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

Abstract

Provided herein are compounds and compositions thereof that may be capable of disrupting, interfering with, and / or preventing the interaction between small GTPase proteins and PI3K proteins (e.g., PI3Kα). The disclosure also provides methods of treating cancer and other indications using such compounds or compositions thereof. The disclosure provides novel therapeutic approaches for treating cancer and other indications (e.g., cancer and other indications associated with and / or characterized by aberrant activation of PI3K). TIFF2025505666000808.tif60165

Description

[Technical field]

[0001] government support This invention was made with Government support under Contract No. DE-AC52-07NA27344 awarded by the U.S. Department of Energy. The Government has certain rights in this invention.

[0002] Related Applications This application claims priority to and the benefit of U.S. patent application Ser. No. 63 / 307,882, filed February 8, 2022, and U.S. patent application Ser. No. 63 / 416,772, filed October 17, 2022, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0003] An estimated 600,000+ Americans will die from cancer in 2021, equating to more than 1600 deaths per day (Cancer Facts and Figures 2021). The leading causes of death are lung, prostate, and colorectal cancer in men, and lung, breast, and colorectal cancer in women. Nearly one-quarter of all cancer deaths are attributable to lung cancer, 82% of which are directly attributable to smoking. The five-year survival rate for lung cancer patients is only about 20%.

[0004] Aberrant activation of phosphorinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in cancer treatment. PI3K signals downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate multiple cellular activities, including metabolism, proliferation, and migration.

[0005] The high frequency of PI3K-mediated oncogenic events has led to active development and testing of PI3K inhibitors. Most of the PI3K inhibitors that have entered clinical development so far are reversible ATP-competitive kinase inhibitors. Despite considerable efforts, the clinical outcomes of PI3K inhibitor-based therapy for solid tumors have been disappointing, mainly due to unacceptable toxicity and drug resistance. Summary of the Invention

[0006] The present disclosure provides novel therapeutic methods for treating cancer and other indications (e.g., cancer and other indications associated with and / or characterized by aberrant activation of PI3K). The present disclosure encompasses the recognition that therapeutic agents (e.g., therapeutic agents including small molecules such as compounds provided herein) that disrupt, inhibit, and / or prevent the 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) may be particularly useful for treating, ameliorating, slowing progression, ameliorating or eliminating symptoms, and / or inhibiting cancer and / or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K). Without wishing to be bound by theory, it may be possible that the therapeutic agents provided herein (e.g., therapeutic agents including small molecules, e.g., compounds provided herein) bind to a PI3K protein (e.g., PI3Kα) while (i) exhibiting no or minimal binding to small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1), and / or (ii) not substantially affecting 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, for example, ATP-competitive PI3K kinase inhibitors described herein. For example, in some embodiments, such therapeutic agents may reduce instances of hyperglycemia and / or hyperinsulinemia as compared to PI3K kinase inhibitors.

[0007] The present disclosure provides compounds (including any available form, such as salt forms) useful for disrupting, inhibiting, and / or preventing the 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 to 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 the treatment of cancer or other indications, as described herein.

[0008] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a salt thereof (e.g., a pharma- ceutically acceptable salt), wherein ring A, ring B, ring C, ring D, ring R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, q, and r are each as defined herein. In some embodiments, a compound of formula I is capable of binding to a PI3K alpha 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 PI3K alpha protein is disrupted, inhibited, and / or prevented, and / or (ii) the kinase activity of the PI3K alpha protein is not inhibited.

[0009] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula I), or a salt thereof (e.g., a pharma- ceutically acceptable salt), in combination with a pharma- ceutically acceptable carrier.

[0010] In another aspect, the disclosure provides methods of inhibiting, disrupting, and / or preventing the interaction between a PI3K alpha protein and a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1), thereby not inhibiting the kinase activity of the PI3K alpha protein. In some embodiments, the PI3K alpha protein is in a cell, e.g., in a cell of a human or animal subject (e.g., as described herein).

[0011] In a further aspect, the disclosure provides a method of treating, ameliorating, slowing the progression of, ameliorating or eliminating symptoms, and / or suppressing cancer and / or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K) comprising administering a compound provided herein (e.g., a compound of Formula I) or a salt thereof (e.g., a pharma- ceutically acceptable salt).

[0012] In a related aspect, the disclosure provides the use of a compound provided herein (e.g., a compound of Formula I), or a salt thereof (e.g., a pharma- ceutically acceptable salt), in the manufacture of a medicament for treating, ameliorating, or inhibiting cancer or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K). The disclosure also provides a compound (e.g., a compound of Formula I), or a salt thereof (e.g., a pharma- ceutically acceptable salt), for use as a medicament, that can be used to treat, ameliorate, or inhibit cancer or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K). [Brief description of the drawings]

[0013] [Figure 1]The effect of inhibition of PI3Kα by PI3Kα kinase inhibitors such as alpelisib in normal cells (left panel) and tumor cells (right panel) is shown. In normal cells, inhibition of PI3Kα blocks normal cell signaling, resulting in dose-limiting hyperglycemia and insulin-driven resistance. The right panel shows an alternative scheme using PI3Kα blockers to inhibit PI3Kα:RAS protein:protein interactions in tumor cells. This mechanism should circumvent hyperglycemia and insulin-driven resistance by selectively targeting tumor cells and may offer multiple therapeutic advantages. The observation that mutations in the RAS binding domain that impair PI3Kα:RAS interactions block tumor growth of oncogene-driven non-small cell lung cancer (NSCLC) in vivo without affecting glucose metabolism supports the possibility of this mechanism. [Figure 2A] We show that PI3Kα blockers can have a broad range of in vitro activity. One-third of the human tumor cell lines tested have pAKT IC50s below 100 nanomolar (nM), indicating a dependency on RAS:PI3Kα interactions for activation of Akt signaling. Notably, 29 of 50 (58%) G12X cell lines have pAKT IC50s <100 nM. [Figure 2B] This shows that PI3Kα blockers can have a broad range of in vitro activity. The bioinformatics analysis in the figure shows that cell lines with PIK3CA helix mutations are particularly sensitive to PI3Kα blockers without inducing hyperglycemia, and furthermore, 78% of HER2-amplified lines are sensitive to PI3Kα blockers. [Figure 3A]We show that PI3K alpha blockers are orally bioavailable and can achieve near-complete inhibition of signaling in tumors without the risk of hyperglycemia or hyperinsulinemia. We show the pharmacokinetics of PI3K alpha blocker compounds in mice. (IV = intravenous; PO = per os, i.e., oral administration; ng / mL = nanograms per milliliter; mg / kg = milligrams per kilogram; mg / dL = milligrams per deciliter; min = minutes; CDX = cell line derived xenograft; QD = quaque die, i.e., once a day; PK = pharmacokinetics) [Figure 3B] Figure 1 shows that PI3K alpha blockers are orally bioavailable and can achieve near-complete inhibition of signaling in tumors without the risk of hyperglycemia or hyperinsulinemia. Figure 2 shows dose-response pharmacodynamics of PI3K alpha blockers ("BBO") and the PI3K alpha kinase domain inhibitor alpelisib in a xenograft model derived from a BT474 cell line. Dose-response pharmacodynamics show that near-complete target inhibition is achieved at 100 mg / kg of PI3K alpha blocker. (One-way ANOVA with Dunnett's test vs. vehicle; *=p<0.01, **=p<0.0001). From left to right along the x-axis of the figure: vehicle, 30 mg / kg BBO, 100 mg / kg BBO, 300 mg / kg BBO, 50 mg / kg alpelisib. (IV = intravenous; PO = per os, i.e., oral administration; ng / mL = nanograms per milliliter; mg / kg = milligrams per kilogram; mg / dL = milligrams per deciliter; min = minutes; CDX = cell line derived xenograft; QD = quaque die, i.e., once a day; PK = pharmacokinetics). [Figure 3C]The figure shows that PI3K alpha blockers are orally bioavailable and can achieve near-complete inhibition of signaling in tumors without the risk of hyperglycemia or hyperinsulinemia. The figure shows that unlike PI3K alpha kinase domain inhibitors, PI3K alpha blocker compounds do not affect glucose metabolism. Blood glucose levels at and after single doses of vehicle, the PI3K alpha kinase domain inhibitor alpelisib, and a PI3K alpha blocker (compound 58, "BBO") in fasted male mice following an oral glucose tolerance test. Hyperglycemia was observed with alpelisib but not in PI3K alpha blocker-treated mice. (One-way ANOVA with Dunnett's test vs. vehicle, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001) (IV = intravenous; PO = per os; ng / mL = nanograms per milliliter; mg / kg = milligrams per kilogram; mg / dL = milligrams per deciliter; min = minutes; CDX = cell line derived xenograft; QD = quaque die; PK = pharmacokinetics) [Figure 3D]The figure shows that PI3K alpha blockers are orally bioavailable and can achieve near-complete inhibition of signaling in tumors without the risk of hyperglycemia or hyperinsulinemia. The figure shows that unlike PI3K alpha kinase domain inhibitors, PI3K alpha blocker compounds do not affect glucose metabolism. Insulin levels are shown at and 240 minutes after a single oral dose of vehicle, 50 mg / kg alpelisib, or 300 mg / kg compound 58 ("BBO") in fed male mice. Hyperinsulinemia was observed with alpelisib but not in PI3K alpha blocker-treated mice. (One-way ANOVA with Tukey's multiple comparison test vs. all other groups: *p<0.0001) (IV = intravenous; PO = per os; ng / mL = nanograms per milliliter; mg / kg = milligrams per kilogram; mg / dL = milligrams per deciliter; min = minutes; CDX = cell line derived xenograft; QD = quaque die; PK = pharmacokinetics) [Figure 4A] Figure 1 shows that strong efficacy is observed in xenograft models with KRAS G12X mutations with or without PIK3CA mutations. The figure shows the change in tumor volume in a xenograft model derived from the KYSE-410 cell line, characterized by KRAS G12C mutations and HER2 amplification. Significant efficacy was observed in a dose-dependent manner, with tumor regression at 100 mg / kg of PI3K alpha blocker ("BBO"). (p<0.0005, repeated measures two-way ANOVA vs. vehicle; all groups given orally (PO, orally), once daily (QD) (mm3 = millimeters cubic; mg / kg = milligrams per kilogram) [Figure 4B]Figure shows that strong efficacy is observed in xenograft models with KRAS G12X mutations with or without PIK3CA mutations. The figure shows the change in tumor volume in a xenograft model derived from the GP2d cell line, characterized by KRAS G12D and PIK3CA H1047L mutations. Significant tumor volume reduction is observed at doses of 10 mg / kg or higher of PI3K alpha blocker ("BBO"). (p<0.0005, repeated measures two-way ANOVA vs. vehicle; all groups given orally (PO, orally), once daily (QD) (mm3 = cubic millimeters; mg / kg = milligrams per kilogram) [Figure 4C] Figure shows that strong efficacy is observed in xenograft models with KRAS G12X mutations and with or without PIK3CA mutations. The figure shows the change in tumor volume in xenograft models derived from the SNU-601 cell line, characterized by KRAS G12D and PIK3CA E542K mutations. Significant tumor volume reduction is observed at doses of 10 mg / kg or higher of PI3K alpha blocker ("BBO"). (p<0.0005, repeated measures two-way ANOVA vs. vehicle; all groups given orally (PO, orally), once daily (QD) (mm3 = cubic millimeters; mg / kg = milligrams per kilogram) [Figure 4D] Figure shows that strong efficacy is observed in xenograft models with KRAS G12X mutations and with or without PIK3CA mutations. The figure shows the change in tumor volume in a xenograft model derived from the SNU-16 cell line, characterized by a KRAS G12D mutation. Significant tumor volume reduction is observed at doses of 10 mg / kg or higher of PI3K alpha blocker ("BBO"). (p<0.0005, repeated measures two-way ANOVA vs. vehicle; all groups given orally (PO, orally), once daily (QD) (mm3 = cubic millimeters; mg / kg = milligrams per kilogram) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Compounds and Definitions Compounds of the present disclosure include those generally described above, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise stated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, the general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0015] Unless otherwise indicated, structures depicted herein are intended to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropisomeric, or epimeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure, and the D and L isomers of each compound are contemplated as part of the disclosure. Thus, single stereochemical isomers of the provided compounds, as well as enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational) mixtures, are within the scope of the disclosure. For example, in some cases, Tables 1 and 2 depict one or more stereoisomers of a compound, and each stereoisomer is represented alone and / or as a mixture unless otherwise indicated. The disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, e.g., by conversion to a mixture of diastereomers followed by separation, e.g., by recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods. Starting compounds of a particular stereochemistry are either commercially available or can be made and resolved by a variety of techniques. Unless otherwise specified, all tautomeric forms (e.g., rapidly interconverting forms) of the compounds provided are within the scope of this disclosure.

[0016] Unless otherwise stated, structures depicted herein are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14 Compounds having the subject structures including the replacement of carbons with C-enriched carbons are within the scope of this disclosure.

[0017] Aliphatic: As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation (e.g., a multiple bond such as a double bond or a triple bond). Unless otherwise specified, an aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms.

[0018] Alkyl: The term "alkyl" used alone or as part of a larger moiety means an alkyl group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (unless otherwise specified) (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 ), and optionally substituted straight or branched chain hydrocarbon groups having the substituents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109, 110, 111, 112, 113, 114, 115, 116, 1 2 -) refers to a divalent, saturated, optionally substituted straight or branched chain hydrocarbon.

[0019] Alkenyl: The term "alkenyl" when used alone or as part of a larger moiety, refers to an alkyl group having at least one double bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (unless otherwise specified) (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6, C 2-4 , or C 2-3 Examples of alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020] Alkynyl: The term "alkynyl" when used alone or as part of a larger moiety, refers to an alkynyl group having at least one triple bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (unless otherwise specified) (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 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.

[0021] Aryl: The term "aryl" when used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 6 to 14 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. Bicyclic ring systems may include a first and a second ring that are fused together and / or share one or more atoms. The term "aryl" may be used synonymously with the term "aryl ring(s)". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. Examples of aryl groups include phenyl, biphenyl, naphthyl, anthracyl, and the like, which may have one or more substituents as defined herein. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl or tetrahydronaphthyl. Unless otherwise specified, an "aryl" group is a hydrocarbon.

[0022] Carbocyclyl: As used herein, the terms "carbocyclyl", "carbocycle", and "carbocyclic ring" refer to a saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring system having 3 to 14 members, which is optionally substituted as described herein. Carbocycles can include fused ring systems, bridged ring systems, and / or spiro ring systems (e.g., systems containing two rings sharing a single carbon atom). Carbocyclic groups include, but are not limited to, 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 C ring that is fully saturated or contains one or more units of unsaturation but is not aromatic. 3 -C 8 Hydrocarbon or optionally substituted C 6 -C 10It refers to a bicyclic hydrocarbon. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 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 polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0023] Halogen: The term “halogen” or “halo” refers to F, Cl, Br, or I.

[0024] Heteroaryl: The terms "heteroaryl", "heteroaromatic", and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 14 ring atoms, 6, 10, or 14 pi-electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms (e.g., a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl). Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinthyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroara-" also include 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, 4H-quinolizinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Examples of tricyclic heterocyclic groups include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenazinyl, phenanthridinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include optionally substituted rings.The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, where the alkyl and heteroaryl portions are independently optionally substituted. It is understood that certain tautomeric forms of the heteroaryl ring may exist and are encompassed by the term "heteroaryl". Such tautomeric forms include, for example, pyridin-2(1H)-one.

[0025] Heteroatom: The term "heteroatom" refers to 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 on a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl). In some embodiments, the heteroatoms are selected from oxygen, sulfur, and nitrogen.

[0026] Heterocycle: As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has one or more, preferably 1-4, heteroatoms as defined above, in addition to one or more carbon atoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. A heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may 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, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclic", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, where the alkyl and heterocyclyl portions are independently unsubstituted or substituted with one or more substituents (e.g., as described herein).

[0027] Partially unsaturated: As used herein, the term "partially unsaturated" with respect to a ring moiety refers to a ring moiety that contains 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 defined herein.

[0028] Patient or subject: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition is or may be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Exemplary 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, the patient or subject is human. In some embodiments, the patient or subject suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0029] Prevent or prophylaxis: As used herein, "prevent" or "prevention" used in relation to the onset of a disease, disorder, and / or condition refers to reducing the risk of developing a disease, disorder, or condition, delaying the onset of one or more characteristics or symptoms of a disease, disorder, or condition, and / or preventing the disease, disorder, or condition from worsening. Prevention of a disease, disorder, or condition can include complete protection from the disease and / or preventing the progression of the disease (e.g., to a later stage of the disease, disorder, or condition). For example, prevention of a disease may mean preventing the symptoms of the disease, disorder, or condition to a clinically significant or detectable level, rather than completely eliminating any effects associated with the disease at any level. Prevention can be considered complete when the onset of a disease, disorder, or condition is delayed for a predetermined period of time.

[0030] Substituted or Optionally Substituted: As described herein, compounds of the present disclosure may contain "optionally substituted" moieties (e.g., moieties having 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 specified 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., [ka] At least [ka] Refers to, [ka] At least [ka] (refers to "optionally substituted"). Unless otherwise stated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in a given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at all positions. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for the compound's production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes provided herein. Groups described as "substituted" preferably have 1-4 substituents, more preferably 1 or 2 substituents. Groups described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2 ) 0-4 R o ;-(CH 2 ) 0-4 OR o ;-O(CH 2 ) 0-4 R o , -O-(CH 2 ) 0-4 C(O)OR°;-(CH 2 ) 0-4 CH(OR o ) 2 ;-(CH 2 ) 0-4 S.R. o Optionally substituted with R° -(CH 2 ) 0-4 Ph; optionally substituted with R° -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph; -CH=CH, optionally substituted with R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -Pyridyl; -NO 2 ;-CN;-N 3 ;-(CH 2 ) 0-4 N(R o ) 2 ;-(CH 2 ) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH 2 ) 0-4 N(R o )C(O)NR o 2 ;-N(R o )C(S)NR o 2 ;-(CH 2 ) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(Ro )C(O)NR o 2 ;-N(R o )N(R o )C(O)OR o ;-(CH 2 ) 0-4 C(O)R o ;-C(S)R o ;-(CH 2 ) 0-4 C(O)OR o ;-(CH 2 ) 0-4 C(O)SR o ;-(CH 2 ) 0-4 C(O)OSiR o 3 ;-(CH 2 ) 0-4 OC(O)R o ;-OC(O)(CH 2 ) 0-4 SR°;-(CH 2 ) 0-4 SC(O)R o ;-(CH 2 ) 0-4 C(O)NR o 2 ;-C(S)NR o 2 ;-C(S)SR°;-SC(S)SR°、-(CH 2 ) 0-4 OC(O)NR o 2 ;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH 2 C(O)R o ;-C(NOR o )R o ;-(CH 2 ) 0-4 SSR o ;-(CH 2 ) 0-4 S(O) 2 R o ;-(CH 2 ) 0-4 S(O) 2 OR o ;-(CH 2 )0-4 OS(O) 2 R o ;-S(O) 2 NR o 2 ;-(CH 2 ) 0-4 S(O)R o ;-N(R o )S(O) 2 NR o 2 ;-N(R o )S(O) 2 R o ;-N(OR o )R o ;-C(NH)NR o 2 ;-P(O) 2 R o ;-P(O)R o 2 ;-OP(O)R o 2 ;-OP(O)(OR o ) 2 ;-SiR o 3 ;-(C 1-4 Linear or branched alkylene)ON(R o ) 2 ; or -(C 1-4 Linear or branched alkylene)C(O)ON(R o ) 2 where each R o are optionally substituted as defined below and independently represent hydrogen, C 1-6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R oThe occurrences, together with the intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below.

[0032] R o (or two separate R o Preferred monovalent substituents on the ring formed by the presence of -(CH) together with the intervening atoms are independently halogen, -(CH 2 ) 0-2 R ● , -(Halo R ● ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ● , -(CH 2 ) 0-2 CH(OR ● ) 2 , -O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R ● , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ● , -(CH 2 ) 0-2 S.R. ● , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ● , -(CH 2 ) 0-2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1-4Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens; and C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 R is independently selected from Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. o Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0033] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O ("oxo"), ═S, ═NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O-, or -S(C(R * 2 )) 2-3 S-, wherein each R * Each occurrence of is hydrogen, optionally substituted as defined below, 1-6 The "optionally substituted" group is selected from the group consisting of an aliphatic, unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of the "optionally substituted" group include -O(CR * 2 ) 2-3 O-, wherein each R * Each occurrence of is hydrogen, optionally substituted as defined below, 1-6It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 In the formula, each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R †In the formula, each R † are independently hydrogen, optionally substituted as defined below, 1-6 an unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent R † The occurrences, together with the intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1-4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Treat: As used herein, the term "treat" (also "treatment" or "treating") refers to administering a therapy (e.g., a therapeutic agent) that partially or completely relieves, improves, alleviates, inhibits, delays onset, reduces severity, and / or reduces incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. Treatment can also refer to any objective or subjective parameter, such as remission, remission, disappearance of symptoms, or making the injury, pathology, disease, disorder, or condition tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, and / or improving the patient's physical or mental well-being. The treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical exam, a neuropsychiatric exam, and / or a psychiatric evaluation. In some embodiments, such treatment may be treatment of a subject who does not show signs of the relevant disease, disorder, and / or condition, and / or a subject who shows only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be treatment of a subject who exhibits one or more established symptoms of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be treatment of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.

[0038] Composition: As used herein, the term "composition" refers to a discrete physical entity that includes one or more specified components (e.g., a product that includes one or more specified components (e.g., in specified amounts), or a product that is produced directly or indirectly from a combination of specified components in specified amounts). Unless otherwise specified, a composition may be in any form, e.g., a gas, a gel, a liquid, a solid, etc. A composition may include one or more pharma- ceutically acceptable components, such as a carrier, diluent, or excipient. "Pharmaceutically acceptable" generally means that a carrier, diluent, or excipient is required to be compatible with other ingredients of the formulation and not deleterious to the recipient thereof. For example, a "pharma-ceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to, and absorption by, a subject.

[0039] PI3K and small GTPase proteins Aberrant activation of phosphorinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and its inhibition is an attractive therapeutic approach in cancer treatment. PI3K signals downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate numerous cellular activities, including metabolism, proliferation, and migration. Upon activation, PI3K catalyzes the synthesis of the secondary messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2). Signaling proteins, such as the 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 by direct phosphorylation, including mammalian target of rapamycin complex 1 (mTORC1), cyclin D1, GSK3(B), BAD, MDM2, FOXO, TSC1 / 2, and PRAS40, which act as regulators of cell proliferation and survival pathways. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates this pathway by dephosphorylating PIP3 to PIP2, thus preventing activation of downstream kinases.

[0040] Based on sequence homology and substrate preference, PI3Ks have been classified into three separate classes (e.g., class I, II, and III). Class I PI3Ks are further divided into two subclasses, IA and IB, depending on their mode of regulation. Class IA PI3Ks are heterodimers containing a p110 catalytic subunit and a p85 regulatory subunit and are most clearly implicated in human cancer. Class IA PI3Ks contain p110α, p110β, and p110δ catalytic subunits produced from distinct genes (PIK3CA, PIK3CB, and PIK3CD, respectively), whereas p110γ produced by PIK3CG represents the only catalytic subunit of class IB PI3Ks. Expression of PI3K isoforms (e.g., PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) is cell type specific. The p110α and β isoforms are expressed in all cell types, whereas p110δ expression is primarily restricted to leukocytes, and the p110γ isoform is expressed primarily in myeloid cell lines.

[0041] The PIK3CA gene encodes the 1068 amino acid p110α protein, which contains five domains: an N-terminal adaptor-binding domain (ABD) that binds to the regulatory subunit p85α, a RAS-binding domain (RBD), a C2 domain, a helical domain, and a kinase catalytic domain. RAS directly contributes to the activation of the PI3K pathway through direct binding of RAS proteins (e.g., HRAS, NRAS, and KRAS) to the 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, gastric, endometrial, bladder, and lung cancers. The most frequent hotspot mutations in PIK3CA are E542K, E545K, H1047R, and H1047L, which account for 80-90% of all PIK3CA mutations detected in human malignancies. These PIK3CA mutations result in increased catalytic activity of p110α, causing downstream effects such as uncontrolled cell growth, proliferation, and viability.

[0042] Mutations in RAS proteins are found in more than 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 the activation of multiple downstream signaling pathways. Oncogenic RAS mutations are found primarily at amino acid positions G12, G13, and Q61, and these mutations impair GTPase activity, leading to the accumulation of active RAS proteins. The most common oncogenic RAS mutations are G12C, G12D, G12S, G12V, G12R, G13D, and Q61H.

[0043] RAS signaling through PI3K is required for normal lymphoid development and RAS-induced transformation, and in lung cancer in particular, the interaction of mutant RAS with p110a-RBD is essential for tumor initiation and maintenance. The interaction of RAS with p110α-RBD has been shown to be essential for epidermal growth factor (EGF) signaling to PI3K. Recent studies have shown that disruption of RAS-PI3K interaction inhibits activation of AKT and RAC1 in EGFR-mutated lung cancer cells, leading to reduced proliferation and viability, and suppressing the development of EGFR-mutation-induced tumors. These results suggest that p110α binding to endogenous RAS proteins in EGFR-driven lung adenocarcinomas is important not only in tumors in which RAS is activated by mutational induction, but also in tumors driven by upstream activators of the RAS pathway.

[0044] Small GTPases (e.g., other than RAS) are also expected to bind to the RBD of PI3Kα, resulting in activation of signal transduction. Small GTPases Rac1 and CDC42 have been shown to bind to the RBD of PI3Kβ and are hypothesized to also bind to the RBD of PI3Kα. Thus, in some embodiments, the present disclosure encompasses the recognition that disrupting the interaction between PI3Kα and any small GTPase that binds to the RBD of PI3Kα may be a useful therapeutic strategy for treating cancer and other indications. In some embodiments, the small GTPase is selected from Rac1, CDC42, and RAS proteins (including HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1).

[0045] The high frequency of oncogenic PIK3CA hotspot mutations across cancers has led to active development and testing of numerous PI3K (e.g., PI3Kα) inhibitors. Most of the PI3K inhibitors that have moved into clinical development to date are reversible ATP-competitive kinase inhibitors. Despite substantial efforts, clinical outcomes of PI3K inhibitor-based therapy for solid tumors have been disappointing, primarily due to unacceptable toxicity and drug resistance. In 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (BYL719; Novartis Pharma AG), a PI3Kα isoform-specific inhibitor, in combination with fulvestrant for the treatment of patients diagnosed with HR+ / HER2-PIK3CA- mutations. The therapeutic window of PI3K inhibitors is primarily limited by isoform selectivity and extratumoral toxicity. In addition, hyperglycemia and hyperinsulinemia have been observed as the major dose-limiting toxicities of p110α inhibitors, preventing the use of doses high enough to completely suppress PI3Kα signaling in tumors. Hyperglycemia and hyperinsulinemia are considered on-target effects of PI3Kα inhibition, because inhibition of the PI3K / AKT pathway reduces glucose uptake, which in turn increases insulin secretion and leads to activation of insulin / insulin-like growth factor I receptors in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic effect of PI3Kα inhibitors. Indeed, in a Phase III clinical trial of alpelisib, hyperglycemia was observed in 65% of patients, leading to significant dose interruptions.

[0046] To overcome the limitations of current PI3Kα inhibitors, novel strategies for targeting PI3Kα need to be explored. Previous studies have suggested that inhibiting RAS-p110α (RBD) interactions effectively regresses tumors with minimal toxicity in adult animals. The present disclosure encompasses the recognition that this therapeutic approach may be effective in a variety of cancers, including RAS mutation-driven cancers and / or cancers driven by receptor tyrosine kinase (RTK) mutations or amplifications. The present disclosure also recognizes 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, the provided technology may avoid hyperglycemia and insulin-driven resistance common to PI3Kα inhibitors, for example, because such technology targets activation of PI3Kα by RAS, which is mostly present in transformed cells.

[0047] Provided compounds In some embodiments, the disclosure provides compounds useful for disrupting, inhibiting, and / or preventing the interaction of a small GTPase (e.g., a RAS protein described herein) with a PI3Kα protein. In some embodiments, the disclosure provides compounds capable of binding to PI3Kα, such that (i) the interaction between a small GTPase (e.g., a RAS protein 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 reversibly to PI3Kα. As used herein, a compound that binds "reversibly" refers to a compound that can bind to and dissociate from a target protein kinase (e.g., PI3Kα). Often, but not necessarily, a reversible inhibitor cannot form a covalent bond with a target protein kinase. In some embodiments, such compounds bind irreversibly to PI3Kα. As used herein, a compound that binds "irreversibly" refers to a compound that can interact (e.g., form a covalent bond) with a target protein kinase (e.g., PI3Kα) in a substantially irreversible manner. In some embodiments, the reversible or irreversible inhibitor may be capable of covalently interacting with PI3K alpha. For example, in some embodiments, the present disclosure provides a compound that includes an electrophilic moiety (e.g., a Michael acceptor, etc.) that can bind (e.g., reversibly or irreversibly) to a cysteine ​​residue (e.g., C242) in, for example, the catalytic subunit of PI3K alpha. In some embodiments, the provided compound that covalently interacts with PI3K alpha is a compound of formula I, where -LW includes an electrophilic moiety (e.g., a Michael acceptor, etc.) that can bind (e.g., reversibly or irreversibly) to, for example, a cysteine ​​residue (e.g., C242) of PI3K alpha.

[0048] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from phenyl, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and a 9-10 membered bicyclic ring containing at least one 5- or 6-membered heteroaryl ring; Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered bicyclic carbocycle; a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl, heteroaryl, and heterocycle being optionally fused to Ring E; Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl and heteroaryl rings being optionally fused to Ring F; Ring E is selected from a 5- to 6-membered carbocycle, a 5- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered spiro-fused heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ is replaced by Ring F is selected from phenyl, a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring F is selected from u -LW and y R 2’ is replaced by R 1is -LW, a ring D', or a bivalent C substituted with a ring D' 1-6 aliphatic chains, Each -LW is -CN, or Each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered mono- or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently a halogen, -OR, or -CN; each ring D' is independently a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW; Each R 2 and R 2’ are independently oxo, halogen, -CN, -OR, and C 1-6 alkyl, Each R 3 are independently halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR or any substituted C 1-6 It is aliphatic, Each Cy is independently a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy is independently selected from 0 to 2 R 6is replaced by Each R 4 are independently selected from halogen and optionally substituted C 1-6 selected from aliphatic, R 5 and R 5’ Each of is independently oxo, ═NH, —CN, halogen, —OR, —N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -C(O)N(R) 2 , -C(O)N(R)(CH 2 ) x Cy, -(CH 2 ) x C(O)Cy, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -N=S(O)(R) 2 , -SO 2 N(R) 2 , -P(O)R 2 , -(CH 2 ) x Cy, -O(CH 2 ) x Cy and optionally substituted C 1-6 selected from aliphatic, Each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6an optionally substituted group selected from aliphatic; a 3-6 membered carbocyclic ring; a phenyl; a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10 membered aryl ring; and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic; a 3- to 6-membered carbocyclic ring; a phenyl; a 3- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1; r is 0, 1, or 2; s is 0, 1, 2, or 3; t is 0, 1, or 2; u is 0 or 1; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; y is 0, 1, or 2.

[0049] In some embodiments, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the disclosure provides compounds of Formula I, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from phenyl, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and a 9-10 membered bicyclic ring containing at least one 5- or 6-membered heteroaryl ring; Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl, heteroaryl, and heterocyclic ring being optionally fused to Ring E; Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl and heteroaryl rings being optionally fused to Ring F; Ring E is selected from a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ is replaced by Ring F is selected from phenyl, a 5- to 6-membered carbocyclic ring, a 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW; R 1 is -LW, a ring D', or a bivalent C substituted with a ring D' 1-6 aliphatic chains, Each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2-, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered mono- or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen or -CN; each ring D' is independently a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW; Each R 2 are independently oxo, halogen, -CN, -OR, and C 1-6 alkyl, Each R 3 are independently halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR or any substituted C 1-6 It is aliphatic, Each Cy is independently a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy is independently selected from 0 to 2 R 6 is replaced by Each R 4 are independently selected from halogen and optionally substituted C 1-6 selected from aliphatic, R 5 and R 5’ Each of is independently oxo, ═NH, —CN, halogen, —OR, —N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy and optionally substituted C 1-6 selected from aliphatic, Each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 an optionally substituted group selected from aliphatic; a 3-6 membered carbocyclic ring; a phenyl; a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10 membered aryl ring; and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic; a 3- to 6-membered carbocyclic ring; a phenyl; a 3- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, or 2; q is 0 or 1; r is 0, 1, or 2; s is 0, 1, or 2; t is 0, 1, or 2; u is 0 or 1; each v is independently 0, 1, or 2; Each x is independently 0, 1, or 2.

[0051] In some embodiments, the disclosure provides compounds of Formula I, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl; Ring B is selected from 9-10 membered bicyclic rings containing at least one 5- or 6-membered heteroaryl ring; Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered bicyclic carbocycle; a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl, heteroaryl, and heterocycle being optionally fused to Ring E; Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl and heteroaryl rings being optionally fused to Ring F; Ring E is selected from a 5- to 6-membered carbocycle, a 5- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered spiro-fused heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ is replaced by Ring F is selected from phenyl, a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring F is selected from u -LW and y R 2’ is replaced by R 1 is -LW, a ring D', or a bivalent C substituted with a ring D' 1-6 aliphatic chains, Each -LW is -CN, or Each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered mono- or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently a halogen, -OR, or -CN; each ring D' is independently a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW; Each R 2 and R 2’ are independently oxo, halogen, -CN, -OR, and C 1-6 alkyl, Each R 3 are independently halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2OR or any substituted C 1-6 It is aliphatic, Each Cy is independently a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy is independently selected from 0 to 2 R 6 is replaced by Each R 4 are independently selected from halogen and optionally substituted C 1-6 selected from aliphatic, R 5 and R 5’ Each of is independently oxo, ═NH, —CN, halogen, —OR, —N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -C(O)N(R) 2 , -C(O)N(R)(CH 2 ) x Cy, -(CH 2 ) x C(O)Cy, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -N=S(O)(R) 2 , -SO 2 N(R) 2 , -P(O)R 2 , -(CH 2 ) x Cy, -O(CH 2 ) x Cy and optionally substituted C 1-6 selected from aliphatic, Each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6an optionally substituted group selected from aliphatic; a 3-6 membered carbocyclic ring; a phenyl; a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10 membered aryl ring; and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic; a 3- to 6-membered carbocyclic ring; a phenyl; a 3- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 2 or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0 or 1; r is 0, 1, or 2; s is 0, 1, 2, or 3; t is 0, 1, or 2; u is 0 or 1; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; y is 0, 1, or 2.

[0052] In some embodiments, the disclosure provides compounds of Formula I, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl; Ring B is selected from 9-10 membered bicyclic rings containing at least one 5- or 6-membered heteroaryl ring; Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered bicyclic carbocycle; a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl, heteroaryl, and heterocycle being optionally fused to Ring E; Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl and heteroaryl rings being fused to Ring F; Ring E is selected from a 5- to 6-membered carbocycle, a 5- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered spiro-fused heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ is replaced by Ring F is selected from phenyl, a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring F is selected from u -LW and y R 2’ is replaced by Each -LW is -CN, or Each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered mono- or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently a halogen, -OR, or -CN; Each R 2 and R 2’ are independently oxo, halogen, -CN, -OR, and C 1-6 alkyl, Each R 3 are independently halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR or any substituted C 1-6 It is aliphatic, Each Cy is independently a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy is independently selected from 0 to 2 R 6 is replaced by Each R 4 are independently selected from halogen and optionally substituted C 1-6 selected from aliphatic, R 5 and R 5’ Each of is independently oxo, ═NH, —CN, halogen, —OR, —N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -C(O)N(R) 2 , -C(O)N(R)(CH 2 ) x Cy, -(CH 2 ) x C(O)Cy, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -N=S(O)(R) 2 , -SO 2N(R) 2 , -P(O)R 2 , -(CH 2 ) x Cy, -O(CH 2 ) x Cy and optionally substituted C 1-6 selected from aliphatic, Each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 an optionally substituted group selected from aliphatic; a 3-6 membered carbocyclic ring; a phenyl; a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10 membered aryl ring; and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic; a 3- to 6-membered carbocyclic ring; a phenyl; a 3- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 2 or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, r is 0, 1, or 2; s is 0, 1, 2, or 3; u is 0 or 1; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; y is 0, 1, or 2.

[0053] In some embodiments, the disclosure provides compounds of Formula I, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is phenyl; Ring B is selected from 9-10 membered bicyclic rings containing at least one 5- or 6-membered heteroaryl ring; Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered bicyclic carbocycle; a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl, heteroaryl, and heterocycle is fused to Ring E; Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl and heteroaryl rings being fused to Ring F; Ring E is selected from a 5- to 6-membered carbocycle, a 5- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered spiro-fused heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ is replaced by Ring F is selected from phenyl, a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring F is selected from u -LW and y R 2’is replaced by Each -LW is -CN, or Each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, each W is independently hydrogen, halogen, -CN, or an optionally substituted 3-10 membered mono- or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently a halogen, -OR, or -CN; Each R 2 and R 2’ are independently oxo, halogen, -CN, -OR, and C 1-6 alkyl, Each R 3 are independently halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR or any substituted C 1-6 It is aliphatic, Each Cy is independently a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy is independently selected from 0 to 2 R 6 is replaced by Each R 4 are independently selected from halogen and optionally substituted C 1-6 selected from aliphatic, R 5 and R 5’Each of is independently oxo, ═NH, —CN, halogen, —OR, —N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -C(O)N(R) 2 , -C(O)N(R)(CH 2 ) x Cy, -(CH 2 ) x C(O)Cy, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -N=S(O)(R) 2 , -SO 2 N(R) 2 , -P(O)R 2 , -(CH 2 ) x Cy, -O(CH 2 ) x Cy and optionally substituted C 1-6 selected from aliphatic, Each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 an optionally substituted group selected from aliphatic; a 3-6 membered carbocyclic ring; a phenyl; a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10 membered aryl ring; and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6an optionally substituted group selected from aliphatic; a 3- to 6-membered carbocyclic ring; a phenyl; a 3- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 2 or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, r is 0, 1, or 2; s is 0, 1, 2, or 3; u is 0 or 1; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; y is 0, 1, or 2.

[0054] In some embodiments, the present disclosure provides a compound selected from formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, and Ik: [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: 1 , R 2 , R 3 , R 4 , R 5, m, n, p, q, and r are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ic, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Id, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ie, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula If, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ig, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ih, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ij, or a pharma- ceutically acceptable salt thereof.In some embodiments, the disclosure provides a compound of formula Ik, or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the present disclosure provides a compound selected from formula Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, Ihi, Iii, Iji, and Iki: [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: 1 , R 2 , R 3 , R 4 , R5 , R 5’ , m, n, p, q, r, and s are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula Iai, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ibi, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ici, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Idi, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Iei, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ifi, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Igi, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ihi, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula Iji, or a pharma- ceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula Iki, or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments, the present disclosure provides a compound selected from formula Ia-ii, Ib-ii, Ic-ii, Id-ii, Ie-ii, If-ii, Ig-ii, Ih-ii, Ii-ii, Ij-ii, and Ik-ii: [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring A, ring C, ring D, ring F, ring R2 , R 3 , R 4 , R 5 , L, W, m, n, p, r, and u are as defined above for Formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of Formula Ia-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ib-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ic-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Id-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ie-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula If-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ig-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ih-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ii-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ij-ii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ik-ii, or a pharma- ceutically acceptable salt thereof.

[0057] In some embodiments, the present disclosure provides a compound selected from formula Ia-ii', Ib-ii', Ic-ii', Id-ii', Ie-ii', If-ii', Ig-ii', Ih-ii', Ii-ii', Ij-ii', and Ik-ii': [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring A, ring C, ring D, ring F, ring R 2 , R 2’ , R 3 , R 4 , R 5 , L, W, m, n, p, r, u, and y are as defined above for Formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula Ia-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ib-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ic-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Id-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ie-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula If-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ig-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ih-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ii-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ij-ii', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ik-ii', or a pharma- ceutically acceptable salt thereof.

[0058] In some embodiments, the present disclosure provides a compound selected from formula Ia-iii, Ib-iii, Ic-iii, Id-iii, Ie-iii, If-iii, Ig-iii, Ih-iii, Ii-iii, Ij-iii, and Ik-iii: [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: 2 , R 3 , R 4 , R 5 , W, m, n, p, r, and t are as defined above for Formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of Formula Ia-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ib-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ic-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Id-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ie-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula If-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ig-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula Ih-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ii-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ij-iii, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ik-iii, or a pharma- ceutically acceptable salt thereof.

[0059] In some embodiments, the present disclosure provides a compound selected from formula Ia-iv, Ib-iv, Ic-iv, Id-iv, Ie-iv, If-iv, Ig-iv, Ih-iv, Ii-iv, Ij-iv, and Ik-iv: [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring A, ring C, ring D', L, R 2 , R 3 , R 4 , R 5 , W, m, n, p, r, and t are as defined above for Formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides compounds of formula Ia-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula Ib-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula Ic-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula Id-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula Ie-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula If-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula Ig-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides compounds of formula Ih-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ii-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ij-iv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ik-iv, or a pharma- ceutically acceptable salt thereof.

[0060] In some embodiments, the present disclosure provides a compound selected from formula Iav, Ibv, Icv, Idv, Iev, Ifv, Igv, Ihv, Iiv, Ijv, and Ikv: [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring A, ring C, ring D, ring E, ring F, ring H, ring I, ring I, ring II, ring I ... 2 , R 3 , R 4 , R 5 , R 5’, L, W, m, n, p, r, s, and u are as defined above for Formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula Iav, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ibv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Icv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Idv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Iev, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ifv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Igv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ihv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Iiv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ijv, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ikv, or a pharma- ceutically acceptable salt thereof.

[0061] In some embodiments, the present disclosure provides a compound selected from formula Ia-v', Ib-v', Ic-v', Id-v', Ie-v', If-v', Ig-v', Ih-v', Ii-v', Ij-v', and Ik-v': [ka] [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring A, ring C, ring D, ring E, ring F, ring H, ring I, ring I, ring II, ring I ... 2 , R 2’, R 3 , R 4 , R 5 , R 5’ , L, W, m, n, p, r, s, u, and y are as defined above for Formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula Ia-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ib-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ic-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Id-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ie-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula If-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ig-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ih-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ii-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ij-v', or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ik-v', or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the present disclosure provides a compound selected from formulae Il, Im, In, Ip, Iq, and Ir: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring A, ring B, ring C, ring D′, L, R 3 , R 4 , R 5, W, m, n, p, and t are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula Il, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Im, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula In, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ip, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Iq, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula Ir, or a pharma- ceutically acceptable salt thereof.

[0063] In some embodiments, the present disclosure provides a compound of formula IA: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring B, ring C, ring D, ring R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, q, and r are as defined above for formula I, and as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IA, or a pharma- ceutically acceptable salt thereof.

[0064] In some embodiments, the present disclosure provides a compound of formula IA1: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring B, ring C, ring D, ring R 1 , R2 , R 3 , R 4 , R 5 , n, p, q, and r are as defined above for formula I, and as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IA1, or a pharma- ceutically acceptable salt thereof.

[0065] In some embodiments, the present disclosure provides a compound of formula IB: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring C, ring D, ring R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, q, and r are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IB, or a pharma- ceutically acceptable salt thereof.

[0066] In some embodiments, the present disclosure provides a compound of formula IB1: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring C, ring D, ring R 1 , R 2 , R 3 , R 4 , R 5 , n, p, q, and r are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IB1, or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments, the present disclosure provides a compound of formula IC: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring B, ring C, L, R 2’ , R 3 , R 4 , R 5 , W, m, n, p, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IC, or a pharma- ceutically acceptable salt thereof.

[0068] In some embodiments, the present disclosure provides a compound of formula IC1: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring B, ring C, L, R 2’ , R 3 , R 4 , R 5 , W, n, p, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IC1, or a pharma- ceutically acceptable salt thereof.

[0069] In some embodiments, the present disclosure provides a compound of formula ID: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein rings C, L, R 2’ , R 3 , R4 , R 5 , W, m, n, p, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula ID, or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, the present disclosure provides a compound of formula ID1: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein rings C, L, R 2’ , R 3 , R 4 , R 5 , W, n, p, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula ID1, or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, the present disclosure provides a compound of formula IE: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring B, ring C, ring E, L, R 2’ , R 3 , R 4 , R 5 , R 5’ , W, m, n, p, s, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IE, or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments, the present disclosure provides a compound of formula IE1: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring B, ring C, ring E, L, R 2’ , R 3 , R 4 , R 5 , R 5’ , W, n, p, s, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IE1, or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, the present disclosure provides a compound of formula IF: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring C, ring E, ring L, ring R 2’ , R 3 , R 4 , R 5 , R 5’ , W, m, n, p, s, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IF, or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the present disclosure provides a compound of formula IF1: [ka] or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein ring C, ring E, ring L, ring R 2’ , R3 , R 4 , R 5 , R 5’ , W, n, p, s, and y are as defined above for formula I, and are as described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides a compound of formula IF1, or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments of any formula described herein, ring A is phenyl or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in some embodiments, ring A is phenyl or a 6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] In some embodiments of any of the formulas described herein, Ring A is phenyl. In some embodiments, Ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is selected from: [ka] In some embodiments, ring A is selected from [ka] It is.

[0077] In some embodiments of any formula described herein, ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a pyrazole. In some embodiments, ring A is a 6 membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, ring A is a pyridine or pyridone.

[0078] In some embodiments of any of the formulas described herein, m R 3 Ring A substituted with [ka] [ka] is selected from.

[0079] In some embodiments of any of the formulas described herein, each R 3 are independently oxo, halogen (e.g., F or Cl), -CN, -OR, -O(CH 2 ) v Cy, -O-(C 1-4 alkylene)-OR (e.g., -OCH 2 CH 2 OR), -CH 2 CH 2 OR, C 1-6 Aliphatic and C 1-6 In some embodiments, each R 3 are independently oxo, halogen (e.g., F or Cl), -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2OR, -CH 2 CH 2 OR, C 1-6 Aliphatic and C 1-6 In some embodiments, each R 3 are independently halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR and optionally substituted C 1-6 In some embodiments, each R 3 are independently oxo, halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR and optionally substituted C 1-6 In some embodiments, each R 3 are independently oxo, halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR and C optionally substituted with one or more halogens or -OR° 1-6 In some such embodiments, R° is selected from C 1-4 alkyl. Thus, in some embodiments, each R 3 are independently oxo, halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR and one or more halogens or -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, each R 3 are independently oxo, halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR and one or more halogens or -O(C 1-4 C optionally substituted with alkyl 1-6In some embodiments, at least one R 3 is halogen, -OR, -O(CH 2 ) v Cy, and -OCH 2 CH 2 In some embodiments, at least one R 3 -OR, -O(CH 2 ) v Cy, and -OCH 2 CH 2 In some embodiments, ring A is selected from: [ka] where each R 3 are independently halogen, -OR, -O(CH 2 ) v Cy, and -OCH 2 CH 2 In some embodiments, ring A is selected from: [ka] where each R 3 are independently halogen, -OR, -O(CH 2 ) v Cy, and -O-(C 1-4 In some embodiments, ring A is selected from: [ka] where R 3 -OR, -O(CH 2 ) v Cy, and -OCH 2 CH 2 In some embodiments, ring A is selected from: [ka] where each R 3 -OR, -O(CH 2 ) v Cy, and -O-(C1-4 alkylene)-OR.

[0080] In some embodiments of any of the formulas described herein, each R 3 are independently halogen, -OR, -OCH 2 CH 2 OR and one or more halogens or -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, at least one R 3 is selected from halogen (e.g., F). In some embodiments, at least one R 3 -OCH 2 CH 2 OR and one or more halogens or -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, at least one is selected from -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCH 2 CHF 2 , -OCH(CH 2 F) 2 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 CH(CH 3 )OH, -OCH 2 C(CH 3 ) 2 OH, -OCH(CH 3 )CH 2 R selected from OH and -O(cyclopropyl) 3 It is.

[0081] In some embodiments of any of the formulas described herein, R 3 is oxo (e.g., when ring A is not phenyl). In some embodiments, R 3is halogen (e.g., fluoro or chloro). In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is -CN. In some embodiments, R 3 In some embodiments, R 3 is -O(C 1-4 alkyl, optionally substituted with -OH) or -O(C 1-4 haloalkyl). In some embodiments, R 3 -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH(CH 3 )CH 2 OH, -OCH 2 CH(CH 3 )OH, -OCH 2 C(CH 3 ) 2 OH, -OCHF 2 , -OCH 2 CHF 2 , or -OCH(CH 2 F) 2 In some embodiments, R 3 is -O(C 1-4 alkyl) or -O(C 1-4 haloalkyl). In some embodiments, R 3 -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , or -OCH 2 CHF 2 In some embodiments, R 3 -O(CH 2 ) v In some embodiments, R 3 HA-OCH 2 In some embodiments, R 3 -O(CH2 ) v Cy, wherein Cy is 0 to 2 R 6 In some embodiments, R is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with R (e.g., Cy is pyridine substituted with fluoro). 3 -O(CH 2 ) v Cy, wherein Cy is 0 to 2 R 6 (e.g., Cy is cyclopropane or cyclobutane substituted with one or more halogens). 3 -O(CH 2 ) v Cy, where Cy is a 3-6 membered carbocyclic ring (e.g., Cy is cyclopropane). In some embodiments, R 3 -O(CH 2 ) v Cy, where Cy is a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., Cy is C 1-6 In some embodiments, R 3 is -O-(C 1-4 In some embodiments, R 3 is -O-(C 1-4 In some embodiments, R 3 -OCH 2 CH 2 OH, -OCH(CH 3 )CH 2 OH, -OCH 2 CH(CH 3 )OH, -OCH 2 C(CH 3 ) 2 OH, -OCH 2 CH 2 O( C1-4 alkyl), or -OCH 2 CH 2 O(C 1-4haloalkyl). In some embodiments, R 3 HA-OCH 2 CH 2 In some embodiments, R 3 -OCH 2 CH 2 OH or -OCH 2 CH 2 O(C 1-4 In some embodiments, R 3 Ha-CH 2 CH 2 In some embodiments, R 3 Ha-CH 2 CH 2 O(C 1-4 In some embodiments, R 3 is an arbitrarily substituted C 1-6 In some embodiments, R 3 is an arbitrarily substituted C 1-6 In some embodiments, R 3 is one or more halogens (e.g., fluoro) or -OR° (e.g., -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, R 3 is one or more halogens (e.g., fluoro) or -OR° (e.g., -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is C 1-6 It is haloalkyl.

[0082] In some embodiments of any of the formulas described herein, each R 3 are independently oxo, fluoro, chloro, -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCHF 2, -OCH 2 CHF 2 , -OCH(CH 2 F) 2 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OCD 3 , -OCH(CH 3 )CH 2 OH, -OCH 2 CH(CH 3 )OH, -OCH 2 C(CH 3 ) 2 OH, -OCH 2 CH 2 O.C.H.F. 2 , -CH 3 , -CHF 2 , -CH 2 CH 2 OCH 3 , [ka] is selected from.

[0083] In some embodiments of any formula described herein, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0084] In some embodiments of any formula described herein, ring B is selected from a 6-membered heteroaryl ring having 1-3 nitrogen atoms and a 9-10 membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, ring B is selected from a 6-membered heteroaryl ring having 1-2 nitrogen atoms and a 9-10 membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, ring B is selected from a 6-membered heteroaryl ring having 1-2 nitrogen atoms and a 9-membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the bicyclic ring comprises at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom.

[0085] In some embodiments of any of the formulas described herein, Ring B is phenyl.

[0086] In some embodiments of any formula described herein, Ring B is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Ring B is pyridine. In some embodiments, Ring B is pyrazine. In some embodiments, Ring B is pyrimidine. In some embodiments, Ring B is pyridazine.

[0087] In some embodiments of any formula described herein, ring B is a 9-10 membered bicyclic ring containing at least one 5- or 6-membered heteroaryl ring. In some embodiments, ring B is a 9-10 membered bicyclic ring containing at least one 5- or 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, ring B is a 9-10 membered bicyclic ring containing one 5- or 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, ring B is a 9-10 membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the bicyclic ring contains at least one 5- or 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, ring B is a 9-10 membered bicyclic ring containing at least one 6-membered heteroaryl ring. In some embodiments, ring B is a 9-10 membered bicyclic ring containing at least one 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, ring B is a 9-10 membered bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the bicyclic ring includes at least one 6-membered heteroaryl ring having at least one nitrogen atom. In some embodiments, ring B is a 9-membered bicyclic ring including at least one 5- or 6-membered heteroaryl ring. In some embodiments, ring B is a 9-membered bicyclic ring including at least one 5- or 6-membered heteroaryl ring including at least one nitrogen atom. In some embodiments, ring B is a 9-membered bicyclic heteroaryl ring including at least one 5- or 6-membered heteroaryl ring including at least one nitrogen atom. In some embodiments, ring B is a 9-10 membered bicyclic ring including a pyridine ring. In some embodiments, ring B is a 9-10 membered bicyclic ring including a pyrazine ring. In some embodiments, ring B is a 9-10 membered bicyclic ring including a pyrazole ring. In some embodiments, ring B is a 9-10 membered bicyclic ring comprising a thiazole ring. In some embodiments, ring B is a 9-10 membered bicyclic ring comprising a thiophene ring. In some embodiments, ring B is a 9-10 membered bicyclic ring comprising a furan ring.In some embodiments, ring B is a 9-10 membered bicyclic ring containing a cyclopentane or cyclopentene ring. In some embodiments, ring B is thieno[3,2-c]pyridine, thieno[2,3-c]pyridine, thiazolo[4,5-c]pyridine, pyrazolo[1,5-a]pyrazine, furo[3,2-c]pyridine, or 6,7-dihydro-5H-cyclopenta[c]pyridine. In some embodiments, ring B is a 10 membered bicyclic ring containing at least one 6 membered heteroaryl ring. In some embodiments, ring B is a 10 membered bicyclic ring containing at least one 6 membered heteroaryl ring containing at least one nitrogen atom.

[0088] In some embodiments of any of the formulas described herein, n R 4 Ring B substituted with [ka] is selected from.

[0089] In some embodiments of any of the formulas described herein, n R 4 Ring B substituted with [ka] In some embodiments, the n R 4 Ring B substituted with [ka] It is.

[0090] In some embodiments of any of the formulas described herein, each R 4 are independently halogen, C 1-6 Aliphatic and C 1-6 In some embodiments, each R 4 are independently halogen and C 1-6 In some embodiments, R 4 are independently halogen and optionally substituted C 1-6In some embodiments, R 4 is halogen (e.g., fluoro or chloro). In some embodiments, R 4 is fluoro. In some embodiments, R 4 is chloro. In some embodiments, R 4 is an arbitrarily substituted C 1-6 In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is an arbitrarily substituted C 1-6 In some embodiments, R 4 is C 1-6 In some embodiments, R 4 Ha-CF 3 In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is methyl.

[0091] In some embodiments of any formula described herein, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0092] In some embodiments of any of the formulas described herein, Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered bicyclic carbocycle; a 4-8 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered saturated or partially unsaturated spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the phenyl, heteroaryl, and heterocycle is optionally fused to Ring E. In some embodiments, ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9-10 membered saturated or partially unsaturated spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl, heteroaryl, and heterocycle being optionally fused to ring E. In some embodiments, ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered bicyclic carbocycle; a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, ring C is phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is fused to ring E. In some embodiments, ring C is phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is fused to ring E.

[0093] In some embodiments of any of the formulas described herein, ring C is not fused to ring E. In some embodiments, ring C is fused to ring E. In some embodiments, when ring C is fused to ring E, only one of ring C and ring E is aromatic.

[0094] Throughout this disclosure, when a ring is described as being fused to another ring, one of ordinary skill in the art will understand that such fusion may or may not result in additional unsaturation in one or both of the rings that is not described by the name of each ring alone. For example, a cyclopentane ring fused to a phenyl ring has the following structure: [ka] and the phenyl ring fused to the pyrrole ring has the following structure: [ka] has.

[0095] In some embodiments of any formula described herein, ring C is phenyl. In some embodiments, ring C is phenyl that is not fused to ring E. In some embodiments, ring C is phenyl that is fused to ring E.

[0096] In some embodiments of any formula described herein, ring C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is not fused to ring E. In some embodiments, ring C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is fused to ring E. In some embodiments, ring C is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a pyrazole, imidazole, or triazole. In some embodiments, ring C is a pyrazole, imidazole, triazole, oxazole, thiazole, or oxadiazole. In some embodiments, ring C is a 6 membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, Ring C is pyridine, pyridone, pyrimidine, or pyridazinone. In some embodiments, Ring C is pyridine, pyridone, pyrazine, pyrimidine, pyridazine, or pyridazinone.

[0097] In some embodiments of any of the formulas described herein, Ring C is a 5-8 membered bicyclic carbocyclic ring. In some embodiments, Ring C is a 5-8 membered bridged bicyclic carbocyclic ring. In some embodiments, Ring C is a bridged cyclobutane (e.g., bicyclo[1.1.1]pentane).

[0098] In some embodiments of any formula described herein, ring C is a 4-8 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is not fused to ring E. In some embodiments, ring C is a 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is fused to ring E. In some embodiments, ring C is a 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 4 membered heterocycle having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is azetidine. In some embodiments, ring C is a 5 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is pyrrolidine. In some embodiments, ring C is a 6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is piperidine, tetrahydropyridine, piperazine, piperazinone, or thiomorpholine-1,1-dioxide. In some embodiments, ring C is a 7-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a bridged ring system. In some embodiments, Ring C is a 7-8 membered bridged heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a bridged piperazine (e.g., 3,8-diazabicyclo[3.2.1]octane).In some embodiments, Ring C is a bridged piperidine (eg, 3-azabicyclo[3.1.1]heptane).

[0099] In some embodiments of any formula described herein, ring C is a 7-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7-10 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is not fused to ring E. In some embodiments, ring C is a 7-10 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C is fused to ring E. In some embodiments, ring C is a 7-10 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-10 membered saturated or partially unsaturated spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7 membered spiro-fused heterocycle having two 4 membered rings. In some embodiments, ring C is 2-azaspiro[3.3]heptane or 2,6-diazaspiro[3.3]heptane. In some embodiments, ring C is an 8 membered spiro-fused heterocycle having a 4 membered ring and a 5 membered ring. In some embodiments, ring C is 2,6-diazaspiro[3.4]octane. In some embodiments, ring C is a 9 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9 membered spiro-fused heterocycle having a 4 membered ring and a 6 membered ring. In some embodiments, Ring C is 2-azaspiro[3.5]nonane, 2-azaspiro[3.5]non-6-ene, 2,7-diazaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane, or 2-thia-7-azaspiro[3.5]nonane-2,2-dioxide. In some embodiments, Ring C is a 10-membered spiro-fused heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, Ring C is 2,8-diazaspiro[4.5]decan-3-one or 2,8-diazaspiro[4.5]decane.

[0100] In some embodiments of any of the formulas described herein, ring C is not fused to ring E and p R 5 Ring C substituted with [ka] [ka] [ka] [ka] [ka] is selected from.

[0101] In some embodiments of any of the formulas described herein, ring E is selected from a 5-6 membered saturated or partially unsaturated carbocycle, a 5-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring E is selected from s R 5’ In some embodiments, ring E is selected from a 5-6 membered saturated or partially unsaturated carbocycle, a 5-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring E is substituted with s R 5’ has been replaced by

[0102] In some embodiments of any of the formulas described herein, ring E is selected from the group consisting of s R 5’ In some embodiments, ring E is a 5-6 membered carbocyclic ring substituted with s R 5’ In some embodiments, ring E is a 5-6 membered saturated or partially unsaturated carbocyclic ring substituted with s R 5’ In some embodiments, ring E is a 5-membered carbocyclic ring substituted with s R 5’ In some embodiments, ring E is cyclopentane substituted with s R 5’ In some embodiments, ring E is a 6-membered carbocyclic ring substituted with s R 5’ is a cyclohexane substituted with

[0103] In some embodiments of any of the formulas described herein, Ring E is a 5-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ In some embodiments, Ring E is a 5-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is substituted with s R 5’ In some embodiments, Ring E is a 5-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is substituted with s R 5’ In some embodiments, ring E is substituted with s R 5’ Pyrrolidine, pyrrolidinone, 1-iminotetrahydro-1H-1λ substituted 6 -thiophene-1-oxide, or tetrahydrothiophene-1,1-dioxide. In some embodiments, ring E is each selected from s R 5’ Pyrrolidine, pyrrolidinone, imidazolidin-2-one, 1-iminotetrahydro-1H-1λ substituted with 6In some embodiments, ring E is a 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring E is a 6-membered heterocycle having s R 5’ In some embodiments, ring E is substituted with s R 5’ In some embodiments, Ring E is a 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is a 7-membered heterocycle having s R 5’ In some embodiments, ring E is substituted with s R 5’ In some embodiments, ring E is an azepane substituted with s R 5’ substituted with azepane or 1,4-diazepan-2-one.

[0104] In some embodiments of any of the formulas described herein, Ring E is a 7-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ...s R 5’ In some embodiments, Ring E is an 8-membered spiro-fused heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is substituted with s R 5’ In some embodiments, ring E is substituted with s R 5’ 5-azaspiro[2.5]octane or 5-azaspiro[2.5]octan-4-one, substituted with

[0105] In some embodiments of any of the formulas described herein, Ring E is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ In some embodiments, Ring E is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is substituted with s R 5’In some embodiments, ring E is substituted with s R 5’ In some embodiments, ring E is a pyrazole or triazole substituted with s R 5’ In some embodiments, ring E is a pyrazole, imidazole, oxazole, or triazole substituted with s R 5’ In some embodiments, ring E is a 6-membered heteroaryl ring having 1-3 nitrogen atoms substituted with s R 5’ In some embodiments, ring E is a pyridazinone substituted with s R 5’ and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 2

[0106] In some embodiments of any of the formulas described herein, ring C is fused to ring E; [ka] teeth, [ka] is selected from.

[0107] In some embodiments of any of the formulas described herein, ring C is fused to ring E and has s R 5’ Ring E substituted with [ka] [ka] [ka] is selected from.

[0108] In some embodiments of any of the formulas described herein, ring C is fused to ring E; [ka] teeth, [ka] [ka] [ka] is selected from.

[0109] In some embodiments of any of the formulas described herein, each R 5 are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -C(O)N(R)(CH 2 ) x Cy, -(CH 2 ) x C(O)Cy, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -N=S(O)(R) 2 , -SO 2 N(R) 2 , -P(O)(R) 2 , -(CH 2 ) x Cy, -O(CH 2 ) x Cy, and C 1-6 aliphatic, in which case C 1-6 Aliphatic is unsubstituted or contains one or more halogens, -CN, -N(R)C(O)R, -N(R) 2 In some embodiments, each R 5 are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy, and C 1-6 aliphatic, in which case C 1-6 An aliphatic is unsubstituted or substituted with one or more halogens or -OR. In some embodiments, each R 5 are independently -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy and optionally substituted C 1-6 Aliphatic (e.g., halogen, -OR, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, each R 5 are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy and optionally substituted C 1-6 Alkyl (e.g., halogen, -OR, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, each R 5 are independently oxo, -CN, halogen, -N(R) 2 , -C(O)R, -C(O)N(R) 2, -SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy and optionally substituted C 1-6 Aliphatic (e.g., halogen, -OR, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, each R 5 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -C(O)R, -(CH 2 ) x C(O)N(R) 2 , -C(O)N(R)(CH 2 ) x Cy, -(CH 2 ) x C(O)Cy, -SO 2 R, -N=S(O)(R) 2 , -SO 2 N(R) 2 , -P(O)(R) 2 , -(CH 2 ) x Cy, -O(CH 2 ) x Cy, and C 1-6 aliphatic, in which case C 1-6 Aliphatic is unsubstituted or contains one or more halogens, -CN, -N(R)C(O)R, -N(R) 2 In some embodiments, each R 5 are independently oxo, -CN, halogen, -NH 2 , -N(C 1-4 Alkyl) 2 , -C(O)(C 1-4 alkyl), -C(O)NH 2 , -SO 2 (C 1-4 Alkyl), -SO 2 NH 2 , -SO 2 N(H)(C 1-4 alkyl), -CH 2(a 3-6 membered carbocyclic ring optionally substituted with one or more halogens), a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and one or more halogens, -OR°, and -C(O)NR°. 2 C optionally substituted with 1-6 In some such embodiments, R is hydrogen. Thus, in some embodiments, each R 5 are independently oxo, -CN, halogen, -NH 2 , -N(C 1-4 Alkyl) 2 , -C(O)(C 1-4 alkyl), -C(O)NH 2 , -SO 2 (C 1-4 Alkyl), -SO 2 NH 2 , -SO 2 N(H)(C 1-4 alkyl), -CH 2 (a 3- to 6-membered carbocyclic ring optionally substituted with one or more halogens), a 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and one or more halogens, -OH, and -CO 2 NH 2 C optionally substituted with 1-6 is selected from alkyl.

[0110] In some embodiments of any of the formulas described herein, R 5 is oxo. In some embodiments, R 5 is ═NH. In some embodiments, R 5 is -CN. In some embodiments, R 5 is halogen (e.g., fluoro or chloro). In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 In some embodiments, R 5 is one or more -N(C 1-4 Alkyl) 2Optionally substituted -O(C 1-4 In some embodiments, R 5 HA-N(R) 2 In some embodiments, R 5 Ha-NH 2 In some embodiments, R 5 -N(C 1-4 Alkyl) 2 In some embodiments, R 5 In some embodiments, R 5 is -C(O)R. In some embodiments, R 5 -C(O)(C 1-4 In some embodiments, R 5 is -N(R)C(O)R. In some embodiments, R 5 Ha-(CH 2 ) x C(O)N(R) 2 In some embodiments, R 5 is -(CH 2 ) x C(O)NH 2 , -(CH 2 ) x C(O)NH(C 1-4 alkyl), -(CH 2 ) x C(O)NH(C 1-4 haloalkyl), -(CH 2 ) x C(O)N(C 1-4 Alkyl) 2 , or -(CH 2 ) x C(O)N(C 1-4 Haloalkyl) 2 In some embodiments, R 5 -C(O)N(R) 2 In some embodiments, R 5 is -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)NH(C 1-4 haloalkyl), -C(O)N(C 1-4 Alkyl) 2, or -C(O)N(C 1-4 Haloalkyl) 2 In some embodiments, R 5 is -C(O)N(R)(CH 2 ) x Cy (e.g., -C(O)NH(CH 2 ) x In some embodiments, R 5 Ha-(CH 2 ) x C(O)Cy. In some embodiments, R 5 is -OC(O)R. In some embodiments, R 5 is -C(O)OR. In some embodiments, R 5 -SO 2 R. In some embodiments, R 5 -SO 2 (C 1-4 In some embodiments, R 5 -N(R)SO 2 R. In some embodiments, R 5 -N=S(O)(R) 2 In some embodiments, R 5 -SO 2 N(R) 2 In some embodiments, R 5 -SO 2 NH 2 OR -SO 2 NH(C 1-4 In some embodiments, R 5 -P(O)R 2 In some embodiments, R 5 Ha-(CH 2 ) x In some embodiments, R 5 Ha-(CH 2 ) x Cy, where Cy is a 3-6 membered carbocyclic ring optionally substituted with one or more halogens. 5 Ha-(CH 2 ) xCy is a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5 Ha-(CH 2 ) x Cy and x is 0. In some embodiments, R 5 Ha-(CH 2 ) x Cy, where x is 0 and Cy is a 3-6 membered carbocyclic ring optionally substituted with one or more halogens. 5 Ha-(CH 2 ) x Cy, x is 0, and Cy is 0 to 2 R 6 In some embodiments, R is a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 5 -O(CH 2 ) x In some embodiments, R 5 is an arbitrarily substituted C 1-6 Aliphatic (e.g., halogen, -OR, -CN, -N(R)C(O)R, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, R 5 is one or more halogens, -OR° (e.g., -OH), and -C(O)NR° 2 (For example, -CO 2 NH 2 ) optionally replaced by C 1-6 In some embodiments, R 5 is an arbitrarily substituted C 1-6 Alkyl (e.g., halogen, -OR, -CN, -N(R)C(O)R, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, R 5 is one or more halogens, -OH, and -CO 2 NH 2C optionally substituted with 1-6 It is an alkyl.

[0111] In some embodiments of any of the formulas described herein, each R 5 are independently oxo, -CN, fluoro, chloro, -NH 2 , -N(CH 3 ) 2 , -OCH 3 , -C(O)CH 3 , -C(O)N(CH 3 ) 2 , -C(O)N(H)CH 3 , -CH 2 C(O)N(H)CH 3 , -CH 2 C(O)N(CH 3 ) 2 , -C(O)N(H)CH 2 CH 2 N(CH 3 ) 2 , -CO 2 NH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 N(H)CH 3 , -N=S(O)(CH 3 ) 2 , -P(O)(CH 3 ) 2 , -CH 3 , -CH 2 F, -CHF 2 , -CH 2 CHF 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 C(CH 3 ) 2 OH, -C(CH 3 ) 2 CH 2 OH, -C(CH 3 ) 2 OH, -C(CH 3 )2 NH 2 、-C(CH 3 ) 2 CN、-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 3 ) 2 、-CH 2 C(CH 3 ) 2 NH 2 、-CH 2 N(H)C(O)CH 3 、-OCH 2 CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 3 ) 2 、-C(O)N(CH 3 ) 2 、-CH 2 C(O)NH 2 、-CH 2 C(O)N(H)(CH 3 )、-CH 2 C(O)N(CH 3 ) 2 、-CH(CH 3 ) 2 、-CH(CF 3 )N(H)CH 3 、-CH(CF 3 )N(CH 3 ) 2 、-C(O)N(H)CH 3 、-C(O)N(H)CH 2 CHF 2 、-OCH 2 CH 2 N(CH 3 ) 2 、-C(O)N(H)CH 2 CH 2 N(CH 3 ) 2 、-C(O)N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 、 [ka] Cyclopropane, cyclobutane, [ka] In some embodiments, each R 5 are independently oxo, -CN, fluoro, chloro, -NH 2 , -N(CH 3 ) 2 , -OCH 3 , -C(O)CH 3 , -C(O)N(CH 3 ) 2 , -C(O)N(H)CH 3 , -CH 2 C(O)N(H)CH 3 , -CH 2 C(O)N(CH 3 ) 2 , -C(O)N(H)CH 2 CH 2 N(CH 3 ) 2 , -CO 2 NH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 N(H)CH 3 , -N=S(O)(CH 3 ) 2 , -P(O)(CH 3 ) 2 , -CH 3 , -CH 2 F, -CHF 2 , -CH 2 CHF 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 C(CH 3 ) 2 OH, -C(CH 3 ) 2 CH 2OH, -C(CH 3 ) 2 OH, -C(CH 3 ) 2 NH 2 , -C(CH 3 ) 2 CN, -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 NH 2 , -OCH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(O)NH 2 , -CH(CH 3 ) 2 , -CH(CF 3 )N(H)CH 3 , and -CH(CF 3 )N(CH 3 ) 2 is selected from.

[0112] In some embodiments of any of the formulas described herein, each R 5 are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -(CH 2 ) x C(O)Cy, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -N=S(O)(R) 2 , -SO 2 N(R) 2 , -P(O)(R) 2 , -(CH 2 ) xCy, -O(CH 2 ) x Cy, and C 1-6 aliphatic, in which case C 1-6 Aliphatic is unsubstituted or contains one or more halogens, -CN, -N(R)C(O)R, -N(R) 2 In some embodiments, each R 5 are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy, and C 1-6 aliphatic, in which case C 1-6 An aliphatic is unsubstituted or substituted with one or more halogens and -OR. In some embodiments, each R 5’ are independently -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy and optionally substituted C 1-6 Aliphatic (e.g., halogen, -OR, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, each R 5’ are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2, -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy and optionally substituted C 1-6 Alkyl (e.g., halogen, -OR, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, each R 5’ are independently oxo, =NH, -OR, -N(R) 2 , and optionally substituted C 1-6 Aliphatic (e.g., halogen, -OR, -C(O)NR 2 , and -N(R) 2 C substituted with one or more substituents selected from 1-6 In some embodiments, each R 5’ are independently oxo, =NH, halogen, -OR, -N(R) 2 , and C 1-6 aliphatic, in which case C 1-6 The aliphatic group is unsubstituted or contains one or more halogens, -N(R) 2 In some embodiments, each R 5’ are independently oxo, =NH, -OH, -NH 2 , -N(C 1-4 Alkyl) 2 and C optionally substituted with one or more -OR° (e.g., -OH). 1-6 is selected from alkyl.

[0113] In some embodiments of any of the formulas described herein, R 5’ is oxo. In some embodiments, R 5’ is ═NH. In some embodiments, R 5’ is -CN. In some embodiments, R 5’ is halogen (e.g., fluoro or chloro). In some embodiments, R5’ is fluoro. In some embodiments, R 5’ is -OR (e.g., -OH or -OCH 3 In some embodiments, R 5’ HA-N(R) 2 In some embodiments, R 5’ Ha-NH 2 In some embodiments, R 5’ -N(C 1-4 Alkyl) 2 In some embodiments, R 5’ In some embodiments, R 5’ is -C(O)R. In some embodiments, R 5’ is -N(R)C(O)R. In some embodiments, R 5’ Ha-(CH 2 ) x C(O)N(R) 2 In some embodiments, R 5’ -C(O)N(R) 2 In some embodiments, R 5’ is -C(O)N(R)(CH 2 ) x In some embodiments, R 5’ Ha-(CH 2 ) x C(O)Cy. In some embodiments, R 5’ is -OC(O)R. In some embodiments, R 5’ is -C(O)OR. In some embodiments, R 5’ -SO 2 R. In some embodiments, R 5’ -N(R)SO 2 R. In some embodiments, R 5’ -N=S(O)(R) 2 In some embodiments, R 5’ -SO 2 N(R) 2 In some embodiments, R 5’ HA-P(O)R 2 In some embodiments, R 5’Ha-(CH 2 ) x In some embodiments, R 5 Ha-(CH 2 ) x Cy, where Cy is a 3-6 membered carbocyclic ring optionally substituted with one or more halogens. 5 Ha-(CH 2 ) x Cy is a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5 Ha-(CH 2 ) x Cy and x is 0. In some embodiments, R 5 Ha-(CH 2 ) x Cy, where x is 0 and Cy is a 3-6 membered carbocyclic ring optionally substituted with one or more halogens. 5 Ha-(CH 2 ) x Cy, x is 0, and Cy is a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5’ -O(CH 2 ) x In some embodiments, R 5’ is an arbitrarily substituted C 1-6 In some embodiments, R 5’ is C optionally substituted with one or more -OR° (e.g., -OH); 1-6 In some embodiments, R 5’ is one or more halogens (e.g., F), -OH, or -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, R 5’ is an arbitrarily substituted C 1-6 In some embodiments, R 5’ is -CH 2 CH 2 C optionally substituted with one or more -OH, e.g., OH1-6 In some embodiments, R 5’ is one or more halogens (e.g., F), -OH, or -O(C 1-4 C optionally substituted with alkyl 1-6 In some embodiments, R 5’ is the unsubstituted C 1-6 In some embodiments, R 5’ is the unsubstituted C 1-6 In some embodiments, R 5’ is methyl, ethyl, or isopropyl.

[0114] In some embodiments of any of the formulas described herein, each R 5’ are independently oxo, =NH, -OH, -OCH 3 , -NH 2 , -N(CH 3 ) 2 , fluoro, cyclopropyl, -CH 3 , -CD 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , and -CH(CH 3 ) 2 In some embodiments, each R 5’ are independently oxo, =NH, -OH, -NH 2 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 2 OH, and -CH(CH 3 ) 2 is selected from.

[0115] In some embodiments of any formula described herein, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0116] In some embodiments of any formula described herein, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.

[0117] In some embodiments of any of the formulas described herein, Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D is fused to Ring F.

[0118] In some embodiments of any formula described herein, ring D is not fused to ring F. In some embodiments, ring D is fused to ring F. In some embodiments, when ring D is fused to ring F, q is 0.

[0119] In some embodiments of any of the formulas described herein, Ring D is phenyl.

[0120] In some embodiments of any formula described herein, ring D is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a pyrazole, imidazole, triazole, oxazole, or thiazole. In some embodiments, ring D is a 6 membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, ring D is a pyridine, pyridone, pyridazinone, or pyrazinone.

[0121] In some embodiments of any of the formulas described herein, ring D is not fused to ring F and has r R 2 and q R 1 Ring D substituted with [ka] is selected from.

[0122] In some embodiments of any of the formulas described herein, ring F is selected from phenyl, a 5-6 membered saturated or partially unsaturated carbocycle, a 5-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring F is selected from u -LW and y R 2’ In some embodiments, ring F is selected from phenyl, a 5-6 membered saturated or partially unsaturated carbocycle, a 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW and.

[0123] In some embodiments of any of the formulas described herein, ring F is selected from u -LW and y R2’ In some embodiments, ring F is phenyl substituted with u -LW.

[0124] In some embodiments of any of the formulas described herein, ring F is selected from u -LW and y R 2’ In some embodiments, ring F is a 5-6 membered carbocycle substituted with u -LW. In some embodiments, ring F is a 5-6 membered saturated or partially unsaturated carbocycle substituted with u -LW. In some embodiments, ring F is a 5 membered carbocycle substituted with u -LW. In some embodiments, ring F is cyclopentane substituted with u -LW. In some embodiments, ring F is a 6 membered carbocycle substituted with u -LW.

[0125] In some embodiments of any of the formulas described herein, ring F is a 5-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is selected from u -LW and y -R. 2’ In some embodiments, ring F is a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW. In some embodiments, ring F is a 5-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW and y R. 2’In some embodiments, ring F is a 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW. In some embodiments, ring F is a 5 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW. In some embodiments, ring F is pyrrolidine substituted with u -LW. In some embodiments, ring F is a 6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW and y R. 2’ In some embodiments, ring F is a 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW. In some embodiments, ring F is piperidine or piperazine, each of which is u -LW and y R. 2’ In some embodiments, ring F is piperidine or piperazine, each substituted with u -LW.

[0126] In some embodiments of any of the formulas described herein, ring F is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is selected from u -LW and y -R. 2’ In some embodiments, ring F is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW. In some embodiments, ring F is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW. In some embodiments, ring F is pyrrole substituted with u -LW. In some embodiments, ring F is a 6 membered heteroaryl ring having 1-3 nitrogen atoms substituted with u -LW.

[0127] In some embodiments of any formula described herein, u is 0. In some embodiments, u is 1. In some embodiments, when u is 1, q is 0.

[0128] In some embodiments of any of the formulas described herein, ring D is fused to ring F, and q is 0; [ka] teeth, [ka] is selected from.

[0129] In some embodiments of any of the formulas described herein, ring D is fused to ring F, and q is 0; [ka] teeth, [ka] is selected from.

[0130] In some embodiments of any of the formulas described herein, ring D is fused to ring F, and has u -LW and y R 2’ Ring F substituted with [ka] [ka] is selected from.

[0131] In some embodiments of any of the formulas described herein, ring D is fused to ring F, and q is 0; [ka] teeth, [ka] [ka] is selected from.

[0132] In some embodiments of any of the formulas described herein, R 1 is -LW or ring D'. In some embodiments, R 1 is a divalent C substituted with ring D' or ring D' 1-6 In some embodiments, R 1 is ring D' or -CH 2 - Ring D'. In some embodiments, R 1 is -LW. In some embodiments, R 1 is ring D'. In some embodiments, R 1 is a divalent C substituted with ring D' 1-6 In some embodiments, R 1 Ha-CH 2 - Ring D'.

[0133] In some embodiments of any of the formulas described herein, R 1 is -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 NH 2 , -CH 2 OH, -OCH(CH 3 ) 2 , [ka] is selected from.

[0134] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-6 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2-, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -. In some embodiments, each L is independently a divalent linear or branched C 1-4 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 - is substituted with a group selected from

[0135] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 It is an aliphatic chain, and one or two methylene units of the aliphatic chain are independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -. In some embodiments, each L is independently a divalent linear or branched C 1-6 It is an aliphatic chain, and one or two methylene units of the aliphatic chain are independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -. In some embodiments, each L is independently a divalent linear or branched C 1-4It is an aliphatic chain, and one or two methylene units of the aliphatic chain are independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 - is substituted with a group selected from

[0136] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 is an aliphatic chain, and one or two methylene units of the aliphatic chain are independently replaced with a group selected from -N(R)-, -O-, -C(O)-, -C(O)N(R)-, and -N(R)C(O)-. In some embodiments, each L is independently a divalent linear or branched C 1-6 is an aliphatic chain, and one or two methylene units of the aliphatic chain are independently replaced with a group selected from -N(R)-, -O-, -C(O)-, -C(O)N(R)-, and -N(R)C(O)-. In some embodiments, each L is independently a divalent linear or branched C 1-4 It is an aliphatic chain, wherein one or two methylene units of the aliphatic chain are independently replaced with a group selected from -N(R)-, -O-, -C(O)-, -C(O)N(R)-, and -N(R)C(O)-.

[0137] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 is an alkyl chain, and one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2-. In some embodiments, each L is independently a divalent linear or branched C 1-6 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -. In some embodiments, each L is independently a divalent linear or branched C 1-4 is an alkyl chain, and one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 - is substituted with a group selected from

[0138] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 In some embodiments, each L is independently a divalent linear or branched C 1-6 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X)2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 In some embodiments, each L is independently a divalent linear or branched C 1-4 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 - is substituted with a group selected from

[0139] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 In some embodiments, each L is independently a divalent linear or branched C 1-6 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 In some embodiments, each L is independently a divalent linear or branched C1-4 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 - is substituted with a group selected from

[0140] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 In some embodiments, each L is independently a divalent linear or branched C 1-6 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 In some embodiments, each L is independently a divalent linear or branched C 1-4 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 - is substituted with a group selected from

[0141] In some embodiments of any of the formulas described herein, each L is independently a divalent linear or branched C 1-8 is an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced with a group selected from -N(R)-, -O-, -C(O)-, -C(O)N(R)-, and -N(R)C(O)-. In some embodiments, each L is independently a divalent linear or branched C alkyl group having one double or triple bond. 1-6 is an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced with a group selected from -N(R)-, -O-, -C(O)-, -C(O)N(R)-, and -N(R)C(O)-. In some embodiments, each L is independently a divalent linear or branched C alkyl group having one double or triple bond. 1-4 is an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently replaced with a group selected from -N(R)-, -O-, -C(O)-, -C(O)N(R)-, and -N(R)C(O)-.

[0142] In some embodiments of any of the formulas described herein, each L is independently -N(R)C(O)CH 2 CH 2 -, -N(R)C(O)CH(CH 3 )CH 2 -, -OCH(CH 3 )CH 2 -, -C(O)-, -C(O)CClH-, -C(O)CClF-, -C(O)CH 2 CH 2 -, -C(O)CH(OH)CH(OH)-, -C(O)N(R)CH(CH 3 )CH 2 -, -C(O)N(R)CH 2 CH(CH 3)CH 2 -, -CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(O)-, -CH 2 C(O)N(R)C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(O)N(R)C(CH 3 ) 2 CH 2 -, -CH 2 N(R)-, -CH 2 N(R)C(O)-, -CH 2 N(R)C(O)CH 2 CH 2 -, -CH 2 N(R)C(O)CH(CH 3 )CH 2 -, -CH 2 N(R)C(O)C(CH 3 ) 2 CH 2 -, -CH 2 N(R)C(O)CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 N(R)C(O)CH(CH 3 )CH 2 - and -CH 2 In some embodiments, each L is independently selected from -N(H)C(O)CH 2 CH 2 -, -N(H)C(O)CH(CH 3 )CH 2 -, -OCH(CH 3 )CH 2 -, -C(O)-, -C(O)CClH-, -C(O)CClF- -C(O)CH 2 CH 2 -, -C(O)CH(OH)CH(OH)-, -C(O)N(H)CH(CH 3)CH 2 -, -C(O)N(H)CH 2 CH(CH 3 )CH 2 -, -CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(O)-, -CH 2 C(O)N(H)C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(O)N(H)C(CH 3 ) 2 CH 2 -, -CH 2 N(H)-, -CH 2 N(H)C(O)-, -CH 2 N(H)C(O)CH 2 CH 2 -, -CH 2 N(H)C(O)CH(CH 3 )CH 2 -, -CH 2 N(H)C(O)C(CH 3 ) 2 CH 2 -, -CH 2 N(H)C(O)CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 N(H)C(O)CH(CH 3 )CH 2 - and -CH 2 O-.

[0143] In some embodiments of any of the formulas described herein, each L is independently -N(R)C(O)CH 2 CH 2 -, -N(R)C(O)CH(CH 3 )CH 2 -, -OCH(CH 3 )CH 2-, -C(O)-, -C(O)CH 2 CH 2 -, -C(O)CH(OH)CH(OH)-, -C(O)N(R)CH(CH 3 )CH 2 -, -C(O)N(R)CH 2 CH(CH 3 )CH 2 -, -CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(O)-, -CH 2 C(O)N(R)C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(O)N(R)C(CH 3 ) 2 CH 2 -, -CH 2 N(R)-, -CH 2 N(R)C(O)-, -CH 2 N(R)C(O)CH 2 CH 2 -, -CH 2 N(R)C(O)CH(CH 3 )CH 2 -, -CH 2 N(R)C(O)C(CH 3 ) 2 CH 2 -, -CH 2 N(R)C(O)CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 N(R)C(O)CH(CH 3 )CH 2 - and -CH 2 In some embodiments, each L is independently selected from -N(H)C(O)CH 2 CH 2 -, -N(H)C(O)CH(CH 3 )CH 2-, -OCH(CH 3 )CH 2 -, -C(O)-, -C(O)CH 2 CH 2 -, -C(O)CH(OH)CH(OH)-, -C(O)N(H)CH(CH 3 )CH 2 -, -C(O)N(H)CH 2 CH(CH 3 )CH 2 -, -CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(O)-, -CH 2 C(O)N(H)C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(O)N(H)C(CH 3 ) 2 CH 2 -, -CH 2 N(H)-, -CH 2 N(H)C(O)-, -CH 2 N(H)C(O)CH 2 CH 2 -, -CH 2 N(H)C(O)CH(CH 3 )CH 2 -, -CH 2 N(H)C(O)C(CH 3 ) 2 CH 2 -, -CH 2 N(H)C(O)CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 N(H)C(O)CH(CH 3 )CH 2 -, and -CH 2 O- are selected from.

[0144] In some embodiments of any of the formulas described herein, each L is independently -C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH 2 )-, -C(O)C(=CHCH 3 )-, -C(O)CH=CH-CH 2 -, -C(O)CH=CHCH 2 OCH 2 -, -C(O)CH=CHCH 2 N(R)-, -CH 2 N(R)C(O)CH=CH-, -CH 2 CH 2 N(R)C(O)CH=CH-, -C(O)C≡C-, -C(O)C≡CCH 2 - and -SO 2 In some embodiments, each L is independently selected from -C(O)CH=CH-, -NHC(O)CH=CH-, -C(O)C(=CH 2 )-, -C(O)C(=CHCH 3 )-, -C(O)CH=CH-CH 2 -, -C(O)CH=CHCH 2 OCH 2 -, -C(O)CH=CHCH 2 N(CH 3 )-, -CH 2 NHC(O)CH=CH-, -CH 2 CH 2 NHC(O)CH=CH-, -C(O)C≡C-, -C(O)C≡CCH 2 - and -SO 2 In some embodiments, each L is independently -C(O)CH=CH-, -C(O)CF=CH-, -NHC(O)CF=CH-, or -NHC(O)CH=CH-. In some embodiments, each L is independently -C(O)CH=CH- or -NHC(O)CH=CH-.

[0145] In some embodiments of any of the formulas described herein, each L is independently selected from -C(O)CClH-, -C(O)CClF-, -C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH 2)-, -C(O)C(=CHCH 3 )-, -C(O)CH=CH-CH 2 -, -C(O)CH=CHCH 2 OCH 2 -, -C(O)CH=CHCH 2 N(R)-, -CH 2 N(R)C(O)CH=CH-, -CH 2 CH 2 N(R)C(O)CH=CH- and -SO 2 In some embodiments, each L is independently selected from -C(O)CClF-, -C(O)CH=CH-, -NHC(O)CH=CH-, -C(O)C(=CH 2 )-, -C(O)C(=CHCH 3 )-, -C(O)CH=CH-CH 2 -, -C(O)CH=CHCH 2 OCH 2 -, -C(O)CH=CHCH 2 N(CH 3 )-, -CH 2 NHC(O)CH=CH-, -CH 2 CH 2 NHC(O)CH=CH-, -C(O)C≡C-, -C(O)C≡CCH 2 - and -SO 2 In some embodiments, each L is independently -C(O)CH=CH- or -NHC(O)CH=CH-.

[0146] In some embodiments of any of the formulas described herein, each W is independently hydrogen, halogen, -CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each W is independently hydrogen, halogen, or an optionally substituted 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each W is independently hydrogen, halogen, or -CN. In some embodiments, W is hydrogen. In some embodiments, W is halogen (e.g., fluoro or chloro). In some embodiments, W is fluoro. In some embodiments, W is chloro. In some embodiments, W is -CN. In some embodiments, W is an optionally substituted 3-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, W is an optionally substituted group selected from phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered carbocycle, and a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, W is an optionally substituted 3-6 membered carbocycle. In some embodiments, W is cyclopentane. In some embodiments, W is an optionally substituted 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, W is pyrrolidine.

[0147] In some embodiments of any of the formulas described herein, each X is independently halogen or -CN. In some embodiments, each X is independently halogen (e.g., chloro or fluoro). In some embodiments, each X is independently chloro. In some embodiments, each X is independently fluoro. In some embodiments, each X is independently -CN. In some embodiments, each X is independently -OR (e.g., -OH).

[0148] In some embodiments of any of the formulas described herein, each -LW is independently -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 OH, -CH 2 NH 2 , -OCH(CH 3 ) 2 , -CN, [ka] is selected from.

[0149] In some embodiments of any of the formulas described herein, each -LW is independently -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 OH, -CH 2 NH 2 , -OCH(CH 3 ) 2 , -CN, -C(O)CH=CH 2 , -C(O)CF=CH 2 , -NHC(O)CF=CH 2 and -NHC(O)CH=CH 2 is selected from.

[0150] In some embodiments of any of the formulas described herein, each -LW is independently -C(O)CH=CH 2 and -NHC(O)CH=CH 2 In some embodiments, -LW is independently selected from -C(O)CH=CH 2 , -C(O)CF=CH 2 , -NHC(O)CF=CH 2 and -NHC(O)CH=CH 2 In some embodiments, each -LW is selected from -C(O)CH=CH 2 In some embodiments, each -LW is -CN.

[0151] In some embodiments of any of the formulas described herein, each ring D' is independently a 4-6 membered saturated or partially unsaturated carbocycle or a 4-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW.

[0152] In some embodiments of any formula described herein, ring D' is a 4-6 membered carbocyclic ring substituted with t -LWs. In some embodiments, ring D' is a 4-6 membered saturated or partially unsaturated carbocyclic ring substituted with t -LWs. In some embodiments, ring D' is a 4-6 membered cycloalkyl ring substituted with t -LWs. In some embodiments, ring D' is a 4 membered carbocyclic ring substituted with t -LWs. In some embodiments, ring D' is a cyclobutane substituted with t -LWs. In some embodiments, ring D' is a 5 membered carbocyclic ring substituted with t -LWs. In some embodiments, ring D' is a 6 membered carbocyclic ring substituted with t -LWs.

[0153] In some embodiments of any formula described herein, ring D' is a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW. In some embodiments, ring D' is a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW. In some embodiments, ring D' is a 4-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW. In some embodiments, ring D' is a 4 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW. In some embodiments, ring D' is an azetidine substituted with t -LW. In some embodiments, ring D' is a 5-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW. In some embodiments, ring D' is pyrrolidine substituted with t -LW. In some embodiments, ring D' is a 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW. In some embodiments, ring D' is piperidine substituted with t -LW.

[0154] In some embodiments of any of the formulas described herein, ring D' substituted with t -LW is [ka] is selected from.

[0155] In some embodiments of any of the formulas described herein, R 1 is a ring D', or a bivalent C substituted with a ring D' 1-6 If it is an aliphatic chain, r R 2 Ring D substituted with [ka] is selected from.

[0156] In some embodiments of any of the formulas described herein, ring D is selected from the group consisting of one R 1 is replaced by R 1 is a ring D', [ka] teeth, [ka] [ka] is selected from.

[0157] In some embodiments of any formula described herein, q is 0. In some embodiments, q is 1.

[0158] In some embodiments of any formula described herein, t is 0 or 1. In some embodiments, t is 1 or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0159] In some embodiments of any of the formulas described herein, each R 2 are independently halogen, -CN, -OR, and C 1-6 In some embodiments, each R 2 are independently oxo, halogen, -CN, -O(C 1-4 alkyl), and C 1-6 In some embodiments, R 2 is oxo. In some embodiments, R 2 is halogen (e.g., fluoro or chloro). In some embodiments, R 2 is -CN. In some embodiments, R 2 In some embodiments, R 2is -O(C 1-4 In some embodiments, R 2 is C 1-6 In some embodiments, each R 2 are independently oxo, fluoro, chloro, -CN, -OCH 3 , -OCH(CH 3 ) 2 , -CH 3 , -CH(CH 3 ) 2 , and -CH 2 C(CH 3 ) 3 is selected from.

[0160] In some embodiments of any formula described herein, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, when q is 1, r is 0 or 1. In some embodiments, when q is 0, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.

[0161] In some embodiments of any of the formulas described herein, each R 2’ are independently halogen, -CN, -OR, and C 1-6 In some embodiments, R 2’ is oxo. In some embodiments, R 2’ is halogen (e.g., fluoro or chloro). In some embodiments, R 2’ is -CN. In some embodiments, R 2’ is -OR. In some embodiments, R 2’ is C 1-6 Alkyl (eg, methyl).

[0162] In some embodiments of any formula described herein, y is 0 or 1. In some embodiments, y is 1 or 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0163] In some embodiments of any of the formulas described herein, each Cy is independently a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated carbocycle, or a 4-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy is selected from 0-2 R 6 In some embodiments, Cy is substituted with 0 to 1 R 6 In some embodiments, Cy is substituted with 1 to 2 R 6 In some embodiments, Cy is substituted with R 6 In some embodiments, Cy is not substituted with one R 6 In some embodiments, Cy is substituted with two R 6 has been replaced with.

[0164] In some embodiments of any of the formulas described herein, Cy is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy is selected from 0-2 R 6 In some embodiments, Cy is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Cy is substituted with 0-2 R 6 In some embodiments, Cy is a 6-membered heteroaryl ring having 1-3 nitrogen atoms and Cy is substituted with 0-2 R 6 In some embodiments, Cy is substituted with 0 to 2 R 6 is a pyridine substituted with

[0165] In some embodiments of any of the formulas described herein, Cy is selected from 0 to 2 R 6 In some embodiments, Cy is a 3-6 membered carbocyclic ring substituted with 0-2 R 6 In some embodiments, Cy is a 3-6 membered saturated or partially unsaturated carbocyclic ring substituted with 0-2 R 6 In some embodiments, Cy is a 3-6 membered cycloalkyl ring substituted with 0-2 R 6 In some embodiments, Cy is a 3-membered carbocyclic ring (e.g., a cyclopropyl ring) substituted with 0 to 2 R 6 In some embodiments, Cy is a 4-membered carbocyclic ring substituted with 0-2 R 6 In some embodiments, Cy is a 5-membered carbocyclic ring substituted with 0-2 R 6 is a 6-membered carbocyclic ring substituted with

[0166] In some embodiments of any formula described herein, Cy is a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a 4 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an azetidine. In some embodiments, Cy is a 5 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is a pyrrolidone. In some embodiments, Cy is a 6 membered heterocycle having 1-2 nitrogen atoms. In some embodiments, Cy is a piperidinone or piperazine.

[0167] In some embodiments of any of the formulas described herein, 0 to 2 R 6 Cy replaced by [ka] is selected from.

[0168] In some embodiments of any of the formulas described herein, each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 aliphatic; a 3-6 membered carbocyclic ring; phenyl; a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10 membered aryl ring; and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 In some embodiments, each R is selected from optionally substituted groups selected from aliphatic, 3-6 membered saturated or partially unsaturated carbocyclic rings, 3-6 membered saturated or partially unsaturated heterocyclic rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 10 membered aryl rings, and 9-10 membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 are independently -CN, halogen, -OR, -N(R) 2, -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 In some embodiments, each R is selected from an optionally substituted group selected from an aliphatic, a 3-6 membered carbocyclic ring, a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10 membered aryl ring, and a 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 are independently oxo, halogen, -OR, -N(R) 2 , -C(O)N(R) 2 , and optionally substituted C 1-6 In some embodiments, each R 6 are independently selected from oxo, halogen, and optionally substituted C 1-6 In some embodiments, each R 6 are independently selected from oxo, halogen, and optionally substituted C 1-6 In some embodiments, each R 6 are independently selected from halogen and optionally substituted C 1-6 In some embodiments, each R 6 are independently halogen and optionally substituted C 1-6 In some embodiments, R 6 is oxo. In some embodiments, R 6 is halogen (e.g., fluoro or chloro). In some embodiments, R 6 is fluoro. In some embodiments, R 6 is -OR (e.g., -OH). In some embodiments, R 6 is -N(R) 2 (For example, -N(C1-4 Alkyl) 2 or -NH 2 In some embodiments, R 6 -C(O)N(R) 2 In some embodiments, R 6 is an arbitrarily substituted C 1-6 In some embodiments, R 6 is an arbitrarily substituted C 1-6 In some embodiments, R 6 is C 1-6 Alkyl (eg, methyl).

[0169] In some embodiments of any formula described herein, each v is independently 0 or 1. In some embodiments, each v is independently 1 or 2. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2.

[0170] In some embodiments of any formula described herein, each x is independently 0 or 1. In some embodiments, each x is independently 1 or 2. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0171] In some embodiments of any of the formulas described herein, each R is independently hydrogen, C 1-6 aliphatic, C 1-6 haloaliphatic, 3-6 membered carbocyclic ring, 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 10 membered aryl ring, and 9-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or C 1-6In some embodiments, each R is independently selected from hydrogen, an optionally substituted C ... 1-6 In some embodiments, each R is independently selected from hydrogen, C optionally substituted with one or more halogens (e.g., fluoro), or an optionally substituted 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 alkyl, or nitrogen, oxygen, and sulfur; 1-6 In some embodiments, each R is independently hydrogen or an optionally substituted C 1-6 In some embodiments, each R is independently hydrogen or an optionally substituted C 1-6 In some embodiments, each R is independently hydrogen or C optionally substituted with one or more halogens (e.g., fluoro). 1-6 In some embodiments, R is an optionally substituted C alkyl. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is C 1-6 In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is C optionally substituted with one or more halogens (e.g., fluoro). 1-6 It is an alkyl.

[0172] Also provided herein are embodiments in which any embodiment described herein can be combined with any one or more of these embodiments, unless the combinations are mutually exclusive. As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other. For example, an embodiment in which two groups are bonded 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 in which one group is CH 2 The embodiment where is is mutually exclusive with the embodiment where the same group is NH.

[0173] In some embodiments of any of the preceding aspects, the compound is a compound in Table 1 or 2, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound in Table 1, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound in Table 1, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound in Table 2, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound in Table 2, or a salt (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof.

[0174] Also provided herein is a compound selected from Table 1 or 2, or any of the Examples set forth herein, or a salt thereof (e.g., a pharma- ceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the disclosure provides a compound selected from Table 1 or 2, or any of the Examples set forth herein, or a salt thereof (e.g., a pharma- ceutically acceptable salt).

[0175] Compounds of the present disclosure, for example compounds of the formulae shown in Tables 1 or 2, may be synthesized by one of the general routes outlined in Synthetic Examples 1-88, or by a variety of other methods generally known in the art.

[0176] Table 1 shows selected compounds of the present disclosure. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

[0177] In some embodiments, the disclosure provides a compound selected from the compounds included in Table 2, or a pharma- ceutically acceptable salt thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15]

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

Table 2-74

Table 2-75

Table 2-76

Table 2-77

Table 2-78

Table 2-79

Table 2-80

Table 2-81

Table 2-82

Table 2-83

Table 2-84

Table 2-85

Table 2-86

Table 2-87

Table 2-88

Table 2-89

Table 2-90

Table 2-91

Table 2-92

Table 2-93

Table 2-94

Table 2-95

Table 2-96

Table 2-97

Table 2-98

Table 2-99

Table 2-100

Table 2-101

Table 2-102

Table 2-103

Table 2-104

Table 2-105

Table 2-106

Table 2-107

Table 2-108

Table 2-109

Table 2-110

Table 2-111

Table 2-112

Table 2-113

Table 2-114

Table 2-115

Table 2-116

Table 2-117

Table 2-118

Table 2-119

Table 2-120

Table 2-121

Table 2-122

Table 2-123

Table 2-124

Table 2-125

Table 2-126

Table 2-127

Table 2-128

Table 2-129

Table 2-130

Table 2-131

Table 2-132

Table 2-133

Table 2-134

Table 2-135

Table 2-136

Table 2-137

Table 2-138

Table 2-139

Table 2-140

Table 2-141

Table 2-142

Table 2-143

Table 2-144

Table 2-145

Table 2-146

Table 2-147

Table 2-148

Table 2-149

Table 2-150

Table 2-151

Table 2-152

Table 2-153

Table 2-154

Table 2-155

Table 2-156

Table 2-157

Table 2-158

Table 2-159

Table 2-160

Table 2-161

Table 2-162

Table 2-163

Table 2-164

Table 2-165

Table 2-166

Table 2-167

Table 2-168

Table 2-169

Table 2-170

Table 2-171

Table 2-172

Table 2-173

Table 2-174

Table 2-175

Table 2-176

Table 2-177

Table 2-178

Table 2-179

Table 2-180

Table 2-181

Table 2-182

Table 2-183

Table 2-184

Table 2-185

Table 2-186

Table 2-187

Table 2-188

Table 2-189

Table 2-190

Table 2-191

Table 2-192

Table 2-193

Table 2-194

Table 2-195

Table 2-196

Table 2-197

Table 2-198

Table 2-199

Table 2-200

Table 2-201

Table 2-202

Table 2-203

Table 2-204

Table 2-205

Table 2-206

Table 2-207

Table 2-208

Table 2-209

Table 2-210

Table 2-211

Table 2-212

Table 2-213

Table 2-214

Table 2-215

Table 2-216

Table 2-217

Table 2-218

Table 2-219

Table 2-220

Table 2-221

Table 2-222

Table 2-223

Table 2-224

Table 2-225

Table 2-226

Table 2-227

Table 2-228

Table 2-229

Table 2-230

Table 2-231

Table 2-232

Table 2-233

Table 2-234

Table 2-235

Table 2-236

Table 2-237

Table 2-238

Table 2-239

Table 2-240

Table 2-241

Table 2-242

Table 2-243

Table 2-244

Table 2-245

Table 2-246

Table 2-247

Table 2-248

Table 2-249

Table 2-250

Table 2-251

Table 2-252

Table 2-253

Table 2-254

Table 2-255

Table 2-256

Table 2-257

Table 2-258

Table 2-259

Table 2-260

Table 2-261

Table 2-262

Table 2-263

Table 2-264

Table 2-265

Table 2-266

Table 2-267

Table 2-268

Table 2-269

Table 2-270

Table 2-271

Table 2-272

Table 2-273

Table 2-274

Table 2-275

Table 2-276

Table 2-277

Table 2-278

Table 2-279

Table 2-280

Table 2-281

Table 2-282

Table 2-283

Table 2-284

Table 2-285

Table 2-286

Table 2-287

Table 2-288

Table 2-289

Table 2-290

Table 2-291

Table 2-292

Table 2-293

Table 2-294

Table 2-295

Table 2-296

Table 2-297

Table 2-298

Table 2-299

Table 2-300

Table 2-301

Table 2-302

Table 2-303

Table 2-304

Table 2-305

Table 2-306

Table 2-307

Table 2-308

Table 2-309

Table 2-310

Table 2-311

Table 2-312

Table 2-313

Table 2-314

Table 2-315

Table 2-316

Table 2-317

Table 2-318

Table 2-319

Table 2-320

Table 2-321

Table 2-322

Table 2-323

Table 2-324

Table 2-325

Table 2-326

Table 2-327

Table 2-328

Table 2-329

Table 2-330

Table 2-331

Table 2-332

Table 2-333

Table 2-334

Table 2-335

Table 2-336

Table 2-337

Table 2-338

Table 2-339

Table 2-340

Table 2-341

Table 2-342

Table 2-343

Table 2-344

Table 2-345

Table 2-346

Table 2-347

Table 2-348

Table 2-349

Table 2-350

Table 2-351

Table 2-352

Table 2-353

Table 2-354

Table 2-355

Table 2-356

Table 2-357

Table 2-358

Table 2-359

Table 2-360

Table 2-361

Table 2-362

Table 2-363

Table 2-364

Table 2-365

Table 2-366

Table 2-367

Table 2-368

Table 2-369

Table 2-370

Table 2-371

Table 2-372

Table 2-373

Table 2-374

Table 2-375

Table 2-376

Table 2-377

Table 2-378

Table 2-379

Table 2-380

Table 2-381

Table 2-382

Table 2-383

Table 2-384

Table 2-385

Table 2-386

Table 2-387

Table 2-388

Table 2-389

Table 2-390

Table 2-391

Table 2-392

Table 2-393

Table 2-394

Table 2-395

Table 2-396

Table 2-397

Table 2-398

Table 2-399

Table 2-400

Table 2-401

Table 2-402

Table 2-403

Table 2-404

Table 2-405

Table 2-406

Table 2-407

Table 2-408

Table 2-409

Table 2-410

Table 2-411

Table 2-412

Table 2-413

Table 2-414

Table 2-415

Table 2-416

Table 2-417

[0178] In some embodiments, the provided compounds are provided and / or utilized in the form of salts (e.g., pharma- ceutically acceptable salts). Reference to a provided compound herein is understood to include reference to its salts unless otherwise stated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge et al. describe pharma- ceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Examples of pharma- ceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-phenylalanine salts, such as sodium phosphate, sodium lauryl sulfate, sodium phosphate ... + (C 1-4 Alkyl) 4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0179] It will be appreciated that the compounds described herein may be provided and / or utilized in any available form (e.g., salt form), and all such forms are contemplated by this disclosure. The disclosure also contemplates such forms as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers of the compounds provided herein.

[0180] Throughout this disclosure, unless otherwise indicated, references to compounds of formula I refer to compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, Ihi, Iii, IjI, Iki, Ia-ii, Ib-ii, Ic-ii, Id-ii, Ie-ii, If-ii, Ig-i i, Ih-ii, Ii-ii, Ij-ii, Ik-ii, Ia-ii', Ib-ii', Ic-ii', Id-ii', Ie-ii', If-ii', Ig-ii', I h-ii', Ii-ii', Ij-ii', Ik-ii', Ia-iii, Ib-iii, Ic-iii, Id-iii, Ie-iii, If-iii, Ig-iii, Ih-iii, Ii-iii, Ij-iii, Ik-iii, Ia-iv, Ib-iv, Ic-iv, Id-iv, Ie-iv, If-iv, Ig-iv, Ih-iv, Ii-iv, Ij-iv, Ik-iv, Iav, Ibv, Icv, Idv, Iev, Ifv, Igv, Ihv, Iiv, Ijv, Ikv, Ia-v', Ib-v', Ic -v', Id-v', Ie-v', If-v', Ig-v', Ih-v', Ii-v', Ij-v', Ik-v', Il, Im, In, Ip, Iq, Ir, IA, IA1 , IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, and IF1, as well as species of such formulas disclosed herein.

[0181] In some embodiments, provided compounds are prepared as described herein, for example, according to any one of Synthetic Examples 1-88.

[0182] composition The present disclosure also provides compositions that include a compound provided herein, together with one or more other ingredients. In some embodiments, provided compositions contain a compound described herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Iai , Ibi, Ici, Idi, Iei, Ifi, Igi, Ihi, Iii, IjI, Iki, Ia-ii, Ib-ii, Ic-ii, Id-ii, Ie-ii, If-ii, Ig-ii, Ih-ii, Ii-ii, Ij-ii, Ik-ii, Ia-ii', Ib-ii', Ic-ii', Id-ii', Ie-ii', If-ii', Ig-ii ', Ih-ii', Ii-ii', Ij-ii', Ik-ii', Ia-iii, Ib-iii, Ic-iii, Id-iii, Ie-iii, If-iii, Ig-iii , Ih-iii, Ii-iii, Ij-iii, Ik-iii, Ia-iv, Ib-iv, Ic-iv, Id-iv, Ie-iv, If-iv, Ig-iv, Ih-iv, Ii-iv, Ij-iv, Ik-iv, Iav, Ibv, Icv, Idv, Iev, Ifv, Igv, Ihv, Iiv, Ijv, Ikv, Ia-v', Ib-v', Ic-v The pharmaceutical composition comprises and / or delivers a compound selected from Table 1 or Table 2, wherein the compound is a compound of Table 1, Table 2, or a compound selected from Table 1 or Table 2.

[0183] In some embodiments, the provided compositions contain a compound provided herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, Ihi, Iii, IjI, Iki, Ia-ii, Ib-ii, Ic-ii, Id-ii, Ie-ii, If-ii, Ig-ii , Ih-ii, Ii-ii, Ij-ii, Ik-ii, Ia-ii', Ib-ii', Ic-ii', Id-ii', Ie-ii', If-ii', Ig-ii', Ih-ii', Ii-ii', Ij-ii', Ik-ii', Ia-iii, Ib-iii, Ic-iii, Id-iii, Ie-iii, If-iii, Ig-iii, Ih-iii, Ii-i ii, Ij-iii, Ik-iii, Ia-iv, Ib-iv, Ic-iv, Id-iv, Ie-iv, If-iv, Ig-iv, Ih-iv, Ii-iv, Ij-iv, Ik- iv, Iav, Ibv, Icv, Idv, Iev, Ifv, Igv, Ihv, Iiv, Ijv, Ikv, Ia-v', Ib-v', Ic-v', Id-v', Ie-v', If-v The pharmaceutical composition is a pharmaceutical composition that contains and / or delivers a compound of the formula (Ig-v', Ih-v', Ii-v', Ij-v', Ik-v', Il, Im, In, Ip, Iq, Ir, IA, IA1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, or IF1, or a compound selected from Table 1 or Table 2), and further comprises a pharma- ceutical acceptable carrier. Pharmaceutical compositions typically contain an amount of an active agent (e.g., a compound described herein) effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, the pharmaceutical composition provided comprises a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adhesives, and / or anti-static agents, and the like.The pharmaceutical compositions provided may be in a variety of forms, including oral dosage forms, topical creams, topical patches, iontophoretic forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, depot forms, and injectable and infusible solutions. Methods for preparing pharmaceutical compositions are well known in the art.

[0184] In some embodiments, the provided compounds are formulated in unit dosage forms for ease of administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically separate unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, the unit dosage form contains an entire single dose of the agent. In some embodiments, multiple unit dosage forms are administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is necessary or expected to be necessary to achieve an intended effect. The unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., tablet, capsule, etc.) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents.

[0185] The provided compositions may be administered using any amount and any dosage form effective to treat or lessen the severity of any disease or disorder described herein. use

[0186] The present disclosure describes the compounds and compositions described herein (e.g., Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Iai, Ibi, Ici, I di, Iei, Ifi, Igi, Ihi, Iii, IjI, Iki, Ia-ii, Ib-ii, Ic-ii, Id-ii, Ie-ii, If-ii, Ig-ii, Ih -ii, Ii-ii, Ij-ii, Ik-ii, Ia-ii', Ib-ii', Ic-ii', Id-ii', Ie-ii', If-ii', Ig-ii', Ih-i i', Ii-ii', Ij-ii', Ik-ii', Ia-iii, Ib-iii, Ic-iii, Id-iii, Ie-iii, If-iii, Ig-iii, Ih -iii, Ii-iii, Ij-iii, Ik-iii, Ia-iv, Ib-iv, Ic-iv, Id-iv, Ie-iv, If-iv, Ig-iv, Ih-iv, I i-iv, Ij-iv, Ik-iv, Iav, Ibv, Icv, Idv, Iev, Ifv, Igv, Ihv, Iiv, Ijv, Ikv, Ia-v', Ib-v', Ic -v', Id-v', Ie-v', If-v', Ig-v', Ih-v', Ii-v', Ij-v', Ik-v', Il, Im, In, Ip, Iq, Ir, IA, IA 1, IB, IB1, IC, IC1, ID, ID1, IE, IE1, IF, or IF1, or a compound selected from Table 1 or Table 2). In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapeutic agents for use in treating, ameliorating, slowing the progression of, ameliorating or eliminating symptoms, and / or suppressing a disease or disorder as described herein). In some embodiments, provided compounds and compositions are useful in medicine. In some embodiments, provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0187] In some embodiments, provided compounds are useful for interfering with (e.g., inhibiting and / or preventing and / or modulating) 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 a PI3K alpha protein. In some embodiments, the disclosure provides a method of disrupting, interrupting, and / or preventing 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 a PI3K alpha protein in a subject comprising administering a provided compound or composition. In some embodiments, the disclosure provides a method 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 PI3K alpha protein in a biological sample, comprising administering a provided compound or composition. In some embodiments, the disclosure provides a method 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 PI3K alpha protein with a provided compound or composition. In some such embodiments, the small GTPase can bind to the RAS binding domain (RBD) of the PI3K alpha protein. In some embodiments, the small GTPase is selected from Rac1, CDC42, and a RAS protein. In some embodiments, the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, the RAS protein is a wild-type RAS protein. In some embodiments, the RAS protein is a mutant RAS protein.In some embodiments, the RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation at codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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. In some embodiments, the NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, the PI3K alpha protein is a wild-type PI3K alpha protein. In some embodiments, the PI3K alpha protein is a mutant PI3K alpha protein. In some embodiments, the PI3K alpha protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the PI3K alpha protein comprises an E542K, an E545K, an H1047R, and / or an H1047L mutation.

[0188] In some embodiments, the disclosure provides a method comprising administering a compound or composition provided to a subject in need thereof. In some such embodiments, the subject has a disease, disorder, or condition associated with the interaction of a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) with a PI3Kα protein. In some embodiments, the subject has a disease, disorder, or condition that is ameliorated by disrupting the interaction of a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) with a PI3Kα protein. In some embodiments, the small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) can bind to the RAS binding domain (RBD) of the PI3Kα protein. In some embodiments, the small GTPase is selected from Rac1, CDC42, and RAS proteins. In some embodiments, the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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. In some embodiments, the NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation.In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, the RAS protein is a wild-type RAS protein. In some embodiments, the PI3K alpha protein is a wild-type PI3K alpha protein. In some embodiments, the PI3K alpha protein is a mutant PI3K alpha protein. In some embodiments, the PI3K alpha protein comprises an N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the PI3K alpha protein comprises an E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the subject has cancer or other indications described herein. In some embodiments, the subject has previously undergone a cancer treatment regimen. In some embodiments, the subject has previously been in remission from cancer.

[0189] In some embodiments, provided methods include 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.

[0190] In some embodiments, the disclosure provides a method of treating cancer comprising administering to a subject a provided compound or composition. In some embodiments, the cancer is associated with and / or characterized by aberrant activation of PI3K alpha. In some embodiments, the cancer is characterized by a mutation in a RAS protein (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In some embodiments, the cancer is characterized by a mutation in a KRAS protein. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, the cancer is characterized by a mutation in the NRAS protein. In some embodiments, 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. In some embodiments, the NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, the cancer is characterized by a mutation in the HRAS protein. In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, the cancer is characterized by a mutation in the PI3K alpha protein.In some embodiments, the PI3K alpha protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the PI3K alpha protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0191] As used herein, "cancer" (also referred to as "malignancy," "neoplasm," "tumor," and "carcinoma") refers to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth and thus exhibit an abnormal growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, a tumor may be or include pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic cells. In some embodiments, a cancer may be characterized by a solid tumor. In some embodiments, a cancer may be characterized by a hematological tumor. Many different types of cancer are known.

[0192] In some embodiments, the cancer is pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancer of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary tract, bone, connective tissue, skin, cervix, uterus, endometrial corpus, testis, bladder, kidney and other urinary tract tissues, including renal cell carcinoma (RCC); eye, brain, spinal cord, and other tissues of the central and peripheral nervous system. cancer of the thyroid and other endocrine glands; Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma; and hematopoietic malignancies, including leukemias, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas. Further exemplary types of cancer include adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial sarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary cancer, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphatic system cancer, lymphoma, lymphangiosarcoma, lymphangioendothelial sarcoma , medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myeloma, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian carcinoma, papillary carcinoma, papillary adrenocortical carcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pinealoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synovium, thyroid cancer, uveal melanoma, and Wilms' tumor. In some embodiments, 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.

[0193] In some embodiments, the cancer is characterized by one or more mutations. In some such embodiments, a subject may be diagnosed with cancer and / or selected for treatment based on detection of one or more mutations in a biological sample taken from the subject. In some embodiments, the cancer is characterized by a mutation in a RAS protein (e.g., KRAS, HRAS, or NRAS). In some embodiments, the cancer is characterized by a mutation in a KRAS protein. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, the cancer is characterized by a mutation in the NRAS protein. In some embodiments, 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. In some embodiments, the NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, the cancer is characterized by a mutation in the HRAS protein. In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, the cancer is characterized by a mutation in the PI3K alpha protein.In some embodiments, the PI3K alpha protein comprises a N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the PI3K alpha protein comprises a E542K, E545K, H1047R, and / or H1047L mutation. In some embodiments, the cancer is characterized by mutation, overexpression, and / or amplification of a receptor tyrosine kinase (e.g., the HER family (e.g., HER2 and / or HER3), Met, FGFR, Alk, PDGF, EGFR, or ROS kinase). In some embodiments, the cancer is characterized by mutation or deletion of the PTEN protein. In some embodiments, the cancer has demonstrable sensitivity to Avastin. For example, the cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, the cancer is ER positive (e.g., has an estrogen receptor). In some embodiments, the cancer is PR positive (e.g., has a progesterone receptor).

[0194] In some embodiments, the disclosure provides a method of treating metabolic syndrome, comprising administering to a subject a provided compound or composition, hi some embodiments, the metabolic syndrome is selected from hyperinsulinemia and type 2 diabetes.

[0195] In some embodiments, the disclosure provides a method of treating a RASosis (e.g., a genetic syndrome caused by a germline mutation in a gene encoding a component or regulator of the RAS / MAPK pathway) comprising administering to a subject a provided compound or composition. In some embodiments, the RASosis is selected from the group consisting of capillary malformation-arteriovenous malformation syndrome and Legius syndrome. In some embodiments, the RASosis is neurofibromatosis type 1 (NF1).

[0196] In some embodiments, the disclosure provides a method of treating a vascular disorder comprising administering a provided compound or composition to a subject. In some embodiments, the vascular disorder is selected from PIK3CA-associated overproliferative syndromes (PROS) and vascular malformations (e.g., venous malformations, lymphatic malformations, CLOVES syndrome (CLOVES), Klippel-Trenaunay syndrome, PTEN hamartoma syndrome (PHTS), and fibrofatty vascular anomalies (FAVA)).

[0197] In some embodiments, the disclosure provides a method for treating pulmonary hypertension, e.g., pulmonary arterial hypertension, comprising administering to a subject a provided compound or composition.

[0198] In some embodiments, the disclosure provides a method for treating age-related macular degeneration or diabetic macular edema comprising administering to a subject a provided compound or composition.

[0199] In some embodiments, the disclosure provides a compound or composition for use in the manufacture of a medicament. In some embodiments, the provided compound or composition is useful for the manufacture of a medicament for treating a disease, disorder, or condition associated with or ameliorated by the interaction of a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) with a PI3Kα protein. In some embodiments, the small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) can bind to the RAS binding domain (RBD) of the PI3Kα protein. In some embodiments, the small GTPase is selected from Rac1, CDC42, and a RAS protein. In some embodiments, the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, the RAS protein is a wild-type RAS protein. In some embodiments, the RAS protein is a mutant RAS protein. In some embodiments, the RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation at codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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.In some embodiments, the NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, the PI3K alpha protein is a wild-type PI3K alpha protein. In some embodiments, the PI3K alpha protein is a mutant PI3K alpha protein. In some embodiments, the PI3K alpha protein comprises N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutations. In some embodiments, the PI3K alpha protein comprises E542K, E545K, H1047R, and / or H1047L mutations. In some embodiments, the provided compounds or compositions are useful in the manufacture of a medicament for treating a disease, disorder, or condition described herein. In some embodiments, the provided compounds or compositions are useful in the manufacture of a medicament for treating cancer or other indications described herein.

[0200] In some embodiments, the disclosure provides a compound or composition for use in a subject in need of treatment of a disease, disorder, or condition. In some embodiments, the provided compound or composition is useful for treating a disease, disorder, or condition that is associated with or ameliorated by the interaction of a small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) with a PI3Kα protein. In some embodiments, the small GTPase (e.g., Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) can bind to the RAS binding domain (RBD) of the PI3Kα protein. In some embodiments, the small GTPase is selected from Rac1, CDC42, and a RAS protein. In some embodiments, the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In some embodiments, the RAS protein is a wild-type RAS protein. In some embodiments, the RAS protein is a mutant RAS protein. In some embodiments, the RAS protein (e.g., HRAS, NRAS, or KRAS) comprises a mutation at codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some embodiments, 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.In some embodiments, the NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some embodiments, the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some embodiments, the HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In some embodiments, the PI3K alpha protein is a wild-type PI3K alpha protein. In some embodiments, the PI3K alpha protein is a mutant PI3K alpha protein. In some embodiments, the PI3K alpha protein comprises N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutations. In some embodiments, the PI3K alpha protein comprises E542K, E545K, H1047R, and / or H1047L mutations. In some embodiments, the provided compounds or compositions are useful for treating a disease, disorder, or condition described herein. In some embodiments, the provided compounds or compositions are useful for treating cancer or other indications described herein.

[0201] In some embodiments, the provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic or preventive regimens (e.g., two or more therapeutic or preventive agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, the regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any dose of the second regimen is administered), and in some embodiments, the agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agents or therapies in combination to a subject receiving another agent or therapy. For clarity, combination therapy does not require that the 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 combined composition.

[0202] In some embodiments, a provided compound or composition is administered to a subject who is receiving or has been receiving one or more additional therapeutic agents (e.g., anti-cancer agents and / or therapies to address one or more side effects of anti-cancer therapy or to otherwise provide palliative care). Exemplary anti-cancer agents include, but are not limited to, alkylating agents, mitotic inhibitors, checkpoint inhibitors, antimetabolites, plant alkaloids, terpenoids, cytotoxic agents, antibiotics, topoisomerase inhibitors, aromatase inhibitors, angiogenesis inhibitors, antisteroids, antiandrogens, mTOR inhibitors, monoclonal antibodies, kinase inhibitors, HIF2α inhibitors, or tyrosine kinase inhibitors. The alkylating agent may be, for example, almustine, 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). The antimetabolite 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. The antimitotic agent 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).The checkpoint inhibitor may be an anti-PD-1 or anti-PD-L1 antibody, such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, or MPDL3280A; the 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). The topoisomerase inhibitor may be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), or etoposide (EPOSIN). The cytotoxic agent 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. The aromatase inhibitor may be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN). The angiogenesis inhibitor may be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN). Antisteroids or antiandrogens can be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON). Tyrosine kinase inhibitors can be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA). mTOR inhibitors can be, for example, everolimus, temsirolimus (TORISEL), or sirolimus.The monoclonal antibody can be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). The kinase inhibitor can be, for example, a BRAF inhibitor, a MEK inhibitor, or a KRAS inhibitor (e.g., a KRAS G12C inhibitor, such as sotrasib, adagrasib, or BBO-8520). Further examples of agents that may be useful in combination with the compounds provided herein include amsacrine; Bacillus Calmette-Guerin (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); Clodronate, pamidronate, and other bisphosphonates; Colchicine; Demethoxyviridin; Dichloroacetate; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Goserelin (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUPRON); Levamisole; Lonidamine; Mesna; Metformin; Mitotane (o,r'-DDD, LYSO DREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (especially in combination with phototherapy and radiation therapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone.

[0203] Exemplary embodiments The following numbered embodiments are illustrative, though non-limiting, of certain aspects of the present disclosure.

[0204] 1. A compound of formula I: [ka] or a salt thereof (e.g., a pharma- ceutically acceptable salt), wherein: Ring A is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from phenyl, a 6-membered heteroaryl ring having 1-2 nitrogen atoms, and a 9-10 membered bicyclic ring containing at least one 5- or 6-membered heteroaryl ring; Ring C is selected from phenyl; a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 9-10 membered spiro-fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of said phenyl, heteroaryl, and heterocyclic ring being optionally fused to Ring E; Ring D is selected from phenyl and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of the phenyl and heteroaryl rings being optionally fused to Ring F; Ring E is selected from a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring E is selected from s R 5’ is replaced by Ring F is selected from phenyl, a 5- to 6-membered carbocyclic ring, a 5- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW; R 1 is -LW, a ring D', or a bivalent C substituted with a ring D' 1-6 aliphatic chains, Each L is independently a divalent linear or branched C 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently selected from -N(R)-, -O-, -S-, -C(O)-, -SO 2-, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, each W is independently hydrogen, halogen, -CN, or a 3-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each X is independently halogen or -CN; each ring D' is independently a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW; Each R 2 are independently oxo, halogen, -CN, -OR, and C 1-6 alkyl, Each R 3 are independently oxo, halogen, -CN, -OR, -O(CH 2 ) v Cy, -OCH 2 CH 2 OR, -CH 2 CH 2 OR, C 1-6 Aliphatic and C 1-6 selected from haloaliphatic, Each Cy is independently a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 6-membered carbocycle, or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Cy is selected from 0 to 2 R 6 is replaced by Each R 4 are independently halogen, and C 1-6 selected from aliphatic, Each R 5 and R 5’ are independently oxo, =NH, -CN, halogen, -OR, -N(R) 2, -SR, -C(O)R, -N(R)C(O)R, -(CH 2 ) x C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy, and C 1-6 aliphatic, in which case C 1-6 aliphatic is unsubstituted or substituted with one or more halogens and -OR; Each R 6 are independently oxo, -CN, halogen, -OR, -N(R) 2 , -SR, -C(O)R, -N(R)C(O)R, -C(O)N(R) 2 , -OC(O)R, -C(O)OR, -SO 2 R, -N(R)SO 2 R, -SO 2 N(R) 2 , and C 1-6 aliphatic; a 3- to 6-membered carbocyclic ring; phenyl; a 3- to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered aryl ring; and a 9- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Each R is independently hydrogen, C 1-6 aliphatic, C 1-6 haloaliphatic, 3- to 6-membered carbocyclic ring, phenyl, 3- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 10-membered aryl ring, and 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, or 2; q is 0 or 1; r is 0, 1, or 2; s is 0, 1, or 2; t is 0, 1, or 2; u is 0 or 1; each v is independently 0, 1, or 2; each x is independently 0, 1, or 2; The compound or a salt thereof.

[0205] 2. L is a divalent linear or branched C 1-8 an aliphatic chain, wherein one or two methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, wherein the compound is substituted with a group selected from:

[0206] 3. L is a divalent linear or branched C 1-8 The compound of embodiment 1 or 2, which is an aliphatic chain, and one or two methylene units of the aliphatic chain are optionally and independently substituted with a group selected from -N(R)-, -O-, C(O)-, -C(O)N(R)-, and -N(R)C(O)-.

[0207] 4. L is a divalent linear or branched C having one or more unsaturated units. 1-8 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently selected from -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2-, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,

[0208] 5. L is a divalent linear or branched C having one or more unsaturated units. 1-4 an aliphatic chain, wherein one or more methylene units of the aliphatic chain are optionally and independently selected from -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,

[0209] 6. L is a divalent linear or branched C having one double bond 1-4 an aliphatic chain, wherein one or two methylene units of the aliphatic chain are optionally and independently -N(R)-, -O-, -C(O)-, -SO 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,

[0210] 7. L is a divalent linear or branched C having one double bond 1-4 The compound of embodiment 6, wherein the aliphatic chain is an aliphatic chain, and one or two methylene units of the aliphatic chain are optionally and independently substituted with a group selected from -N(R)-, -C(O)-, and -N(R)C(O)-.

[0211] 8. L is -C(O)CClF-, -C(O)CH=CH-, -N(R)C(O)CH=CH-, -C(O)C(=CH 2 )-, -C(O)CH=CH-CH 2 -, -C(O)CH=CHCH 2 OCH 2 -, -C(O)CH=CHCH2 N(R)-, -CH 2 N(R)C(O)CH=CH- and -CH 2 CH 2 The compound of embodiment 1, wherein the compound is selected from N(R)C(O)CH=CH-.

[0212] 9. L is -C(O)CClF-, -C(O)CH=CH-, -NHC(O)CH=CH-, -C(O)C(=CH 2 )-, -C(O)CH=CH-CH 2 -, -C(O)CH=CHCH 2 OCH 2 -, -C(O)CH=CHCH 2 N(CH 3 )-, -CH 2 NHC(O)CH=CH- and -CH 2 CH 2 The compound of embodiment 8, wherein the compound is selected from NHC(O)CH=CH-.

[0213] 10. Each L is a divalent linear or branched C 1-8 an alkyl chain, wherein one or more methylene units of the aliphatic chain are optionally and independently selected from -N(R)-, -O-, -S-, -C(O)-, -SO 2 -, -CH(X)-, -C(X) 2 -, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -SO 2 N(R)- and -N(R)SO 2 -, wherein the compound is substituted with a group selected from:

[0214] 11. L is -N(R)C(O)CH 2 CH 2 -, -N(R)C(O)CH(CH 3 )CH 2 -, -OCH(CH 3 )CH 2 -, -C(O)-, -C(O)CH 2 CH 2 -, -C(O)N(R)CH(CH 3 )CH 2-, -C(O)N(R)CH 2 CH(CH 3 )CH 2 -, -CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(O)-, -CH 2 C(O)N(R)C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(O)N(R)C(CH 3 ) 2 CH 2 -, -CH 2 N(R)-, -CH 2 N(R)C(O)-, -CH 2 N(R)C(O)CH 2 CH 2 -, -CH 2 N(R)C(O)CH(CH 3 )CH 2 -, -CH 2 N(R)C(O)C(CH 3 ) 2 CH 2 -, -CH 2 N(R)C(O)CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 N(R)C(O)CH(CH 3 )CH 2 -, and -CH 2 O- selected from the group consisting of, the compound according to Embodiment 1.

[0215] 12. L is, -N(H)C(O)CH 2 CH 2 -, -N(H)C(O)CH(CH 3 )CH 2 -, -OCH(CH 3 )CH 2 -, -C(O)-, -C(O)CH 2 CH2 -, -C(O)N(H)CH(CH 3 )CH 2 -, -C(O)N(H)CH 2 CH(CH 3 )CH 2 -, -CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 C(O)-, -CH 2 C(O)N(H)C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(O)N(H)C(CH 3 ) 2 CH 2 -, -CH 2 N(H)-, -CH 2 N(H)C(O)-, -CH 2 N(H)C(O)CH 2 CH 2 -, -CH 2 N(H)C(O)CH(CH 3 )CH 2 -, -CH 2 N(H)C(O)C(CH 3 ) 2 CH 2 -, -CH 2 N(H)C(O)CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 N(H)C(O)CH(CH 3 )CH 2 - and -CH 2 The compound of embodiment 11, wherein the compound is selected from O-.

[0216] 13. The compound according to any one of embodiments 1-12, wherein W is hydrogen.

[0217] 14. The compound of any one of embodiments 1-12, wherein W is halogen.

[0218] 15. -LW, -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 OH, -CH 2 NH 2 , -OCH(CH 3 ) 2 , [ka] The compound of embodiment 1, selected from:

[0219] 16. -LW is -C(O)CH=CH 2 , -C(O)CF=CH 2 , -NHC(O)CF=CH 2 and -NHC(O)CH=CH 2 The compound of embodiment 1, selected from:

[0220] 17. R 1 But -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 NH 2 , -CH 2 OH, -OCH(CH 3 ) 2 , [ka] The compound of embodiment 1, selected from:

[0221] 18. The compound according to any one of embodiments 1-17, wherein Ring B is a 9-10 membered bicyclic ring containing at least one 5- or 6-membered heteroaryl ring containing at least one nitrogen atom.

[0222] 19. n R’s 4 Ring B substituted with [ka] 19. The compound according to any one of embodiments 1 to 18, selected from:

[0223] 20. The compound has the formula Ia, Ib, Ic, Id, Ie, If, Ig, and Ih: [ka] or a pharma- ceutically acceptable salt thereof.

[0224] 21. Each R 4 The compound of any one of embodiments 1-20, wherein is halogen.

[0225] 22. The compound according to any one of embodiments 1 to 20, wherein n is 0.

[0226] 23. The compound of any one of embodiments 1-22, wherein Ring A is phenyl.

[0227] 24. Ring A [ka] The compound of any one of embodiments 1-23, wherein

[0228] 25. Ring A is [ka] 25. The compound of embodiment 24, selected from:

[0229] 26. Ring A is [ka] 26. The compound of embodiment 25, selected from:

[0230] 27. R 3 is halogen, -OR, -O(CH 2 ) v Cy, and -OCH 2 CH 2 The compound according to embodiment 26, selected from OR.

[0231] 28. m R 3 Ring A substituted with [ka] The compound according to any one of embodiments 1 to 27, selected from:

[0232] 29. The compound according to any one of embodiments 1-22, wherein ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0233] 30. m R 3 Ring A substituted with [ka] 30. The compound of embodiment 29, selected from:

[0234] 31. The compound according to any one of embodiments 1-30, wherein m is 1, 2, or 3.

[0235] 32. At least one R 3 is halogen, -OR, -O(CH 2 ) v Cy, and -OCH 2 CH 2 The compound according to any one of embodiments 1 to 31, selected from OR.

[0236] 33. The compound according to any one of embodiments 1-32, wherein Ring C is phenyl.

[0237] 34. The compound according to any one of embodiments 1-32, wherein Ring C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0238] 35. The compound according to any one of embodiments 1-32, wherein Ring C is a 5-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0239] 36. The compound according to any one of embodiments 1-32, wherein Ring C is a 9-10 membered spiro-fused heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0240] 37. p R 5 Ring C substituted with [ka] The compound according to any one of embodiments 1 to 32, selected from:

[0241] 38. The compound according to any one of embodiments 1-36, wherein ring C is fused to ring E.

[0242] 39. The compound is represented by the formula Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, and Ihi: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0243] 40. [ka] but, [ka] The compound of embodiment 39, selected from:

[0244] 41. Ring E is a 5-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring E is a 5-7 membered heterocycle having s R 5’ The compound according to any one of embodiments 38-40, substituted with:

[0245] 42. s R 5’ Ring E substituted with [ka] The compound of embodiment 41, selected from:

[0246] 43. Ring E is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring E is a 5-6 membered heteroaryl ring having s R 5’ The compound according to any one of embodiments 38-40, substituted with:

[0247] 44. s R 5’ Ring E substituted with [ka] 20. The compound of embodiment 19, selected from:

[0248] 45. A ring E has s R 5’ The compound according to any one of embodiments 38-40, wherein R is a 5-6 membered carbocycle substituted with R.

[0249] 46. ​​s R 5’ Ring E substituted with [ka] The compound of embodiment 45, selected from:

[0250] 47. [ka] but, [ka] The compound according to any one of embodiments 38 to 40, selected from:

[0251] 48. The compound according to any one of embodiments 1-47, wherein p is 1 or 2.

[0252] 49. Each R 5 are independently oxo, -CN, halogen, -N(R) 2 , -(CH 2 ) x C(O)N(R) 2 , -SO 2 R, -SO 2 N(R) 2 , -(CH 2 ) x Cy, and C 1-6 aliphatic, C 1-6 The compound according to any one of the preceding embodiments, wherein aliphatic is unsubstituted or substituted with one or more halogens and -OR.

[0253] 50. Each R 5’ are independently oxo, =NH, -OR, -N(R) 2 , and C 1-6 aliphatic, C 1-6 The compound according to any one of embodiments 1-49, wherein aliphatic is unsubstituted or substituted with one or more halogens and -OR.

[0254] 51. The compound of any one of embodiments 1-50, wherein Ring D is phenyl.

[0255] 52. The compound according to any one of embodiments 1-50, wherein ring D is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0256] 53. r R 2 and q R 1 Ring D substituted with [ka] The compound according to any one of embodiments 1 to 52, selected from:

[0257] 54. The compound according to any one of embodiments 1-52, wherein ring D is fused to ring F.

[0258] 55. The compound according to embodiment 54, wherein q is 0.

[0259] 56. The compound has the formula Ia-ii, Ib-ii, Ic-ii, Id-ii, Ie-ii, If-ii, Ig-ii, and Ih-ii: [ka] or a pharma- ceutically acceptable salt thereof.

[0260] 57. [ka] but, [ka] 57. The compound of embodiment 56, selected from:

[0261] 58. The compound according to any one of embodiments 1-52, and 54-57, wherein ring F is phenyl substituted with u -LW.

[0262] 59. A ring F substituted with u -LWs is [ka] The compound of embodiment 58, selected from:

[0263] 60. [ka] but, [ka] 57. The compound of embodiment 56, selected from:

[0264] 61. The compound according to any one of embodiments 1-52, 54-57, and 60, wherein ring F is a 5-6 membered carbocyclic ring substituted with u -LW.

[0265] 62. A ring F substituted with u -LWs is [ka] 62. The compound of embodiment 61, wherein

[0266] 63. The compound according to any one of embodiments 1-52, 54-57, and 60, wherein ring F is a 5-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW.

[0267] 64. A ring F substituted with u -LWs is [ka] The compound according to embodiment 63, selected from:

[0268] 65. The compound according to any one of embodiments 1-52, 54-57, and 60, wherein ring F is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring F is substituted with u -LW.

[0269] 66. A ring F substituted with u -LWs is [ka] The compound of embodiment 65, wherein

[0270] 67. [ka] but, [ka] 57. The compound of embodiment 56, selected from:

[0271] 68. R 1 is Ring D'.

[0272] 69. The compound according to embodiment 68, wherein ring D is not fused to ring F.

[0273] 70. The compound has the formula Ia-iii, Ib-iii, Ic-iii, Id-iii, Ie-iii, If-iii, Ig-iii, and Ih-iii: [ka] or a pharma- ceutically acceptable salt thereof.

[0274] 71. r R 2 Ring D substituted with [ka] The compound of embodiment 70, selected from:

[0275] 72. The compound according to any one of embodiments 1-52 and 68-71, wherein Ring D' is a 4-6 membered carbocyclic ring substituted with t -LW.

[0276] 73. The compound according to any one of embodiments 1-52 and 68-71, wherein ring D' is a 4-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D' is substituted with t -LW.

[0277] 74. A ring D' substituted with t -LW is [ka] The compound according to any one of embodiments 1-52 and 68-71, selected from:

[0278] 75. [ka] but, [ka] [ka] The compound of embodiment 70, selected from:

[0279] 76. The compound has the formula Ia-iv, Ib-iv, Ic-iv, Id-iv, Ie-iv, If-iv, Ig-iv, and Ih-iv: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0280] 77. The compound has the formula Iav, Ibv, Icv, Idv, Iev, Ifv, Igv, and Ihv: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0281] 78. The compound has the formula Il, Im, In, Ip, and Iq: [ka] or a pharma- ceutically acceptable salt thereof.

[0282] 79. A compound according to any one of embodiments 1-78, wherein t is 1.

[0283] 80. A compound according to any one of embodiments 1-79, wherein q is 1.

[0284] 81. The compound according to any one of the preceding embodiments, wherein v is 0 or 1.

[0285] 82. The compound according to any one of the preceding embodiments, wherein x is 0 or 1.

[0286] 83. Each R is independently hydrogen, C 1-6 Aliphatic, or C 1-6 The compound of any one of embodiments 1-82, which is haloaliphatic.

[0287] 84. A compound selected from Table 1, or a pharma- ceutically acceptable salt thereof.

[0288] 85. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 84, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0289] 86. A method comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-84, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0290] 87. The method of embodiment 86, wherein the subject has a disease, disorder, or condition that is ameliorated by disrupting, inhibiting, and / or preventing the interaction between a small GTPase and a PI3K alpha protein.

[0291] 88. The method of embodiment 87, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

[0292] 89. The method of embodiment 88, wherein the small GTPase is a RAS protein.

[0293] 90. The method of embodiment 89, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0294] 91. The method of any one of embodiments 86 to 90, wherein the subject has cancer.

[0295] 92. A method for treating cancer, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-84, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0296] 93. The method of embodiment 91 or 92, wherein the cancer is associated with and / or characterized by aberrant activation of PI3K alpha and / or mutations in PI3K alpha.

[0297] 94. The method of embodiment 93, wherein the PI3K alpha protein comprises N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutations.

[0298] 95. The method of any one of embodiments 91 to 94, wherein the cancer is characterized by a mutation in a RAS protein.

[0299] 96. The method of embodiment 95, wherein the RAS protein comprises a mutation at codon 12, 13, or 61.

[0300] 97. The method of embodiment 95 or 96, wherein the RAS protein is KRAS.

[0301] 98. The method of embodiment 97, 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.

[0302] 99. The method of embodiment 95 or 96, wherein the RAS protein is HRAS.

[0303] 100. The method of embodiment 99, 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.

[0304] 101. The method of embodiment 95 or 96, wherein the RAS protein is NRAS.

[0305] 102. The method of embodiment 101, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0306] 103. The cancer is selected from the group consisting of: pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancer of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary tract, bone, connective tissue, skin, cervix, uterus, endometrial corpus, testes, bladder, kidney and other urinary tract tissues, including renal cell carcinoma (RCC); eye, brain, spinal cord, and other components of the central and peripheral nervous system, and associated structures such as the meninges. The method of any one of embodiments 91-102, wherein the cancer is selected from hematopoietic malignancies including: cancer of the thyroid gland; cancer of the thyroid and other endocrine glands; Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma; and hematopoietic malignancies including leukemias, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

[0307] 104. The method of embodiment 103, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0308] 105. The method of any one of embodiments 91 to 104, wherein the cancer is characterized by mutation, overexpression, and / or amplification of a receptor tyrosine kinase (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinase).

[0309] 106. The method of any one of embodiments 91 to 105, wherein the cancer is characterized by a mutation or deficiency in the PTEN protein.

[0310] 107. The method of any one of embodiments 86-106, wherein the subject has previously undergone a cancer treatment regimen.

[0311] 108. The method of any one of embodiments 86-107, wherein the subject has previously entered remission of cancer.

[0312] 109. A method for treating a metabolic disorder, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-84, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0313] 110. The method of embodiment 109, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes.

[0314] 111. A method for treating RAS disease, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 84, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0315] 112. The method of embodiment 111, wherein the RAS disease is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Regius syndrome.

[0316] 113. A method for 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 1-84, or a pharma- ceutically acceptable salt thereof.

[0317] 114. The method of embodiment 113, wherein the vascular disorder or condition is selected from PIK3CA-associated overgrowth syndrome (PROS), and vascular malformation (e.g., venous malformation, lymphatic malformation, CLOVES syndrome (CLOVES), Klippel-Trenaunay syndrome, PTEN hamartoma tumor syndrome (PHTS), and fibrofatty vascular anomaly (FAVA)).

[0318] 115. A method for disrupting the interaction between a small GTPase and a PI3K alpha protein in a subject, the method comprising administering to the subject a compound described in any one of embodiments 1 to 84 or a pharma- ceutically acceptable salt thereof.

[0319] 116. A method for disrupting the interaction between a small GTPase and a PI3K α protein, comprising contacting a cell containing the small GTPase and the PI3K α protein with a compound described in any one of embodiments 1 to 84 or a pharma- ceutically acceptable salt thereof.

[0320] 117. A method comprising contacting a cell containing a small GTPase and a PI3K alpha protein with a compound according to any one of embodiments 1 to 84, or a pharma- ceutically acceptable salt thereof.

[0321] 118. The method of embodiment 116 or 117, wherein the cells are contained in a subject.

[0322] 119. A method according to any one of embodiments 115 to 118, wherein the small GTPase is selected from Rac1, CDC42, and RAS proteins.

[0323] 120. The method of embodiment 119, wherein the small GTPase is a RAS protein.

[0324] 121. The method of embodiment 120, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1.

[0325] 122. The method of embodiment 121, wherein the RAS protein is KRAS.

[0326] 123. The method of embodiment 122, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0327] 124. The method of embodiment 121, wherein the RAS protein is HRAS.

[0328] 125. The method of embodiment 124, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0329] 126. The method of embodiment 121, wherein the RAS protein is NRAS.

[0330] 127. The method of embodiment 126, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0331] 128. A compound according to any one of embodiments 1-84, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0332] 129. Use of a compound according to any one of embodiments 1 to 84, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament.

[0333] 130. The compound or use according to embodiment 128 or 129, wherein the medicament is for treating cancer.

[0334] 131. The compound or use according to embodiment 130, wherein the cancer is associated with and / or characterized by aberrant activation of PI3K alpha and / or mutations in PI3K alpha.

[0335] 132. The compound or use of embodiment 131, wherein the PI3K alpha protein comprises N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutations.

[0336] 133. A compound or use according to any one of embodiments 130 to 132, wherein the cancer is characterized by a mutation in a RAS protein.

[0337] 134. The compound or use of embodiment 133, wherein the RAS protein comprises a mutation at codon 12, 13, or 61.

[0338] 135. The compound or use according to embodiment 133 or 134, wherein the RAS protein is KRAS.

[0339] 136. The compound or use of embodiment 135, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0340] 137. The compound or use according to embodiment 133 or 134, wherein the RAS protein is HRAS.

[0341] 138. The compound of embodiment 137, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0342] 139. The compound or use according to embodiment 133 or 134, wherein the RAS protein is NRAS.

[0343] 140. The compound or use of embodiment 139, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0344] 141. The cancer is of the following: pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancer of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary tract, bone, connective tissue, skin, cervix, uterus, endometrial corpus, testes, bladder, kidney and other urinary tract tissues, including renal cell carcinoma (RCC); eye, brain, spinal cord, and other components of the central and peripheral nervous system, and associated structures such as the meninges. A compound or use according to any one of embodiments 130 to 140 selected from cancers of the thyroid and other endocrine glands; Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma; and hematopoietic malignancies including leukemias, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

[0345] 142. The compound or use according to embodiment 141, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0346] 143. A compound or use according to any one of embodiments 130 to 142, wherein the cancer is characterized by mutation, overexpression, and / or amplification of a receptor tyrosine kinase (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinase).

[0347] 144. A compound or use according to any one of embodiments 130 to 143, wherein the cancer is characterized by a mutation or deficiency in the PTEN protein.

[0348] 145. The compound or use according to embodiment 128 or 129, wherein the medicament is for treating a metabolic disorder, a RAS disorder, or a vascular disorder.

[0349] 146. The compound or use of embodiment 145, wherein (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes mellitus; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Regius syndrome; or (iii) the vascular disorder or condition is selected from PIK3CA-associated overproliferative syndrome (PROS) and vascular malformation (e.g., venous malformation, lymphatic malformation, CLOVES syndrome (CLOVES)), Klippel-Trenaunay syndrome, PTEN hamartoma syndrome (PHTS), or fibrofatty vascular anomaly (FAVA)).

[0350] 147. A compound according to any one of embodiments 1-84, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition.

[0351] 148. A compound for use according to embodiment 147, for use in the treatment of cancer.

[0352] 149. The compound for use according to embodiment 148, wherein the cancer is associated with and / or characterized by aberrant activation of PI3K alpha and / or mutations in PI3K alpha.

[0353] 150. The compound for use according to embodiment 149, wherein the PI3K alpha protein comprises N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutations.

[0354] 151. A compound for use according to any one of embodiments 148 to 150, wherein the cancer is characterized by a mutation in a RAS protein.

[0355] 152. The compound for use according to embodiment 151, wherein the RAS protein comprises a mutation at codon 12, 13, or 61.

[0356] 153. The compound for use according to embodiment 151 or 152, wherein the RAS protein is KRAS.

[0357] 154. The compound for use according to embodiment 153, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0358] 155. The compound for use according to embodiment 151 or 152, wherein the RAS protein is HRAS.

[0359] 156. The compound for use according to embodiment 155, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0360] 157. The compound for use according to embodiment 151 or 152, wherein the RAS protein is NRAS.

[0361] 158. The compound for use according to embodiment 157, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0362] 159. The cancer is of the following: pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; cancer of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary tract, bone, connective tissue, skin, cervix, uterus, endometrial corpus, testes, bladder, kidney and other urinary tract tissues, including renal cell carcinoma (RCC); eye, brain, spinal cord, and other components of the central and peripheral nervous system, and associated structures such as the meninges. ; cancers of the thyroid and other endocrine glands; Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma; and hematopoietic malignancies including leukemias, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

[0363] 160. The compound for use according to embodiment 159, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0364] 161. A compound for use according to any one of embodiments 148 to 160, wherein the cancer is characterized by mutation, overexpression, and / or amplification of a receptor tyrosine kinase (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR, or ROS kinase).

[0365] 162. A compound for use according to any one of embodiments 148 to 161, wherein the cancer is characterized by a mutation or deficiency of the PTEN protein.

[0366] 163. A compound for use according to embodiment 147, for use in the treatment of a metabolic disorder, a RAS disorder, or a vascular disorder.

[0367] 164. The compound for use according to embodiment 163, wherein (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes mellitus; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Regius syndrome; or (iii) the vascular disorder or condition is selected from PIK3CA-associated overproliferative syndrome (PROS) and vascular malformations (e.g., venous malformations, lymphatic malformations, CLOVES syndrome (CLOVES)), Klippel-Trenaunay syndrome, PTEN hamartoma syndrome (PHTS), and fibrofatty vascular anomalies (FAVA)).

[0368] 165. A compound capable of disrupting the interaction between small GTPases and the PI3Kα protein.

[0369] 166. The compound described in embodiment 165, wherein the compound is capable of binding to PI3Kα such that (i) the interaction between the small GTPase and PI3Kα is at least partially disrupted, prevented, or inhibited, and / or (ii) the kinase activity of PI3Kα is not significantly inhibited.

[0370] 167. The compound, (i) <5 μM or ≧5 μM and ≦25 μM in an assay of Biological Example 1 (e.g., a surface plasmon resonance (SPR) binding assay assessing inhibition of KRAS-PI3Kα interaction); (ii) in an assay of Biological Example 2 (e.g., matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS) of covalent modification of Cys242 in human PIK3CA(157-299)), ≧75%, <75% and ≧50%, or <50% and ≧25%, (iii) <1 μM or ≧1 μM and ≦10 μM in an assay of Biological Example 3 (e.g., a matrix-supported cell-based pAKT homogeneous time-resolved fluorescence (HTRF) assay in Tet-on KRAS G12D HeLa cells); and / or (iv) The compound according to embodiment 165 or 166, having an activity in the assay of Biological Example 4 (e.g., a matrix-supported cell-based pAKT HTRF assay in BT474 cells) of <0.1 μM, ≧0.1 μM and ≦1 μM, or ≧1 μM and ≦3 μM.

[0371] 168. The compound of any one of embodiments 165-167, wherein the compound comprises an electrophilic moiety.

[0372] 169. The compound according to any one of embodiments 165-168, wherein the compound is capable of interacting with the Cys242 residue in the catalytic subunit of PI3K α.

[0373] 170. The compound of any one of embodiments 165-169, wherein the compound is capable of irreversibly binding to the PI3K α protein.

[0374] 171. The compound of any one of embodiments 165-169, wherein the compound is capable of reversibly binding to the PI3K α protein.

[0375] 172. The compound according to any one of embodiments 165-171, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

[0376] 173. The compound of embodiment 172, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0377] 174. The compound of embodiment 173, wherein the RAS protein comprises a mutation at codon 12, 13, or 61.

[0378] 175. The compound of embodiment 173 or 174, wherein the RAS protein is KRAS.

[0379] 176. The compound of embodiment 175, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0380] 177. The compound of embodiment 173 or 174, wherein the RAS protein is HRAS.

[0381] 178. The compound of embodiment 177, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0382] 179. The compound of embodiment 173 or 174, wherein the RAS protein is NRAS.

[0383] 180. The compound of embodiment 179, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0384] 181. The compound of any one of embodiments 165-180, wherein the compound is a compound of any one of embodiments 1-84.

[0385] 182. A method for disrupting, inhibiting, or preventing the interaction between a small GTPase and a PI3K alpha protein, the method comprising contacting a cell containing the small GTPase and the PI3K alpha protein with a compound described in any one of embodiments 165 to 181 or a pharma- ceutically acceptable salt thereof.

[0386] 183. The method of embodiment 182, wherein the cell is within a subject.

[0387] 184. The method of embodiment 182 or 183, wherein the small GTPase is Rac1, CDC42, or a RAS protein.

[0388] 185. The method of embodiment 184, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0389] 186. The method of embodiment 185, wherein the RAS protein comprises a mutation at codon 12, 13, or 61.

[0390] 187. The method of embodiment 185 or 186, wherein the RAS protein is KRAS.

[0391] 188. The method of embodiment 187, wherein the KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0392] 189. The method of embodiment 185 or 186, wherein the RAS protein is HRAS.

[0393] 190. The method of embodiment 189, wherein the HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation.

[0394] 191. The method of embodiment 185 or 186, wherein the RAS protein is NRAS.

[0395] 192. The method of embodiment 191, wherein the NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. EXAMPLES

[0396] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods illustrate the synthesis of specific compounds of the present disclosure, it will be understood that the general methods below, as well as other methods known to those of skill in the art, can be applied to all compounds described herein, as well as each subclass and species of these compounds.

[0397] Selected abbreviations used in the above sections and examples are summarized in Table 3. [Table 3-1] [Table 3-2]

[0398] Materials and Methods Preparative thin layer chromatography (PTLC) separations described herein were typically performed on 20×20 cm plates (500 μm thick silica gel).

[0399] Chromatographic purification was typically performed using a Biotage Isolera, an automated system running Biotage Isolera One 2.0.6 software (Biotage LLC, Charlotte, NC). Flow rates were the default values ​​specified for the column used. Reversed-phase chromatography was performed on KP-C18-HS Flash+ columns of various sizes (Biotage LLC) using an elution gradient of water and acetonitrile. Typical loading was crude sample by weight: RP SiO 2 =1:50 to 1:1000. Normal phase chromatography was performed using an elution gradient 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) (Biotage LLC) of various sizes. The typical loading was crude sample:SiO by weight. 2 = 1:10 to 1:150. Alternatively, silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0400] Intermediates and example compounds 1 HNMR analysis was typically performed at 298°K on a Bruker Ascend™ 400 spectrometer (operating at 400 MHz), a Bruker Ascend 500 MHz Avance Neo Spectrometer (Bruker-Biospin) or a Bruker Avance Neo Nanobay (operating at 400 MHz) following standard operating procedures recommended by the manufacturer. The reference frequency was set using TMS as an internal standard. Chemical shift values ​​(δ) are reported in parts per million (ppm) and splitting patterns are abbreviated as follows: s (singlet), br.s (broad singlet), d (doublet), dd (double doublet), t (triplet), and m (multiplet). Coupling constants (J) are given in Hz. Typical deuterated solvents were used as indicated in the individual examples.

[0401] LCMS analyses were typically performed using one of the following conditions:

[0402] (1) LCMS spectra were acquired on an Agilent Technologies 6120B quadrupole spectrometer. The LC mobile phase was acetonitrile with 0.1% formic acid (A) and water with 0.1% formic acid (B), with an eluent gradient of 5-95% A at 6.0 min, 5%-40% A at 6.0 min, and 80-100% A at 6.0 min, using a poroshell 120 EC-C18 50 mm x 3.0 mm x 2.7 μM capillary column, flow rate: 0.7 mL / min. Mass spectra (MS) were recorded by electrospray ion mass spectrometry (ESI). All temperatures are in degrees Celsius (°C) unless otherwise noted.

[0403] (2) LCMS spectra were acquired on an Agilent Technologies 1290-6420 triple quadrupole spectrometer. The LC mobile phase was acetonitrile (A) with 0.05% formic acid, and water (B) with 0.05% formic acid, with an eluent gradient of 5 to 95% A in 5.0 min using a ZORBAX SB-C18 50 mm × 2.1 mm × 1.8 μM capillary column, flow rate: 0.3 mL / min. Mass spectra (MS) were measured by electrospray ion mass spectrometry (ESI). All temperatures are in degrees Celsius (°C) unless otherwise noted.

[0404] (3) LC-MS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer equipped with an Agilent 1260 infinity II chromatographic separation module and an Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software. The HPLC column used was an Agilent ZORBAX Eclipse XDB-C18 4.6 mm × 150 mm × 3.5 μM RapidResol column, the mobile phase was water (0.1% formic acid) / MeCN (0.1% formic acid), and the gradient was 5–95% MeCN in 10 min at a flow rate of 1 mL / min. Accurate mass data was obtained using a Thermo Fisher extractive plus EMR orbitrap LCMS system. Accurate mass values ​​were calculated by ChemCalc.

[0405] (4) LCMS spectra were acquired on an alliance Waters 2695 coupled with a Waters 2487 Dual Wavelength Absorbance Detector and a Waters Micromass-ZQ-2000 single quadrupole spectrometer. The LC mobile phase was acetonitrile (A) and water with 0.01% formic acid (B), with an eluent gradient of 5 to 100% A in 10.0 min using a Kromasil 100-5-C18 150 mm × 4.6 mm × 5 μm column. Mass spectra (MS) were measured by electrospray ion mass spectrometry (ESI). All temperatures are in degrees Celsius (°C) unless otherwise noted.

[0406] (5) LCMS spectra were acquired on a Waters Micromass-ZQ 2000 quadrupole spectrometer. The LC mobile phase was (A) 0.1% formic acid in water, (B) 100% acetonitrile, and the eluent gradient was 10-90% B at 10.0 min, 90% B up to 12 min, 90-10% B at 12-13 min, and 90-10% B at 13-15 min, using a Phenomenex Gemini-C18 (50 mm × 4.6 mm × 5 μm), flow rate: 0.5 mL / min. Mass spectrometry (MS) was measured by electrospray ion mass spectrometry (ESI).

[0407] Typically, analytical HPLC conditions were as follows:

[0408] LC1: Column: poroshell 120 EC-C18 150 mm × 4.6 mm × 4 μm combined with Agilent Technologies 1260 Infinity; 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.

[0409] 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: time / B concentration: 0 / 5, 2 / 5, 20 / 50, 25 / 50, 30 / 90, 35 / 90, 37 / 05, 40 / 05.

[0410] LC3: Shimadzu LC-2010A HT, column: XBRIDGE-C18 3.5 μm 2.1 × 50 mm; temperature: 45 °C; mobile phase: water (0.05% TFA)-ACN (0.05% TFA), 0–60% ACN over 7 min, 7–8 min, 60%–100% ACN; flow rate: 0.8 mL / min; detection: PDA, 214 nm, 254 nm.

[0411] LC4: Shimadzu LC-2050c, Column: XBRIDGE-C18 3.5 μm 2.1 × 50 mm; Temperature: 45 °C; Mobile phase: water (0.05% TFA)-ACN (0.05% TFA), 0–60% ACN over 7 min, 7–8 min, 60%–100% ACN; Flow rate: 0.8 mL / min; Detection: VWD, PDA, 214 nm, 254 nm. PDA, 214 nm, 254 nm.

[0412] Preparative HPLC was performed under one of the following conditions:

[0413] Condition 1: GILSON preparative HPLC system; Column: Ultimate XB-C18, 21.2 mm x 250 mm, 5 μm; Mobile phase: water with 0.1% trifluoroacetic acid; MeCN with 0.1% trifluoroacetic acid; Method: 15 min gradient elution; Initial organic: 10%-30%; Final organic: 60%-80%; UVl: 240; UV2: 230; Flow rate: 15 mLl / min.

[0414] Condition 2: C18-reverse phase preparative HPLC was performed using a Waters purification system equipped with a 2489 UV / Vis detector, a 2545 gradient module, and a Fraction collector III controlled by Waters Chromescope v1.6. The preparative HPLC column used was a Waters XBridge® Prep C18 5 μM OBD™ 19×250 mm column, and the mobile phase was water / MeCN or water (0.1% TFA) / MeCN (0.1% TFA).

[0415] Condition 3: Shimadzu preparative HPLC system; Column: Phenomenex Luna C18, 21.1 mm x 250 mm, 10 μm; Mobile phase; MP-A 10 mm ammonium acetate buffer, MP-B: methanol (100%), 35 min gradient elution UV: 254, Flow rate: 10 mL / min. Gradient: time / B concentration: 0 / 50, 25 / 90, 30 / 90, 32 / 50, 35 / 50.

[0416] Chiral supercritical fluid chromatography (SFC) was carried out under one of the following conditions:

[0417] Condition 1: SFC Thar prep80, column: CHIRALPAK (registered trademark) AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% EtOH / CO 2 (0.2%NH 4 OH content); 40g / min.

[0418] Condition 2: SFC Thar prep80, column: CHIRALPAK (registered trademark) OD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% MeOH / CO 2 (0.2%NH 4 OH content); 40g / min.

[0419] Condition 3: SFC Thar prep80, column: CHIRALPAK (registered trademark) IC 250 mm x 20 mm, 5 μm; mobile phase: 40% IPA / CO 2 (Contains 0.2% DEA); 40g / min.

[0420] Compound names were generated in ChemDraw Professional.

[0421] Each of the compounds provided herein, including various forms such as salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc., may be prepared according to a variety of methods, including those described in the Examples below.

[0422] Synthesis of the provided compounds Synthesis Example 1: Synthesis of N-(3-(4-(2-(2-methoxyethoxy)phenyl)-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)benzyl)acrylamide (Compound 1) [ka] Step A: Preparation of N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acrylamide: To a stirred solution of [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine hydrochloride (100 mg, 0.371 mmol) and triethylamine (0.16 mL, 1.1 mmol) in DCM (5 mL) was added acrylic anhydride (70 mg, 0.56 mmol). The solution was stirred at 25° C. for 1 h. The mixture was concentrated and purified by preparative TLC (petroleum ether / EtOAc: 3 / 1) to give N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acrylamide (100 mg, 94% yield) as a colorless oil. LCMS ESI (+) m / z 288.2 (M+H).

[0423] Step B: Preparation of 1-benzyloxy-4-bromo-3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine: To a stirred solution of benzyl alcohol (3.80 mL, 36.3 mmol) in DMF (50 mL) at 0 °C was added sodium hydride (0.870 g, 36.3 mmol) in small portions. The mixture was stirred at 0 °C for 30 min. 4-Bromo-3-methoxy-1-methylsulfonyl-6,7-dihydro-5H-cyclopenta[c]pyridine (3.70 g, 12.1 mmol) was added and the resulting mixture was stirred at 0 °C to 25 °C for an additional 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C. and concentrated. The residue was purified by silica gel column (EtOAc / petroleum ether: 0-10%) to give 1-benzyloxy-4-bromo-3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine (3.90 g, 97% yield). LCMS ESI (+) m / z 334.0 (M+H).

[0424] Step C: Preparation of 1-(benzyloxy)-3-methoxy-4-(2-(2-methoxyethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridine: A mixture of 1-benzyloxy-4-bromo-3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine (1.00 g, 2.99 mmol), [2-(2-methoxyethoxy)phenyl]boronic acid (0.65 g, 3.29 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (219 mg, 0.299 mmol) and sodium carbonate (634 mg, 5.98 mmol) in 1,4-dioxane (30 mL) / water (3 mL) was stirred at 85° C. for 6 h. The mixture was concentrated and purified by silica gel column (petroleum ether: EtOAc = 10: 1) to give 1-benzyloxy-3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (1.10 g, 91% yield). LCMS ESI (+) m / z 406.2 (M+H).

[0425] Step D: Preparation of 3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-ol: A mixture of 1-benzyloxy-3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine (1.10 g, 2.71 mmol) and Pd / C (100 mg) in methanol (10 mL) / THF (10 mL) was stirred at 12° C. for 12 h. The mixture was filtered and concentrated. The residue was purified by silica gel column (petroleum ether:EtOAc=1:1) to give 3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-ol (870 mg, 100% yield). LCMS ESI (+) m / z 316.2 (M+H).

[0426] Step E: Preparation of [3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]trifluoromethanesulfonate: To a stirred solution of 3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-ol (870 mg, 2.76 mmol) and N,N-diisopropylethylamine (1.40 mL, 8.28 mol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (0.560 mL, 3.31 mmol) at 0° C. The mixture was stirred at 10° C. for 1 h. The mixture was diluted with EtOAc, washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and purified by silica gel column (petroleum ether:EtOAc=20:1 to 10:1) to give [3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]trifluoromethanesulfonate (690 mg, 56% yield). LCMS ESI (+) m / z 448.2 (M+H).

[0427] Step F: Preparation of tert-butyl 6-[3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: [3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]trifluoromethacrylate in MeCN (10 mL) / water (1.2 mL). To a stirred solution of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (300 mg, 0.670 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (289 mg, 0.805 mmol) and potassium carbonate (185 mg, 1.34 mmol) was added palladium(II) acetate (15 mg, 0.067 mmol) and X-PHOS (64 mg, 0.13 mmol). The mixture was stirred at 100° C. for 12 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column (petroleum ether: EtOAc = 10: 1 to 4: 1) to give tert-butyl 6-[3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (312 mg, 88% yield). LCMS ESI (+) m / z 531.4 (M+H).

[0428] Step G: Preparation of 4-(2-(2-methoxyethoxy)phenyl)-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol: To a stirred solution of tert-butyl 6-[3-methoxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (280 mg, 0.528 mmol) in MeCN (4 mL) was added sodium iodide (237 mg, 1.58 mmol) and trimethylchlorosilane (0.67 mL, 5.3 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was cooled to ambient temperature and quenched with water. The product was extracted with DCM and eluted with Na 2 SO 4 and concentrated to dryness to give the crude product 4-(2-(2-methoxyethoxy)phenyl)-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (208 mg), which was used directly in the next step. LCMS ESI (+) m / z 417.2 (M+H).

[0429] Step H: Preparation of tert-butyl 6-[3-hydroxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: Ethanol (4 mL) and H 2 To a solution of 4-(2-(2-methoxyethoxy)phenyl)-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (208 mg, 0.600 mmol) and potassium carbonate (219 mg, 1.58 mmol) in 2 mL of O was added di-tert-butyl dicarbonate (0.25 mL, 1.1 mmol). The mixture was stirred at ambient temperature for 2 h. The mixture was diluted with water and the product was extracted with EtOAc. The combined organic layers were washed with brine and concentrated with Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated and purified by silica gel column (EtOAc) to give tert-butyl 6-[3-hydroxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (280 mg, 90%). LCMS ESI (+) m / z 517.3.

[0430] Step I: Preparation of tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[3-hydroxy-4-[2-(2-methoxyethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (260 mg, 0.503 mmol) and N,N-diisopropylethylamine (0.260 mL, 1.51 mmol) in DCM (5 mL) was added trifluoromethanesulfonic anhydride (0.100 mL, 0.604 mmol). The mixture was stirred at 7 °C for 1 h. The mixture was diluted with NaHCO 3 The product was extracted with EtOAc, washed with brine and poured into Na 2 SO 4 The mixture was dried at 40° C. and concentrated. The residue was purified by silica gel column (petroleum ether:EtOAc=4:1) to give tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (180 mg, 55% yield). LCMS ESI (+) m / z 649.3 (M+H).

[0431] Step J: Preparation of tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-[3-[(prop-2-enoylamino)methyl]phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: Dissolve 6-[4-[2-(2-methoxyethoxy)phenyl]-3-butyl(trifluoromethylsuccinimide) in acetonitrile (2 mL) and water (0.2 mL). To a solution of tert-butyl 3,4-dihydro-1H-isoquinoline-2-carboxylate (40 mg, 0.062 mmol) and N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]prop-2-enamide (35 mg, 0.12 mmol), X-Phos (5.9 mg, 0.012 mmol), K 2 CO 3 (17 mg, 0.12 mmol), and palladium(II) acetate (1.4 mg, 0.0062 mmol) were added. The solution was then rinsed with N 2 The mixture was stirred at 100° C. for 2 h under reduced pressure. The mixture was concentrated and purified by preparative TLC (petroleum ether:EtOAc=1:1) to give tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-[3-[(prop-2-enoylamino)methyl]phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 mg, 70% yield) as a pale yellow oil. LCMS ESI (+) m / z 660.2 (M+H).

[0432] Step K: Preparation of N-[[3-[4-[2-(2-methoxyethoxy)phenyl]-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl]phenyl]methyl]prop-2-enamide: To tert-butyl 6-[4-[2-(2-methoxyethoxy)phenyl]-3-[3-[(prop-2-enoylamino)methyl]phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 mg, 0.043 mmol) in DCM (2 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The solution was stirred at ambient temperature for 1 h. The solution was concentrated and purified by reverse phase preparative HPLC to give N-[[3-[4-[2-(2-methoxyethoxy)phenyl]-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl]phenyl]methyl]prop-2-enamide (11 mg, 0.44% yield) as the trifluoroacetate salt. LCMS ESI (+) m / z 560.2 (M+H). 1 H NMR (400 MHz, CD 3 OD) δ:7.74-7.76 (m, 2H), 7.48-7.50 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.26-7.35 (m, 4H), 7.02-7.04 (d, J = 8.4 Hz, 1H), 6.96-6.98 (d, J = 7.6 Hz, 1H), 6.86-6.90 (t, J = 7.2Hz, 1H), 6.24-6.25 (d, J = 7.2Hz, 2H), 5.69-5.72 (t, J = 5.2Hz, 1H), 4.50 (s,2H), 4.33-4.61 (m, 2H), 4.12-4.15 (m, 1H), 3.95-3.98 (m, 1H), 3.57-3.61 (m, 4H), 3.06-3.28 (m, 8H), 2.85-2.93 (m, 1H), 2.18-2.24 (m, 2H).

[0433] Synthesis Example 2: Synthesis of 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridine (Compound 4) [ka] Step A: Preparation of 1-(2-methoxyethoxy)-2-(phenylethynyl)benzene: To a solution of 1-iodo-2-(2-methoxyethoxy)benzene (300 mg, 1.08 mmol), phenylacetylene (0.120 mL, 1.13 mmol), triethylamine (0.75 mL, 5.4 mmol), and CuI (41 mg, 0.22 mmol) in THF (7.5 mL) was added Pd(PPh 3 ) 2 Cl 2 (76 mg, 0.11 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. The reaction was then heated to 50° C. and stirred under nitrogen for 4 h. The reaction was quenched with water and extracted with EtOAc (×3). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated by rotary evaporation. The product was purified by column chromatography on silica gel (EtOAc / petroleum ether: 1 / 15) to give 1-(2-methoxyethoxy)-2-(2-phenylethynyl)benzene (237 mg, 87% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.47-7.50 (m, 3H), 7.25-7.36 (m, 4H), 6.90-6.97(m, 2H), 4.22(t, J = 4.8 Hz, 2H), 3.84 (t, J = 4.8 Hz, 2H), 3.51 (s, 3H).

[0434] Step B: Preparation of 6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-5H-thieno[3,2-c]pyridin-4-one and 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-5H-thieno[3,2-c]pyridin-4-one: To a solution of 1-(2-methoxyethoxy)-2-(2-phenylethynyl)benzene (230 mg, 0.912 mmol), thiophene-3-carbonitrile (99 mg, 0.91 mmol), potassium hexafluorophosphate (34 mg, 0.18 mmol), and cupric acetate monohydrate (50 mg, 0.27 mmol) in acetic acid (10 mL) was added [{RuCl 2 (p-cymene)} 2 ] (28 mg, 0.046 mmol) was added. The reaction was stirred at 120° C. for 10 h. The reaction was concentrated to dryness and the residue was taken up in EtOAc. The organic layer was washed with water and brine, dried and concentrated. The crude product was purified by column chromatography (5% MeOH in DCM) to give a mixture of 6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-5H-thieno[3,2-c]pyridin-4-one and 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-5H-thieno[3,2-c]pyridin-4-one (201 mg, 58% yield). LCMS ESI (+) m / z 378.1 (M+H).

[0435] Step C: Preparation of 4-chloro-6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-thieno[3,2-c]pyridine and 4-chloro-7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridine: POCl 3A solution of 6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-5H-thieno[3,2-c]pyridin-4-one and 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-5H-thieno[3,2-c]pyridin-4-one (201 mg, 0.533 mmol) in (5.0 mL) was stirred at 100° C. for 3 h. The reaction was concentrated to dryness and the residue was taken up in EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried and concentrated. The crude product was then purified by column chromatography (20% EtOAc in hexanes) to give a mixture of two isomers, which was further purified by reverse phase HPLC to give 4-chloro-6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-thieno[3,2-c]pyridine (41 mg, 19% yield) and 4-chloro-7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridine (64 mg, 30% yield). LCMS ESI (+) m / z 396.1 (M+H).

[0436] Step D: Preparation of tert-butyl 6-[7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: 4-chloro-6-[2-(2-methoxyethoxy)phenyl]-7-phenyl-thieno[3,2-c]pyridine and 4-chloro-7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridine in 1,4-dioxane (2 mL) and water (0.2 mL). To a suspension of a mixture of [,2-c]pyridine (18 mg, 0.046 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (20 mg, 0.056 mmol) and sodium carbonate (14 mg, 0.13 mmol) was added 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (4.0 mg, 0.0055 mmol). The mixture was stirred at 85° C. under Ar for 4 h. The mixture was concentrated and purified by preparative TLC (EtOAc / petroleum ether: 1 / 4) to give tert-butyl 6-[7-[2-(2-methoxyethoxy)phenyl]-6-phenylthieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 mg, 82%) as a pale yellow solid.

[0437] Step E: Preparation of 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridine: To a solution of tert-butyl 6-[7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 mg, 0.037 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 10° C. for 2 h. The mixture was concentrated and purified by reverse phase preparative HPLC to give 7-[2-(2-methoxyethoxy)phenyl]-6-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[ 3,2-c]pyridine (15 mg, 83% yield) as the trifluoroacetate salt. LCMS ESI (+) m / z 493.2 (M+H). 1 H NMR (400 MHz, CD 3 OD) δ: 7.95 (d, J = 4.8 Hz, 1H), 7.85-7.88 (m, 2H),7.72 (d, J = 5.6 Hz, 1H), 7.47-7.55 (m, 3H), 7.42 (t, J = 8.0 Hz, 1H), 7.24-7.38 (m, 4H), 7.08 (d, J =8.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.52 (s, 2H), 4.00-4.08 (m, 1H), 3.84-3.88 (m, 1H), 3.60 (t, J = 6.2 Hz, 2H), 3.42-3.53 (m, 2H), 3.15 (s, 3H).

[0438] Synthesis Example 3: Synthesis of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]benzonitrile (Compound 8) [ka] Step A: Preparation of 6-(3-iodophenyl)-5H-thieno[3,2-c]pyridin-4-one: To a solution of 2-methylthiophene-3-carboxylic acid (2.00 g, 14.1 mmol) in THF (20 mL) was added n-butyllithium (12.0 mL, 2.5 M in hexanes, 30.0 mmol) dropwise under Ar at -78°C. The mixture was stirred at -60°C for 0.5 h under Ar. Then 3-iodobenzonitrile (3.50 g, 15.3 mmol) was added at -60°C. The temperature was warmed to 0°C and the resulting mixture was stirred at 0°C for an additional 1 h. The mixture was poured into water and the pH was adjusted to 5 with 1N HCl. The mixture was concentrated to remove THF and diluted with water. The solid was filtered, washed with water (20 mL) and EtOAc (20 mL), then dried in vacuo to give the crude product 6-(3-iodophenyl)-5H-thieno[3,2-c]pyridin-4-one (2.30 g, 46% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.14 (s, 1H), 7.77-7.83(m, 2H), 7.64 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.27-7.31 (m, 2H).

[0439] Step B: Preparation of 3-(4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile: A suspension of copper(I) cyanide (76 mg, 0.85 mmol) and 6-(3-iodophenyl)-5H-thieno[3,2-c]pyridin-4-one (200 mg, 0.566 mmol) in DMF (5 mL) was stirred at 130° C. for 16 h. The mixture was cooled to ambient temperature. Ammonia (1 mL) was added and the mixture was stirred for an additional 2 h. The pH was adjusted to 6 with 3N HCl. The solid was collected by filtration and then washed with water and EtOAc / petroleum ether (1 / 1). The solid was dried in vacuum to give 3-(4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (110 mg, 77% yield) as a yellow solid. LCMS ESI (+) m / z 253.0 (M+H).

[0440] Step C: Preparation of 3-(7-bromo-4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile: To a solution of crude 3-(4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (1.27 g, 5.03 mmol) in DMF (15 mL) was added N-bromosuccinimide (941 mg, 5.29 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was poured into water and the solid was filtered, washed with water and EtOAc / petroleum ether (1 / 1), then dried in vacuum to give 3-(7-bromo-4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (870 mg, 52% yield) as a yellow solid. LCMS ESI (+) m / z 331, 333 (M+H).

[0441] Step D: Preparation of 3-(7-bromo-4-methoxy-thieno[3,2-c]pyridin-6-yl)benzonitrile: To a suspension of 3-(7-bromo-4-oxo-5H-thieno[3,2-c]pyridin-6-yl)benzonitrile (870 mg, 2.63 mmol) and silver carbonate (761 mg, 2.76 mmol) in toluene (20 mL) was added methyl iodide (0.41 mL, 6.6 mmol). The mixture was stirred at 90° C. for 16 h in a sealed tube. The mixture was filtered through Celite® and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc / petroleum ether: 1 / 5) to give 3-(7-bromo-4-methoxy-thieno[3,2-c]pyridin-6-yl)benzonitrile (592 mg, 65% yield) as a pale yellow solid.

[0442] Step E: Preparation of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methoxy-thieno[3,2-c]pyridin-6-yl]benzonitrile: To a solution of 3-(7-bromo-4-methoxy-thieno[3,2-c]pyridin-6-yl)benzonitrile (290 mg, 0.840 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added [4-fluoro-2-(2-methoxyethyl)phenyl]boronic acid (216 mg, 1.09 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (61 mg, 0.084 mmol), and sodium carbonate (178 mg, 1.68 mmol). The mixture was stirred at 100° C. for 4 h. After cooling, the mixture was poured into water (20 mL) and the product was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by preparative TLC (petroleum ether: EtOAc = 3:1) to give 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methoxy-thieno[3,2-c]pyridin-6-yl]benzonitrile (280 mg, 77% yield). LCMS ESI (+) m / z 435 (M+H).

[0443] Step F: Preparation of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridin-6-yl]benzonitrile: To a solution of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methoxy-thieno[3,2-c]pyridin-6-yl]benzonitrile (205 mg, 0.472 mmol) in acetonitrile (20 mL) was added sodium iodide (212 mg, 1.42 mmol) and trimethylchlorosilane (0.180 mL, 1.42 mmol). The mixture was stirred at 0° C. for 2 h. The mixture was poured into water (20 mL) and the solid was filtered to give 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridin-6-yl]benzonitrile (150 mg, 76% yield). LCMS ESI (+) m / z 421 (M+H).

[0444] Step G: Preparation of 3-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]benzonitrile: A solution of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridin-6-yl]benzonitrile (150 mg, 0.357 mmol) in phosphorus oxychloride (3.00 mL, 32.2 mmol) was stirred at 90° C. for 1 h. After cooling, the mixture was poured into ice water (20 mL). NaHCO 3 was carefully added and the pH was adjusted to 8. The product was extracted with EtOAc (50 mL). The combined organic layers were washed with brine and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by preparative TLC (petroleum ether:EA=5:1) to give 3-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]benzonitrile (130 mg, 83% yield). LCMS ESI (+) m / z 439.0 (M+H).

[0445] Step H: Preparation of tert-butyl 6-[6-(3-cyanophenyl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: 3-[4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-yl]benzonitrile (III) in 1,4-dioxane (2 mL) and water (0.2 mL). 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 (130 mg, 0.296 mmol), sodium carbonate (63 mg, 0.59 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (22 mg, 0.030 mmol) were added. The mixture was stirred at 95° C. under Ar for 2 h. After cooling, the mixture was poured into water (20 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by preparative TLC (petroleum ether:EA=3:1) to give tert-butyl 6-[6-(3-cyanophenyl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (160 mg, 85% yield). LCMS ESI (+) m / z 636 (M+H).

[0446] Step I: Preparation of 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]benzonitrile: To a solution of tert-butyl 6-[6-(3-cyanophenyl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (17 mg, 0.027 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC to give 3-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)thieno[3,2-c]pyridin-6-yl]benzonitrile (4.5 mg, 31% yield) as the trifluoroacetate salt. LCMS ESI (+) m / z 536 (M+H). 1H NMR (400 MHz, CD 3 OD) δ 7.89 (s, 1H), 7.81-7.86 (m, 3H), 7.68-7.72 (m, 2H), 7.63 (d, J = 8 Hz, 1H), 7.39-7.47 (m, 2H), 7.32-7.35 (m, 1H), 6.90 (dd, J = 11.1, 2.2 Hz, 1H), 6.79-6.83 (m, 1H), 4.49 (s, 2H), 3.98-4.01 (m, 1H), 3.83-3.86 (m, 1H), 3.60 (t, J = 6.4 Hz, 2H), 3.44 (t, J = 4.8, 2H), 3.26-3.30 (m, 2H), 3.15 (s, 3H).

[0447] Synthesis Example 4: 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]phenyl]methyl]prop-2-enamide (compound 11) [ka] Step A: Preparation of tert-butyl 6-[6-[3-(aminomethyl)phenyl]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[6-(3-cyanophenyl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (178 mg, 0.280 mmol) in methanol (5 mL) was added cobalt chloride (73 mg, 0.56 mmol) and sodium borohydride (106 mg, 2.80 mmol). The mixture was stirred at 25° C. for 12 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine and sodium 2 SO 4 The mixture was dried at 40° C. and concentrated. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give tert-butyl 6-[6-[3-(aminomethyl)phenyl]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (135 mg, 75% yield). LCMS ESI (+) m / z 640.3 (M+H).

[0448] Step B: Preparation of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-[(prop-2-enoylamino)methyl]phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: To a solution of tert-butyl 6-[6-[3-(aminomethyl)phenyl]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (12 mg, 0.019 mmol) in DCM (2 mL) was added triethylamine (0.0078 mL, 0.056 mmol). The mixture was cooled to -20 °C. To this was added a solution of prop-2-enoylprop-2-enoate (2.8 mg, 0.023 mmol) in DCM. The mixture was stirred at -20°C for 15 min. The reaction was diluted with H 2 The mixture was quenched with 2H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layer was concentrated and the residue was purified by preparative TLC (EtOAc / petroleum ether: 50-100% EtOAc) to give tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-[(prop-2-enoylamino)methyl]phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (12 mg, 92% yield). LCMS ESI (+) m / z 694.3 (M+H).

[0449] Step C: Preparation of N-[[3-[7-[4-f...

Claims

1. Compound of formula I-av': 【Chemistry 246】 or a pharmaceutically acceptable salt thereof, wherein: portion 【Chemistry 247】 but 【Chemistry 248】 and Ring C is selected from the group consisting of a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from the group consisting of phenyl, nitrogen, oxygen, and sulfur, and a 4-8 membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Ring D is selected from the group consisting of a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and phenyl; Ring E is selected from the group consisting of a 5- to 6-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Ring F is a 5- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Each -L-W is -CN, 【Chemistry 249】 or is selected from the group consisting of each L is independently selected from the group consisting of —C(O)CClH—, —C(O)CClF—, —C(O)CH═CH—, —N(R)C(O)CH═CH—, —C(O)C(═CH 2 )—, —C(O)C(═CHCH 3 )—, —C(O)CH═CH—CH 2 —, —C(O)CH═CHCH 2 OCH 2 —, —C(O)CH═CHCH 2 N(R)—, —CH 2 N(R)C(O)CH═CH—, —CH 2 CH 2 N(R)C(O)CH═CH—, —C(O)C≡C—, —C(O)C≡CCH 2 —, and —SO 2 CH═CH—; each W is independently hydrogen, halogen, or —CN; Each R ２ and R ２’ are independently halogen or C １－６ is alkyl, Each R ３ are independently selected from halogen, —OR, —O(CH ２ ) ｖ Cy, and —O—(C 1-4 alkylene)-OR; Each Cy is independently a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Cy is selected from 0 to 2 R ６ is replaced by Each R ４ are independently halogen or C alkyl; R ５ and R ５’ each independently represents oxo, ═NH, halogen, —OR, —N(R) ２ and C 1-6 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR, and —N(R) 2 ; Each R ６ is independently selected from the group consisting of oxo, halogen, —OR, and C 1-6 alkyl unsubstituted or substituted with one or more halogens or —OR; each R is independently hydrogen or C 1-6 alkyl unsubstituted or substituted with one or more halogens; m is 1, 2, or 3; n is 0 or 1, p is 0, 1, or 2; r is 0 or 1; s is 0, 1, 2, or 3; u is 1, each v is independently 0, 1, or 2; y is 0, 1, or 2; The compound, or a pharmaceutically acceptable salt thereof.

2. The compound is a compound of formula IF or IF1: 【Chemical Engineering 212】 【Chemistry 213】 2. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

3. The part [Chemical 250] but 【Chemistry 221】 2. The compound of claim 1, wherein:

4. The part 【Chemistry 251】 but, 【Chemistry 252】 4. The compound of claim 3, wherein:

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R 3 is —OCH 2 CH 2 OCH 3 .

6. The part 【Chemistry 253】 but, 【Chemistry 254-1】 【Chemistry 254-2】 4. The compound of claim 3, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2 or 3.

8. At least one R ３ is halogen, or —O—(C １－４ 2. The compound of claim 1, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 11; R is 11 or 12; R is 13 or 14; R is 15 or 16; R is

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 4 is halogen.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R 4 is F.

12. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl. 【Request Item 13】 【Chemistry 229】 but, 【Chemistry 230】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 229】 but, 【Chemistry 255】 14. The compound of claim 13, wherein:

15. 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein ring E is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

16. s R ５’ Ring E substituted with 【Chemistry 256-1】 【Chemistry 256-2】 【Chemistry 256-3】 14. The compound of claim 13, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request Item 17】 【Chemistry 232】 but, 【Chemistry 257-1】 【Chemistry 257-2】 【Chemistry 257-3】 【Chemistry 257-4】 14. The compound of claim 13, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein s is 1, 2, or 3.

20. Each R ５’ are independently oxo, ═NH, —OR, —N(R) ２ , and C １－６ alkyl, C １－６ The alkyl may be unsubstituted or may contain one or more halogens, -N(R) ２ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with -OR.

21. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2.

22. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein s is 1 and R 5' is C 1-6 alkyl.

23. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring D is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 【Request Item 24】 【Chemistry 234】 but, 【Chemical 235】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. u -L-W and y R ２’ Ring F substituted with 【Chemistry 258】 25. The compound of claim 24, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request Item 26】 【Chemistry 237】 but, 【Chemistry 259-1】 【Chemistry 259-2】 25. The compound of claim 24, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein y is 1 or 2.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein each R 2' is independently C 1-6 alkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein y is 1.

30. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein r is 0.

31. each -L-W is independently -CN; 【Chemical 260】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

32. Each -L-W is independently -C(O)CH=CH ２ , -C(O)CF=CH ２ , -NHC(O)CF=CH ２ and —NHC(O)CH═CH ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

33. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

34. Structure: 【Chemistry 261】 10. A compound having the formula:

35. Structure: 【Chemistry 262】 35. The compound of claim 34, having the formula: or an atropisomer thereof.

36. Structure: 【Chemical 263】 10. A compound having the formula:

37. Structure: 【Chemistry 264】 37. The compound of claim 36, having the formula:

38. 38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

39. 38. A pharmaceutical composition for treating a disease, disorder, or condition ameliorated by disrupting, inhibiting, and / or preventing the interaction of a small GTPase with a PI3Kα protein, comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of claim 39, wherein the small GTPase is a RAS protein selected from the group consisting of KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, and RIT1.

41. The pharmaceutical composition of claim 40, wherein the disease, disorder, or condition that is ameliorated by disrupting, inhibiting, and / or preventing the interaction between a small GTPase and a PI3Kα protein is cancer.

42. The pharmaceutical composition of claim 41, wherein the cancer is associated with and / or characterized by abnormal activation of PI3Kα and / or mutation of PI3Kα.

43. The pharmaceutical composition of claim 42, wherein the PI3Kα protein comprises N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L mutations.

44. The pharmaceutical composition of claim 41, wherein the cancer is characterized by a mutation in the KRAS protein.

45. The pharmaceutical composition of claim 44, 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.

46. ​​The pharmaceutical composition of claim 45, wherein the KRAS protein comprises a G12C or G12D mutation.

47. The pharmaceutical composition described in claim 41, wherein the cancer is characterized by mutation, overexpression, and / or amplification of a receptor tyrosine kinase, and / or mutation or deficiency of a PTEN protein.

48. The cancer is selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, cancer of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, liver and biliary tract, bone, connective tissue, skin, cervix, uterus, endometrial corpus, testis, bladder, kidney and other urinary tract tissues including renal cell carcinoma (RCC), eye, brain, spinal cord, and other components of the central and peripheral nervous system, and meninges, etc.

42. The pharmaceutical composition of claim 41, wherein the tumor is selected from the group consisting of cancers of the thyroid and related structures, cancers of the thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin's lymphoma, 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.

49. The pharmaceutical composition described in claim 40, wherein the disease, disorder, or condition that is ameliorated by disrupting, inhibiting, and / or preventing the interaction between a small GTPase and a PI3Kα protein is a metabolic disorder, RAS disease, or vascular disorder.

50. The pharmaceutical composition of claim 49, wherein (i) the metabolic disorder is hyperinsulinemia or type 2 diabetes, (ii) the RAS disease is selected from the group consisting of neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, and Legius syndrome, and / or (iii) the vascular disorder or condition is PIK3CA-associated overgrowth syndrome (PROS), or a vascular malformation (e.g., venous malformation, lymphatic malformation, CLOVES syndrome (CLOVES), Klippel-Trenaunay syndrome, PTEN hamartoma tumor syndrome (PHTS), and fibrolipovascular anomaly (FAVA)).

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