulae described herein, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. [000172] In some embodiments of any Formulae described herein, R5is -C(O)R9or -(CH2)xN(R)C(O)R9. In some embodiments, R5is -C(O)R9or -N(R)C(O)R9. In some embodiments, R5is -C(O)R9. In some embodiments, R5is -(CH2)xN(R)C(O)R9(e.g., -CH2N(R)C(O)R9or -N(R)C(O)R9). In some embodiments, R5is –CN. In some embodiments, R5is selected from: -CN ,and nts, C2-6alkenyl or optionally substituted C2-6alkynyl. In some embodiments, R9is optionally substituted C2-4alkenyl or optionally substituted C2-4alkynyl. In some embodiments, R9is C2-6alkenyl optionally substituted with one or more R10, C2-6alkynyl optionally substituted with one or more R10, or a 4-membered bicyclic carbocyclic ring. In some embodiments, R9is C2-6alkenyl optionally substituted with one or more R10or C2-6alkynyl optionally substituted with one or more R10. In some embodiments, R9is optionally substituted C2-6alkenyl. In some embodiments, R9is optionally substituted C2-4alkenyl. In some embodiments, R9is C2-6alkenyl optionally substituted with one or more R10(e.g., one or more halogen). In some embodiments, R9is optionally substituted C2-6alkynyl. In some embodiments, R9is optionally substituted C2-4alkynyl. In some embodiments, R9is C2-6alkynyl optionally substituted with one or more R10(e.g., one or more –N(C1-6alkyl)2). In some embodiments, R9is a 4-membered bicyclic carbocyclic ring. [000174] In some embodiments of any of Formulae I, I’, I’’, IA, IA’, IB, IB’, IB1, IB1’, ID, and ID’, L is a covalent bond. In some embodiments, L is a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-. In some embodiments, L is a bivalent straight or branched C2-6hydrocarbon chain having at least one triple bond, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-. In some embodiments, L is a bivalent straight or branched C2-6 hydrocarbon chain having at least one triple bond (e.g., a C2-6 alkynylene). In some embodiments, L is selected from: . In some embodiments, L is a bivalent straight or branched C1-4y rocar on c a n, w ere n one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-. In some embodiments, L is a bivalent straight or branched C1-2 hydrocarbon chain, wherein one or more methylene units are optionallyand independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-. In some embodiments, L is ’, a , , , , and[ ] n some emo mens o any o ormuae , , , , , , , , , , , E1, IE1’, IE1-a, IE1-a’, IE1-b, and IE1-b’, R6and R6’are connected with an optionally substituted C4-8hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with – O- or –N(R)-. In some embodiments, R6and R6’are connected with a C4-8hydrocarbon chain, wherein oneor more methylene units are optionally and independently replaced with –O- or –N(R)-. In some embodiments, R6and R6’are connected with an optionally substituted C5-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-. In some embodiments, R6and R6’are connected with an optionally substituted C4-8hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O-. In some embodiments, R6and R6’are connected with an optionally substituted C5-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O-. In some embodiments, R6and R6’are connected with: -O(CH2)5-, -O(CH2)4-, –O(CH2)2OCH2-, or –O(CH2)3OCH2-. [000177] In some embodiments of any of Formulae Formulae I, I’, I’’, IA, IA’, IB, IB’, IB1, IB1’, IE, IE’, IE1, IE1’, IE1-a, IE1-a’, IE1-b, and IE1-b’, r is 0. In some embodiments, r is 1. It will be appreciated that r has the same value for both R6and R6’, such that either both R6and R6’are present or both R6and R6’are absent. [000178] In some embodiments of any Formulae described herein, each x is independently 1 or 2. In some embodiments, each x is independently 0 or 1. In some embodiments, each x is 0. In some embodiments, each x is 1. In some embodiments, each x is 2. [000179] In some embodiments of any Formulae described herein, each R is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each R is independently hydrogen or optionally substituted C1-4 alkyl. In some embodiments, each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more R10. In some embodiments, each R is independently hydrogen or C1-6 alkyl optionally substituted with one or more R10. In some embodiments, each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, an R is hydrogen. In some embodiments, an R is optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, an R is C1-6 aliphatic optionally substituted with one or more R10(e.g., C1-6 alkyl optionally substituted with one or more R10). In some embodiments, an R is C1-6 aliphatic (e.g., C1-6 alkyl). [000180] In some embodiments of any Formulae described herein, each Cy is independently selected from phenyl and 3- to 7-membered carbocyclic ring, wherein each Cy is substituted with 0-3 instances of R8. In some embodiments, each Cy is independently selected from 5- to 6-membered heteroaryl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8. In some embodiments, each Cy is independently selected from phenyl and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8. In some embodiments, each Cy is independently selected from 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy issubstituted with 0-3 instances of R8. In some embodiments, a Cy is phenyl substituted with 0-3 instances of R8. In some embodiments, a Cy is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrazolyl), wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 3- to 7-membered carbocyclic ring, wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 3- to 5-membered carbocyclic ring, wherein Cy is substituted with 0- 3 instances of R8. In some embodiments, a Cy is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., an azetidinyl or an oxetanyl), wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 5-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., a pyrrolidinyl), wherein Cy is substituted with 0-3 instances of R8. In some embodiments, a Cy is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a piperidinyl or piperazinyl), wherein Cy is substituted with 0-3 instances of R8. In some embodiments, each Cy is independently substituted with 0-2 instances of R8. [000181] In some embodiments of any Formulae described herein, each R8is independently selected from oxo, halogen, and optionally substituted C1-6 alkyl. In some embodiments, each R8is independently selected from oxo, halogen, and C1-6 aliphatic. In some embodiments, each R8is independently selected from oxo, halogen, and C1-6 alkyl. In some embodiments, each R8is independently selected from halogen and optionally substituted C1-6 aliphatic. In some embodiments, a R8is oxo. In some embodiments, a R8is halogen (e.g., fluoro). In some embodiments, a R8is optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6alkyl). In some embodiments, a R8is C1-6aliphatic (e.g., C1-6alkyl). In some embodiments, each R8is independently fluoro or methyl. [000182] In some embodiments of any of Formulae II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, J is a covalent bond. In some embodiments, J is a bivalent straight or branched C1-4hydrocarbon chain. In some embodiments, J is a bivalent straight or branched C1-2hydrocarbon chain. In some embodiments, when J is a covalent bond, X is not –OR or –N(R)2.[000183] In some embodiments of any of Formulae II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7 IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, X is –OR or –N(R)2. In some embodiments, X is an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is a group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C1-6 alkyl. In some embodiments, X is a group selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C1-6 alkyl. In some embodiments, X is –OR (e.g., -OH or –OCH3). In some embodiments, X is –N(R)2 (e.g., -N(CH3)2). In some embodiments, X is -C(O)N(R)2. In some embodiments, X is optionally substituted phenyl. In some embodiments, X is optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., pyrazolyl optionally substituted with one or more C1-6 alkyl). In some embodiments, X is optionally substituted 6-membered heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 3- to 7- membered carbocyclic ring. In some embodiments, X is optionally substituted 5- to 10-membered bicyclic carbocyclic ring. In some embodiments, X is optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is optionally substituted 4-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., azetidinyl optionally substituted with one or more C1-6alkyl). In some embodiments, X is optionally substituted 5-membered heterocyclic ring having 1 heteroatom independentlyselected from nitrogen, oxygen, and sulfur (e.g., pyrrolidine optionally substituted with one or more C1-6alkyl). In some embodiments, X is optionally substituted 6-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., piperidinyl optionally substituted with one or more C1-6alkyl). In some embodiments, X is optionally substituted 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000184] In some embodiments of any of Formulae II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, a . ompoundselected from Table P1. Table P1 88)a)2a)3a)[000186] In some embodiments of any Formulae described herein, the compound is not a compound selected from Table P2. Table P2 62)[000187] In some embodiments of any Formulae described herein, the compound is not a compound selected from Table P3. Table P3 34)[000188] In some embodiments of any Formulae described herein, the compound is not a compound selected from Table P4. Table P4 42)[000189] 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. [000190] In some embodiments, the present disclosure provides a compound selected from Table 1, Table 2, or any of the Examples provided herein, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the present disclosure provides a compound selected from Table 1, Table 2, or any of the Examples provided herein, or a salt (e.g., pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound selected from Table 1 or a salt (e.g., pharmaceutically acceptable salt) thereof. In some embodiments, the present disclosure provides a compound selected from Table 2 or a salt (e.g., pharmaceutically acceptable salt) thereof. [000191] 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 otherwise 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, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3– phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p– toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [000192] 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. [000193] 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 IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3- b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, and IE1-b, and compound species of such formulae disclosed herein; reference to a compound of Formula I’ is intended to also include Formulae IA’, IB’, IB1’, IC’, IC1’, IC1-a’, IC1-b’, IC1-c’, IC1-d’, IC1-e’,’IC1-f’, IC1-g’, IC2’, IC2-a’, IC2-b’, IC2-c’, IC2-d’, IC2-e’, IC2-f’, IC2-g’, IC3-a’, IC3-b’, IC3-c’, IC3-d', IC3-e’, IC3-f’, IC3-g’, IC3-h’, IC3-I’, IC3-j’, IC3-k’, IC3-l’, IC3-m’, IC4’, ID’, IE’, IE1’, IE1-a’, IE1-b’, IF’, IF1’, IF2’, and IF3’ and compound species of such formulae disclosed herein; and reference to a compound of Formula II is intended to also include Formulae IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, and compound species of such formulae disclosed herein. Compositions [000194] 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, IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1- c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, IE1-b, I’, IA’, IB’, IB1’, IC’, IC1’, IC1-a’, IC1-b’, IC1-c’, IC1-d’, IC1-e’,’IC1-f’, IC1-g’, IC2’, IC2-a’, IC2-b’, IC2-c’, IC2-d’, IC2-e’, IC2-f’, IC2-g’, IC3-a’, IC3-b’, IC3-c’, IC3-d', IC3-e’, IC3-f’, IC3-g’, IC3-h’, IC3-I’, IC3- j’, IC3-k’, IC3-l’, IC3-m’, IC4’, ID’, IE’, IE1’, IE1-a’, IE1-b’, IF’, IF1’, IF2’, IF3’, II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG). [000195] 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, IA, IB, IB1, IC, IC1, IC1- a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a,IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, IE1-b, I’, IA’, IB’, IB1’, IC’, IC1’, IC1-a’, IC1-b’, IC1-c’, IC1-d’, IC1-e’,’IC1-f’, IC1-g’, IC2’, IC2-a’, IC2-b’, IC2-c’, IC2-d’, IC2-e’, IC2-f’, IC2-g’, IC3-a’, IC3-b’, IC3-c’, IC3-d', IC3-e’, IC3-f’, IC3-g’, IC3- h’, IC3-I’, IC3-j’, IC3-k’, IC3-l’, IC3-m’, IC4’, ID’, IE’, IE1’, IE1-a’, IE1-b’, IF’, IF1’, IF2’, IF3’, II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG) 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, glidants, anti-adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art. [000196] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc. [000197] 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 [000198] The present disclosure provides uses for compounds and compositions described herein (e.g., compounds of Formulae I’’, I, IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, IE1-b, I’, IA’, IB’, IB1’, IC’, IC1’, IC1-a’, IC1-b’, IC1-c’, IC1-d’, IC1-e’,’IC1-f’, IC1-g’, IC2’, IC2-a’, IC2-b’, IC2-c’, IC2-d’, IC2-e’, IC2-f’, IC2-g’, IC3- a’, IC3-b’, IC3-c’, IC3-d', IC3-e’, IC3-f’, IC3-g’, IC3-h’, IC3-I’, IC3-j’, IC3-k’, IC3-l’, IC3-m’, IC4’, ID’, IE’, IE1’, IE1-a’, IE1-b’, IF’, IF1’, IF2’, IF3’, II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG). 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. [000199] 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, the present disclosure provides methods of disrupting, interrupting, and / or preventing an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein in 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα 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 PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wild- type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R,G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. [000200] 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, a subject has a disease, disorder, or condition ameliorated by disruption of an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a 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 RAS protein is a wild-type RAS protein. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, 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.[000201] 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. [000202] 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 PI3Kα. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in a PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. [000203] 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. [000204] In some embodiments, a cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary passages, bone, connective tissue, skin, cervix, uterus, corpus endometrium,testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; cancers of the thyroid and other endocrine glands; Hodgkin’s disease; non- Hodgkin’s lymphomas; multiple myeloma; and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. Additional exemplary types of cancer include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, cranioph’ryngioma, 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 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. [000205] In some embodiments, a cancer is characterized by one or more mutations. In some such embodiments, a subject may be diagnosed with cancer and / or selected for therapy based on the detection of one or more mutations in a biological sample obtained from the subject. In some embodiments, a cancer is characterized by a mutation in a RAS protein (e.g., KRAS, HRAS, or NRAS). In some embodiments, a cancer is characterized by a mutation in a KRAS protein. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, a cancer is characterized by a mutation in an NRAS protein. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / orQ61R mutation. In some embodiments, a cancer is characterized by a mutation in an HRAS protein. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a cancer is characterized by a mutation in a PI3Kα protein. In some embodiments, the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family (e.g., HER2 and / or HER3), Met, FGFR, Alk, PDGF, EGFR, or ROS kinases). In some embodiments, a cancer is characterized by a mutation in or a deletion of a PTEN protein. In some embodiments, a cancer has demonstrable sensitivity to Avastin. For example, a cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, a cancer is ER positive (e.g., having estrogen receptors). In some embodiments, a cancer is PR positive (e.g., having progesterone receptors). [000206] 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. [000207] 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. In some 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 (NF1). [000208] 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 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)). [000209] 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.[000210] 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. [000211] 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., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions 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. [000212] 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 orameliorated by an interaction between a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS-binding domain (RBD) of a PI3Kα protein. In some embodiments, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, a RAS protein is a wild-type RAS protein. In some embodiments, a RAS protein is a mutant RAS protein. In some embodiments, a RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, a PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, a PI3Kα protein is a mutant PI3Kα protein. In some embodiments, a PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, a PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, provided compounds or compositions are useful for treating a disease, disorder, or condition described herein. In some embodiments, provided compounds or compositions are useful for treating a cancer or other indication as described herein. [000213] 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 doesnot 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. [000214] 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 HIF2α 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 anti- metabolite may be, for example, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate (RHEUMATREX), or raltitrexed. An antimitotic may be, for example, a taxane such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL), or a vinca alkaloid such as vincristine (ONCOVIN), vinblastine, vindesine, or vinorelbine (NAVELBINE). A checkpoint inhibitor may be an anti-PD-1 or anti-PD-L1 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), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin-domain containing-3), or 0X40 (tumor necrosis factor receptor superfamily member 4). A topoisomerase inhibitor may be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), or etoposide (EPOSIN). A cytotoxic antibiotic may be, for example, actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or plicamycin. An aromatase inhibitor may be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN). An angiogenesis inhibitor may be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN). An anti-steroid or anti- androgen may be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON). A tyrosine kinase inhibitor may be,for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA). An mTOR inhibitor may be, for example, everolimus, temsirolimus (TORISEL), or sirolimus. Monoclonal antibody may be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). A kinase inhibitor may be, for example, a BRAF inhibitor, MEK inhibitor, or a KRAS inhibitor (e.g., KRAS G12C inhibitor, such as sotorasib, adagrasib, or BBO- 8520). Additional examples of agents that may be useful in combination with a compound provided herein include, but are not limited to, amsacrine; Bacillus Calmette-Guerin (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZO’ADEX); interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,r'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone. Exemplary Embodiments [000215] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure: [000216] 1. A compound of Formula I: (I) or a salt (e.g., a pharmaceuticallyRing A is phenyl; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-memberedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and when L is C2-5 alkynyl, then Ring D may be absent; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, - C(O)N(R)-, or –C(O)-; each R1is independently selected from halogen and –OR7; each R7is independently selected from optionally substituted C1-6 aliphatic and –(C1-4 alkylene)OR; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic; each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2)xC(O)OR, - (CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, and optionally substituted C1-6 aliphatic; each R4is independently optionally substituted C1-6 aliphatic; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with an optionally substituted C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; each x is independently 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6aliphatic;each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; and each R8is independently selected from oxo, halogen, and optionally substituted C1-6aliphatic. [000217] 2. The compound of embodiment 1, wherein the compound is of Formula IC: C) or a salt (e.g., a pharmaceutically[000218] 3. The compound of embodiment 1, wherein the compound is of Formula ID: D) or a salt (e.g., a pharmaceuticallL is a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-. [000219] 4. The compound of embodiment 1, wherein the compound is of Formula IE: E) or a salt (e.g., a pharmaceutically.[000220] 5. The compound of any one of embodiments 1-4, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-membered carbocyclic ring. [000221] 6. The compound of embodiment 5, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000222] 7. The compound of embodiment 5, wherein Ring B is a 5-membered carbocyclic ring. [000223] 8. The compound of any one of embodiments 1-4, wherein Ring B is selected from: ,,3-b, IC3-c, IC3-d, IC3-e, IC3-f, or IC3-g:or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000226] 11. The compound of embodiment 10, wherein the compound is of Formula IC3-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000227] 12. The compound of embodiment 11, wherein the compound is not a compound selected from Table P1. [000228] 13. The compound of embodiment 10, wherein the compound is of Formula IC3-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000229] 14. The compound of embodiment 13, wherein the compound is not a compound selected from Table P2. [000230] 15. The compound of embodiment 10, wherein the compound is of Formula IC3-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.[000231] 16. The compound of embodiment 10, wherein the compound is of Formula IC3-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000232] 17. The compound of embodiment 16, wherein the compound is not a compound selected from Table P3. [000233] 18. The compound of embodiment 10, wherein the compound is of Formula IC3-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000234] 19. The compound of embodiment 18, wherein the compound is not a compound selected from Table P4. [000235] 20. The compound of embodiment 10, wherein the compound is of Formula IC3-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000236] 21. The compound of embodiment 10, wherein the compound is of Formula IC3-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000237] 22. The compound of any one of embodiments 1-21, wherein each R2is independently selected from halogen and C1-6 alkyl. [000238] 23. The compound of any one of embodiments 1-22, wherein n is 0 or 1. [000239] 24. The compound of embodiment 23, wherein n is 1. [000240] 25. The compound of any one of embodiments 1-24, wherein at least one R1is –OR7. [000241] 26. The compound of embodiment 25, wherein one R1is –OR7and any other R1groups are halogen. [000242] 27. The compound of any one of embodiments 1-26, wherein a moie is.[000243] 28. The compound of embodiment 27, wherein a moiet or.[000244] 29. The compound of any one of embodiments 1-28, wherein each R7is independently selected from C1-6alkyl and –(C1-4alkylene)OR. [000245] 30. The compound of any one of embodiments 1-29, wherein m is 2 or 3. [000246] 31. The compound of any one of embodiments 1-30, wherein Ring C is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000247] 32. The compound of any one of embodiments 1-30, wherein Ring C is selected from 9- to 10- membered bicyclic aryl ring, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000248] 33. The compound of embodiment 32, wherein Ring C is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000249] 34. The compound of any one of embodiments 1-30, wherein Ring C substituted with p R3groups wherein: Rinom phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring C1 is fused to Ring C2; and Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000250] 35. The compound of embodiment 34, wherein Ring C1 is a phenyl, and Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.[000251] 36. The compound of embodiment 34, wherein Ring C1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000252] 37. The compound of embodiment 34, wherein Ring C1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, or 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000253] 38. The compound of any one of embodiments 1-37, wherein each R3is independently selected from halogen, -C(O)N(R)2, and optionally substituted C1-6 alkyl. [000254] 39. The compound of any one of embodiments 1-38, wherein p is 1, 2, or 3. [000255] 40. The compound of any one of embodiments 1-39, wherein a moiety is selected from: , , ,, , , ,, , , , ,, . nyl,5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000257] 42. The compound of any one of embodiments 1-40, wherein Ring D is selected from 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000258] 43. The compound of embodiment 42, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000259] 44. The compound of any one of embodiments 1-40, wherein a moiet iswherein:ected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D1 is fused to Ring D2; andRing D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000260] 45. The compound of embodiment 44, wherein Ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000261] 46. The compound of embodiment 44, wherein Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000262] 47. The compound of any one of embodiments 1-40, wherein a moiet is. he co4mpound of any one of embodiments 1-47, wherein each R is independently C1-6 alkyl optionally substituted with one or more –OH. [000264] 49. The compound of any one of embodiments 1-48, wherein q is 0 or 1. [000265] 50. The compound of any one of embodiments 1-49, wherein R5is -C(O)R9or - (CH2)xN(R)C(O)R9. [000266] 51. The compound of any one of embodiments 1-50, wherein R9is optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl. [000267] 52. The compound of any one of embodiments 1-51, wherein R5.[000268] 53. The compound of any one of embodiments 1-52, wherein a moiet is selected from:, andC2-6hydrocarbon chain having at least one triple bond. [000270] 55. The compound of embodiment 1 or 3, wherein L is a bivalent straight or branched C1-2hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with – N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-. [000271] 56. The compound of embodiment 1 or 4, wherein R6and R6’are connected with an optionally substituted C5-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-. [000272] 57. The compound of embodiment 56, wherein R6and R6’are connected with: -O(CH2)5-, - O(CH2)4-, or –O(CH2)3OCH2-. [000273] 58. The compound of any one of embodiments 1-57, wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen. [000274] 59. A compound of Formula II: II) or a salt (e.g., a pharmaceutically, Ring A is phenyl and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain; X is –OR, -N(R)2, -C(O)N(R)2, or an optionally substituted group selected from phenyl, 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen and –OR7; each R7is independently selected from optionally substituted C1-6 aliphatic and –(C1-4 alkylene)OR; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic; each R4is independently selected from optionally substituted C1-6 aliphatic; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6aliphatic. [000275] 60. The compound of embodiment 63, wherein the compound is of Formula IIF:F) or a salt (e.g., a pharmaceutically X is -C(O)N(R)2 or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000276] 61. The compound of embodiment 59, wherein the compound is of Formula IIG: G) or a salt (e.g., a pharmaceuticallJ is a bivalent straight or branched C1-4hydrocarbon chain; and X is –OR or -N(R)2. [000277] 62. The compound of embodiment 59 or 60, wherein X is a group selected from 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C1-6alkyl.[000278] 63. The compound of any one of embodiments 59-62, wherein a moiet is selected. wherein Ring B is a 5-memberedheteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5- membered carbocyclic ring. [000280] 65. The compound of embodiment 64, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000281] 66. The compound of embodiment 64, wherein Ring B is a 5-membered carbocyclic ring. [000282] 67. The compound of any one of embodiments 59-66, wherein Ring B is selected from: ,ntly selected from halogen and C1-6alkyl. [000284] 69. The compound of any one of embodiments 59-68, wherein n is 0 or 1. [000285] 70. The compound of any one of embodiments 59-69, wherein Ring A is phenyl. [000286] 71. The compound of any one of embodiments 59-70, wherein at least one R1is –OR7. [000287] 72. The compound of embodiment 71, wherein one R1is –OR7and any other R1groups are halogen.[000288] 73. The compound of any one of embodiments 59-72, wherein a moie is.[000289] 74. The compound of embodiment 73, wherein a moiet or. [000290] 75. The compound of any one of embodiments 59-74, wherein each R7is independently selected from C1-6 alkyl and –(C1-4 alkylene)OR. [000291] 76. The compound of any one of embodiments 59-75, wherein m is 2 or 3. [000292] 77. The compound of any one of embodiments 59-76, wherein Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000293] 78. The compound of any one of embodiments 59-76, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000294] 79. The compound of embodiment 78, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.[000295] 80. The compound of any one of embodiments 59-76, wherein a moie is, wherein: selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D1 is fused to Ring D2; and Ring D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000296] 81. The compound of embodiment 80, wherein Ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000297] 82. The compound of embodiment 80, wherein Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000298] 83. The compound of any one of embodiments 59-82, wherein a moie is.. he compound of any one of embodiments 59-83, wherein each R4is independently C1-6 alkyl optionally substituted with one or more –OH. [000300] 85. The compound of any one of embodiments 59-84, wherein q is 0 or 1.[000301] 86. The compound of any one of embodiments 59-85, wherein R5is -C(O)R9or - (CH2)xN(R)C(O)R9. [000302] 87. The compound of any one of embodiments 59-86, wherein R9is optionally substituted C2-6alkenyl or optionally substituted C2-6alkynyl. [000303] 88. The compound of any one of embodiments 59-87, wherein R5.[000304] 89. The compound of any one of embodiments 59-88, wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen. [000305] 90. A compound selected from Table 1, or a salt (e.g., a pharmaceutically acceptable salt) thereof. [000306] 91. A pharmaceutical composition comprising a compound according to any one of embodiments 1-90, or a salt (e.g., pharmaceutically acceptable salt) thereof, and a pharmaceutically acceptable carrier or excipient. [000307] 92. A method comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof to a subject in need thereof. [000308] 93. The method of embodiment 92, 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 PI3Kα protein. [000309] 94. The method of embodiment 93, wherein the small GTPase is Rac1, CDC42, or a RAS protein. [000310] 95. The method of embodiment 94, wherein the small GTPase is a RAS protein. [000311] 96. The method of embodiment 95, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1. [000312] 97. The method of any one of embodiments 92-96, wherein the subject has a cancer. [000313] 98. 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 1-90 or a pharmaceutically acceptable salt thereof. [000314] 99. The method of embodiment 97 or 98, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.[000315] 100. The method of embodiment 99, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. [000316] 101. The method of embodiment 100, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. [000317] 102. The method of any one of embodiments 97-101, wherein the cancer is characterized by a mutation in a RAS protein. [000318] 103. The method of embodiment 102, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. [000319] 104. The method of embodiment 102 or 103, wherein the RAS protein is KRAS. [000320] 105. The method of embodiment 104, 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. [000321] 106. The method of embodiment 105, wherein the KRAS protein comprises a G12C or G12D mutation. [000322] 107. The method according to embodiment 102 or 103, wherein the RAS protein is HRAS. [000323] 108. The method according to embodiment 107, 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. [000324] 109. The method according to embodiment 102 or 103, wherein the RAS protein is NRAS. [000325] 110. The method according to embodiment 109, 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. [000326] 111. The method according to any one of embodiments 97-110, 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 (ChronicLymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. [000327] 112. The method according to embodiment 111, 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. [000328] 113. The method according to any one of embodiments 97-112, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases). [000329] 114. The method according to any one of embodiments 97-113, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. [000330] 115. The method according to any one of embodiments 92-114, wherein the subject has previously undergone a treatment regimen for cancer. [000331] 116. The method according to any one of embodiments 92-115, wherein the subject has previously entered remission from cancer. [000332] 117. 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- 90 or a pharmaceutically acceptable salt thereof. [000333] 118. The method according to embodiment 117, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes. [000334] 119. 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 1-90 or a pharmaceutically acceptable salt thereof. [000335] 120. The method according to embodiment 119, wherein the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome. [000336] 121. A method of treating a vascular disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof. [000337] 122. The method according to embodiment 121, 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)).[000338] 123. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein in a subject, comprising administering to the subject a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof. [000339] 124. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein, comprising contacting a cell containing the small GTPase and the PI3Kα protein with a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof. [000340] 125. A method comprising contacting a cell containing a small GTPase and a PI3Kα protein with a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof. [000341] 126. The method of embodiment 124 or 125, wherein the cell is included in a subject. [000342] 127. The method of any one of embodiments 123-126, wherein the small GTPase is selected from Rac1, CDC42, and a RAS protein. [000343] 128. The method of embodiment 127, wherein the small GTPase is a RAS protein. [000344] 129. The method of embodiment 128, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. [000345] 130. The method of embodiment 129, wherein the RAS protein is KRAS. [000346] 131. The method of embodiment 130, 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. [000347] 132. The method of embodiment 131, wherein the KRAS protein comprises a G12C or G12D mutation. [000348] 133. The method according to embodiment 129, wherein the RAS protein is HRAS. [000349] 134. The method according to embodiment 133, 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. [000350] 135. The method according to embodiment 129, wherein the RAS protein is NRAS. [000351] 136. The method according to embodiment 135, 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. [000352] 137. A compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof for use as a medicament. [000353] 138. Use of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.[000354] 139. The compound or use according to embodiment 137 or 138, wherein the medicament is for treating a cancer. [000355] 140. The compound or use according to embodiment 139, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα. [000356] 141. The compound or use according to embodiment 140, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. [000357] 142. The compound or use according to embodiment 141, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. [000358] 143. The compound or use according to any one of embodiments 139-142, wherein the cancer is characterized by a mutation in a RAS protein. [000359] 144. The compound or use according to embodiment 143, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. [000360] 145. The compound or use according to embodiment 143 or 144, wherein the RAS protein is KRAS. [000361] 146. The compound or use according to embodiment 145, 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. [000362] 147. The compound or use according to embodiment 146, wherein the KRAS protein comprises a G12C or G12D mutation. [000363] 148. The compound or use according to embodiment 143 or 144, wherein the RAS protein is HRAS. [000364] 149. The compound according to embodiment 148, 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. [000365] 150. The compound or use according to embodiment 143 or 144, wherein the RAS protein is NRAS. [000366] 151. The compound or use according to embodiment 150, 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. [000367] 152. The compound or use according to any one of embodiments 139-151, 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. [000368] 153. The compound or use according to embodiment 152, 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. [000369] 154. The compound or use according to any one of embodiments 139-151, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases). [000370] 155. The compound or use according to any one of embodiments 139-151, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. [000371] 156. The compound or use according to embodiment 137 or 138, wherein the medicament is for treating a metabolic disorder, a RASopathy, or a vascular disorder. [000372] 157. The compound or use according to embodiment 156, 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; 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)). [000373] 158. A compound according to any one of embodiment 1-90 or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition. [000374] 159. The compound for use according to embodiment 158 for use in treating a cancer. [000375] 160. The compound for use according to embodiment 159, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.[000376] 161. The compound for use according to embodiment 160, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. [000377] 162. The compound for use according to embodiment 161, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. [000378] 163. The compound for use according to any one of embodiments 159-162, wherein the cancer is characterized by a mutation in a RAS protein. [000379] 164. The compound for use according to embodiment 163, wherein the RAS protein comprises a mutation in codon 12, 13, or 61. [000380] 165. The compound for use according to embodiment 163 or 164, wherein the RAS protein is KRAS. [000381] 166. The compound for use according to embodiment 165, 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. [000382] 167. The compound for use according to embodiment 166, wherein the KRAS protein comprises a G12C or G12D mutation. [000383] 168. The compound for use according to embodiment 163 or 164, wherein the RAS protein is HRAS. [000384] 169. The compound for use according to embodiment 168, 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. [000385] 170. The compound for use according to embodiment 163 or 164, wherein the RAS protein is NRAS. [000386] 171. The compound for use according to embodiment 170, 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. [000387] 172. The compound for use according to any one of embodiments 159-171, 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’slymphomas; 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. [000388] 173. The compound for use according to embodiment 172, 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. [000389] 174. The compound for use according to any one of embodiments 159-173, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases). [000390] 175. The compound for use according to any one of embodiments 159-174, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein. [000391] 176. The compound for use according to embodiment 158 for use in treating a metabolic disorder, a RASopathy, or a vascular disorder. [000392] 177. The compound for use according to embodiment 176, 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; 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)). EXAMPLES [000393] 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. [000394] Selected abbreviations used in the preceding sections and the Examples are summarized in the following table:Abbreviation Term MeCN acetonitrileAbbreviation Term µm micronMaterials & Methods [000395] Preparative thin layer chromatography (Prep-TLC) separations described herein were typically performed on 20 x 20 cm plates (500-µm thick silica gel). [000396] Chromatographic purifications were typically performed using Biotage Isolera. One automated system running Biotage Isolera One 2.0.6 software (Biotage LLC, Charlotte, NC). Flow rates were the default values specified for the column in use. Reverse phase chromatography was performed using elution gradients of water and acetonitrile on KP-C18-HS Flash+ columns (Biotage LLC) of various sizes. Typical loading was between 1:50 and 1:1000 crude sample: RP SiO2 by weight. Normal phase chromatography was performed using elution gradients of various solvents (e.g., hexane, ethyl acetate, methylene chloride, methanol, acetone, chloroform, MTBE, etc.). The columns were SNAP Cartridges containing KP-SIL or SNAP Ultra (25 pm spherical particles) of various sizes (Biotage LLC). Typical loading was between 1:10 to 1:150 crude sample: SiO2 by weight. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system. [000397]1H NMR analyses of intermediates and exemplified compounds were typically performed on a Bruker Ascend TM 400 spectrometer (operating at 400 MHz), Bruker Ascend 500 MHz Avance Neo Spectrometer (Bruker-Biospin) or Bruker Avance Neo Nanobay (operating at 400 MHz) at 298 °K following standard operating procedure suggested by manufacturer. Reference frequency was set using TMS as an internal standard. Chemical shift values (δ) are reported in parts per million (ppm) with splitting patterns abbreviated to: s (singlet), br. s (broad singlet), d (doublet), dd (double doublet), t (triplet), and m (multiplet). The coupling constant (J) is given in Hz. Typical deuterated solvents were utilized as indicated in the individual examples. [000398] LCMS analyses were typically performed using one of the following conditions: [000399] (1) LCMS spectra were taken on an Agilent Technologies 6120B Quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) with 0.1% formic acid, and water (B) with 0.1% formic acid, and the eluent gradient was from 5-95% A in 6.0 min, 5%-40% A in 6.0 min, 80-100% A in 6.0 min using a poroshell 120 EC-C1850 mm x 3.0 mm x 2.7 μm capillary column; Flow Rate: 0.7 mL / min. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius (°C) unless otherwise noted. [000400] (2) LCMS spectra were taken on an Agilent Technologies 1290-6420 Triple Quadrupole spectrometer: The mobile phase for the LC was acetonitrile (A) with 0.05% formic acid, and water (B) with 0.05% formic acid, and the eluent gradient was from 5-95% A in 5.0 min, using a ZORBAX SB-C1850 mm x 2.1 mm x 1.8 μm capillary column; Flow Rate: 0.3 mL / min. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI).[000401] (3) LC-MS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C184.6 mm x150 mm x 3.5 μm RapidResol column with a mobile phase of water (0.1 % formic acid) / MeCN (0.1% formic acid) and a gradient of 5-95% MeCN over 10 minutes at a flow rate of 1 mL / min. Accurate mass data was obtained using a Thermo Fisher extractive plus EMR orbitrap LCMS system. Exact mass values were calculated by ChemCalc. [000402] (4) LCMS spectra were taken on an alliance Waters 2695 coupled to a dual absorbance detector waters 2487 and a waters micro mass ZQ-2000 single quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was from 5-100% A in 10.0 minute using a Kromasil 100-5-C18150 mm x 4.6 mm x 5 µm column. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). [000403] (5) LCMS spectra were taken on Waters Micromass-ZQ 2000 Quadrupole spectrometer. The mobile phase for the LC was (A) 0.1% formic acid in water; (B) acetonitrile 100% and the eluent gradient was from 10-90% B in 10.0 min, 90% up to 12 min B, 12-13 min 90-10% B, 13-15 min 90-10% B using Phenomenex Gemini-C18 (50 mm x 4.6 mm x 5 μm); Flow Rate: 0.5 mL / min. Mass spectra (MS) were measured by Electrospray Ion-Mass spectroscopy (ESI). [000404] Typically, analytical HPLC spectrometry conditions were as follows: [000405] LC1: Agilent Technologies 1260 Infinity coupled, Column: poroshell 120 EC-C18150 mm x 4.6 mm x 4 μm; Temperature: 40 °C; Eluent: 5:95 v / v acetonitrile / water + 0.02% trifluoroacetic acid in 20 min; Flow Rate: 1.2 mL / min; Detection: VWD, 190-600 nm. [000406] LC2: Shimadzu 2010 CHT, Column Waters X-select CSH C18 (150 x 4.6) mm x 3.5 µm, Temperature: 30 °C; MP-A 10 mM 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. [000407] Preparative HPLC were carried out with one of the following conditions: [000408] Condition 1: GILSON Preparative HPLC System; Column: Ultimate XB-C18, 21.2mm x 250mm, 5 μm; Mobile phase: Water with 0.1% trifluoroacetic acid; MeCN with 0.1% trifluoroacetic acid; Method: 15 minutes gradient elution; Initial organic: 10% to 30%; Final organic: 60% to 80%; UV1: 240; UV2: 230; Flow: 15 mL / min. [000409] Condition 2: C18-Reverse phase preparative HPLC was performed using a Waters purification system with 2489 UV / Vis detector, 2545 Gradient module, and Fraction collector III controlled by Waters Chromescope v1.6. The preparative HPLC column used was a Waters XBridge® Prep C185uMOBDTM19 x 250 mm column with a mobile phase of water / MeCN or water (0.1% TFA) / MeCN (0.1% TFA). [000410] Condition 3: Shimadzu Preparative HPLC System; Column: Phenomenex Luna C18, 21.1 mm × 250 mm, 10 μm; Mobile phase; MP-A 10 mM 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. [000411] Compound names were generated with ChemDraw Professional. Synthesis of Provided Compounds [000412] 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. Synthetic Example 1: Synthesis of N-[3-[[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]amino]phenyl]prop-2-enamide (Compound 1)[000413] Step A: Preparation of methyl 4-fluoro-2-(2-methoxyethoxy)benzoate: To a solution of methyl 4-fluoro-2-hydroxy-benzoate (25.0 g, 147 mmol) in MeCN (500 mL) was added 1-bromo-2-methoxy- ethane (24.5 g, 176 mmol) and cesium carbonate (97.4 g, 220 mmol). The mixture was stirred at 70 °C for 16 h under Ar. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were washed with saturated brine (100 mL), dried over Na2SO4and concentrated in vacuum to give methyl 4-fluoro-2- (2-methoxyethoxy)benzoate (32.6 g, 97 % yield) as a yellow oil. LCMS ESI (+) m / z 229.2 (M+H). [000414] Step B: Preparation of 4-fluoro-2-(2-methoxyethoxy)benzoic acid: To a solution of methyl 4- fluoro-2-(2-methoxyethoxy)benzoate (16.3 g, 71.4 mmol) in THF (82 mL), methanol (27 mL) and water (27 mL) was added lithium hydroxide monohydrate (8.55 g, 357 mmol). The mixture was stirred at 25 °C for 6 h. The reaction was concentrated to remove THF and methanol, and then diluted with water (150 mL). Aqueous HCl (3 N) was added to adjust the pH to 2. The mixture was extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with saturated brine (70 ml), dried over Na2SO4 and concentrated in vacuum to give 4-fluoro-2-(2-methoxyethoxy)benzoic acid (14.8 g, 97% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.8, 6.8 Hz, 1H), 6.80-6.91 (m, 1H), 6.76 (dd, J = 10.0, 2.3 Hz, 1H), 4.34 (t, J = 4.6 Hz, 2H), 3.82 (t, J = 4.6 Hz, 2H), 3.46 (s, 3H), 2.10 (s, 1H). [000415] Step C: Preparation of 4-fluoro-N-methoxy-2-(2-methoxyethoxy)-N-methyl-benzamide: To a solution of 4-fluoro-2-(2-methoxyethoxy)benzoic acid (10.0 g, 46.7 mmol), N,O-dimethylhydroxylamine hydrochloride (5.47 g, 56.0 mmol) and triethylamine (20.0 mL, 140 mmol) in DCM (150 mL) was added HATU (23.1 g, 60.7 mmol). The mixture was stirred at 25 °C for 6 h. The mixture was poured into water and the product was extracted with DCM. The organic fractions were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc) to give 4-fluoro-N-methoxy-2-(2-methoxyethoxy)-N-methyl-benzamide (10.8 g, 89.9% yield).1H NMR (400 MHz, CDCl3) δ 7.23 – 7.34 (m, 1H), 6.61 – 6.76 (m, 2H), 4.13 (t, J = 4.8 Hz, 2H), 3.73 (t, J = 4.8 Hz, 2H), 3.41 (s, 3H), 2.80 (s, 6H). [000416] Step D: Preparation of 2-[4-fluoro-2-(2-methoxyethoxy)benzoyl]thiophene-3-carboxylic acid: To a solution of thiophene-3-carboxylic acid (5.92 g, 46.2 mmol) in THF (130 mL) was added n- butyllithium (37.0 mL, 2.5 M solution in hexanes, 92.4 mmol) dropwise at -60 °C under Ar. The mixture was stirred at -60 °C for 0.5 h under Ar, then 4-fluoro-N-methoxy-2-(2-methoxyethoxy)-N-methyl- benzamide (10.8 g, 42.0 mmol) was added at -60 °C. The temperature was allowed to warm to 0 °C, and the resulting mixture was stirred at 0 °C for an additional 1 h. The mixture was poured into water. 1 N aqueous HCl was added to adjust the pH to 5. The mixture was concentrated to remove THF and diluted with water. The solid was filtered, washed with water and dried in vacuo to give crude 2-[4-fluoro-2-(2-methoxyethoxy)benzoyl] thiophene-3-carboxylic acid (13.0 g, 57% yield). LCMS ESI (+) m / z 325.1 (M+H). [000417] Step E: Preparation of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-thieno[3,2- c]pyran-6-carboxylate: To a solution of 2-[4-fluoro-2-(2-methoxyethoxy)benzoyl]thiophene-3-carboxylic acid (2.15 g, 6.63 mmol) and diethyl 2-bromopropanedioate (1.90 g, 7.96 mmol) in DMF (25 mL) was added potassium carbonate (2.29 g, 16.6 mmol). The mixture was stirred at 25 °C for 76 h. The mixture was poured into water and the product was extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (EtOAc / petroleum ether=1 / 3) to give ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-thieno[3,2- c]pyran-6-carboxylate (2.10 g, 81% yield). LCMS ESI (+) m / z 393.1 (M+H). [000418] Step F: Preparation of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2- c]pyridine-6-carboxylate: To a mixture of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo- thieno[3,2-c]pyran-6- carboxylate (1.80 g, 4.59 mmol) and AcOH (50 mL) under argon was added (NH4)2CO3 (6.61 g, 68.8 mmol) by portions. The mixture was stirred at 95 °C for 14 h. The mixture was allowed to cool to ambient temperature, and the precipitate was collected by filtration. The filter-cake was washed with water and MeOH, and dried in vacuo to give ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]- 4-oxo-5H-thieno[3,2-c]pyridine-6-carboxylate (1.26 g, 70% yield). LCMS ESI (+) m / z 392.1 (M+H). [000419] Step G: Preparation of ethyl 4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridine-6-carboxylate: A suspension of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H- thieno[3,2-c]pyridine-6-carboxylate (3.00 g, 5.37 mmol) in phosphorus oxychloride (10.0 mL, 107 mmol) was stirred at 95 °C for 3 h. The mixture was concentrated in vacuum and diluted with DCM. The mixture was poured into aqueous NaHCO3 solution, and the product was extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel (EtOAc / petroleum ether=1 / 6) to give ethyl 4-chloro-7-[4-fluoro-2-(2- methoxyethoxy) phenyl]thieno[3,2-c]pyridine-6-carboxylate (1.09 g, 49% yield). LCMS ESI (+) m / z 410.1 (M+H). [000420] Step H: Preparation of ethyl 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-7-[4- fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate: To a solution of tert-butyl 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.48 g, 4.12 mmol), ethyl 4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate (1.30 g, 3.17 mmol), and Na2CO3(0.841 g, 7.93 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added Pd(dppf)Cl2(220 mg, 0.300 mmol). The mixture was stirred at 95 °C for 16 h under Ar. The mixture was poured into water and the product was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel (EtOAc / petroleumether=1 / 3) to give ethyl-4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate (1.20 g, 62% yield). LCMS ESI (+) m / z 607.3 (M+H). [000421] Step I: Preparation of 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-7-[4-fluoro- 2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylic acid: To a solution of ethyl 4-(2-tert- butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridine-6-carboxylate (800 mg, 1.32 mmol) in 3:1:1 mixture of tetrahydrofuran, water and methanol (20.0 mL) was added LiOH.H2O (554 mg, 13.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in water. The pH was adjusted to 3 with 1 N HCl. The mixture was extracted with dichloromethane. The combined organic layers were washed water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylic acid (605 mg, 79% yield). LCMS ESI (+) m / z 579.2 (M+H). [000422] Step J: Preparation of tert-butyl 6-[6-(benzyloxycarbonylamino)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: A solution of 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinolin-6-yl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylic acid (40 mg, 0.069 mmol), benzyl alcohol (0.036 mL, 0.35 mmol), triethylamine (0.096 mL, 0.69 mmol) and [azido(phenoxy)phosphoryl]oxybenzene (96 mg, 0.35 mmol) in dry toluene (3 mL) was stirred at 25 °C for 30 min. The mixture was stirred at 90 °C for 4 h. The mixture was poured into water and the product was extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-TLC (EtOAc / Petroleum ether:1 / 3) to give tert-butyl 6-[6-(benzyloxycarbonylamino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (38 mg, 80% yield). [000423] Step K: Preparation of tert-butyl 6-[6-amino-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[6-(benzyloxycarbonylamino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 mg, 0.044 mmol) in 1,4-dioxane (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (61 mg, 1.4 mmol). The mixture was stirred at 100 °C for 6 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4, concentrated and purified by Prep-TLC (EtOAc / hexane=1 / 2) to give tert- butyl 6-[6-amino-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate (21 mg, 87% yield). LCMS ESI (+) m / z 550.2 (M+H).[000424] Step L: Preparation of tert-butyl 6-[6-[3-(tert-butoxycarbonylamino)anilino]-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a suspension of tert-butyl 6-[6-amino-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate (40 mg, 0.073 mmol), tert-butoxypotassium (16 mg, 0.15 mmol) and tert-butyl N-(3-iodophenyl)carbamate (35 mg, 0.11 mmol) in toluene (2 mL) was added 1,1'- bis(diphenylphosphino)ferrocene (8.1 mg, 0.015 mmol). The mixture was stirred at 100 °C for 10 h under Ar. The mixture was poured into water and extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-TLC (EtOAc / petroleum ether:1 / 2) to give tert-butyl 6-[6-[3-(tert-butoxycarbonylamino)anilino]-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (24 mg, 45% yield). LCMS ESI (+) m / z 741.3 (M+H). [000425] Step M to Step N: Preparation of tert-butyl 6-[6-(3-aminoanilino)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[6-[3-(tert-butoxycarbonylamino)anilino]-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (24 mg, 0.032 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to dryness to give N1-(7-(4-fluoro-2-(2- methoxyethoxy)phenyl)-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl)benzene-1,3- diamine (30 mg). The crude product was dissolved in THF (2 mL). Aqueous Na2CO3 solution (2 mL) and di-tert-butyl dicarbonate (7.1 mg, 0.032 mmol) in THF (1 mL) was added at 0 °C. The mixture was stirred at 0 °C for an additional 1 h. Aqueous MeNH2 (1 mL) was added to quench the reaction. The product was extracted with EtOAc, dried over Na2SO4, concentrated and purified by Prep-TLC (EtOAc / petroleum ether:1 / 2) to give tert-butyl 6-[6-(3-aminoanilino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2- c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (18 mg, 87% yield). [000426] Step O: Preparation of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-(prop-2- enoylamino)anilino]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[6-(3-aminoanilino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]- 3,4-dihydro-1H-isoquinoline-2-carboxylate (12 mg, 0.019 mmol) and triethylamine (0.013 mL, 0.094 mmol) in DCM (2 mL) was added acryloyl chloride (1.9 mg, 0.020 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was poured into water and the product was extracted with EtOAc. The organic fractions were dried over anhydrous Na2SO4, concentrated and purified by Prep-TLC (EtOAc / petroleum ether:1 / 2) to give tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-(prop-2- enoylamino)anilino]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (9.6 mg, 74% yield). LCMS ESI (+) m / z 695.2 (M+H).[000427] Step P: Preparation of N-[3-[[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1,2,3,4- tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]amino]phenyl]prop-2-enamide: To a solution of tert- butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-(prop-2-enoylamino)anilino]thieno[3,2-c]pyridin- 4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (9.6 mg, 0.014 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated and purified by Prep-HPLC to give N-[3-[[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4- (1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]amino]phenyl]prop-2-enamide (6.6 mg, 81% yield) as a trifluoroacetic acid salt.1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.99 (s, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 10.7 Hz, 1H), 6.86 - 6.75 (m, 1H), 6.65 - 6.33 (m, 1H), 6.25 - 6.05 (m, 2H), 5.71 - 5.52 (m, 1H), 4.34 - 4.10 (m, 3H), 4.10 - 3.86 (m, 6H), 3.85 - 3.72 (m, 1H), 3.69 - 3.60 (m, 1H), 3.12 - 2.95 (m, 2H), 1.55 - 1.32 (m, 2H). LCMS ESI (+) m / z 595.2 (M+H). Synthetic Example 2: Synthesis of 5-(6-(1-(1-Acryloylazetidin-3-yl)-1H-pyrazol-4-yl)-7- (phenylamino)thieno[3,2-c] pyridin-4-yl)-1-methylpyridin-2(1H)-one (Compound 2)3,2- c]pyridin-4-ol: A solution of N,N-diethyl-2-methyl-thiophene-3-carboxamide (1.4 g, 7.1 mmol) in THF (15 mL) was cooled to -78 °C. n-BuLi (2.5 M) (0.68 g, 10.6 mmol) was slowly added at -78 °C and the stirring was continued for 2.0 h. Neat 1-(2-trimethylsilylethoxy methyl)pyrazole-4-carbonitrile (1.9 g, 8.51 mmol) was added into the reaction mixture at -78 °C. The temperature was slowly allowed to rise to room temperature, and it was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was cooled to 0 °C and pH was adjusted to 5 with 1.0 N HCl solution. The mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with EtOAc (100 mL) and the organiclayer was washed with water (2 x 50 mL), followed by saturated brine solution (50 mL). The organic layer was separated and dried over Na2SO4. The crude compound was purified by column chromatography eluting with 30% EtOAc in hexanes. The desired fractions were concentrated to dryness in vacuum to get 6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol (1.1 g, 44.7%) as a solid.1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.66-7.64 (m, 1H), 7.26-7.25 (m, 1H), 6.97 (s, 1H), 5.52 (s, 2H), 3.64 (t, J = 8.4 Hz, 2H), 0.95 (t, J = 8.4 Hz, 2H), -0.00 to -0.02 (m, 9H). [000429] Step B: Preparation of 7-Iodo-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)thieno[3,2-c]pyridin-4-ol: To a stirred solution of 6-[1-(2-Trimethylsilylethoxymethyl)pyrazol-4- yl]thieno[3,2-c]pyridin-4-ol (1.70 g, 4.89 mmol) in DMF (17 mL) at 10 °C. N-Iodosuccinimide (1.32 g, 5.87 mmol) was added at 10 °C. The reaction mixture was slowly warmed to room temperature and continued stirring for 12 h. The reaction mixture was slowly poured into ice cold water (50 mL) and stirred for 10 min. The solid was filtered and dried under vacuum to afford 7-iodo-6-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol (1.2 g, 52%).1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 5.2 Hz, 1H), 5.52 (s, 2H), 3.66 (t, J = 8.4 Hz, 2H), 0.98-0.94 (m, 2H), -0.011 to -0.014 (m, 9H). [000430] Step C: Preparation of 7-Iodo-4-methoxy-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-4-yl)thieno[3,2-c]pyridine: To a stirred solution of 7-iodo-6-[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-4-ol (100 mg, 0.211 mmol) in toluene (2 mL) at room temperature were added Ag2CO3 (90 mg, 0.33 mmol), and MeI (62 mg, 0.44 mmol). The reaction mixture was heated to 90 °C and stirred for 3 h. The reaction was diluted with EtOAc (10 mL), filtered through a Celite® bed and solvent was removed under reduced pressure. The crude product was purified by column purification to give 7-iodo-4-methoxy-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-4-yl)thieno[3,2-c]pyridine (67 mg, 65%) as a liquid.1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 0.4 Hz, 1H), 8.33 (d, J = 0.4 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 5.6 Hz, 1H), 5.50 (s, 2H), 4.12 (s, 3H), 3.68-3.63 (m, 2H), 0.97-0.92 (m, 2H), -0.003 (m, 9H). [000431] Step D: Preparation of 4-Methoxy-N-phenyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-4-yl)thieno[3,2-c]pyridin-7-amine: To a stirred solution of 2-[[4-(7-iodo-4-methoxy-thieno[3,2- c]pyridin-6-yl)pyrazol-1-yl] methoxy]ethyl-trimethyl-silane (2.5 g, 5.1 mmol) in THF (20 mL) at room temperature with N2-purging, aniline (0.94 mL, 10.3 mmol), Ruphos-Pd-G3 (0.086 g, 0.10 mmol) and t- BuOK (0.69 g, 6.2 mmol) were added. Then the reaction mixture purged with N2-gas for 10 min. The contents were heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with EtOAc (50 mL) and stirred for 10 min. The solids were filtered and the organic layer was evaporated under reduced pressure. The crude product was purified by column chromatography to afford 4-methoxy-N-phenyl-6-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-7-amine (1.3 g, 53%) as a solid.1HNMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.08-7.04 (m, 2H), 6.61 (t, J = 7.2 Hz, 1H), 6.50-6.47 (m, 2H), 5.38 (s, 2H), 4.12 (s, 3H), 3.46 (t, J = 7.6 Hz, 2H), 0.78 (t, J = 8.4 Hz, 2H), -0.07 (m, 9H). [000432] Step E: Preparation of 4-methoxy-N-phenyl-6-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-7- amine: To a stirred solution of 6.0 M HCl in isopropanol (1.0 mL) at 0 °C, 4-methoxy-N-phenyl-6-[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-7-amine (300 mg, 0.0442 mmol) was added and warmed to room temperature. After 1 h, volatiles were removed under reduced pressure to give 208 mg of 4-methoxy-N-phenyl-6-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-7-amine which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 12.79 (bs, 1H), 8.06 (s, 2H), 7.87 (s, 1H), 7.64 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.07 (t, J = 8.0 Hz, 2H), 6.61 (t, J = 7.2 Hz, 1H), 6.48 (d, J = 7.6 Hz, 2H), 4.11 (s, 3H). [000433] Step F: Preparation of tert-butyl 3-(4-(4-methoxy-7-(phenylamino)thieno[3,2-c]pyridin-6-yl)- 1H-pyrazol-1-yl)azetidine-1-carboxylate: To a stirred solution of 4-methoxy-N-phenyl-6-(1H-pyrazol-4- yl)thieno[3,2-c]pyridin-7-amine (20 mg, 0.062 mmol) in DMF (2 mL) at room temperature were added Cs2CO3 (30 mg, 0.092 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (22 mg, 0.078 mmol). The temperature was increased to 80 °C and stirred at same temperature for 12 h. The contents were poured into ice cold water (5 mL). The product was extracted into EtOAc (10 mL), washed with brine (5 mL) and the solvent was removed under reduced pressure followed by a preparative TLC purification to get tert-butyl 3-(4-(4-methoxy-7-(phenylamino)thieno[3,2-c]pyridin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (10 mg, 35%) as a solid. LCMS ESI (+) m / z 378.4 (M-Boc+H). [000434] Step G: Preparation of 6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-methoxy-N-phenylthieno[3,2- c]pyridin-7-amine: To a stirred solution of tert-butyl 3-[4-(7-anilino-4-methoxy-thieno[3,2-c]pyridin-6- yl)pyrazol-1-yl]azetidine-1-carboxylate (20 mg, 0.042 mmol) in dichloromethane (1 mL) at 0 °C was added trifluoroacetic acid (0.016 mL, 0.21 mmol). It was allowed to warm to room temperature and stirred at same temperature for 12 h. The volatiles were removed, co-evaporated with dichloromethane (5 mL). The crude 6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-methoxy-N-phenylthieno[3,2-c]pyridin-7-amine (15 mg) was used as such in the next step without any further purification. [000435] Step H: Preparation of 1-(3-(4-(4-methoxy-7-(phenylamino)thieno[3,2-c]pyridin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)prop-2-en-1-one: To a stirred solution of 6-[1-(azetidin-3-yl)pyrazol-4-yl]-4- methoxy-N-phenyl-thieno[3,2-c]pyridin-7-amine (15 mg, 0.040 mmol) in dichloromethane (1 mL) at 0 °C was added N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) followed by acryloyl chloride (0.0032 mL, 0.040 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The solvents were removed and the crude product was purified by preparative TLC to give 1-(3-(4-(4-methoxy-7- (phenylamino)thieno[3,2-c]pyridin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)prop-2-en-1-one (5 mg, 30%) as asolid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.09-7.05 (m, 2H), 6.62 (t, J = 7.2 Hz, 1H), 6.50-6.47 (m, 2H), 6.37-6.31 (m, 1H), 6.16-6.11 (m, 1H), 5.72-5.61 (m, 1H), 5.36-5.29 (m, 1H), 4.66 (t, J = 8.8 Hz, 1H), 4.44-4.34 (m, 2H), 4.18- 4.14 (m, 1H), 4.11 (s, 3H); LCMS ESI (+) m / z 432.4 (M+H). [000436] Step I: Preparation of 1-(3-(4-(4-hydroxy-7-(phenylamino)thieno[3,2-c]pyridin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)prop-2-en-1-one: To a stirred solution of 1-[3-[4-(7-anilino-4-methoxy- thieno[3,2-c]pyridine-6-yl)pyrazol-1-yl]azetidin-1-yl]prop-2-en-1-one (150 mg, 0.348 mmol) in DMF (15 mL) were added lithium chloride (74 mg, 1.7 mmol) and para-toluenesulfonic acid (299 mg, 1.74 mmol) at room temperature. The contents were heated to 120 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane (10 mL). The organic layer was washed with brine solution (5 mL) and solvent was removed under reduced pressure. A preparative TLC purification afforded 1-(3-(4-(4-hydroxy-7-(phenylamino)thieno[3,2-c]pyridin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)prop-2-en- 1-one (15 mg, 10%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.44 (d, J = 0.4 Hz, 1H), 8.03 (s, 1H), 7.61 (s, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.09-7.05 (m, 2H), 6.63-6.59 (m, 1H), 6.53-6.51 (m, 2H), 6.37-6.30 (m, 1H), 6.16-6.11 (m, 1H), 5.70 (dd, J = 10.0, 2.0 Hz, 1H), 5.29- 5.22 (m, 1H), 4.66 (t, J = 8.8 Hz, 1H), 4.40-4.35 (m, 2H), 4.14-4.10 (m, 1H). [000437] Step J: Preparation of 6-(1-(1-acryloylazetidin-3-yl)-1H-pyrazol-4-yl)-7- (phenylamino)thieno[3,2-c]pyridin-4-yl trifluoromethanesulfonate: A solution of 1-(3-(4-(4-hydroxy-7- (phenylamino)thieno[3,2-c]pyridin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)prop-2-en-1-one (30 mg, 0.072 mmol) in dichloromethane (1 mL) was cooled to 0 °C and triethylamine (15 mg, 0.14 mmol) and trifluoromethanesulfonic anhydride (40 mg, 0.14 mmol) were added. The reaction mixture was stirred at same temperature for 5 h. The volatiles were removed under reduced pressure and the crude product was purified by preparative TLC to get 6-(1-(1-acryloylazetidin-3-yl)-1H-pyrazol-4-yl)-7- (phenylamino)thieno[3,2-c]pyridin-4-yl trifluoromethanesulfonate (8 mg, 20%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 7.6 Hz, 2H), 8.02 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.17-7.13 (m, 2H), 6.77-6.73 (m, 1H), 6.61 (dd, J = 8.4, 0.8 Hz, 2H), 6.37-6.31 (m, 1H), 6.16-6.11 (m, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 5.42-5.35 (m, 1H), 4.65 (t, J = 8.8 Hz, 1H), 4.43-4.34 (m, 2H), 4.16-4.13 (m, 1H). [000438] Step K: Preparation of 5-(6-(1-(1-acryloylazetidin-3-yl)-1H-pyrazol-4-yl)-7-(phenylamino) thieno[3,2-c] pyridin-4-yl)-1-methylpyridin-2(1H)-one: A solution of [7-anilino-6-[1-(1-prop-2- enoylazetidin-3-yl)pyrazol-4-yl]thieno[3,2-c]pyridin-4-yl] trifluoromethanesulfonate (8.0 mg, 0.015 mmol) in 1,4-dioxane (1 mL) was purged with N2for 5 min. Sodium carbonate (4.6 mg, 0.044 mmol), 1-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (4.4 mg, 0.019 mmol)and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.0022 mmol) were added at room temperature. The reaction mixture was heated to 90 °C and stirred for 3 h. The reaction mixture was diluted with 1,4-dioxane (15 mL), filtered through Celite® bed and solvent was removed under reduced pressure. The crude product was purified by preparative TLC with 10% DCM in ethyl acetate as the eluent to give 5-(6-(1-(1- acryloylazetidin-3-yl)-1H-pyrazol-4-yl)-7-(phenylamino)thieno[3,2-c]pyridin-4-yl)-1-methylpyridin- 2(1H)-one (2.85 mg, 38%) as a solid.1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.04 (s, 1H), 7.99-7.79 (m, 2H), 7.54-7.47 (m, 2H), 7.24-7.20 (m, 2H), 6.89 (t, J =7.4 Hz, 1H), 6.76-6.73 (m, 1H), 6.70-6.68 (m, 2H), 6.40-6.35 (m, 1H), 6.23-6.16 (m, 1H), 5.72 (dd, J = 10.2 Hz, 1H), 5.59 (s, 1H), 5.16-5.09 (m, 1H), 4.65-4.51 (m, 3H), 4.45-4.41 (m, 1H), 3.70 (s, 3H). LCMS ESI (+) m / z 509.4 (M+H). Synthetic Example 3: Synthesis of 1-[7-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5- yl)thieno[3,2-c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonan-2-yl]prop-2-en-1-one (Compound 5) [000439]din-6-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate: 4-fluoro-2-hydroxybenzoic acid (25.0 g, 392 mmol) was dissolved in acetone (500 mL). A mixture of 6-chloro-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridine (200 mg, 0.667 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (166 mg, 0.734 mmol), Pd2(dba)3(61 mg, 0.067 mmol), BINAP (83 mg, 0.13 mmol) and cesium carbonate (435 mg, 1.33 mmol) in toluene (6 mL) was stirred at 100 °C for 18 hours under N2. The mixture was concentrated and purified by column chromatography on silica gel (DCM:MeOH=50:1 to 20:1) to give tert-butyl 7-[4-(1-methylindazol-5- yl)thieno[3,2-c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (180 mg, 55% yield). LCMS ESI (+) m / z 490.3 (M+H). [000440] Step B: Preparation of product tert-butyl 7-[7-bromo-4-(1-methylindazol-5-yl)thieno[3,2- c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate: To a stirred solution of tert-butyl 7-[4-(1-methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (130 mg, 0.266 mmol) in DMF (2 mL) was added NBS (47 mg, 0.27 mmol) at 0 °C. After that the mixture was stirred at 0 °C for 30 min. The mixture was quenched with water (4 mL) and extracted with EtOAc. The combined organic fractions were washed with saturated brine solution, dried (Na2SO4) and concentrated to dryness to give crude product tert-butyl 7-[7-bromo-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate (200 mg), which was used in the next step without further purification. LCMS ESI (+) m / z 568.2 / 570.2 (M+H). [000441] Step C: Preparation of tert-butyl 7-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1- methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate: To a stirred solution of tert-butyl 7-[7-bromo-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate (20 mg, 0.035 mmol) in 1,4-dioxane (2 mL) / water (0.2 mL) were added [4-fluoro-2-(2-methoxyethoxy)phenyl]boronic acid (15 mg, 0.070 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (2.6 mg, 0.0035 mmol), tri-tert-butylphosphine tetrafluoroborate (2.0 mg, 0.0070 mmol) and cesium carbonate (23 mg, 0.070 mmol). The mixture was heated to 90 °C and stirred for 12 hours under N2. The mixture was concentrated and the residue was purified by Prep-TLC (petroleum ether:EtOAc=1:1) to give tert-butyl 7-[7-[4-fluoro- 2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate (15 mg, 65% yield). LCMS ESI (+) m / z 658.4 (M+H). [000442] Step D: Preparation of 6-(2,7-diazaspiro[3.5]nonan-7-yl)-7-[4-fluoro-2-(2- methoxyethoxy)phenyl]-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridine: To a solution of tert-butyl 7-[7-[4- fluoro-2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate (15 mg, 0.023 mmol) in DCM (2 mL) was added TFA (0.50 mL, 6.5 mmol). The mixture was stirred at 10 °C for 30 min. The mixture was concentrated to dryness to give crude 6-(2,7-diazaspiro[3.5]nonan-7-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5- yl)thieno[3,2-c]pyridine (15 mg) which was used without further purification. LCMS ESI (+) m / z 558.3 (M+H). [000443] Step E: Preparation of 1-[7-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5- yl)thieno[3,2-c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonan-2-yl]prop-2-en-1-one: To a stirred solution of 6- (2,7-diazaspiro[3.5]nonan-7-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5- yl)thieno[3,2-c]pyridine (15 mg, 0.027 mmol) in ethyl acetate (2 mL) / water (2 mL) was added sodium carbonate to adjust the pH to 8. Additional sodium carbonate (5.7 mg, 0.054 mmol) was added followed by a solution of acryloyl chloride (0.0026 mL, 0.032 mmol) in DCM (0.2 mL) dropwise at 0 °C. The mixture was stirred at 10 °C for 30 min. The mixture was extracted with EtOAc, dried over Na2SO4and concentrated. The residue was purified by Prep-HPLC to give 1-[7-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1-methylindazol-5-yl)thieno[3,2-c]pyridin-6-yl]-2,7-diazaspiro[3.5]nonan-2- yl]prop-2-en-1-one (8.7 mg, 52% yield) as a bis trifluoroacetic acid salt.1H NMR(400 MHz, CD3OD) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 5.6 Hz, 1H), 7.45 (dd, J = 8.4, 6.6 Hz, 1H), 7.12 (dd, J = 11.0, 2.2 Hz, 1H), 6.94 (td, J = 8.2, 2.4 Hz, 1H), 6.35 - 6.29 (m, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.71 (dd, J = 10., 2.0 Hz, 1H), 4.29 - 4.24 (m, 1H), 4.17 (s, 3H), 4.16 - 4.13 (m, 1H), 3.98 (s, 2H), 3.74 (s, 2H), 3.58 (t, J = 4.0 Hz, 2H), 3.18 (s, 3H), 1.76 - 1.73 (m, 4H). LCMS ESI (+) m / z 612.2 (M+H). Synthetic Example 4: Synthesis of 7-[2-(2-methoxyethoxy)phenyl]-4-(1-methylsulfonyl-4- piperidyl)thieno[2,3-d]pyridazine (Compound 24)n of 5,7-dichlorothieno[2,3-c]pyridine (1.00 g, 4.90 mmol), (1-methylindazol-5-yl)boronic acid (1.12 g, 6.37 mmol), tetrakis(triphenylphosphine)palladium(0) (566 mg, 0.490 mmol) and sodium carbonate (1.04 g, 9.80 mmol) in 1,4-dioxane (20 mL) / water (2 mL) was stirred at 95 °C under N2 for 2 hours. The mixture was diluted with EtOAc, washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether:EtOAc=5:1 to 2:1) to give 5-chloro-7-(1- methylindazol-5-yl)thieno[2,3-c]pyridine (707 mg, 48% yield). LCMS ESI (+) m / z 300.0 (M+H). [000445] Step B: Preparation of 5-methoxy-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridine: A solution of 5-chloro-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridine (707 mg, 2.36 mmol), palladium(II) acetate (53 mg, 0.24 mmol), t-Bu XPhos (200 mg, 0.472 mmol) and cesium carbonate (1.54 g, 4.72 mmol) in 1,4- dioxane (4 mL) / methanol (8 mL) was stirred at 85 °C under N2for 10 hours. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=2:1) to give 5-methoxy-7-(1-methylindazol-5- yl)thieno[2,3-c]pyridine (380 mg, 55% yield). LCMS ESI (+) m / z 296.1 (M+H).[000446] Step C: Preparation of 4-bromo-5-methoxy-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridine: To a stirred solution of 5-methoxy-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridine (380 mg, 1.29 mmol) in DMF (2 mL) at 0 °C was added NBS (275 mg, 1.54 mmol). The mixture was stirred at 0 °C for 30 min. The reaction was quenched by water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=2:1) to give 4-bromo-5-methoxy-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridine (440 mg, 91% yield). LCMS ESI (+) m / z 374.0 (M+H). [000447] Step D: Preparation of 4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-5-methoxy-7-(1- methylindazol-5-yl)thieno[2,3-c]pyridine: A solution of 4-bromo-5-methoxy-7-(1-methylindazol-5- yl)thieno[2,3-c]pyridine (100 mg, 0.267 mmol), 2-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-5,5- dimethyl-1,3,2-dioxaborinane (241 mg, 0.802 mmol), Pd(DPEphos)Cl2 (19 mg, 0.027 mmol) and Cs2CO3 (174 mg, 0.534 mmol) in 1,4-dioxane (6 mL) was stirred at 95 °C under N2 for 12 hours. The mixture was concentrated and purified by preparative TLC (petroleum ether:EtOAc=2:1) to give 4-[2,4-difluoro-6-(2- methoxyethoxy)phenyl]-5-methoxy-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridine (52 mg, 40% yield). LCMS ESI (+) m / z 482.2 (M+H). [000448] Step E: Preparation of 4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5- yl)thieno[2,3-c]pyridin-5-ol: A solution of 4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-5-methoxy-7-(1- methylindazol-5-yl)thieno[2,3-c]pyridine (47 mg, 0.098 mmol), trimethylchlorosilane (0.12 mL, 0.98 mmol) and sodium iodide (44 mg, 0.29 mmol) in acetonitrile (6 mL) was stirred at 80 °C for 1 hour. The mixture was cooled to rt. Aqueous Na2SO3 solution was added to quench the reaction. The mixture was extracted with EtOAc, washed by brine, dried over Na2SO4 and concentrated to give crude 4-[2,4-difluoro- 6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridin-5-ol (53 mg) which was used in the next step without further purification. LCMS ESI (+) m / z 468.2 (M+H). [000449] Step F: Preparation of [4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5- yl)thieno[2,3-c]pyridin-5-yl] trifluoromethanesulfonate: To a stirred solution of 4-[2,4-difluoro-6-(2- methoxyethoxy)phenyl]-7-(1-methylindazol-5-yl)thieno[2,3-c]pyridin-5-ol (48 mg, 0.10 mmol) and triethylamine (0.057 mL, 0.41 mmol) in DCM (2 mL) was added trifluoromethanesulfonic anhydride (0.035 mL, 0.21 mmol) at 0 °C. The mixture was stirred at 5 °C for 30 min. Saturated aqueous NaHCO3solution was added and the reaction was stirred for additional 5 min. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 1) to give [4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5- yl)thieno[2,3-c]pyridin-5-yl] trifluoromethanesulfonate (40 mg, 65% yield). LCMS ESI (+) m / z 600.2 (M+H).[000450] Step G: Preparation of tert-butyl (4R)-2-(4-(2,4-difluoro-6-(2-methoxyethoxy)phenyl)-7-(1- methyl-1H-indazol-5-yl)thieno[2,3-c]pyridin-5-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate: A solution of [4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5- yl)thieno[2,3-c]pyridin-5-yl] trifluoromethanesulfonate (30 mg, 0.050 mmol), [(4R)-5-tert- butoxycarbonyl-4-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl]boronic acid (28 mg, 0.100 mmol), palladium(II) acetate (1.1 mg, 0.0050 mmol), Xphos (4.8 mg, 0.010 mmol) and potassium carbonate (21 mg, 0.15 mmol) in acetonitrile (2 mL) / water (1 mL) was stirred at 100 °C for 12 hours under N2. The mixture was concentrated and purified by Prep-TLC (DCM / MeOH = 25 / 1) to give tert-butyl (4R)-2-(4- (2,4-difluoro-6-(2-methoxyethoxy)phenyl)-7-(1-methyl-1H-indazol-5-yl)thieno[2,3-c]pyridin-5-yl)-4- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (5.0 mg, 15% yield). LCMS ESI (+) m / z 687.4 (M+H). [000451] Step H: Preparation of 4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5- yl)-5-[(4R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]thieno[2,3-c]pyridine: To a solution of tert-butyl (4R)-2-[4-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-7-(1-methylindazol-5-yl)thieno[2,3- c]pyridin-5-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate...

Claims

CLAIMS 1. A compound of Formula I’’:or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl, pyridine, or a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 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 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered carbocyclic ring; and phenyl; Ring C is selected from phenyl; 9- to 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is absent or selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7- membered carbocyclic ring; 5- to 10-membered bicyclic or polycyclic carbocyclic ring; 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L is a covalent bond or a bivalent straight or branched C1-6hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-; and when Ring D is absent, then L is absent; each R1is independently selected from halogen, optionally substituted C1-6 alkyl, cycloalkyl, –CN, – C(O)OR, –C(O)NR2, –CH2NR2, –N(R7)2, -N=S(R7)2, –SR7, –(C1-4alkylene)OR, and –OR7, wherein a sulfur atom in R1can be oxidized; each R7is independently selected from hydrogen, optionally substituted C1-6 aliphatic, –(C1-4 alkylene)OR, –(C1-4 alkylene)NR2, optionally substituted 3- to 6-membered carbocyclic ring, optionally substituted 4- to 7-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R7groups, together with the atom(s) to which they are attached, form a 4- to 6-membered hetserocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic, and -OR; each R3is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2)xC(O)OR, -(CH2)xC(O)N(R)2, -(CH2)xN(R)C(O)R, -(CH2)xCy, -O(CH2)xCy, -C(O)Cy, optionally substituted carbocyclic ring, and optionally substituted C1-6 aliphatic; each R4is independently optionally substituted C1-6 aliphatic; R5is absent, optionally substituted C1-6 aliphatic, -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; R6and R6’are connected with an optionally substituted C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; each x is independently 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6aliphatic; each Cy is independently selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 4- to7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is substituted with 0-3 instances of R8; and each R8is independently selected from oxo, halogen, and optionally substituted C1-6aliphatic.

2. The compound of claim 1, wherein the compound is of Formula IC’: or a salt (e.g., a pharmaceu3. The compound of claim 1, wherein the compound is of Formula ID’: or a salt (e.g., a pharmaceuticin: L is a bivalent straight or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, -N(R)C(O)-, -C(O)N(R)-, or –C(O)-.

4. The compound of claim 1, wherein the compound is of Formula IE’:or a salt (e.g., a pharmaceutically acceptable salt) thereof.

5. The compound of any one of claims 1-4, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-membered carbocyclic ring.

6. The compound of claim 5, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound of claim 5, wherein Ring B is a 5-membered carbocyclic ring. om: ,, ,m:

10. The compound of claim 9, wherein a moiet is selected fro.

11. im 1 or 2, wherein the compound is of Formula IC3’-a, IC3’-b, IC3’-c, IC3’-d, IC3’-e, IC3’-f, IC3’-g, IC3’-h, IC3’-i, IC3’-j, IC3’-k, IC3’-l, or IC3’-m:or a salt (e.g., a pharmaceutically acceptable salt) thereof.

12. The compound of claim 11, wherein the compound is of Formula IC3’-a, or a salt (e.g., a pharmaceutically acceptable salt) thereof, optionally wherein the compound is not a compound selected from Table P1.

13. The compound of claim 11, wherein the compound is of Formula IC3’-b, or a salt (e.g., a pharmaceutically acceptable salt) thereof, optionally wherein the compound is not a compound selected from Table P2.

14. The compound of claim 11, wherein the compound is of Formula IC3’-c, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

15. The compound of claim 11, wherein the compound is of Formula IC3’-d, or a salt (e.g., a pharmaceutically acceptable salt) thereof, optionally wherein the compound is not a compound selected from Table P3.

16. The compound of claim 11, wherein the compound is of Formula IC3’-e, or a salt (e.g., a pharmaceutically acceptable salt) thereof, optionally wherein the compound is not a compound selected from Table P4.

17. The compound of claim 11, wherein the compound is of Formula IC3’-f, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

18. The compound of claim 11, wherein the compound is of Formula IC3’-g, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

19. The compound of claim 11, wherein the compound is of Formula IC3’-h, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

20. The compound of claim 11, wherein the compound is of Formula IC3’-i, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

21. The compound of claim 11, wherein the compound is of Formula IC3’-j, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

22. The compound of claim 11, wherein the compound is of Formula IC3’-k, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

23. The compound of claim 11, wherein the compound is of Formula IC3’-l, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

24. The compound of claim 11, wherein the compound is of Formula IC3’-m, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

25. The compound of any one of claims 1-24, wherein each R2is independently selected from halogen and C1-6alkyl.

26. The compound of claim 25, wherein each R2is F.

27. The compound of any one of claims 1-26, wherein n is 1.

28. The compound of any one of claims 1-27, wherein at least one R1is –OR7.

29. The compound of claim 28, wherein one R1is –OR7and any other R1groups are halogen.

30. The compound of any one of claims 1-29, wherein a moiet is32. The compound of any one of claims 1-31, wherein each R7is independently selected from C1-6alkyl and –(C1-4alkylene)OR.

33. The compound of any one of claims 1-31, wherein each R7is independently selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C1-6 aliphatic substituted with an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring. , , .om optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 3- to 6-membered carbocyclic ring.

36. The compound of claim 35, wherein each R7is independently selected from optionally substituted pyrrolidinyl and piperidinyl.

37. The compound of claim 35, wherein each R7is independently selected fro ,, ,38. The compound of any one of claims 1-31, wherein a moie is selected from:, , , ,, , , , , , ,, , , , , , ,, .

39. is. 40.one of claims 1-37, wherein m is 2 or 3.

41. The compound of any one of claims 1-40, wherein Ring C is selected from phenyl; 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

42. The compound of any one of claims 1-40, wherein Ring C is selected from 9- to 10-membered bicyclic aryl ring; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

43. The compound of claim 42, wherein Ring C is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

44. The compound of any one of claims 1-40, wherein Ring C substituted with p R3groups is n:Ring C1 is fused to Ring C2; Ring C1 is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Ring C2 is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

45. The compound of claim 44, wherein Ring C1 is a phenyl, and Ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

46. The compound of claim 44, wherein Ring C1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

47. The compound of claim 44, wherein Ring C1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, or 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

48. The compound of any one of claims 1-47, wherein each R3is independently selected from halogen, -C(O)N(R)2, and optionally substituted C1-6 alkyl.

49. The compound of any one of claims 1-48, wherein p is 1, 2, or 3.

50. The compound of any one of claims 1-49, wherein a moiety is selected from:, , , ,N, , , , ,, , , ,, , ,, , , , ,,52. The compound of claim 51, wherein a moiet is selected from:, ,, , , , ,53. The compound of any one of claims 1-52, wherein Ring D is selected from phenyl; 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

54. The compound of any one of claims 1-52, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 10-membered bicyclic or polycyclic carbocyclic ring; and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

55. The compound of claim 54, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

56. The compound of any one of claims 1-52, wherein a moiety iswherein:to Ring D2; Ring D1 is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Ring D2 is selected from phenyl; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbocyclic ring; and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

57. The compound of claim 56, wherein Ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

58. The compound of claim 56, wherein Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

59. The compound of any one of claims 1-52, wherein a moiet .

60. The compound of any one of claims 1-59, wherein each R4is independently C1-6 alkyl optionally substituted with one or more –OH.

61. The compound of any one of claims 1-60, wherein q is 0 or 1.

62. The compound of any one of claims 1-61, wherein R5is -C(O)R9or -(CH2)xN(R)C(O)R9.

63. The compound of any one of claims 1-62, wherein R9is optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl.

64. The compound of any one of claims 1-63, wherein R5.

65. The compound of any one of claims 1-64, wherein a moiet om:, , , ,, , , , , , , ,,66. The compound of claim 59, wherein a moiet , wherein each R4is independently methyl.om: ,, ,om: , ainhaving at least one triple bond.

70. The compound of claim 1 or 3, wherein L is a bivalent straight or branched C1-2 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –N(R)-, - N(R)C(O)-, -C(O)N(R)-, or –C(O)-.

71. The compound of claim 1 or 4, wherein R6and R6’are connected with an optionally substituted C5- 6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with –O- or –N(R)-.

72. The compound of claim 71, wherein R6and R6’are connected with: -O(CH2)5-, -O(CH2)4-, – O(CH2)2OCH2-, or –O(CH2)3OCH2-.

73. The compound of any one of claims 1-72, wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen.

74. The compound of claim 1, wherein the compound is a compound of Formula IF’: F (R4)qR5 or a salt (e.g., a pharmaceuca y accep a e sa , e eo , wherein:Ring C2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

75. The compound of claim 74, wherein the compound is a compound of Formula IF1’: or a salt (e.g., a pharmac76. The compound of claim 74 or 75, wherein the compound is a compound of Formula IF2’: or a salt (e.g., a pharmaceu77. The compound of any one of claims 74-76, wherein the compound is a compound of Formula IF3’:or a salt (e.g., a pharmaceu78. The compound of any one of claims 74-76, wherein R1is –OR7.

79. The compound of claim 77 or 78, wherein R7is selected from optionally substituted C1-6 aliphatic and –(C1-4 alkylene)OR.

80. The compound of claim 77 or 78, wherein R7is selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C1-6 aliphatic substituted with an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring. , ,7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 3- to 6-membered carbocyclic ring.

83. The compound of claim 82, wherein R7is selected from optionally substituted pyrrolidinyl and piperidinyl.

84. ,, .R185. is.F 86. . 87.88 The compound of claim 74, 75, or 87, wherein R2is halogen. , ,, om: ,91. The compound of any one of claims 74-90, wherein a moiety is selected from:, ,, , , , ,, , ,or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein: Ring A is phenyl and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered carbocyclic ring, and phenyl; Ring D is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered carbocyclic ring, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain; X is –OR, -N(R)2, -C(O)N(R)2, or an optionally substituted group selected from phenyl, 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen and –OR7; each R7is independently selected from optionally substituted C1-6 aliphatic and –(C1-4 alkylene)OR; each R2is independently selected from halogen and optionally substituted C1-6 aliphatic; each R4is independently selected from optionally substituted C1-6 aliphatic; R5is -C(O)R9, -(CH2)xN(R)C(O)R9, or -CN; R9is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or a 4-membered bicyclic carbocyclic ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; each R is independently hydrogen or optionally substituted C1-6aliphatic.

94. The compound of claim 93, wherein the compound is of Formula IIF:or a salt (e.g., a pharmaceutically aX is -C(O)N(R)2 or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, 5- to 10-membered bicyclic carbocyclic ring, 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

95. The compound of claim 93, wherein the compound is of Formula IIG: or a salt (e.g., a pharmaceutically aJ is a bivalent straight or branched C1-4 hydrocarbon chain; and X is –OR or -N(R)2.

96. The compound of claim 93 or 94, wherein X is a group selected from 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally substituted with C1-6alkyl.

97. The compound of any one of claims 93-96, wherein a moiet is selected fro ,.

98. g B is a 5-membered heteroaryl ring having1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-membered carbocyclic ring.

99. The compound of claim 98, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

100. The compound of claim 98, wherein Ring B is a 5-membered carbocyclic ring.

101. The compound of any one of claims 93-100, wherein Ring B is selected from: ,om halogen and C1-6alkyl.

103. The compound of any one of claims 93-102, wherein n is 0 or 1.

104. The compound of any one of claims 93-103, wherein Ring A is phenyl.

105. The compound of any one of claims 93-104, wherein at least one R1is –OR7.

106. The compound of claim 105, wherein one R1is –OR7and any other R1groups are halogen.

107. The compound of any one of claims 93-106, wherein a moiet is108.or.

109. of7any one of claims 93-108, wherein each R is independently selected from C1-6 alkyl and –(C1-4 alkylene)OR.

110. The compound of any one of claims 93-109, wherein m is 2 or 3.

111. The compound of any one of claims 93-110, wherein Ring D is selected from phenyl, 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

112. The compound of any one of claims 93-110, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered bicyclic or polycyclic carbocyclic ring, and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

113. The compound of claim 112, wherein Ring D is selected from 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6- to 11-membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

114. The compound of any one of claims 93-107, wherein a moiet iswherein: ected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring D1 is fused to Ring D2; and Ring D2 is selected from phenyl, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbocyclic ring, and 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

115. The compound of claim 114, wherein Ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

116. The compound of claim 114, wherein Ring D1 is a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D2 is a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

117. The compound of any one of claims 93-116, wherein a moiety is. 118.any one of claims 93-117, wherein each R4is independently C1-6 alkyl optionally substituted with one or more –OH.

119. The compound of any one of claims 93-118, wherein q is 0 or 1.

120. The compound of any one of claims 93-119, wherein R5is -C(O)R9or -(CH2)xN(R)C(O)R9.

121. The compound of any one of claims 93-119, wherein R9is optionally substituted C2-6alkenyl or optionally substituted C2-6alkynyl.

122. The compound of any one of claims 93-121, wherein R5.

123. The compound of any one of claims 93-122, wherein ea 6 alkyl optionallysubstituted with one or more halogen.

124. A compound selected from Table 1, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

125. A compound selected from Table 2, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

126. A pharmaceutical composition comprising a compound according to any one of claims 1-125, or a salt (e.g., pharmaceutically acceptable salt) thereof, and a pharmaceutically acceptable carrier or excipient.

127. A method comprising administering a therapeutically effective amount of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

128. The method of claim 127, 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 PI3Kα protein.

129. The method of claim 128, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

130. The method of claim 129, wherein the small GTPase is a RAS protein.

131. The method of claim 130, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

132. The method of any one of claims 127-131, wherein the subject has a cancer.

133. 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 1-125 or a pharmaceutically acceptable salt thereof.

134. The method of claim 132 or 133, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.

135. The method of claim 134, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

136. The method of claim 135, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

137. The method of any one of claims 132-136, wherein the cancer is characterized by a mutation in a RAS protein.

138. The method of claim 137, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

139. The method of claim 137 or 138, wherein the RAS protein is KRAS.

140. The method of claim 139, 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.

141. The method of claim 140, wherein the KRAS protein comprises a G12C or G12D mutation.

142. The method according to claim 137 or 138, wherein the RAS protein is HRAS.

143. The method according to claim 142, 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.

144. The method according to claim 137 or 138, wherein the RAS protein is NRAS.

145. The method according to claim 144, 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.

146. The method according to any one of claims 132-145, 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.

147. The method according to claim 146, 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.

148. The method according to any one of claims 132-147, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

149. The method according to any one of claims 132-148, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein.

150. The method according to any one of claims 127-149, wherein the subject has previously undergone a treatment regimen for cancer.

151. The method according to any one of claims 127-150, wherein the subject has previously entered remission from cancer.

152. 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 1-125 or a pharmaceutically acceptable salt thereof.

153. The method according to claim 152, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes.

154. 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 1-125 or a pharmaceutically acceptable salt thereof.

155. The method according to claim 154, wherein the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome.

156. A method of treating a vascular disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1- 125 or a pharmaceutically acceptable salt thereof.

157. The method according to claim 156, 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)).

158. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein in a subject, comprising administering to the subject a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

159. A method of disrupting, inhibiting, and / or preventing an interaction between a small GTPase and a PI3Kα protein, comprising contacting a cell containing the small GTPase and the PI3Kα proteinwith a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

160. A method comprising contacting a cell containing a small GTPase and a PI3Kα protein with a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

161. The method of claim 159 or 160, wherein the cell is included in a subject.

162. The method of any one of claims 158-161, wherein the small GTPase is selected from Rac1, CDC42, and a RAS protein.

163. The method of claim 162, wherein the small GTPase is a RAS protein.

164. The method of claim 163, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.

165. The method of claim 164, wherein the RAS protein is KRAS.

166. The method of claim 165, 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.

167. The method of claim 166, wherein the KRAS protein comprises a G12C or G12D mutation.

168. The method according to claim 164, wherein the RAS protein is HRAS.

169. The method according to claim 168, 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.

170. The method according to claim 164, wherein the RAS protein is NRAS.

171. The method according to claim 170, 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.

172. A compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof for use as a medicament.

173. Use of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

174. The compound or use according to claim 172 or 173, wherein the medicament is for treating a cancer.

175. The compound or use according to claim 174, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.

176. The compound or use according to claim 175, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

177. The compound or use according to claim 176, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

178. The compound or use according to any one of claims 174-177, wherein the cancer is characterized by a mutation in a RAS protein.

179. The compound or use according to claim 178, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

180. The compound or use according to claim 178 or 179, wherein the RAS protein is KRAS.

181. The compound or use according to claim 179, 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.

182. The compound or use according to claim 181, wherein the KRAS protein comprises a G12C or G12D mutation.

183. The compound or use according to claim 178 or 179, wherein the RAS protein is HRAS.

184. The compound according to claim 183, 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.

185. The compound or use according to claim 178 or 179, wherein the RAS protein is NRAS.

186. The compound or use according to claim 184, 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.

187. The compound or use according to any one of claims 174-186, 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.

188. The compound or use according to claim 187, 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.

189. The compound or use according to any one of claims 174-186, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

190. The compound or use according to any one of claims 174-186, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein.

191. The compound or use according to claim 172 or 173, wherein the medicament is for treating a metabolic disorder, a RASopathy, or a vascular disorder.

192. The compound or use according to claim 191, 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; 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)).

193. A compound according to any one of claim 1-125 or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition.

194. The compound for use according to claim 193 for use in treating a cancer.

195. The compound for use according to claim 192, wherein the cancer is associated with and / or characterized by aberrant activation of PI3Kα and / or a mutation in PI3Kα.

196. The compound for use according to claim 195, wherein the PI3Kα protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation.

197. The compound for use according to claim 196, wherein the PI3Kα protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

198. The compound for use according to any one of claims 194-197, wherein the cancer is characterized by a mutation in a RAS protein.

199. The compound for use according to claim 198, wherein the RAS protein comprises a mutation in codon 12, 13, or 61.

200. The compound for use according to claim 198 or 199, wherein the RAS protein is KRAS.

201. The compound for use according to claim 200, 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.

202. The compound for use according to claim 201, wherein the KRAS protein comprises a G12C or G12D mutation.

203. The compound for use according to claim 198 or 199, wherein the RAS protein is HRAS.

204. The compound for use according to claim 203, 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.

205. The compound for use according to claim 198 or 199, wherein the RAS protein is NRAS.

206. The compound for use according to claim 204, 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.

207. The compound for use according to any one of claims 194-206, 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.

208. The compound for use according to claim 207, 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.

209. The compound for use according to any one of claims 194-208, wherein the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).

210. The compound for use according to any one of claims 194-209, wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein.

211. The compound for use according to claim 193 for use in treating a metabolic disorder, a RASopathy, or a vascular disorder.

212. The compound for use according to claim 211, 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; 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)).

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