Fused pyridines for the treatment of cancer and other indications

Abstract

Provided herein are compounds of Formulae I" and II and compositions thereof capable of disrupting, interrupting, and / or preventing the interaction between a small GTPase protein and a PI3K protein (e.g., PI3Ka). The present disclosure also provides methods of treating cancer and other indications with such compounds or compositions thereof.

Description

[0001] Government support This invention was completed with government support under patent 75N91019D00024 granted by the National Institutes of Health and patent DE-AC52-07NA27344 granted by the U.S. Department of Energy. The government holds certain rights to this invention.

[0002] Cross-references to related applications This application claims priority and interest in U.S. Application No. 63 / 518,242, filed August 8, 2023, and U.S. Application No. 63 / 666,479, filed July 1, 2024, the entire contents of each of which are hereby incorporated by reference. Background Technology

[0003] An estimated 600,000 Americans will die from cancer in 2021, corresponding to more than 1,600 deaths per day (Cancer Facts & Figures 2021). Men are the leading cause of death from lung, prostate, and colorectal cancer, while women are the leading cause of death from these cancers. Nearly a quarter of all cancer deaths are due to lung cancer, with 82% of those deaths directly caused by smoking. The 5-year survival rate for lung cancer is only about 20%.

[0004] Aberrant activation of phosphoinositol 3-kinase (PI3K) is one of the most common oncogenic events in human cancers, and its inhibition is an attractive therapeutic approach. PI3K signaling is downstream of receptor tyrosine kinase (RTK), G protein-coupled receptor (GPCR), and RAS proteins to regulate a wide range of cellular activities, including metabolism, proliferation, and migration.

[0005] The frequency of PI3K-induced carcinogenic events has driven the development and testing of PI3K inhibitors. Most PI3K inhibitors currently in clinical development are reversible ATP-competitive kinase inhibitors. Despite considerable effort, clinical results for PI3K-based therapy in solid tumors have been disappointing, primarily due to intolerable toxicity and drug resistance. Summary of the Invention

[0006] This disclosure provides novel treatments for cancer and other indications (e.g., cancers and other indications associated with and / or characterized by aberrant activation of PI3K). This disclosure covers the understanding that therapeutic agents (e.g., therapeutic agents comprising small molecules, such as the compounds provided herein) that disrupt, inhibit, and / or prevent the interaction between PI3K proteins (e.g., PI3Kα) and small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) may be particularly useful for treating, improving, or eliminating symptoms of cancer and / or other indications (e.g., those associated with and / or characterized by aberrant activation of PI3K), delaying their progression, and / or inhibiting their symptoms. Unbound by theory, the therapeutic agents described herein (e.g., those comprising small molecules, such as the compounds described herein) may be able to bind to PI3K proteins (e.g., PI3Kα) while exhibiting (i) 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) no substantial effect on the kinase activity of PI3K proteins (e.g., PI3Kα). In some embodiments, such therapeutic agents may offer advantages such as improved efficacy or reduced side effects, for example, compared to ATP-competitive PI3K kinase inhibitors as described herein. For example, in some embodiments, such therapeutic agents may reduce hyperglycemia and / or hyperinsulinemia relative to PI3K kinase inhibitors.

[0007] This disclosure provides compounds (including those in any available form, such as salts) that can be used to disrupt, inhibit, and / or prevent the interaction between PI3K proteins (e.g., PI3Kα) and small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). In some embodiments, this disclosure provides compounds capable of binding to the PI3Kα protein such that (i) the interaction between the small GTPase (e.g., Rac1, CDC42, or RAS proteins 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 can be used to treat cancer or other indications as described herein.

[0008] In some embodiments, this disclosure provides a compound of formula I'': I'' Or its salts (e.g., pharmaceutically acceptable salts), wherein ring A, ring B, ring C, ring D, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' Each of m, n, p, q, and r is as defined in this document.

[0009] In some embodiments, this disclosure provides a compound of formula I': I' Or its salts (e.g., pharmaceutically acceptable salts), wherein ring A, ring B, ring C, ring D, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' Each of m, n, p, q, and r is as defined in this document.

[0010] In some embodiments, this disclosure provides a compound of formula I: I Or its salts (e.g., pharmaceutically acceptable salts), wherein ring A, ring B, ring C, ring D, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' Each of m, n, p, q, and r is as defined in this document.

[0011] In some embodiments, this disclosure provides a compound of formula II: II Or its salts (e.g., pharmaceutically acceptable salts), wherein rings A, B, D, J, R 1 R 2 R 4 R 5 Each of X, m, n and q is as defined in this document.

[0012] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of formula I'', I', I, or II) or a salt thereof (e.g., a pharmaceutically acceptable salt), and a pharmaceutically acceptable carrier.

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

[0014] In some embodiments, this disclosure provides a method for treating, improving, or otherwise treating cancer and / or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K), delaying their progression, improving or eliminating their symptoms, and / or inhibiting cancer and / or other indications, the method comprising administering a compound provided herein (e.g., a compound of formula I'', I', I, or II) or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0015] In some embodiments, this disclosure provides the use of compounds provided herein (e.g., compounds of formula I'', I', I, or II) or salts thereof (e.g., pharmaceutically acceptable salts) in the manufacture of medicaments for treating, improving, or inhibiting cancer or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K). This disclosure also provides a compound (e.g., compounds of formula I'', I', I, or II) or a salt thereof (e.g., pharmaceutically acceptable salts) used as a medicament for treating, improving, or inhibiting cancer or other indications (e.g., indications associated with and / or characterized by aberrant activation of PI3K).

[0016] Detailed Implementation Plan Compounds and definitions The compounds disclosed herein include those generally described above, and are further illustrated by the categories, subclasses, and species disclosed herein. Unless otherwise specified, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry," 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0017] Unless otherwise stated, the structures described herein are intended to include all stereoisomers (e.g., enantiomers, diastereomers, trans-restricted isomers, or epimers) of the structures, as well as all geometric or conformational isomers of the structures. For example, the R and S configurations of each stereocenter are considered as part of this disclosure; and the D and L isomers of each compound are considered as part of this disclosure. Thus, single stereochemical isomers of the provided compounds, as well as enantiomers, diastereomers, trans-restricted isomers, and geometric (or conformational) mixtures, are within the scope of this disclosure. For example, in some cases, Table 1, Table 2, or Table 3 shows one or more stereoisomers of the compounds, and unless otherwise specified, represents each stereoisomer individually and / or as a mixture. This disclosure includes all cis, trans, cis-trans-trans (entgegen, E), and cis (zusammen, Z) isomers, and mixtures thereof. The various stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomers and then separating them (such as converting to a mixture of diastereomers and then separating by, for example, recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral column, or any other suitable method). Starting compounds with specific stereochemistry are commercially available or can be prepared and resolved by various techniques. Unless otherwise stated, all tautomeric forms of the provided compounds (e.g., rapid interconversion forms) are within the scope of this disclosure.

[0018] Unless otherwise specified, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures disclosed herein (including hydrogen replaced by deuterium or tritium, or carbon replaced by...) 13C or 14 Compounds enriched with carbon (substituted with C) are within the scope of this disclosure.

[0019] Fat group: As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units (e.g., multiple bonds, such as double or triple bonds). Unless otherwise stated, an aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms; and in yet another embodiment, the aliphatic group contains 1-2 aliphatic carbon atoms.

[0020] alkyl: The term "alkyl" as used alone or as part of a larger part refers to having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3 or 1-2 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 1-12 C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 Or C 1-2 Alkyl groups are saturated, optionally substituted, straight-chain or branched hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl), isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, and nonyl. As used herein, the term "alkylene" alone or in combination refers to a divalent, saturated, optionally substituted, straight-chain or branched hydrocarbon, such as methylene (-CH2-).

[0021] Alkenyl: The term "alkenyl" used alone or as part of a larger part refers to having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 Alkenyl groups are optionally substituted straight-chain or branched hydrocarbon chains. Examples of alkenyl groups include vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0022] alkynyl group:The term "alkynyl" used alone or as part of a larger part refers to a group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The alkynyl group is a straight-chain or branched hydrocarbon group that may be optionally substituted. Examples of alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, butyrynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hextriynyl.

[0023] Aryl The term "aryl" as used alone or as part of a larger part (such as in "aralkyl", "aralkyloxy", or "aryloxyalkyl") refers to a monocyclic or bicyclic ring system having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aryl ring". Examples of aryl groups include phenyl, naphthyl, anthracene, etc., which may carry one or more substituents as defined herein. As used herein, the term "aryl" also includes, within the scope of the term, a group in which an aromatic ring is fused with one or more non-aromatic rings (such as indanyl or tetrahydronaphthyl). Unless otherwise stated, "aryl" is a hydrocarbon.

[0024] Carbon cyclo group: As used herein, the terms “carbocyclic group,” “carbocycle,” and “carbocyclic ring” refer to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic system having 3 to 14 members, as described herein, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups may include fused ring systems, bridged ring systems, and / or spirocyclic systems (e.g., systems comprising 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, “carbocyclic group” (or “alicyclic”) refers to a fully saturated or optionally substituted monocyclic C3-C8 hydrocarbon or optionally substituted C5-C hydrocarbon containing one or more unsaturated units but not aromatic. 10Bicyclic hydrocarbons. The term "cycloalkyl" refers to a saturated ring system with optional substitution of 3 to 10 carbon atoms. In some embodiments, the cycloalkyl has 3 to 6 carbons. Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having 3 to 10 carbon atoms with optional substitution. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0025] Composition As used herein, the term "composition" refers to a discrete physical entity comprising one or more specified components (e.g., a product comprising one or more specified components (e.g., in specified amounts) or a product obtained directly or indirectly from a combination of specified amounts of specified components). Unless otherwise stated, a composition can be in any form—e.g., gas, gel, liquid, solid, etc. A composition may comprise one or more pharmaceutically acceptable components, such as carriers, diluents, or excipients. "Pharmaceutically acceptable" generally means that a carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipient. For example, a "pharmaceutically acceptable excipient" is a substance that helps administer the active agent to a subject and helps it be absorbed by the subject.

[0026] halogen The term "halogen" or "halogenated" refers to F, Cl, Br, or I.

[0027] heteroaryl The terms "heteroaryl," "heteroarylene," and "heteroarylene" used alone or as part of a larger portion (e.g., "heteroarylene alkyl" or "heteroarylene alkoxy") refer to a group having 5 to 14 ring atoms (e.g., a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in the ring array; and having optionally substituted groups with one to five heteroatoms other than carbon atoms. Examples of heteroaryl groups include thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, and pteridinyl. As used herein, "heteroaryl" also includes groups in which the heteroarylene ring is fused with one or more aryl, alicyclic, or heterocyclic rings. Examples of bicyclic heteroaromatic groups include indolyl, isoindolyl, benzothiophene, benzofuranyl, indazole, indolazinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, benzothiadiazolyl, tetrazolpyridazinyl, thienopyridyl, furanopyridyl, pyrrolopyridyl, chromonel, coumarinyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, and 4-hydroxyl. H-Quinazinyl. Examples of tricyclic heterocyclic groups include carbazole, phenanthroline, dibenzofuranyl, acridineyl, phenazinyl, phenanthiazinyl, phenoxazinyl, and xanthonyl. It should be understood that certain tautomeristic forms of heteroaryl rings may exist and are covered by the term "heteroaryl". Such tautomeristic forms include, for example, pyridine-2(1 H )-ketone.

[0028] heteroatoms The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon); any quaternized form of basic nitrogen or a substituted nitrogen of a heterocycle, such as N (e.g., in 3,4-dihydro-2- H -pyrrole group), NH (as in pyrroleyl group) or NR + (e.g., in N-substituted pyrroleyl groups). In some embodiments, the heteroatom is selected from oxygen, sulfur, and nitrogen.

[0029] Heterocyclic As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (preferably one to four) heteroatoms in addition to one or more carbon atoms, as defined above. When used to refer to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. Heterocycles may include fused ring systems, bridged ring systems, and / or spirocyclic systems (e.g., systems comprising two rings sharing a single carbon atom). Heterocycles may be attached to their side groups at any heteroatom or carbon atom that produces 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 groups include tetrahydrofuranyl, tetrahydrophenylthio, pyrrolyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxalyl, dioxopentyl, diazaphenyl, oxazphenyl, thioazphenyl, morpholinyl, and quininecycloyl. As used herein, "heterocycle" also includes groups in which the heterocycle is fused with one or more aryl, heteroaryl, or alicyclic rings (such as indolinel, 3...). H- (Indole, benzodihydropyranyl, phenanthridine, or tetrahydroquinolinyl).

[0030] Partially unsaturated As used herein, the term "partially unsaturated" in the context of ring motifs means a ring motif containing at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to cover rings with multiple unsaturated sites, but not to include aryl or heteroaryl motifs as defined herein.

[0031] Patient or subject: As used herein, the terms "patient" or "subject" refer to any organism to which, for example, a compound or composition is administered or may be administered for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, hamsters, guinea pigs, cats, dogs, goats, pigs, sheep, cattle, deer, horses, non-human primates, and / or humans). In some embodiments, the patient or subject is a human. In some embodiments, the patient or subject suffers from or is susceptible to one or more conditions or disorders. In some embodiments, the patient or subject exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or subject has been diagnosed with one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received certain therapies for the diagnosis and / or treatment of a disease, condition, or disorder.

[0032] Prevention or prevention: As used herein, when used in conjunction with the occurrence of a disease, condition, and / or disorder, “prevent” or “prevention” means reducing the risk of developing a disease, condition, or disorder; delaying the onset of one or more features or symptoms of a disease, condition, or disorder; and / or preventing the escalation of a disease, condition, or disorder. Preventing a disease, condition, or disorder may involve completely preventing the disease and / or preventing its progression (e.g., to a later stage of the disease, condition, or disorder). For example, preventing a disease may not mean completely eliminating any level of influence associated with the disease, but may mean preventing the symptoms of the disease, condition, or disorder to a clinically significant or detectable level. Prevention is considered complete when the onset of a disease, condition, or disorder has been delayed for a predetermined period of time.

[0033] Alternative or optional alternative: As described herein, the compounds disclosed may contain an "optionally substituted" moiety (e.g., a moiety with one or more substituents). Generally, regardless of whether the preceding term "optionally" is used, the term "substituted" means that one or more hydrogens of the specified moiety are replaced by suitable substituents. "Substituent" applies to one or more hydrogens in a structure that is explicit or implicit (e.g., At least refers to ;and At least refers to , or Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions permissible for the production, detection, and, in some embodiments, recovery, purification, and use for one or more purposes provided herein. A group described as "substituted" preferably has between 1 and 4 substituents, more preferably 1 or 2 substituents. A group described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0034] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°、-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted with R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2)0-4 SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0- 4SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° can be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5 to 6-membered heteroaryl ring) or 3 to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, although defined above, two independently occurring R° together with one or more intermediate atoms to form a 3 to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0035] The suitable monovalent substituents on R° (or the ring formed by two independently occurring R° along with their intermediate atoms) are independently halogens, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● )2、-O(halogenated R ● -CN, -N3, -(CH2) 0-2 C(O)R ●-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0- 2SH、-(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● All are either unsubstituted or, in the case of a preceding "halogenation," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0036] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O ("oxo"), =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic or unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6Aliphatic or unsubstituted 5-6 saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0037] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogenated" halogen, substituted by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † S(O)2R † S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, it is hydrogen, and C can be substituted as defined below. 1-6 Aliphatic, or having 0-4 unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl rings independently selected from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring R... † Together with one or more intermediate atoms, they form unsubstituted 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0039] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogenated" halogen, substituted by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0- 1Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] treat: As used herein, the term "treat" (also "treatment" or "treating") refers to any application of a therapy (e.g., a therapeutic agent) that partially or completely reduces, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, features, and / or causes of a particular disease, condition, and / or disorder. Treatment may also refer to any other successful indication of treatment or improvement in an injury, lesion, disease, condition, or disorder, including any objective or subjective parameter such as reduction; alleviation; weakening of symptoms or making the injury, lesion, disease, condition, or disorder more tolerable to the patient; slowing the rate of degeneration or decline; reducing the debilitating nature of the degenerative endpoint; and / or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. In some implementations, such treatment may be directed at subjects who do not exhibit signs of the relevant disease, condition, and / or disorder and / or at subjects who only exhibit early signs of the disease, condition, and / or disorder. Alternatively, such treatment may be directed at a subject exhibiting one or more identified signs of a relevant disease, condition, and / or disorder. In some embodiments, treatment may be directed at a subject who has been diagnosed with a relevant disease, condition, and / or disorder.

[0041] PI3K and small GTPase protein Aberrant activation of phosphatidylinositol 3-kinase (PI3K) is one of the most common oncogenic events in human cancers, and its inhibition is an attractive therapeutic approach. PI3K signaling is downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and RAS proteins to regulate a wide range of cellular activities, including metabolism, proliferation, and migration. Upon activation, PI3K catalyzes the synthesis of the second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2). Signaling proteins such as Ser / Thr kinase AKT (e.g., protein kinase B (PKB)) can bind to PIP3 and thereby localize to the cell membrane. Phosphorylated AKT activates or inhibits a variety of signaling proteins through direct phosphorylation, including mammalian target-complex 1 (mTORC1) (which acts as a regulator of cell growth and survival pathways), cyclin D1, GSK3(B), BAD, MDM2, FOXO, TSC1 / 2, and PRAS40. Chromosome 10-deficient phosphatase and tensin homolog (PTEN) regulate this pathway by dephosphorylating PIP3 to PIP2, thereby preventing the activation of downstream kinases.

[0042] Based on sequence homology and substrate preference, PI3K has been grouped into three independent classes (e.g., class I, class II, and class III). Class I PI3K is further subdivided into two subclasses, IA and IB, according to its regulatory pattern. Class IA PI3K is a heterodimer containing the p110 catalytic subunit and the p85 regulatory subunit, and is most closely associated with human cancer. Class IA PI3K contains the p110α, p110β, and p110δ catalytic subunits produced by different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110γ, produced by PIK3CG, represents the only catalytic subunit in class IB PI3K. The expression of PI3K isotypes (e.g., PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) is cell type specific. The p110α and β isotypes are expressed in all cell types, while p110δ expression is mainly limited to leukocytes. The p110γ isotype is mainly expressed in myeloid cell lineages.

[0043] The PIK3CA gene encodes a 1068-amino acid p110α protein containing 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 by binding directly to the RAS-binding domain (RBD) of the p110α catalytic subunit of PI3Kα via RAS proteins (e.g., HRAS, NRAS, and KRAS). 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 cancer types, including breast cancer, colon cancer, liver cancer, gastric cancer, endometrial cancer, bladder cancer, and lung cancer. The most common hotspot mutations in PIK3CA are E542K, E545K, H1047R, and H1047L, accounting for 80%-90% of all PIK3CA mutations detected in human malignancies. PIK3CA Mutations lead to increased catalytic activity of p110α, which causes downstream effects such as unregulated cell growth, proliferation, and survival.

[0044] Mutations in the RAS protein have been found in over 20% of all cancers. The RAS protein acts as a molecular switch, cycling between an active GTP-binding state and an inactive GDP-binding state. In its active state, the RAS protein interacts with various effector proteins, including PI3K, RAF kinase, and RalGDS, leading to the activation of multiple downstream signaling pathways. Oncogenic RAS mutations primarily occur at amino acid positions G12, G13, and Q61, and these mutations impair GTPase activity, resulting in the accumulation of active RAS protein. The most common oncogenic RAS mutations are G12C, G12D, G12S, G12V, G12R, G13D, and Q61H.

[0045] RAS signaling via PI3K is essential for normal lymphoid development and RAS-induced transformation, particularly in lung cancer, where the interaction between mutant RAS and p110a-RBD is necessary for tumorigenesis and maintenance. The interaction between RAS and p110a-RBD has been shown to be crucial for epidermal growth factor (EGF) to PI3K signaling. Recent studies have demonstrated that disruption of the RAS-PI3K interaction inhibits AKT and RAC1 activation in EGFR-mutant lung cancer cells, leading to reduced growth and survival, and suppressing EGFR mutant-induced tumorigenesis. These results suggest that in EGFR-driven lung adenocarcinoma, the binding of p110a to endogenous RAS proteins is crucial in tumors driven by upstream activators of the RAS pathway, and not only in tumors where RAS mutations are activated.

[0046] Small GTPases (e.g., in addition to RAS) are expected to bind to the RBD of PI3Kα, thereby activating signal transduction. Small GTPases Rac1 and CDC42 have been shown to bind to the RBD of PI3Kβ, and it is hypothesized they will also bind to the RBD of PI3Kα. Therefore, in some embodiments, this disclosure covers the understanding 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).

[0047] The frequency of oncogenic PIK3CA hotspot mutations in cancer has driven the development and testing of numerous PI3K (e.g., PI3Kα) inhibitors. Most PI3K inhibitors currently in clinical development are reversible ATP-competitive kinase inhibitors. Despite considerable effort, clinical outcomes for PI3K-based inhibitors in solid tumors have been disappointing, primarily due to intolerable toxicity and resistance. In 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (BYL719; Novartis Pharma AG), an isotype-specific inhibitor of PI3Kα, 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 isotype selectivity and off-tumor toxicity. Furthermore, hyperglycemia and hyperinsulinemia have been observed as major dose-limiting toxicities of p110α inhibitors, preventing the use of sufficiently high doses to completely inhibit PI3Kα signaling in tumors. Hyperglycemia and hyperinsulinemia are considered targeted effects of PI3Kα inhibition because inhibiting the PI3K / AKT pathway reduces glucose uptake, which in turn leads to increased insulin secretion and subsequent activation of insulin / insulin-like growth factor I receptors in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of PI3Kα inhibitors. In fact, in the phase III clinical trial of apelelis, hyperglycemia was observed in 65% of patients, leading to serious dose interruptions.

[0048] To overcome the limitations of current PI3Kα inhibitors, novel strategies for targeting PI3Kα are needed. Previous studies have shown that inhibiting the RAS-p110α (RBD) interaction has low toxicity in adult animals while effectively inducing tumor regression. This disclosure covers the understanding that such a treatment approach may be effective in a variety of cancers, including those driven by RAS mutants and / or those driven by mutations or amplifications of receptor tyrosine kinases (RTKs). This disclosure also recognizes that such a treatment approach may offer certain advantages over known PI3Kα inhibitors, such as those targeting the ATP-binding pocket of PI3Kα. For example, the provided techniques avoid the hyperglycemia and insulin-driven resistance common with PI3Kα inhibitors, for example, because such techniques target RAS activation of PI3Kα, which is predominantly present in transformed cells.

[0049] The provided compounds In some embodiments, this disclosure provides compounds that can be used to disrupt, inhibit, and / or prevent the interaction between small GTPases (e.g., RAS proteins as described herein) and PI3Kα proteins. In some embodiments, this disclosure provides compounds capable of binding to PI3Kα such that (i) the interaction between small GTPases (e.g., RAS proteins as described herein) and PI3Kα is disrupted, inhibited, and / or prevented; and / or (ii) the kinase activity of PI3Kα is not significantly inhibited. In some embodiments, such compounds reversibly bind to PI3Kα. As used herein, a compound that "reversibly" binds means a compound capable of binding to and dissociating from a target protein kinase (e.g., PI3Kα). Typically (but not always), reversible inhibitors cannot form a covalent bond with the target protein kinase. In some embodiments, such compounds irreversibly bind to PI3Kα. As used herein, a compound that "irreversibly" binds means a compound capable of interacting with a target protein kinase (e.g., PI3Kα) in a substantially irreversible manner (e.g., forming a covalent bond). In some embodiments, reversible or irreversible inhibitors may be able to covalently interact with PI3Kα. For example, in some embodiments, this disclosure provides compounds comprising an electrophilic moiety (e.g., Michael receptor, etc.) capable of binding (e.g., reversibly or irreversibly) to a cysteine ​​residue (e.g., C242) in, for example, the catalytic subunit of PI3Kα. In some embodiments, the provided compounds that covalently interact with PI3Kα are compounds of formula I or II, wherein -R 5 It includes an electrophilic portion (e.g., Michael receptor, etc.) that is capable of binding to cysteine ​​residues of, for example, PI3Kα (e.g., C242) (e.g., reversibly or irreversibly).

[0050] In some embodiments, this disclosure provides a compound of formula I'': I'' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: Ring A is a phenyl, pyridyl, or 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl; The ring C is selected from phenyl; 9- to 10-membered bicyclic aryl ring; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbon ring; 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring D is absent or selected from phenyl; 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbon rings; 5- to 10-membered bicyclic or polycyclic carbon rings; 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. L is a covalent bond, a divalent straight chain, or a branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-; Furthermore, if ring D does not exist, then L also does not exist; Each R 1 C, independently selected from halogens, with optional substitution 1-6 Alkyl, cycloalkyl, -CN, -C(O)OR, -C(O)NR2, -CH2NR2, -N(R 7 )2、-N=S(R 7 )2、-SR 7 -(C 1-4 Alkylene) OR and -OR 7 , where R 1 The sulfur atoms in it can be oxidized; Each R 7 Independently selected from hydrogen, or optionally substituted C 1-6 Aliphatic, -(C 1-4 alkylene)OR, -(C 1-4 Alkylene)NR2, optionally substituted 3 to 6-membered carbon rings, optionally substituted 4 to 7-membered heteroaryl rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 4 to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Or two Rs 7 The groups, together with one or more atoms to which they are attached, form 4- to 6-membered heterocycles having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2C independently selected from halogens and optionally substituted C 1-6 Aliphatic, and -OR; Each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, optionally substituted carbocyclic rings and optionally substituted C 1-6 aliphatic; Each R 4 C is independently optional substitution 1-6 aliphatic; R 5 C does not exist and is an optional substitution. 1-6 Aliphatic, -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; R 6 and R 6' With optional substitution of C 4-8 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; Each x is independently 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8 The instance is replaced; and Each R 8 C independently selected from oxo, halogenated, and optionally substituted C1-6 Aliphatic.

[0051] In some embodiments, this disclosure provides a compound of formula I'' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0052] In some embodiments, this disclosure provides a compound of formula I': I' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: Ring A is a phenyl, pyridyl, or 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; The ring C is selected from phenyl; 9- to 10-membered bicyclic aryl ring; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbon ring; 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring D is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered carbon ring; a 5- to 10-membered bicyclic or polycyclic carbon ring; a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. And when L is C 2-5 In the case of an alkynyl group, ring D may not be present; L is a covalent bond, a divalent straight chain, or a branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-; Each R 1 C, independently selected from halogens, with optional substitution 1-6 Alkyl, cycloalkyl, -CN, -C(O)OR, -C(O)NR2, -CH2NR2, -SR 7 -(C 1-4 Alkylene) OR and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic, -(C 1-4 alkylene)OR, -(C 1-4 Alkylene)NR2, optionally substituted 3 to 6-membered carbon rings, optionally substituted 4 to 7-membered heteroaryl rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 4 to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Each R 2 C independently selected from halogens and optionally substituted C 1-6 aliphatic; Each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, optionally substituted carbon rings, and optionally substituted C rings 1-6 aliphatic; Each R 4 C is independently optional substitution 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; R 6 and R 6' With optional substitution of C 4-8 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; Each x is independently 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8 The instance is replaced; and Each R 8 C independently selected from oxo, halogenated, and optionally substituted C 1-6 Aliphatic.

[0053] In some embodiments, this disclosure provides a compound of formula I' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0054] In some embodiments, this disclosure provides a compound of formula I: I Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: Ring A is a phenyl group; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; The ring C is selected from phenyl, 9 to 10-membered bicyclic aryl ring, 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9 to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 7-membered carbon ring, 4 to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6 to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 12 to 13-membered polycyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. And when L is C 2-5 In the case of an alkynyl group, ring D may not be present; L is a covalent bond, a divalent straight chain, or a branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-; Each R 1Independently selected from halogens and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 C independently selected from halogens and optionally substituted C 1-6 aliphatic; Each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy and optionally substituted C 1-6 aliphatic; Each R 4 C is independently optional substitution 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; R 6 and R 6' With optional substitution of C 4-8 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; Each x is independently 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8The instance is replaced; and Each R 8 C independently selected from oxo, halogenated, and optionally substituted C 1-6 Aliphatic.

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

[0056] In some embodiments, this disclosure provides a compound of formula I, I', or I'', wherein: Ring A is a phenyl group; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; The ring C is selected from phenyl, 9 to 10-membered bicyclic aryl ring, 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9 to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 7-membered carbon ring, 4 to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6 to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 12 to 13-membered polycyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. And when L is C 2-5 In the case of an alkynyl group, ring D may not be present; L is a covalent bond, a divalent straight chain, or a branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Selected independently from C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 Independently selected from halogens and C 1-6 aliphatic; Each R 3Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, and optionally by one or more R 10 Replacement C 1-6 aliphatic; Each R 4 Independently selected by one or more R 10 Replacement C 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 It is optionally controlled by one or more R 10 Replacement C 2-6 alkenyl, optionally with one or more R 10 Replacement C 2-6 Alkyne group, or 4-membered bicyclic carbon ring; R 6 and R 6' With C 4-8 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; Each x is independently 0, 1, or 2; Each R is independently hydrogen or optionally composed of one or more R... 10 Replacement C 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8 Instance replacement; Each R 8 Independently selected from oxidative, halogenated, and C 1-6 aliphatic; and Each R10 Independently selected from halogens, -CN, -OH, -O(C) 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2.

[0057] In some embodiments, this disclosure provides a compound of formula I', wherein: Ring A is a phenyl group; Ring B is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The ring C is selected from phenyl, 9- to 10-membered bicyclic aryl ring, 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 12- to 13-membered polycyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring D is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 10-membered bicyclic or polycyclic carbon rings, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. L is a covalent bond; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic, -(C 1-4 Alkylene rings (OR) and optionally substituted 4- to 6-membered heterocycles having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur; Each R 2 Independently selected from halogens and C 1-6 aliphatic; Each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, carbide rings, and optionally one or more R 10 Replacement C 1-6 aliphatic; Each R 4 Independently selected by one or more R 10 Replacement C1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 It is optionally controlled by one or more R 10 Replacement C 2-6 alkenyl, optionally with one or more R 10 Replacement C 2-6 Alkyne group, or 4-membered bicyclic carbon ring; R 6 and R 6' With C 4-8 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0; Each x is independently 0, 1, or 2; Each R is independently hydrogen or optionally composed of one or more R... 10 Replacement C 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8 Instance replacement; Each R 8 Independently selected from oxidative, halogenated, and C 1-6 aliphatic; and Each R 10 Independently selected from halogens, -CN, -OH, -O(C) 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2.

[0058] In some embodiments, this disclosure provides a compound of formula IA: IA Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring D, L, R 1 R2 R 3 R 4 R 5 R 6 R 6' , m, n, p, q and r are as defined above for Equation I, and are described individually and in combination in the categories and subclasses of this paper, and wherein: The C1 ring is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring C1 and ring C2 are fused together; and The ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0059] In some embodiments, this disclosure provides a compound of formula IA': IA' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring D, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' , m, n, p, q and r are as defined above for equation I', and are described individually and in combination in the categories and subclasses of this paper, and wherein: The C1 ring is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring C1 and ring C2 are fused together; and The ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0060] In some embodiments, this disclosure provides a compound of formula IB: IB Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' , m, n, p, q and r are as defined above for Equation I, and are described individually and in combination in the categories and subclasses of this paper, and wherein: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Among them, ring D1 and ring D2 are fused; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0061] In some embodiments, this disclosure provides a compound of formula IB1: IB1 Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, q, and r are as defined above for Equation I and are described individually and in combination in the categories and subclasses of this paper; rings C1 and C2 are as defined above for Equation IA and are described individually and in combination in the categories and subclasses of this paper; and rings D1 and D2 are as defined above for Equation IB and are described individually and in combination in the categories and subclasses of this paper.

[0062] In some embodiments, this disclosure provides a compound of formula IB': IB' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, L, R 1 R 2 R 3 R4 R 5 R 6 R 6' , m, n, p, q and r are as defined above for equation I', and are described individually and in combination in the categories and subclasses of this paper, and wherein: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Among them, ring D1 and ring D2 are fused; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0063] In some embodiments, this disclosure provides a compound of formula IB1': IB1' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, q, and r are as defined above for equation I' and are described individually and in combination in the categories and subclasses of this paper; rings C1 and C2 are as defined above for equation IA' and are described individually and in combination in the categories and subclasses of this paper; and rings D1 and D2 are as defined above for equation IB' and are described individually and in combination in the categories and subclasses of this paper.

[0064] It should be understood that for compounds of formula IA, IA', IB1, or IB1', any R 3 All groups can attach to either ring C1 or ring C2. It should also be understood that for compounds of formula IB, IB', IB1, or IB1', any R... 4 R 5 Or R 6' Both groups can attach to ring D1 or ring D2.

[0065] In some embodiments, this disclosure provides a compound of formula IA or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IA' or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IB or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IB' or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IB1 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IB1' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0066] In some embodiments, this disclosure provides a compound of formula IC: IC Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 m, n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula I or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0067] In some embodiments, this disclosure provides a compound of formula IC1: IC1 Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 R 7 n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula I1 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0068] In some embodiments, this disclosure provides a compound selected from formulas IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, and IC1-g: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein the ring C, ring D, ring R 1 R 2 R 3 R 4 R 5 R 7 n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula I-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula I-b or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula I-c or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula I-d or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula I-e or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula I-f or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula I-g or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0069] In some embodiments, this disclosure provides a compound of formula IC2: IC2 Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, or ring R 1 R 2 R 3 R 4 R 5 m, n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IC2 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0070] In some embodiments, this disclosure provides a compound selected from formulas IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, and IC2-g: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring C, ring R 1 R2 R 3 R 4 R 5 m, n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IC2-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2-b or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2-c or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2-d or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2-e or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2-f or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2-g or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0071] In some embodiments, this disclosure provides a compound selected from formulas IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, or IC3-m: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5m, n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IC3-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-b or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-c or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-d or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-e or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-f or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-g or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IC3-h or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3-i or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3-j or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3-k or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3-l or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3-m or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0072] In some embodiments, this disclosure provides a compound of formula IC4: IC4 Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, and ring R 1 R 2 R 3 R 4 R 5 R 7 n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IC4 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0073] In some embodiments, this disclosure provides a compound of formula IC': IC' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IC' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0074] In some embodiments, this disclosure provides a compound of formula IC1': IC1' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 R 7 n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula I1' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0075] In some embodiments, this disclosure provides a compound selected from formulas IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, and IC1'-g: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein the ring C, ring D, ring R 1 R 2 R 3 R 4 R 5 R 7n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula I'-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula I'-b or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula I'-c or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula I'-d or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula I'-e or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula I'-f or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula I'-g or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0076] In some embodiments, this disclosure provides a compound of formula IC2': IC2' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, or ring R 1 R 2 R 3 R 4 R 5 m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IC2' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0077] In some embodiments, this disclosure provides a compound selected from formulas IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, and IC2'-g: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring C, ring R 1 R 2 R 3 R 4 R 5m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IC2'-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2'-b or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2'-c or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2'-d or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2'-e or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2'-f or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC2'-g or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0078] In some embodiments, this disclosure provides a compound selected from formulas IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, or IC3'-m: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IC3'-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-b or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-c or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-d or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-e or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-f or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-g or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-h or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-i or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-j or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-k or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-l or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IC3'-m or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0079] In some embodiments, this disclosure provides a compound of formula IC4': IC4' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, and ring R 1 R 2 R 3 R 4 R 5 R 7 n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IC4' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0080] In some embodiments, this disclosure provides a compound of formula ID: ID Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 , m, n, p, and q are as defined above for Equation I, and are described individually and in combination in the categories and subclasses of this paper; and where: L is a binary straight chain or branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-.

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

[0082] In some embodiments, this disclosure provides a compound of formula ID': ID' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 , m, n, p, and q are as defined above for equation I', and are described individually and in combination in the categories and subclasses of this paper; and where: L is a binary straight chain or branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-.

[0083] In some embodiments, this disclosure provides a compound of formula ID' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0084] In some embodiments, this disclosure provides a compound of formula IE: IE Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, ring D, or ring R 1 R2 R 3 R 4 R 5 R 6 R 6' m, n, p, and q are as defined above for Formula I and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IE or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0085] In some embodiments, this disclosure provides a compound of formula IE1: IE1 Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, and ring R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IE1 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0086] In some embodiments, this disclosure provides a compound selected from formulas IE1-a and IE1-b: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, and ring R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IE1-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IE1-b or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0087] In some embodiments, this disclosure provides a compound of formula IE': IE' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, ring C, ring D, or ring R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IE' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0088] In some embodiments, this disclosure provides a compound of formula IE1': IE1' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, and ring R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IE1' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0089] In some embodiments, this disclosure provides a compound selected from formulas IE1'-a and IE1'-b: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring C, and ring R 1 R 2 R 3 R 4 R 5 R 6 R 6' m, n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IE1'-a or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula IE1'-b or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0090] In some embodiments, this disclosure provides a compound of formula IF': IF' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 2 R 3 R 4 R 5 , n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein; and ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, this disclosure provides a compound of formula IF' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0091] In some embodiments, this disclosure provides a compound of formula IF1': IF1' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 2 R 3 R 4 , n, p, and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein; and ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, this disclosure provides a compound of formula IF1' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0092] In some embodiments, this disclosure provides a compound of formula IF2': IF2' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 3 R 4p and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein; and ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, this disclosure provides a compound of formula IF2' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0093] In some embodiments, this disclosure provides a compound of formula IF3': IF3' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 3 R 4 R 7 p and q are as defined above for formula I' and are described individually and in combination in the categories and subcategories herein; and ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, this disclosure provides a compound of formula IF3' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0094] In some embodiments, this disclosure provides a compound of formula II: II Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: Ring A is a phenyl group and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; J is a covalent bond, a divalent straight chain, or a branched chain. 1-4 hydrocarbon chain; X is -OR, -N(R)2, -C(O)N(R)2 or optionally substituted with a group selected from the following: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 C independently selected from halogens and optionally substituted C 1-6 aliphatic; Each R 4 Independently selected from the arbitrarily substituted C 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 Aliphatic.

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

[0096] In some embodiments, this disclosure provides a compound of formula II, wherein: Ring A is a phenyl group and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; J is a covalent bond, a divalent straight chain, or a branched chain. 1-4 hydrocarbon chain; X is -OR, -N(R)2, -C(O)N(R)2, or a group selected from: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally C 1-6 Alkyl substitution; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Selected independently from C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 Independently selected from halogens and C 1-6 aliphatic; Each R 4 Independently selected by one or more R 10 Replacement C 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 It is optionally controlled by one or more R 10 Replacement C 2-6 alkenyl, optionally with one or more R 10 Replacement C 2-6 Alkyne group, or 4-membered bicyclic carbon ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; Each R is independently hydrogen or optionally composed of one or more R... 10 Replacement C 1-6 aliphatic; and Each R 10 Independently selected from halogens, -CN, -OH, -O(C) 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2.

[0097] In some embodiments, this disclosure provides a compound of formula IIA: IIA Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, J, R 1 R 2 R 4 R 5 X, m, n, and q are as defined above for Equation II, and are described individually and in combination in the categories and subclasses of this paper, wherein: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Among them, ring D1 and ring D2 are fused; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

[0099] It should also be understood that, for compounds of formula IIA, any R 4 Or R 5 Both groups can attach to ring D1 or ring D2.

[0100] In some embodiments, this disclosure provides a compound of formula IIB: IIB Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring B, ring D, J, R 1 R 2 R 4 R5 R 7 X, n, and q are as defined above for Formula II and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIB or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0101] In some embodiments, this disclosure provides a compound selected from formulas IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, or IIB7: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein rings D, J, R 1 R 2 R 4 R 5 R 7 X, n, and q are as defined above for Formula II and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIB1 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIB2 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIB3 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIB4 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIB5 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIB6 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIB7 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0102] In some embodiments, this disclosure provides a compound of formula IIC: IIC Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring B, J, R 1 R 2 R 4 R 5 X, m, n, and q are as defined above for Formula II and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIC or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0103] In some embodiments, this disclosure provides a compound selected from formulas IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, and IIC7: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein rings A, J, R 1 R 2 R 4 R 5 X, m, n, and q are as defined above for Formula II and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIC1 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIC2 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIC3 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIC4 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIC5 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIC6 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IIC7 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0104] In some embodiments, this disclosure provides a compound selected from formulas IID1, IID2, IID3, IID4, IID5, IID6, and IID7: Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein ring A, ring D, J, R 1 R 2 R 4 R 5X, m, n, and q are as defined above for Formula II and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IID1 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IID2 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IID3 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IID4 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IID5 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IID6 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of Formula IID7 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0105] In some embodiments, this disclosure provides a compound of formula IIE: IIE Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein rings B, J, R 1 R 2 R 4 R 5 R 7 X, n, and q are as defined above for Formula II and are described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIe or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0106] In some embodiments, this disclosure provides a compound of formula IIF: IIF Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: X is -C(O)N(R)2 or optionally substituted with a group selected from the following: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0107] In some embodiments, this disclosure provides a compound of formula IIF or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0108] In some embodiments, this disclosure provides a compound of formula IIG: IIG Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: J is a binary straight chain or a side chain. 1-4 hydrocarbon chain; and X is either -OR or -N(R)2.

[0109] In some embodiments, this disclosure provides a compound of formula IIG or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0110] In the formula I, I', I'', IA, IA', IB, IB', IC, IC', IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3- In some embodiments of any one of f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, and IE', ring A is phenyl. In some embodiments, ring A is pyridyl. In some embodiments, ring A is a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0111] In some embodiments of formulas II, IIA, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring A is phenyl. In some embodiments, ring A is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some implementations of any of the forms described herein, R 1 It is a halogen (e.g., fluorine). In some implementations, R 1 Selected from C (optional substitution) 1-6 Alkyl, cycloalkyl (e.g., 3-6 membered cycloalkyl, such as cyclopropyl), -CN, -C(O)OR, -C(O)NR2, -CH2NR2, -SR 7 and -(C 1-4 Alkylene (OR). In some embodiments, R 1 C is an optional substitute 1-6 Alkyl group. In some such embodiments, R 1 C is an optional substitute 1-2 Alkyl group. In some embodiments, R 1 It is -CH3. In some implementations, R 1 It is a cycloalkyl group (e.g., a 3-6 membered cycloalkyl group, such as a cyclopropyl group). In some embodiments, R 1 It is cyclopropyl. In some implementations, R 1 Yes -CN. In some implementations, R 1 It is -C(O)OR. In some such implementations, R 1 It is -C(O)OH. In some embodiments, R 1 It is -C(O)NR2. In some implementations, R 1 It is -C(O)N(CH3)2. In some implementations, R 1 It is -CH2NR2. In some implementations, R 1 It is -CH2N(CH3)2. In some implementations, R 1 It is -SR 7 In some implementations, R 1 It is -SCH3. In some implementations, R 1 Yes - (C 1-4 Alkylene (OR). In some embodiments, R 1 It is -CH2OR. In some implementations, R 1 It is -CH2OH. In some implementations, R 1 It is -CH2OCH3. In some implementations, R 1 Yes - OR 7 In some implementations, at least one R 1 Yes - OR 7 In some implementations, an R 1 Yes - OR 7 And any other R 1The groups are all halogens (e.g., fluorine). In some embodiments, an R 1 Yes - OR 7 And another R 1 The group is a halogen (e.g., fluorine). In some embodiments, an R 1 Yes - OR 7 And two other R 1 The group is halogen (e.g., fluorine).

[0113] In some implementations of any of the forms described herein, each R 7 Selected independently from C 1-6 Aliphatic and -(C 1-4 Alkylene (OR). In some implementations, each R 7 Selected independently from C 1-6 Alkyl and -(C 1-4 Alkylene (OR). In some implementations, each R 7 C is an optional substitute 1-6 Aliphatic. In some implementations, each R 7 It is C 1-6 Aliphatic. In some implementations, each R 7 C is a C substituted with a group selected from the following groups. 1-6 Aliphatic: -(CH2) 0-4 R°、-(CH2) 0-4 OR°、-(CH2) 0- 4N(R°)2、-(CH2) 0-4 N(R°)C(O)R°、-(CH2) 0-4 NHC(O)R°、-(CH2) 0-4 C(O)NHR° and -(CH2) 0-4 C(O)N(R°)2. In some implementations, each R 7 C is replaced by -R°, -OR°, -N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, -C(O)NHR° and -C(O)N(R°)2 1-6 Aliphatic. In some such embodiments, R° is selected from C 1-6 Aliphatic, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 4- to 6-membered carbon ring. In some embodiments, R° is halogenated, oxidized, or -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH and -(CH2)0-2 OR ● Replacement. In some implementations, R° is replaced by halogen, oxidized, or -R. ● -(halogenated R) ● -OH and -OR ● Replacement. In some implementations, R ● It is C 1-4 Aliphatic. In some implementations, R ● It is -CH3 or -CH2CH3. In some embodiments, R° is replaced by halogen, oxo, -CH3, -CH2CF3, -OH and -OCH3.

[0114] In some implementations, each R 7 C is an optional substitute 1-6 Alkyl group. In some embodiments, each R 7 C is a C substituted with a group selected from the following groups. 1-6 Alkyl group: -(CH2) 0-4 R°、-(CH2) 0-4 OR°、-(CH2) 0-4 N(R°)2、-(CH2) 0-4 N(R°)C(O)R°、-(CH2) 0-4 NHC(O)R°、-(CH2) 0-4 C(O)NHR°、-(CH2) 0-4 C(O)N(R°)2. In some implementations, each R 7 C is replaced by -R°, -OR°, -N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, -C(O)NHR° and -C(O)N(R°)2 1-6 Alkyl group. In some embodiments, each R 7 C is replaced by -R°, -OR°, -N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, -C(O)NHR° and -C(O)N(R°)2 1-2 Alkyl group. In some embodiments, R° is selected from C10. 1-6 Aliphatic, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted groups of a 4- to 6-membered carbon ring. In some embodiments, each R 7 It is C 1-6 Alkyl group. In some embodiments, each R 7 Yes - (C 1-4 Alkylene (OR). In some implementations, each R 7 Yes - (C 1-4Alkylene) NR2. In some embodiments, each R 7 C-membered heteroaryl rings independently selected from those of 5- to 6-membered heteroaryl rings independently selected from nitrogen, oxygen, and sulfur, which are optionally substituted. 1-6 Aliphatic; C-shaped compounds with optional substitution of 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Aliphatic; and C-rings substituted with optional 3-7 membered carbon rings. 1-6 Aliphatic. In some implementations, each R 7 C-membered heteroaryl rings independently selected from those of 5- to 6-membered heteroaryl rings independently selected from nitrogen, oxygen, and sulfur, which are optionally substituted. 1-6 Aliphatic. In some implementations, each R 7 C-membered heterocycles independently selected from 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are optionally substituted. 1-6 Aliphatic. In some implementations, R 7 It is an optionally substituted 4- to 6-membered heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, each R 7 C-membered carbon rings independently selected from those substituted by optional 3-7 membered carbon rings 1-6 Aliphatic. In some implementations, each R 7 Selected independently , , , , , , , , , and .

[0115] In some implementations, each R 7 Selected independently , , , , , , , , , , , , , , , , , , , , , and .

[0116] In some implementations, each R 7 Independently selected from optionally substituted 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 4- to 7-membered heteroaryl rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and optionally substituted 3- to 6-membered carbon rings. In some embodiments, each R 7 The heterocycle is independently selected from optionally substituted 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R 7 Independently selected from optionally substituted pyrrolidinyl and piperidinyl groups. In some embodiments, each R 7 The aryl ring is independently selected from 4- to 7-membered heteroaryl rings with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, using optional substitution. In some embodiments, each R 7 The carbon rings are independently selected from optionally substituted 3- to 6-membered carbon rings. In some embodiments, each R... 7 Selected independently , , , , , , , , , , , , and .

[0117] In some implementations, each R 7 Selected independently , , , , , , , , , , , , , , and .

[0118] In some embodiments of any of the forms described herein, at least one R 1 Yes - OR 7 And -OR 7Selected from: -OCH3, -OCH(CH3)2, -O(CH2)2OH, -O(CH2)CH(CH3)OH, -O(CH2)2OCH3 and -O(CH2)2OCHF2.

[0119] In some implementation schemes, R 1 It is -N=S(R) 7 )2, where two R 7 The groups, together with one or more atoms to which they are attached, form a 4- to 6-membered heterocycle having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 yes .

[0120] In some embodiments of any of the forms described herein, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0121] In some embodiments of any of the forms described herein, part yes In some implementation schemes, part yes or In some implementation schemes, part yes or In some implementation schemes, part Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , , , , , , , and In some implementation schemes, part yes .

[0122] In some implementations, for compounds of any one of formulas IF', IF1', and IF2', R 1 Yes - OR 7 .

[0123] In some implementations, for compounds of any one of the formulas IF', IF1', IF2', and IF3', R 7 Selected from C (optional substitution) 1-6 Aliphatic and -(C 1-4 Alkylene (OR). In some embodiments, R 7 Selected from C 1-6 Alkyl and -(C 1-4 Alkylene (OR). In some embodiments, R7 C is an optional substitute 1-6 Aliphatic. In some implementations, R 7 It is C 1-6 Aliphatic. In some implementations, R 7 C is an optional substitute 1-6 Alkyl group. In some embodiments, each R 7 C is a C substituted with a group selected from the following groups. 1-6 Aliphatic: -(CH2) 0-4 R°、-(CH2) 0-4 OR°、-(CH2) 0-4 N(R°)2、-(CH2) 0-4 N(R°)C(O)R°、-(CH2) 0-4 NHC(O)R°、-(CH2) 0-4 C(O)NHR° and -(CH2) 0-4 C(O)N(R°)2. In some implementations, each R 7 C is replaced by -R°, -OR°, -N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, -C(O)NHR° and -C(O)N(R°)2 1-6 Aliphatic. In some such embodiments, R° is selected from C 1-6 Aliphatic, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 4- to 6-membered carbon ring. In some embodiments, R° is halogenated, oxidized, or -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH and -(CH2) 0-2 OR ● Replacement. In some implementations, R° is replaced by halogen, oxidized, or -R. ● -(halogenated R) ● -OH and -OR ● Replacement. In some implementations, R ● It is C 1-4 Aliphatic. In some implementations, R ● It is -CH3 or -CH2CH3. In some embodiments, R° is replaced by halogen, oxo, -CH3, -CH2CF3, -OH and -OCH3.

[0124] In some implementations, for compounds of any one of formulas IF', IF1', IF2', and IF3', each R 7 C is an optional substitute1-6 Alkyl group. In some embodiments, each R 7 C is a C substituted with a group selected from the following groups. 1-6 Alkyl group: -(CH2) 0-4 R°、-(CH2) 0-4 OR°、-(CH2) 0-4 N(R°)2、-(CH2) 0-4 N(R°)C(O)R°、-(CH2) 0-4 NHC(O)R°、-(CH2) 0-4 C(O)NHR°、-(CH2) 0-4 C(O)N(R°)2. In some implementations, each R 7 C is replaced by -R°, -OR°, -N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, -C(O)NHR° and -C(O)N(R°)2 1-6 Alkyl group. In some embodiments, each R 7 C is replaced by -R°, -OR°, -N(R°)2, -N(R°)C(O)R°, -NHC(O)R°, -C(O)NHR° and -C(O)N(R°)2 1-2 Alkyl group. In some embodiments, R° is selected from C10. 1-6 Aliphatic, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted groups of a 4- to 6-membered carbon ring. In some embodiments, R 7 It is C 1-6 Alkyl group. In some embodiments, R 7 Yes - (C 1-4 Alkylene (OR). In some embodiments, R 7 Yes - (C 1-4 (alkylene)NR2. In some embodiments, R 7 C-membered heteroaryl rings independently selected from those of 5- to 6-membered heteroaryl rings independently selected from nitrogen, oxygen, and sulfur, which are optionally substituted. 1-6 Aliphatic; C-shaped compounds with optional substitution of 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Aliphatic; and C-rings substituted with optional 3-7 membered carbon rings. 1-6 Aliphatic. In some implementations, R 7 C-membered heteroaryl rings selected from those of 5- to 6-membered heteroaryl rings that are optionally substituted, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Aliphatic. In some implementations, R 7C selected from 4- to 7-membered heterocyclic compounds with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are optionally substituted. 1-6 Aliphatic. In some implementations, R 7 It is an optionally substituted 4- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 C selected from substituted 3-7 membered carbon rings 1-6 Aliphatic. In some implementations, R 7 Selected from , , , , , , , , , and .

[0125] In some implementations, for compounds of any one of formulas IF', IF1', IF2', and IF3', each R 7 Selected independently , , , , , , , , , , , , , , , , , , , , , and .

[0126] In some implementations, for compounds of any one of the formulas IF', IF1', IF2', and IF3', R 7 The alternative is selected from 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 6-membered carbon rings with optional substitutions. In some embodiments, R 7 Selected from 4- to 7-membered heterocycles with 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, with optional substitution. In some embodiments, R 7 Selected from optionally substituted pyrrolidinyl and piperidinyl groups. In some embodiments, R7 Selected from substituted 3- to 6-membered carbon rings. In some embodiments, for compounds of any one of the formulas IF', IF1', IF2', and IF3', R 7 Selected from , , , , , , , , , , , , and .

[0127] In some implementations, for compounds of any one of formulas IF', IF1', IF2', and IF3', each R 7 Selected independently , , , , , , , , , , , , , , and .

[0128] In some implementations, for compounds of any one of formulas IF', IF1', and IF2', a portion yes .

[0129] In some implementations, for compounds of formula IF3', a portion yes .

[0130] In some embodiments of any of the formulas described herein, ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered carbon ring; and a phenyl ring. In some embodiments of any of the formulas described herein, ring B is selected from a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered carbon ring. In some embodiments, ring B is selected from a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-membered carbon ring, and a phenyl ring. In some embodiments, ring B is selected from a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-membered carbon ring. In some embodiments, ring B is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is selected from thiophene, furan, or isothiazole. In some embodiments, ring B is thiophene. In some embodiments, ring B is furan. In some embodiments, ring B is isothiazole. In some embodiments, ring B is a 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5- to 6-membered heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5- to 6-membered carbon ring. In some embodiments, ring B is a 5- to 6-membered cycloalkyl ring. In some embodiments, ring B is a 5-membered carbon ring (e.g., cyclopentyl). In some embodiments, ring B is a 6-membered carbon ring. In some embodiments, ring B is a phenyl ring.

[0131] In some implementations of any of the forms described herein, each R 2 C independently selected from halogens and optionally substituted C 1-6 Alkyl group. In some embodiments, each R 2 Independently selected from halogens and C 1-6 Aliphatic. In some implementations, each R 2 Independently selected from halogens and C 1-6 Alkyl group. In some embodiments, R 2 It is a halogen (e.g., fluorine or chlorine). In some embodiments, R 2 C is an optional substitute 1-6 Aliphatic. In some implementations, R 2 It is C 1-6 Aliphatic. In some implementations, R 2 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 2It is C 1-6 Alkyl (e.g., methyl).

[0132] In some embodiments of any of the forms described herein, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0133] In some embodiments of any of the forms described herein, part Selected from: , , , , , , , , , , , , , , , , , and In some embodiments of any of the forms described herein, a portion Selected from: , , , , , , , , , , , , , , , and In some embodiments of any of the forms described herein, a portion Selected from: , , , , , and In some embodiments of any of the forms described herein, a portion Selected from: , , , , and In some embodiments of any of the forms described herein, a portion Selected from: , , , , , , , , , and In some embodiments of any of the forms described herein, a portion Selected from: , , and In some implementation schemes, part yes In some implementation schemes, part yes (For example, or In some implementation schemes, part Selected from and In some implementation schemes, part yes (For example, or In some implementation schemes, part yes In some implementation schemes, part yes (For example, or In some implementation schemes, part yes In some implementation schemes, part yes (For example, or In some implementation schemes, part yes In some implementation schemes, part yes In some implementation schemes, part Selected from and In some implementation schemes, part yes (For example, In some implementation schemes, part Selected from: , , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , , , , , , , , and .

[0134] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC In some embodiments of any one of 3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, the ring C is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is selected from 9- to 10-membered bicyclic aryl rings, 9- to 10-membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 11-membered bicyclic heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 12- to 13-membered polycyclic heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is selected from phenyl, 9- to 10-membered bicyclic aryl rings, and 3- to 7-membered carbon rings. In some embodiments, ring C is selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is selected from 9- to 10-membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 6- to 11-membered bicyclic heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0135] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f , IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3- In some embodiments of any one of IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, the ring C is phenyl.

[0136] I C1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC In some embodiments of any one of 3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 9- to 10-membered bicyclic aryl ring. In some embodiments, ring C is a 9-membered bicyclic aryl ring (e.g., indene). In some embodiments, ring C is a 10-membered bicyclic aryl ring.

[0137] In formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'-g , IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3-d In some embodiments of IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a pyrazolyl group. In some embodiments, ring C is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a pyridyl group.

[0138] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3-d, I In some embodiments of any one of C3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is indole, indazole, benzimidazolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, imidazo[1,2-a]pyridyl, or imidazo[4,5-b]pyridyl. In some embodiments, ring C is a 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0139] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, In some embodiments of any one of IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 3- to 7-membered carbon ring. In some embodiments, ring C is a 3- to 7-membered alkyl ring. In some embodiments, ring C is a 3- to 5-membered carbon ring. In some embodiments, ring C is a 3- to 5-membered alkyl ring. In some implementations, cyclic C is cyclopropyl.

[0140] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'- g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3- In some embodiments of any one of d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 4- to 7-membered 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 an azo-butyl ring. In some embodiments, ring C is a 5-membered heterocycle having one heteroatom independently selected from nitrogen, oxygen, and sulfur. 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 a piperazine ring. In some embodiments, ring C is a 1,2,3,6-tetrahydropyridinyl ring. In some embodiments, ring C is a 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0141] In some implementations, ring C is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0142] In formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'-g , IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3-d, In some embodiments of any one of IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a fused 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocycle fused with an aryl, heteroaryl, cycloalkyl, or heterocyclic group, wherein the attachment point to the remainder of the molecule is on any ring). In some embodiments, ring C is a spirocyclic 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocycle spirofused with a cycloalkyl or heterocyclic group, wherein the attachment point to the remainder of the molecule is on any ring). In some embodiments, ring C is a 6-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is an 8-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 10-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is selected from: , , and Each of them is p R 3Group substitution. In some embodiments, ring C is an 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f, IC1'-g , IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c, IC3-d, In some embodiments of any one of IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, ring C is a 12- to 13-membered polycyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 12- to 13-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, comprising two or more fused and / or bridged rings. In some embodiments, ring C is a 12-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 13-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f , IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3 In some implementations of any one of IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, p R 3 The ring C with substituted groups is ,in: Ring C1 and ring C2 are fused together; The C1 ring is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and The ring C2 is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0145] In some such embodiments, ring C1 is a phenyl group, and ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C2 is a 5- to 6-membered heteroaryl ring, a 3- to 7-membered carbon ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments of any one of formulas IA, IA', IB1, and IB1', ring C1 is selected from phenyl and 3 to 7-membered carbon rings. In some embodiments, ring C1 is selected from 5 to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4 to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is selected from phenyl and 5 to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is selected from 3 to 7-membered carbon rings and 4 to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is phenyl. In some embodiments, ring C1 is a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 5-membered heteroaryl ring (e.g., pyrrolidinyl or imidazolyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 6-membered heteroaryl ring (e.g., pyridinyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 3- to 7-membered carbon ring. In some embodiments, ring C1 is a 3- to 7-membered alkyl ring. In some embodiments, ring C1 is a 3- to 5-membered carbon ring. In some embodiments, ring C1 is a 3- to 5-membered alkyl ring (e.g., cyclopropyl). In some embodiments, ring C1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 5- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 5-membered heterocycle (e.g., pyrrolidinyl) having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 6-membered heterocycle (e.g., piperidinyl or imidazolyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0147] In some embodiments of any one of formulas IA, IA', IB1, IB1', IF', IF1', IF2', and IF3', ring C2 is selected from phenyl and 3- to 7-membered carbon rings. In some embodiments, ring C2 is selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is selected from phenyl and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is selected from 3- to 7-membered carbon rings and 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is phenyl. In some embodiments, ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 5-membered heteroaryl ring (e.g., pyrrolo, pyrazol, or imidazolyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 6-membered heteroaryl ring (e.g., pyridinyl or pyridonel) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 3- to 7-membered carbon ring. In some embodiments, ring C2 is a 3- to 7-membered alkyl ring. In some embodiments, ring C2 is a 3- to 5-membered carbon ring. In some embodiments, ring C2 is a 3- to 5-membered alkyl ring (e.g., cyclopropyl or cyclopentyl). In some embodiments, ring C2 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 5- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 5-membered heterocycle (e.g., pyrrolidinyl) having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 6-membered heterocycle (e.g., piperidinyl or imidazolyl) having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 7-membered heterocycle (e.g., azirheptanyl) having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0148] In some embodiments of any one of formulas IA, IA', IB1, and IB1', ring C1 is phenyl, and ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring C2 is a 5- to 6-membered heteroaryl ring, a 3- to 7-membered carbon ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0149] In some embodiments of any one of formulas IF', IF1', IF2', and IF3', ring C2 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C2 is a 3- to 7-membered carbon ring.

[0150] In some implementations of any one of IF', IF1', IF2', and IF3', partially Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , In some implementation schemes, Selected from: , , , , , , , , , , , , , , and In some implementation schemes, Selected from: , , , , , , , , , , , , , , , , and .

[0151] In the formula I, I', I'', IA, IA', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'- f, IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC In some implementations of any one of IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, IE1'-b, IF', IF1', IF2', and IF3', each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, optionally substituted carbon rings, and optionally substituted C rings 1-6 Alkyl group. In some embodiments, each R 3 Independently selected from halogens, -CN, -OR, -C(O)R, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy and optionally substituted C 1-6 Aliphatic. In some implementations, each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2) xC(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, and optionally by one or more R 10 Replacement C 1-6 Aliphatic. In some implementations, each R 3 Independently selected from halogens, -C(O)N(R)2 and optionally substituted C 1-6 Alkyl groups (e.g., optionally composed of one or more R groups) 10 Replacement C 1-6 Alkyl). In some embodiments, each R 3 Independently selected from halogens, -C(O)N(R)2 and C 1-6 Alkyl group. In some embodiments, R 3 It is an oxidation process. In some implementations, R... 3 It is a halogen (e.g., fluorine). In some implementations, R 3 Yes -CN. In some implementations, R 3 It is -OR (e.g., -OH). In some implementations, R 3 It is -C(O)R. In some implementations, R 3 It is -C(O)(C 1-6 Alkyl groups (e.g., -C(O)CH3). In some embodiments, R 3 It is -(CH2) x C(O)OR, such as -CH2C(O)OR. In some implementations, R 3 It is -(CH2) x C(O)OH (e.g., -CH2C(O)OH). In some embodiments, R 3 It is -(CH2) x C(O)N(R)2 (e.g., -CH2C(O)N(R)2 or -C(O)N(R)2). In some embodiments, R 3 It is -(CH2) x C(O)NH(C 1-6 Alkyl groups (e.g., -CH2C(O)NHCH3 or -C(O)NHCH3). In some embodiments, R 3 It is -(CH2) x C(O)N(C 1-6 Alkyl)2 (e.g., -CH2C(O)N(CH3)2 or -C(O)N(CH3)2). In some embodiments, R 3 It is -(CH2)x N(R)C(O)R, such as -CH2N(R)C(O)R. In some implementations, R 3 It is -(CH2) x N(H)C(O)(C 1-6 Alkyl groups (e.g., -N(H)C(O)CH3 or -CH2N(H)C(O)CH3). In some embodiments, R 3 It is -(CH2) x Cy (e.g., phenyl, -(CH2)) x Azahexacyclic butyl, -(CH2) x Pyrroloalkyl, -(CH2) x Piperidinyl, oxetyl, or pyrazolyl, each of which is surrounded by 0-3 R groups. 8 (Instance replacement). In some implementations, R 3 It is -O(CH2) x Cy, such as -O(CH2)2Cy. In some implementations, R 3 It is -O(CH2)2Cy, where Cy is separated by 0-3 R... 8 Examples of substituted nitrogen-containing heterocyclic butyl groups. In some embodiments, R 3 It is -C(O)Cy (for example, -C(O)Cy, where Cy is cyclobutyl or aziridine, either of which is surrounded by 0-3 R groups). 8 (Instance replacement). In some implementations, R 3 C is an optional substitute 1-6 Aliphatic (e.g., optionally by one or more R) 10 Replacement C 1-6 (Aliphatic). In some implementations, R 3 C is an optional substitute 1-6 Alkyl groups (e.g., optionally composed of one or more R groups) 10 Replacement C 1-6 Alkyl group). In some embodiments, R 3 It is optionally reacted with one or more halogens (e.g., fluorine), -OH, -O (C 1-6 Alkyl groups (e.g., -OCH3) or -N(C 1-6 alkyl)2 (e.g., -N(CH3)2) substituted C 1-6 Alkyl group. In some embodiments, R 3 Selected from -CH3, -CH2F, -CF3, -CH2OH, -CH2N(CH3)2, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2OCH3, -CH(CH3)2, -CH2CH(OH)CH2OH and -CH2CH(OH)CH2OCH3.

[0152] In the formula I, I', I'', IA, IA', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'-f , IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC3-b, IC3-c In some embodiments of any one of IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, IE1'-b, IF', IF1', IF2', and IF3', p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0153] In the formula I, I', I'', IB, IB', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e, IC1'- f, IC1'-g, IC2, IC2', IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC2'-a, IC2'-b, IC2'-c, IC2'-d, IC2'-e, IC2'-f, IC2'-g, IC3-a, IC In some implementations of any one of 3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, IC4, IC4', ID, ID', IE, IE', IE1, IE1', IE1-a, IE1-b, IE1'-a, and IE1'-b, partially Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and In some implementation schemes, part Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0154] In some implementation schemes, part Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and In some implementation schemes, part Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0155] I C1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, I In some embodiments of any one of C3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is selected from 9- to 10-membered bicyclic heteroaryl rings, 5- to 10-membered bicyclic or polycyclic carbocyclic rings, and 6- to 11-membered bicyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is selected from phenyl, 3- to 7-membered carbocyclic rings, and 5- to 10-membered bicyclic or polycyclic carbocyclic rings. In some embodiments, ring D is selected from 5- to 6-membered heteroaryl rings, 9- to 10-membered bicyclic heteroaryl rings, 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0156] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'- d, IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC In some embodiments of any one of 3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is phenyl.

[0157] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'- e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC In some embodiments of any one of 3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0158] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'-e , IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC3 In some embodiments of any one of '-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, pyrazolo[1,5-a]pyrimidinyl. In some embodiments, ring D is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0159] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d , IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3' In some embodiments of any one of -a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is a 3- to 7-membered carbon ring. In some embodiments, ring D is a 3- to 7-membered cycloalkyl ring. In some embodiments, ring D is a 3- to 5-membered carbon ring. In some embodiments, ring D is a 3- to 5-membered cycloalkyl ring.

[0160] In formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, C1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, In some embodiments of any one of IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is a 5- to 10-membered bicyclic or polycyclic carbon ring. In some embodiments, ring D is a 5- to 10-membered bicyclic carbon ring. In some embodiments, ring D is a bridged 5- to 10-membered bicyclic carbon ring. In some embodiments, ring D is a bridged 5- to 7-membered bicyclic carbon ring (e.g., bicyclic [1.1.1]pentane). In some implementations, ring D is an 8- to 10-membered polycyclic carbon ring (e.g., cubane).

[0161] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'- e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, I In some embodiments of any one of C3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 4-membered heterocycle having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is an azahexacyclic butyl ring. In some embodiments, ring D is a 5-membered heterocycle having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is pyrroloalkyl. In some embodiments, ring D is a 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is piperidinyl or piperazineyl. In some embodiments, ring D is a 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0162] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1'-d, IC1'- e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC3'-a, IC3'-b, IC In some embodiments of any one of 3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', IE, IE', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, ring D is a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a fused 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocycle fused with an aryl, heteroaryl, cycloalkyl, or heterocyclic group, wherein the attachment point to the remainder of the molecule is on any ring). In some embodiments, ring D is a spirocyclic 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a heterocycle spirofused with a cycloalkyl or heterocyclic group, wherein the attachment point to the remainder of the molecule is on any ring). In some embodiments, ring D is a 6-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 7-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is an 8-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 9-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is a 10-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is an 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D is absent.

[0163] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1 '-d, IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3 In some implementations of any one of -m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, partial Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, part yes , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, part yes .

[0164] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1 '-d, IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3 In some implementations of any one of -m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, L is C 2-5 It has an alkynyl group and the ring D is absent.

[0165] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1 '-d, IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3 In some implementations of any one of -m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, partial yes ,in: Ring D1 and ring D2 are fused; Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0166] In some such embodiments, ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0167] In some embodiments of any one of formulas IB, IB', IB1, and IB1', ring D1 is selected from phenyl and a 3- to 7-membered carbon ring. In some embodiments, ring D1 is selected from a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 3- to 7-membered carbon ring and a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is phenyl. In some embodiments, ring D1 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 5-membered heteroaryl ring (e.g., pyrazolyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 6-membered heteroaryl ring (e.g., pyridyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 3- to 7-membered carbon ring. In some embodiments, ring D1 is a 3- to 7-membered alkyl ring. In some embodiments, ring D1 is a 3- to 5-membered carbon ring. In some embodiments, ring D1 is a 3- to 5-membered alkyl ring (e.g., cyclopropyl). In some embodiments, ring D1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 5- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 5-membered heterocycle (e.g., pyrrolidinyl) having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 6-membered heterocycle (e.g., piperidinyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0168] In some embodiments of any one of formulas IB, IB', IB1, and IB1', ring D2 is selected from phenyl and a 3- to 7-membered carbon ring. In some embodiments, ring D2 is selected from a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is selected from phenyl and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is selected from a 3- to 7-membered carbon ring and a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is phenyl. In some embodiments, ring D2 is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is a 6-membered heteroaryl ring (e.g., pyrimidinyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is a 3- to 7-membered carbon ring. In some embodiments, ring D2 is a 3- to 7-membered alkyl ring. In some embodiments, ring D2 is a 3- to 5-membered carbon ring. In some embodiments, ring D2 is a 3- to 5-membered alkyl ring (e.g., cyclopropyl). In some embodiments, ring D2 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is a 5- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is a 5-membered heterocycle (e.g., pyrrolidinyl) having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D2 is a 6-membered heterocycle (e.g., piperidinyl or imidazolyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some implementations, ring D2 is a 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0169] In some embodiments of any one of formulas IB, IB', IB1, and IB1', ring D1 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring D1 is a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0170] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1 '-d, IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3 In some implementations of any one of -m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, partial Selected from; , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, part yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0171] In the formula I, I', I'', IA, IA', IC, IC', IC1, IC1', IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC1'-a, IC1'-b, IC1'-c, IC1 '-d, IC1'-e, IC1'-f, IC1'-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3 In some implementations of any one of -m, IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, IC3'-m, ID, ID', II, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIF, and IIG, partial yes In some implementation schemes, part yes , where each R 4 It is methyl independently. In some embodiments, part of it is... Selected from: , , , , , , , , , , , , and In some implementation schemes, part Selected from: , , , , , , and .

[0172] In some implementations of formula IF' Selected from: , , , , , , , , , , and .

[0173] In some implementations of any of IF1', IF2' and IF3' Selected from: , , , , , and .

[0174] In some implementations of any of the forms described herein, each R 4 C is independently optional substitution 1-6 Alkyl group. In some embodiments, each R 4 Independently selected by one or more R 10 Replacement C 1-6 Aliphatic. In some implementations, each R 4 Independently selected by one or more R 10 Replacement C 1-6 Alkyl group. In some embodiments, each R 4 C is independent 1-6 Aliphatic (e.g., C) 1-6 Alkyl). In some embodiments, each R 4 Independently, C is optionally substituted with one or more -OH groups. 1-6 Alkyl group. In some embodiments, each R 4 It is independently selected from -CH3, -CH2OH, -CH2CH3 and -CH(CH3)2.

[0175] In some embodiments of any of the forms described herein, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0176] In some implementations of any of the forms described herein, R 5 It is -C(O)R 9 Or -(CH2) x N(R)C(O)R 9 In some implementations, R 5 It is -C(O)R 9 or -N(R)C(O)R 9 In some implementations, R 5 It is -C(O)R9 In some implementations, R 5 It is -(CH2) x N(R)C(O)R 9 (For example, -CH2N(R)C(O)R) 9 or -N(R)C(O)R 9 In some implementations, R 5 Yes -CN. In some implementations, R 5 Selected from: -CN , , , , , , , , and In some implementations, R 5 yes , ,or In some implementations, R 5 yes .

[0177] In some implementations of any of the forms described herein, R 9 C is an optional substitute 2-6 alkenyl or optionally substituted C 2-6 Alkyne group. In some embodiments, R 9 C is an optional substitute 2-4 alkenyl or optionally substituted C 2-4 Alkyne group. In some embodiments, R 9 It is optionally controlled by one or more R 10 Replacement C 2-6 alkenyl, optionally with one or more R 10 Replacement C 2-6 Alkyne group, or a four-membered bicyclic carbocyclic ring. In some embodiments, R 9 It is optionally controlled by one or more R 10 Replacement C 2-6 alkenyl, or optionally with one or more R 10 Replacement C 2-6 Alkyne group. In some embodiments, R 9 C is an optional substitute 2-6 Alkenyl. In some embodiments, R 9 C is an optional substitute 2-4 Alkenyl. In some embodiments, R 9 It is optionally controlled by one or more R 10 (e.g., one or more halogens) substituted C2-6 Alkenyl. In some embodiments, R 9 C is an optional substitute 2-6 Alkyne group. In some embodiments, R 9 C is an optional substitute 2-4 Alkyne group. In some embodiments, R 9 It is optionally controlled by one or more R 10 (For example, one or more -N(C) 1-6 alkyl)2) substituted C 2-6 Alkyne group. In some embodiments, R 9 It is a 4-membered bicyclic carbon ring.

[0178] In some implementations of any of Equations I, I', I'', IA, IA', IB, IB', IB1, IB1', ID, and ID', L is a covalent bond. In some implementations, L is a divalent linear or branched C. 1-6 A hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -C(O)-. In some embodiments, L is a divalent straight-chain or branched C having at least one triple bond. 2-6 A hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -C(O)-. In some embodiments, L is a divalent straight-chain or branched C having at least one triple bond. 2-6 Hydrocarbon chains (e.g., C) 2-6 (Alynyl group). In some embodiments, L is selected from: , and In some implementations, L is a bivalent straight chain or a branched chain C. 1-4 A hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -C(O)-. In some embodiments, L is a divalent straight-chain or branched C. 1-2 A hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -C(O)-. In some embodiments, L is selected from: , , , , and .

[0179] In some implementations of any one of Equations I, I', I'', IA, IA', IB, IB', IB1, IB1', ID, and ID', partially Selected from: , , , , , , , , , , , , , , , , , and .

[0180] In some implementations of any one of Equations I, I', I'', IA, IA', IB, IB', IB1, IB1', IE, IE', IE1, IE1', IE1-a, IE1-a', IE1-b, and IE1-b', R 6 and R 6' With optional substitution of C 4-8 The hydrocarbon chain is linked, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-. In some embodiments, R 6 and R 6' With C 4-8 The hydrocarbon chain is linked, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-. In some embodiments, R 6 and R 6' With optional substitution of C 5-6 The hydrocarbon chain is linked, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-. In some embodiments, R 6 and R 6' With optional substitution of C 4-8 The hydrocarbon chain is linked, wherein one or more methylene units are optionally and independently substituted with -O-. In some embodiments, R 6 and R 6' With optional substitution of C 5-6 The hydrocarbon chain is linked, wherein one or more methylene units are optionally and independently substituted with -O-. In some embodiments, R 6 and R 6' Connected to the following: -O(CH2)5-, -O(CH2)4-, -O(CH2)2OCH2- or -O(CH2)3OCH2-.

[0181] In some implementations of any of Equations I, I', I'', IA, IA', IB, IB', IB1, IB1', IE, IE', IE1, IE1', IE1-a, IE1-a', IE1-b, and IE1-b', r is 0. In some implementations, r is 1. It should be understood that for R... 6 and R 6' Both have the same value for r, such that R 6 and R 6' Both exist, or R 6 and R 6' Neither exists.

[0182] In some embodiments of any of the forms described herein, each x is independently 1 or 2. In some embodiments, each x is independently 0 or 1. In some embodiments, each x is 0. In some embodiments, each x is 1. In some embodiments, each x is 2.

[0183] In some embodiments of any of the forms described herein, each R is independently hydrogen or optionally substituted C. 1-6 Alkyl group. In some embodiments, each R is independently hydrogen or optionally substituted C. 1-4 Alkyl group. In some embodiments, each R is independently hydrogen or optionally composed of one or more R groups. 10 Replacement C 1-6 Aliphatic. In some embodiments, each R is independently hydrogen or optionally composed of one or more R... 10 Replacement C 1-6 Alkyl group. In some embodiments, each R is hydrogen or C optionally substituted with one or more halogens (e.g., fluorine). 1-6 Alkyl group. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C. 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl group). In some embodiments, R is optionally composed of one or more R groups. 10 Replacement C 1-6 Aliphatic (e.g., optionally by one or more R) 10 Replacement C 1-6 Alkyl group). In some embodiments, R is C. 1-6 Aliphatic (e.g., C) 1-6 alkyl).

[0184] In some embodiments of any of the formulations described herein, each Cy is independently selected from phenyl and 3 to 7-membered carbon rings, wherein each Cy is composed of 0-3 R... 8The examples are replaced. In some embodiments, each Cy is independently selected from 5- to 6-membered heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is replaced by 0-3 R 8 Examples of [the following] are replaced. In some embodiments, each Cy is independently selected from phenyl and has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, of a 5- to 6-membered heteroaryl group, wherein each Cy is replaced by 0-3 R [elements]. 8 The examples are replaced. In some embodiments, each Cy is independently selected from 3 to 7-membered carbon rings and 4 to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is replaced by 0 to 3 R atoms. 8 Instances are replaced. In some implementations, Cy is replaced by 0-3 R. 8 Examples of substituted phenyl groups. In some embodiments, Cy is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is surrounded by 0-3 R groups. 8 Examples of [other compounds] are replaced. In some embodiments, Cy is a 5-membered heteroaryl ring (e.g., pyrazolyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is replaced by 0-3 R [elements]. 8 The examples are replaced by others. In some embodiments, Cy is a 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is replaced by 0-3 R atoms. 8 Examples of [other carbon rings] are used instead. In some implementations, Cy is a 3- to 7-membered carbon ring, wherein Cy is replaced by 0-3 R [members]. 8 Examples of [other carbon rings] are used instead. In some implementations, Cy is a 3- to 5-membered carbon ring, wherein Cy is replaced by 0-3 R [elements]. 8 The examples are replaced by others. In some embodiments, Cy is a 4- to 7-membered heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein Cy is replaced by 0-3 R atoms. 8 The examples are replaced by others. In some embodiments, Cy is a 5- to 6-membered heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein Cy is replaced by 0-3 R atoms. 8 Examples of [other compounds] are replaced. In some embodiments, Cy is a four-membered heterocycle (e.g., azirrobutane or oxobutane) having one independent heteroatom selected from nitrogen, oxygen, and sulfur, wherein Cy is surrounded by 0-3 R [elements]. 8 Examples of [other compounds] are replaced. In some embodiments, Cy is a 5-membered heterocycle (e.g., pyrrolidinyl) having one independent heteroatom selected from nitrogen, oxygen, and sulfur, wherein Cy is replaced by 0-3 R [elements]. 8 Examples of [other compounds] are replaced. In some embodiments, Cy is a 6-membered heterocycle (e.g., piperidinyl or piperazine) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is replaced by 0-3 R [elements]. 8Instances are replaced. In some implementations, each Cy is independently replaced by 0-2 R. 8 The instance is replaced.

[0185] In some implementations of any of the forms described herein, each R 8 C independently selected from oxo, halogenated, and optionally substituted C 1-6 Alkyl group. In some embodiments, each R 8 Independently selected from oxidative, halogenated, and C 1-6 Aliphatic. In some implementations, each R 8 Independently selected from oxidative, halogenated, and C 1-6 Alkyl group. In some embodiments, each R 8 C independently selected from halogens and optionally substituted C 1-6 Aliphatic. In some implementations, R 8 It is an oxidation process. In some implementations, R... 8 It is a halogen (e.g., fluorine). In some implementations, R 8 C is an optional substitute 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl group). In some embodiments, R 8 It is C 1-6 Aliphatic (e.g., C) 1-6 Alkyl). In some embodiments, each R 8 It is either fluorine or methyl.

[0186] In some embodiments of any of Equations II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, J is a covalent bond. In some embodiments, J is a divalent linear or branched C. 1-4 Hydrocarbon chain. In some embodiments, J is a divalent straight-chain or branched C. 1-2 Hydrocarbon chain. In some implementations, when J is a covalent bond, X is not -OR or -N(R)2.

[0187] In some implementations of any of Equations II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, X is -OR or -N(R)2. In some embodiments, X is an optionally substituted group selected from: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is a group selected from: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally C 1-6 Alkyl substitution. In some embodiments, X is a group selected from: a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally C-substituted. 1-6 Alkyl substitution. In some embodiments, X is -OR (e.g., -OH or -OCH3). In some embodiments, X is -N(R)2 (e.g., -N(CH3)2). In some embodiments, X is -C(O)N(R)2. In some embodiments, X is an optionally substituted phenyl group. In some embodiments, X is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., optionally surrounded by one or more C atoms). 1-6Alkyl-substituted pyrazolyl group). In some embodiments, X is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is an optionally substituted 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is an optionally substituted 3- to 7-membered carbon ring. In some embodiments, X is an optionally substituted 5- to 10-membered bicyclic carbon ring. In some embodiments, X is an optionally substituted 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, X is an optionally substituted 4-membered heterocycle having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., optionally substituted by one or more C atoms). 1-6 Alkyl-substituted nitrogen-containing heterocyclic butyl groups. In some embodiments, X is an optionally substituted 5-membered heterocycle having one heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., optionally substituted by one or more C atoms). 1-6 Alkyl-substituted pyrrolidines). In some embodiments, X is an optionally substituted six-membered heterocycle having one heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., optionally substituted by one or more C atoms). 1-6 Alkyl-substituted piperidinyl). In some embodiments, X is an optionally substituted 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some implementations of any one of Formulas II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, partially Selected from: , , , , , and .

[0189] In some embodiments of any of the formulas described herein, the compound is not selected from the compounds in Table P1.

[0190] Table P1 In some embodiments of any of the formulas described herein, the compound is not selected from the compounds in Table P2.

[0191] Table P2 In some embodiments of any of the formulations described herein, the compound is not selected from the compounds in Table P3.

[0192] Table P3 In some embodiments of any of the formulations described herein, the compound is not selected from the compounds in Table P4.

[0193] Table P4 This document also provides the following embodiments, wherein any of the embodiments described herein may be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive. As used herein, when one embodiment is defined as an embodiment different from another embodiment, the two embodiments are “mutually exclusive.” For example, an embodiment in which two groups are combined to form a ring is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive with an embodiment in which the same group is NH.

[0194] In some embodiments, this disclosure provides a compound selected from Tables 1 and 2 or any of the embodiments provided herein, or a salt thereof (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer. In some embodiments, this disclosure provides a compound selected from Tables 1 and 2 or any of the embodiments provided herein, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound selected from Table 1 or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound selected from Table 2 or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0195] In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise specified, reference to the compounds provided herein should be understood to include reference to their salts. Pharmaceutically acceptable salt forms are known in the art. For example, pharmaceutically acceptable salts are described in detail by SM Berge et al. in J. Pharmaceutical Sciences, 66:1-19 (1977). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0196] It should be understood 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 in this disclosure. This disclosure also contemplates forms such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers of the compounds provided herein.

[0197] It should be understood that, unless otherwise specified, references to compounds of formula I in this disclosure are intended to also include formulas IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, and IE1-b, as well as the types of compounds of this type disclosed herein; reference to compounds of formula I' is intended to also include formulas IA', IB', IB1', IC', IC1', IC1-a', IC1-b', IC1-c', IC1-d', IC1-e', IC1-f', IC1-g', IC2', IC2-a', IC2 -b', IC2-c', IC2-d', IC2-e', IC2-f', IC2-g', IC3-a', IC3-b', IC3-c', IC3-d', IC3-e', IC3-f', IC3-g', IC 3-h', IC3-I', IC3-j', IC3-k', IC3-l', IC3-m', IC4', ID', IE', IE1', IE1-a', IE1-b', IF', IF1', IF2' and IF3' The list of compounds of formula II is intended to include, as well as the types of compounds of such formula disclosed herein; and the reference to compounds of formula II is intended to also include, as well as, the types of compounds of formulas IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF and IIG, as well as the types of compounds of such formula disclosed herein.

[0198] Composition This disclosure also provides compositions comprising the compounds provided herein with one or more other components. In some embodiments, the provided compositions comprise and / or deliver the compounds described herein (e.g., formulas I'', I, IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3-b, IC3-c, ...). IC3-d, IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, IE 1-b, I', IA', IB', IB1', IC', IC1', IC1-a', IC1-b', IC1-c', IC1-d', IC1-e', 'IC1-f', IC1-g', IC2 ', IC2-a', IC2-b', IC2-c', IC2-d', IC2-e', IC2-f', IC2-g', IC3-a', IC3-b', IC3-c', IC3-d', IC3 -e', IC3-f', IC3-g', IC3-h', IC3-I', IC3-j', IC3-k', IC3-l', IC3-m', IC4', ID', IE', IE1', IE1- a', IE1-b', IF', IF1', IF2', IF3', II, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, II C2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF and IIG compounds).

[0199] In some embodiments, the provided composition comprises and / or delivers compounds described herein (e.g., formulas I'', I, IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3-b, IC3-c, IC3-d). , IC3-e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, IE1-b, I', I A', IB', IB1', IC', IC1', IC1-a', IC1-b', IC1-c', IC1-d', IC1-e', 'IC1-f', IC1-g', IC2', IC2-a', IC 2-b', IC2-c', IC2-d', IC2-e', IC2-f', IC2-g', IC3-a', IC3-b', IC3-c', IC3-d', IC3-e', IC3-f', IC3 -g', IC3-h', IC3-I', IC3-j', IC3-k', IC3-l', IC3-m', IC4', ID', IE', IE1', IE1-a', IE1-b', IF', IF1 The pharmaceutical composition comprises compounds I1, I2, I3, IIA, IIB, IIB1, IIB2, IIB3, IIB4, IIB5, IIB6, IIB7, IIC1, IIC2, IIC3, IIC4, IIC5, IIC6, IIC7, IID, IID1, IID2, IID3, IID4, IID5, IID6, IID7, IIE, IIF, and IIG, and further comprises a pharmaceutically acceptable carrier. The pharmaceutical composition typically contains an effective amount of an active agent (e.g., the compounds described herein) to achieve the desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, the provided pharmaceutical composition comprises the compounds described herein and one or more fillers, disintegrants, lubricants, flow aids, anti-adhesives, and / or antistatic agents, etc. The provided pharmaceutical compositions can be in various forms, including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, reservoir forms, and injectable and infusionable solutions. Methods for preparing the pharmaceutical compositions are well known in the art.

[0200] In some embodiments, the provided compound is formulated as a unit dosage form to facilitate administration and achieve dosage consistency. As used herein, "unit dosage form" refers to a physically discrete unit of an active agent (e.g., the compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, a unit dosage form contains a complete single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, multiple unit dosage forms are required or anticipated to achieve the desired effect. A unit dosage form can be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., tablets, capsules, 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, etc.

[0201] The provided compositions may be administered in any amount and via any route of administration that is effective in treating or reducing the severity of any disease or condition described herein.

[0202] use This disclosure provides compounds and compositions described herein (e.g., formulas I'', I, IA, IB, IB1, IC, IC1, IC1-a, IC1-b, IC1-c, IC1-d, IC1-e, IC1-f, IC1-g, IC2, IC2-a, IC2-b, IC2-c, IC2-d, IC2-e, IC2-f, IC2-g, IC3-a, IC3-b, IC3-c, IC3-d, IC3- e, IC3-f, IC3-g, IC3-h, IC3-i, IC3-j, IC3-k, IC3-l, IC3-m, IC4, ID, IE, IE1, IE1-a, IE1-b, I', IA ',IB',IB1',IC',IC1',IC1-a',IC1-b',IC1-c',IC1-d',IC1-e','IC1-f',IC1-g',IC2',IC2-a' , IC2-b', IC2-c', IC2-d', IC2-e', IC2-f', IC2-g', IC3-a', IC3-b', IC3-c', IC3-d', IC3-e', IC3 -f', IC3-g', IC3-h', IC3-I', IC3-j', IC3-k', IC3-l', IC3-m', IC4', ID', IE', IE1', IE1-a', IE1 The compounds and compositions provided are intended for use in medicine (e.g., as therapeutic agents for treating, improving, delaying the progression of, improving or eliminating symptoms of, and / or inhibiting diseases or conditions, as described herein). In some embodiments, the compounds and compositions provided are intended for use as pharmaceuticals. In some embodiments, the compounds and compositions provided are intended for use in research, such as as analytical tools and / or control compounds in bioassays.

[0203] In some embodiments, the provided compounds can be used to disrupt (e.g., inhibit and / or block and / or regulate) the interaction between small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and PI3Kα proteins. In some embodiments, this disclosure provides a method for disrupting, interrupting, and / or blocking the interaction between small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and PI3Kα proteins in a subject, said method comprising administering the provided compound or composition. In some embodiments, this disclosure provides a method for disrupting, interrupting, and / or blocking the interaction between small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and PI3Kα proteins in a biological sample, said method comprising administering the provided compound or composition. In some embodiments, this disclosure provides a method of contacting cells containing a small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein with a provided compound or composition. In some such embodiments, the small GTPase is capable of binding 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 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) contains a mutation in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H.In some embodiments, the NRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12D, G12V, G13D, and / or Q61R. In some embodiments, the HRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein contains G12V, G13R, and / or Q61R mutations. In some embodiments, the PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, the PI3Kα protein is a mutant PI3Kα protein. In some embodiments, the PI3Kα protein contains 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 PI3Kα protein contains E542K, E545K, H1047R, and / or H1047L mutations.

[0204] In some embodiments, this disclosure provides a method of administering the provided compound or composition to a subject in need. In some such embodiments, the subject suffers from a disease, condition, or disorder associated with the interaction between a small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3Kα protein. In some embodiments, the subject suffers from a disease, condition, or disorder that is improved by disrupting the interaction between the small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3Kα protein. In some embodiments, the small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding 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 G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutations. In some embodiments, the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutations. In some embodiments, the NRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12D, G12V, G13D, and / or Q61R. In some embodiments, the HRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein contains G12V, G13R, and / or Q61R mutations. In some embodiments, the RAS protein is a wild-type RAS protein. In some embodiments, the PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, the PI3Kα protein is a mutant PI3Kα protein.In some embodiments, the PI3Kα protein contains mutations in N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L. In some embodiments, the PI3Kα protein contains mutations in E542K, E545K, H1047R, and / or H1047L. In some embodiments, the subject has the cancer or other indications described herein. In some embodiments, the subject has previously received cancer treatment. In some embodiments, the subject has previously entered cancer remission.

[0205] In some implementations, the provided method includes administering the provided compound or composition to the subject in need according to a protocol that prevents the subject from experiencing hyperglycemia or insulin-driven resistance.

[0206] In some embodiments, this disclosure provides a method of treating cancer, the method comprising administering a provided compound or composition to a subject. In some embodiments, the cancer is associated with and / or characterized by aberrant activation of PI3Kα. In some embodiments, the cancer is characterized by mutations in RAS proteins (e.g., HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In some embodiments, the cancer is characterized by mutations in KRAS proteins. In some embodiments, the KRAS proteins comprise mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H. In some embodiments, cancer is characterized by mutations in the NRAS protein. In some embodiments, the NRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12D, G12V, G13D, and / or Q61R. In some embodiments, cancer is characterized by mutations in the HRAS protein. In some embodiments, the HRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein contains mutations in G12V, G13R, and / or Q61R. In some embodiments, the cancer is characterized by mutations in the PI3Kα protein. In some embodiments, the PI3Kα protein contains mutations in N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L. In some embodiments, the PI3Kα protein contains mutations in E542K, E545K, H1047R, and / or H1047L.

[0207] As used herein, “cancer” (and “malignant tumor,” “growth,” “tumor,” and “carcinoma”) refers to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, resulting in an abnormal growth phenotype characterized by a significant loss of control over cell proliferation. In some embodiments, a tumor may be or include precancerous (e.g., benign) cells, malignant cells, pre-metastatic cells, metastatic cells, and / or non-metastatic cells. In some embodiments, cancer may be characterized as a solid tumor. In some embodiments, cancer may be characterized as a hematologic malignancy. Many different types of cancer are known.

[0208] In some implementation schemes, the cancers selected are pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancer; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; and endometrial corpus cancer. Cancers of the endometrium, testis, bladder, kidneys and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas. Other exemplary cancer types include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoma, chondrosarcoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial sarcoma, embryonal carcinoma, ependymoma, and Ewing's tumor. Tumors, epithelial carcinoma, fibrosarcoma, gastric cancer, urogenital tract cancer, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, liver cancer, Kaposi's sarcoma. Sarcoma), large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphatic system carcinoma, lymphoma, lymphangiosarcoma, lymphangioendothelial sarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma, mesothelioma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteosarcoma, epithelial ovarian cancer, papillary carcinoma, papillary gland carcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pineal tumor, 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, synovial tumor, thyroid cancer, uveal melanoma, and nephroblastoma (Wilm's (tumor). In some implementations, 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.

[0209] 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 the detection of one or more mutations in a biological sample obtained from the subject. In some embodiments, the cancer is characterized by mutations in a RAS protein (e.g., KRAS, HRAS, or NRAS). In some embodiments, the cancer is characterized by mutations in a KRAS protein. In some embodiments, the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutations. In some embodiments, the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutations. In some embodiments, the cancer is characterized by mutations in a NRAS protein. In some embodiments, the NRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12D, G12V, G13D, and / or Q61R. In some embodiments, cancer is characterized by mutations in the HRAS protein. In some embodiments, the HRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein contains G12V, G13R, and / or Q61R mutations. In some embodiments, the cancer is characterized by mutations in the PI3Kα protein. In some embodiments, the PI3Kα protein contains 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 PI3Kα protein contains E542K, E545K, H1047R, and / or H1047L mutations. In some implementations, the cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g., HER family (e.g., HER2 and / or HER3), Met, FGFR, Alk, PDGF, EGFR, or ROS kinases).In some embodiments, the cancer is characterized by mutations in or absence of the PTEN protein. In some embodiments, the cancer has a proven sensitivity to Avastin. For example, the cancer might be non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, the cancer is ER-positive (e.g., having an estrogen receptor). In some embodiments, the cancer is PR-positive (e.g., having a progesterone receptor).

[0210] In some embodiments, this disclosure provides a method for treating metabolic syndrome, the method comprising administering a provided compound or composition to a subject. In some embodiments, metabolic syndrome is selected from hyperinsulinemia and type 2 diabetes.

[0211] In some embodiments, this disclosure provides a method for treating RASopathy (e.g., a genetic syndrome caused by germline mutations in genes encoding components or regulators of the RAS / MAPK pathway), said method comprising administering a provided compound or composition to a subject. In some embodiments, RASopathy is selected from the group consisting of capillary malformation-arteriovenous malformation syndrome and Legius syndrome. In some embodiments, RASopathy is neurofibromatosis type 1 (NF1).

[0212] In some embodiments, this disclosure provides a method of treating vascular conditions, the method comprising administering a provided compound or composition to a subject. In some embodiments, the vascular condition is selected from... PIK3CA Related overgrowth syndromes (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Klippel-Trenaunay Syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibrofatty vascular abnormalities (FAVA)).

[0213] In some embodiments, this disclosure provides a method for treating pulmonary hypertension, such as pulmonary arterial hypertension, the method comprising administering a provided compound or composition to a subject.

[0214] In some embodiments, this disclosure provides a method for treating age-related macular degeneration or diabetic macular edema, the method comprising administering a provided compound or composition to a subject.

[0215] In some embodiments, this disclosure provides compounds or compositions for manufacturing medicaments. In some embodiments, the provided compounds or compositions can be used to manufacture medicaments for treating or improving diseases, conditions, or disorders associated with or improved by the interaction between small GTPases (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and PI3Kα proteins. In some embodiments, the small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding 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 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) contains mutations in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12D, G12V, G13D, and / or Q61R. In some embodiments, the HRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein contains G12V, G13R, and / or Q61R mutations. In some embodiments, the PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, the PI3Kα protein is a mutant PI3Kα protein.In some embodiments, the PI3Kα protein comprises mutations of N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L. In some embodiments, the PI3Kα protein comprises mutations of E542K, E545K, H1047R, and / or H1047L. In some embodiments, the provided compounds or compositions can be used to manufacture medicaments for treating the diseases, conditions, or disorders described herein. In some embodiments, the provided compounds or compositions can be used to manufacture medicaments for treating cancer or other indications described herein.

[0216] In some embodiments, this disclosure provides compounds or compositions for treating a disease, condition, or disorder in a subject of need. In some embodiments, the provided compounds or compositions can be used to treat a disease, condition, or disorder associated with or improved by the interaction between a small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Kα protein. In some embodiments, the small GTPase (e.g., Rac1, CDC42, or RAS proteins such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding 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 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) contains mutations in codon 12 (e.g., G12), codon 13 (e.g., G13), or codon 61 (e.g., Q61). In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the KRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the NRAS protein contains mutations in G12D, G12V, G13D, and / or Q61R. In some embodiments, the HRAS protein contains mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H. In some embodiments, the HRAS protein contains G12V, G13R, and / or Q61R mutations. In some embodiments, the PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, the PI3Kα protein is a mutant PI3Kα protein.In some embodiments, the PI3Kα protein comprises mutations of N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, E110del, Q546P, E542K, E545K, H1047R, and / or H1047L. In some embodiments, the PI3Kα protein comprises mutations of E542K, E545K, H1047R, and / or H1047L. In some embodiments, the provided compounds or compositions are used to treat the diseases, conditions, or disorders described herein. In some embodiments, the provided compounds or compositions are used to treat cancer or other indications as described herein.

[0217] In some embodiments, the provided compound or composition is administered as part of a combination therapy. As used herein, the term "combination therapy" refers to those situations in which a subject is simultaneously exposed to two or more treatment or preventative regimens (e.g., two or more treatment or preventative agents). In some embodiments, two or more regimens may be administered simultaneously. In some embodiments, such regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any dose of the second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administration" of the combination therapy may involve administering one or more agents or methods to a subject who is receiving other agents or methods in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even simultaneously), although in some embodiments, two or more agents may be administered together in a combination composition.

[0218] In some embodiments, the provided compound or composition is administered to a subject who is receiving or has received one or more other therapeutic agents (e.g., anticancer agents and / or therapies to address one or more side effects of such anticancer therapies, or other therapies to provide palliative care). Exemplary anticancer agents include, but are not limited to, alkylating agents, antimitotic agents, checkpoint inhibitors, antimetabolites, plant alkaloids, terpenoids, cytotoxic drugs, antibiotics, topoisomerase inhibitors, aromatase inhibitors, angiogenesis inhibitors, antisteroids, antiandrogens, mTOR inhibitors, monoclonal antibodies, kinase inhibitors, HIF2α inhibitors, or tyrosine kinase inhibitors. Alkylating agents can be, for example, amustine, chlorambucil, cisplatin, carboplatin, oxaliplatin, streptozotocin, busulfan, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, thiotepa, or cyclophosphamide. Antimetabolites can 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. Antimitotic agents can be, for example, taxanes such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL), or vinblastine alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, or vinorelbine (NAVELBINE). Checkpoint inhibitors can be anti-PD-1 or anti-PD-L1 antibodies, such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, or MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); or agents targeting LAG3 (lymphocyte activation gene 3 protein), KIR (cytotoxic cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T cell immunoglobulin and mucin-containing domain-3), or OX40 (tumor necrosis factor receptor superfamily member 4).Topoisomerase inhibitors can be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), hycamtidine (HYCAMTIN), teniposide (VUMON), or etoposide (EPOSIN). Cytotoxic antibiotics can be, for example, actinomycin D (COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or procainoxane. Aromatase inhibitors can be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN). Angiogenesis inhibitors can be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN). Antisteroids or antiandrogens can be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone acetate, flutamide (EULEXIN), or 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, tesilolimus (TORISEL), or sirolimus. Monoclonal antibodies can be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). Kinase inhibitors can be, for example, BRAF inhibitors, MEK inhibitors, or KRAS inhibitors (e.g., KRAS G12C inhibitors, such as sotorasib, adagrasib, or BBO-8520).Other examples of agents that can be used in combination with the compounds provided herein include, but are not limited to: acridine; BCG vaccine; ETILAMIDE; chloroquine; clodronate, pamidronate and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetic acid; estradiol; neupogenin; fludrocortisone; and goserelin. ADEX; interferon; leucovorin; leuprolide (LUPRON); levamisole; lonidamycin; mesna; metformin; mitotane (o,r'-DDD, LYSODREN); nocodazole; sandovtide; perifosine; porfimer (especially in combination with phototherapy and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and diethylstilbestrol; progestins such as medroxyprogesterone acetate (MPA) and medroxyprogesterone acetate; and testosterone.

[0219] Exemplary Implementation The following numbered embodiments (though non-limiting) are examples of certain aspects of this disclosure: 1. A compound of formula I: (I) Or its salts (e.g., pharmaceutically acceptable salts), wherein: Ring A is a phenyl group; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; The ring C is selected from phenyl, 9 to 10-membered bicyclic aryl ring, 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9 to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 7-membered carbon ring, 4 to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6 to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 12 to 13-membered polycyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. And when L is C 2-5 In the case of an alkynyl group, ring D may not be present; L is a covalent bond, a divalent straight chain, or a branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 C independently selected from halogens and optionally substituted C 1-6 aliphatic; Each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy and optionally substituted C 1-6 aliphatic; Each R 4 C is independently optional substitution 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; R 6 and R 6' With optional substitution of C 4-8Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; Each x is independently 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8 The instance is replaced; and Each R 8 C independently selected from oxo, halogenated, and optionally substituted C 1-6 Aliphatic.

[0220] 2. The compound as described in embodiment 1, wherein the compound has the formula IC: (IC) Or its salts (e.g., pharmaceutically acceptable salts).

[0221] 3. The compound as described in embodiment 1, wherein the compound has formula ID: (ID) Or its salts (e.g., pharmaceutically acceptable salts), wherein: L is a binary straight chain or branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-.

[0222] 4. The compound as described in embodiment 1, wherein the compound has the formula IE: (IE) Or its salts (e.g., pharmaceutically acceptable salts).

[0223] 5. The compound of any one of embodiments 1-4, wherein ring B is a 5-membered heteroaryl ring and a 5-membered carbon ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0224] 6. The compound as described in embodiment 5, wherein ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0225] 7. The compound as described in embodiment 5, wherein ring B is a 5-membered carbon ring.

[0226] 8. The compound of any one of embodiments 1-4, wherein ring B is selected from: , , , , , , , , , and .

[0227] 9. The compound as described in embodiment 8, wherein ring B is selected from: , , , , , , , , and .

[0228] 10. The compound as described in embodiment 1 or 2, wherein the compound has the formula IC3-a, IC3-b, IC3-c, IC3-d, IC3-e, IC3-f, or IC3-g: Or its salts (e.g., pharmaceutically acceptable salts).

[0229] 11. The compound of embodiment 10, wherein the compound has the formula IC3-a or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0230] 12. The compound as described in embodiment 11, wherein the compound is not selected from the compounds in Table P1.

[0231] 13. The compound of embodiment 10, wherein the compound has the formula IC3-b or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0232] 14. The compound as described in embodiment 13, wherein the compound is not selected from the compounds in Table P2.

[0233] 15. The compound of embodiment 10, wherein the compound has the formula IC3-c or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0234] 16. The compound of embodiment 10, wherein the compound has the formula IC3-d or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0235] 17. The compound as described in embodiment 16, wherein the compound is not selected from the compounds in Table P3.

[0236] 18. The compound of embodiment 10, wherein the compound has the formula IC3-e or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0237] 19. The compound as described in embodiment 18, wherein the compound is not selected from the compounds in Table P4.

[0238] 20. The compound of embodiment 10, wherein the compound has the formula IC3-f or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0239] 21. The compound of embodiment 10, wherein the compound has the formula IC3-g or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0240] 22. The compound as described in any one of embodiments 1-21, wherein each R 2 Independently selected from halogens and C 1-6 alkyl.

[0241] 23. The compound as described in any one of embodiments 1-22, wherein n is 0 or 1.

[0242] 24. The compound as described in embodiment 23, wherein n is 1.

[0243] 25. The compound of any one of embodiments 1-24, wherein at least one R 1 Yes - OR 7 .

[0244] 26. The compound as described in embodiment 25, wherein one of R 1 Yes - OR 7 And any other R 1 The groups are all halogens.

[0245] 27. The compound as described in any one of embodiments 1-26, wherein a portion thereof yes .

[0246] 28. The compound as described in embodiment 27, wherein a portion thereof yes or .

[0247] 29. The compound as described in any one of embodiments 1-28, wherein each R 7 Selected independently from C 1-6 Alkyl and -(C 1-4 (alkylene)OR.

[0248] 30. The compound as described in any one of embodiments 1-29, wherein m is 2 or 3.

[0249] 31. The compound of any one of embodiments 1-30, wherein the ring C is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0250] 32. The compound of any one of embodiments 1-30, wherein the ring C is selected from a 9- or 10-membered bicyclic aryl ring, a 9- or 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6- or 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 12- or 13-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0251] 33. The compound of embodiment 32, wherein ring C is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0252] 34. The compound as described in any one of embodiments 1-30, wherein the compound is subjected to p R 3 The ring C with substituted groups is ,in: The C1 ring is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring C1 and ring C2 are fused together; and The ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0253] 35. The compound of embodiment 34, wherein ring C1 is phenyl and ring C2 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0254] 36. The compound of embodiment 34, wherein ring C1 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and ring C2 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0255] 37. The compound of embodiment 34, wherein ring C1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and ring C2 is a 5- to 6-membered heteroaryl ring, a 3- to 7-membered carbon ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0256] 38. The compound as described in any one of embodiments 1-37, wherein each R 3 Independently selected from halogens, -C(O)N(R)2 and optionally substituted C 1-6 alkyl.

[0257] 39. The compound as described in any one of embodiments 1-38, wherein p is 1, 2 or 3.

[0258] 40. The compound as described in any one of embodiments 1-39, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , and .

[0259] 41. The compound of any one of embodiments 1-40, wherein ring D is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0260] 42. The compound of any one of embodiments 1-40, wherein ring D is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 10-membered bicyclic or polycyclic carbon rings, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0261] 43. The compound of embodiment 42, wherein ring D is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0262] 44. The compound as described in any one of embodiments 1-40, wherein a portion thereof yes ,in: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Among them, ring D1 and ring D2 are fused; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0263] 45. The compound of embodiment 44, wherein ring D1 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0264] 46. ​​The compound of embodiment 44, wherein ring D1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0265] 47. The compound as described in any one of embodiments 1-40, wherein a portion thereof yes .

[0266] 48. The compound as described in any one of embodiments 1-47, wherein each R 4 Independently, C is optionally substituted with one or more -OH groups. 1-6 alkyl.

[0267] 49. The compound as described in any one of embodiments 1-48, wherein q is 0 or 1.

[0268] 50. The compound as described in any one of embodiments 1-49, wherein R 5 It is -C(O)R 9 Or -(CH2) x N(R)C(O)R 9 .

[0269] 51. The compound as described in any one of embodiments 1-50, wherein R 9 C is an optional substitute 2-6 alkenyl or optionally substituted C 2-6 Alkyne group.

[0270] 52. The compound as described in any one of embodiments 1-51, wherein R 5 yes or .

[0271] 53. The compound as described in any one of embodiments 1-52, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0272] 54. The compound as described in embodiment 1 or 3, wherein L is a divalent straight-chain or branched C having at least one triple bond. 2-6 Hydrocarbon chain.

[0273] 55. The compound as described in embodiment 1 or 3, wherein L is a divalent straight-chain or branched C. 1-2 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-.

[0274] 56. The compound as described in embodiment 1 or 4, wherein R 6 and R 6' With optional substitution of C 5-6 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-.

[0275] 57. The compound as described in embodiment 56, wherein R 6 and R 6' Connected to the following: -O(CH2)5-, -O(CH2)4- or -O(CH2)3OCH2-.

[0276] 58. The compound of any one of embodiments 1-57, wherein each R is hydrogen or C optionally substituted with one or more halogens. 1-6 alkyl.

[0277] 59. A compound of formula II: (II) Or its salts (e.g., pharmaceutically acceptable salts), wherein: Ring A is a phenyl group and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; J is a covalent bond, a divalent straight chain, or a branched chain. 1-4 hydrocarbon chain; X is -OR, -N(R)2, -C(O)N(R)2 or optionally substituted with a group selected from the following: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 C independently selected from halogens and optionally substituted C 1-6 aliphatic; Each R 4 Independently selected from the arbitrarily substituted C 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6Aliphatic.

[0278] 60. The compound of embodiment 63, wherein the compound has the formula IIF: (IIF) Or its salts (e.g., pharmaceutically acceptable salts), wherein: X is -C(O)N(R)2 or optionally substituted with a group selected from the following: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0279] 61. The compound of embodiment 59, wherein the compound has the formula IIG: (IIG) Or its salts (e.g., pharmaceutically acceptable salts), wherein: J is a binary straight chain or a side chain. 1-4 hydrocarbon chain; and X is either -OR or -N(R)2.

[0280] 62. The compound as described in embodiment 59 or 60, wherein X is a group selected from: a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally C 1-6 Alkyl substitution.

[0281] 63. The compound as described in any one of embodiments 59-62, wherein a portion thereof Selected from: , , , , , and .

[0282] 64. The compound of any one of embodiments 59-63, wherein ring B is a 5-membered heteroaryl ring and a 5-membered carbon ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0283] 65. The compound of embodiment 64, wherein ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0284] 66. The compound as described in embodiment 64, wherein ring B is a 5-membered carbon ring.

[0285] 67. The compound of any one of embodiments 59-66, wherein ring B is selected from: , , , , , , , , , and .

[0286] 68. The compound as described in any one of embodiments 59-67, wherein each R 2 Independently selected from halogens and C 1-6 alkyl.

[0287] 69. The compound as described in any one of embodiments 59-68, wherein n is 0 or 1.

[0288] 70. The compound of any one of embodiments 59-69, wherein ring A is phenyl.

[0289] 71. The compound as described in any one of embodiments 59-70, wherein at least one R 1 Yes - OR 7 .

[0290] 72. The compound as described in embodiment 71, wherein one of R 1 Yes - OR 7 And any other R 1 The groups are all halogens.

[0291] 73. The compound as described in any one of embodiments 59-72, wherein a portion thereof yes .

[0292] 74. The compound as described in embodiment 73, wherein a portion thereof yes or .

[0293] 75. The compound as described in any one of embodiments 59-74, wherein each R 7 Selected independently from C 1-6 Alkyl and -(C 1-4 (alkylene)OR.

[0294] 76. The compound as described in any one of embodiments 59-75, wherein m is 2 or 3.

[0295] 77. The compound of any one of embodiments 59-76, wherein ring D is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0296] 78. The compound of any one of embodiments 59-76, wherein ring D is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 10-membered bicyclic or polycyclic carbon rings, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0297] 79. The compound of embodiment 78, wherein ring D is selected from 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0298] 80. The compound as described in any one of embodiments 59-76, wherein a portion thereof yes ,in: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Among them, ring D1 and ring D2 are fused; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0299] 81. The compound of embodiment 80, wherein ring D1 is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0300] 82. The compound of embodiment 80, wherein ring D1 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and ring D2 is a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0301] 83. The compound as described in any one of embodiments 59-82, wherein a portion thereof yes .

[0302] 84. The compound as described in any one of embodiments 59-83, wherein each R 4 Independently, C is optionally substituted with one or more -OH groups. 1-6 alkyl.

[0303] 85. The compound as described in any one of embodiments 59-84, wherein q is 0 or 1.

[0304] 86. The compound as described in any one of embodiments 59-85, wherein R 5 It is -C(O)R 9 Or -(CH2) x N(R)C(O)R 9 .

[0305] 87. The compound as described in any one of embodiments 59-86, wherein R 9 C is an optional substitute 2-6 alkenyl or optionally substituted C 2-6 Alkyne group.

[0306] 88. The compound as described in any one of embodiments 59-87, wherein R 5 yes or .

[0307] 89. The compound of any one of embodiments 59-88, wherein each R is hydrogen or C optionally substituted with one or more halogens. 1-6 alkyl.

[0308] 90. A compound selected from Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0309] 91. A pharmaceutical composition comprising a compound or a salt thereof (e.g., a pharmaceutically acceptable salt) according to any one of embodiments 1-90, and a pharmaceutically acceptable carrier or excipient.

[0310] 92. A method comprising administering to a subject in need a therapeutically effective amount of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof.

[0311] 93. The method of embodiment 92, wherein the subject suffers from a disease, condition, or disorder that can be improved by disrupting, inhibiting, and / or preventing the interaction between the small GTPase and the PI3Kα protein.

[0312] 94. The method of embodiment 93, wherein the small GTPase is a Rac1, CDC42, or RAS protein.

[0313] 95. The method of embodiment 94, wherein the small GTPase is a RAS protein.

[0314] 96. The method of embodiment 95, wherein the RAS protein is KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1.

[0315] 97. The method as described in any one of embodiments 92-96, wherein the subject has cancer.

[0316] 98. A method of treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof.

[0317] 99. The method of embodiment 97 or 98, wherein the cancer is associated with and / or characterized by abnormal activation of PI3Kα and / or mutations in PI3Kα.

[0318] 100. The method of embodiment 99, 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.

[0319] 101. The method of embodiment 100, wherein the PI3Kα protein comprises E542K, E545K, H1047R and / or H1047L mutations.

[0320] 102. The method as described in any one of embodiments 97-101, wherein the cancer is characterized by a mutation in the RAS protein.

[0321] 103. The method of embodiment 102, wherein the RAS protein contains a mutation in codons 12, 13 or 61.

[0322] 104. The method as described in embodiment 102 or 103, wherein the RAS protein is KRAS.

[0323] 105. The method of embodiment 104, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0324] 106. The method of embodiment 105, wherein the KRAS protein comprises a G12C or G12D mutation.

[0325] 107. The method as described in embodiment 102 or 103, wherein the RAS protein is HRAS.

[0326] 108. The method of embodiment 107, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0327] 109. The method as described in embodiment 102 or 103, wherein the RAS protein is NRAS.

[0328] 110. The method of embodiment 109, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0329] 111. The method as described in any one of embodiments 97-110, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancer; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney and other urinary tissue cancers, including renal cell carcinoma (RCC). Cancers of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

[0330] 112. The method of embodiment 111, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0331] 113. The method of any one of embodiments 97-112, wherein the cancer is characterized by a mutated, overexpressed and / or amplified receptor tyrosine kinase (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR or ROS kinase).

[0332] 114. The method of any one of embodiments 97-113, wherein the cancer is characterized by a mutation in the PTEN protein or a deficiency of the PTEN protein.

[0333] 115. The method as described in any one of embodiments 92-114, wherein the subject has previously received a cancer treatment regimen.

[0334] 116. The method as described in any one of embodiments 92-115, wherein the subject has previously entered a period of cancer remission.

[0335] 117. A method for treating a metabolic disorder, the method comprising administering to a subject in need a therapeutically effective amount of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof.

[0336] 118. The method of embodiment 117, wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes.

[0337] 119. A method for treating RASopathy, the method comprising administering to a subject in need a therapeutically effective amount of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof.

[0338] 120. The method of embodiment 119, wherein the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome and Legius syndrome.

[0339] 121. A method for treating vascular conditions or disorders, the method comprising administering to a subject in need a therapeutically effective amount of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof.

[0340] 122. The method of embodiment 121, wherein the vascular condition or disorder is selected from PIK3CA-associated overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Kertz syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibrolipovascular abnormality (FAVA)).

[0341] 123. A method for disrupting, inhibiting, and / or preventing the interaction between a subject's small GTPase and PI3Kα protein, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-90.

[0342] 124. A method for disrupting, inhibiting, and / or preventing the interaction between a small GTPase and a PI3Kα protein, the method comprising contacting a cell containing the small GTPase and the PI3Kα protein with a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-90.

[0343] 125. A method comprising contacting cells containing a small GTPase and a PI3Kα protein with a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-90.

[0344] 126. The method as described in embodiment 124 or 125, wherein the cells are contained within the subject.

[0345] 127. The method of any one of embodiments 123-126, wherein the small GTPase is selected from Rac1, CDC42 and RAS proteins.

[0346] 128. The method of embodiment 127, wherein the small GTPase is a RAS protein.

[0347] 129. The method of embodiment 128, wherein the RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS and RIT1.

[0348] 130. The method of embodiment 129, wherein the RAS protein is KRAS.

[0349] 131. The method of embodiment 130, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0350] 132. The method of embodiment 131, wherein the KRAS protein comprises a G12C or G12D mutation.

[0351] 133. The method of embodiment 129, wherein the RAS protein is HRAS.

[0352] 134. The method of embodiment 133, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0353] 135. The method of embodiment 129, wherein the RAS protein is NRAS.

[0354] 136. The method of embodiment 135, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0355] 137. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-90, used as a medicine.

[0356] 138. Use of any compound or pharmaceutically acceptable salt thereof as described in any of embodiments 1-90 in the manufacture of a pharmaceutical product.

[0357] 139. The compound or use as described in embodiments 137 or 138, wherein the drug is used to treat cancer.

[0358] 140. The compound or use as described in embodiment 139, wherein the cancer is associated with and / or characterized by abnormal activation of PI3Kα and / or mutations in PI3Kα.

[0359] 141. The compound or use as described in embodiment 140, 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.

[0360] 142. The compound or use as described in embodiment 141, wherein the PI3Kα protein comprises E542K, E545K, H1047R and / or H1047L mutations.

[0361] 143. The compound or use as described in any one of embodiments 139-142, wherein the cancer is characterized by a mutation in the RAS protein.

[0362] 144. The compound or use as described in embodiment 143, wherein the RAS protein contains a mutation in codons 12, 13 or 61.

[0363] 145. The compound or use as described in embodiment 143 or 144, wherein the RAS protein is KRAS.

[0364] 146. The compound or use as described in embodiment 145, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0365] 147. The compound or use as described in embodiment 146, wherein the KRAS protein comprises a G12C or G12D mutation.

[0366] 148. The compound or use as described in embodiment 143 or 144, wherein the RAS protein is HRAS.

[0367] 149. The compound of embodiment 148, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0368] 150. The compound or use as described in embodiment 143 or 144, wherein the RAS protein is NRAS.

[0369] 151. The compound or use as described in embodiment 150, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0370] 152. The compound or use as described in any one of embodiments 139-151, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancers; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancers; bone cancer; connective tissue cancers; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney and other urinary tissue cancers, including renal cell carcinoma (R... Cancer of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

[0371] 153. The compound or use as described in embodiment 152, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0372] 154. The compound or use as described in any one of embodiments 139-151, wherein the cancer is characterized by a mutated, overexpressed and / or amplified receptor tyrosine kinase (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR or ROS kinase).

[0373] 155. The compound or use as described in any one of embodiments 139-151, wherein the cancer is characterized by a mutation in the PTEN protein or a deficiency of the PTEN protein.

[0374] 156. The compound or use as described in embodiments 137 or 138, wherein the drug is used to treat metabolic disorders, RASopathy, or vascular conditions.

[0375] 157. The compound or use as described in embodiment 156, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome and Legius syndrome; and / or (iii) the vascular disease or disorder is selected from PIK3CA-associated overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Kertz syndrome; PTEN hamartoma tumor syndrome (PHTS); or fibrolipovascular abnormality (FAVA)).

[0376] 158. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-90, used to treat a disease, symptom or ailment.

[0377] 159. The compound used according to implementation scheme 158 is used to treat cancer.

[0378] 160. The compound used according to embodiment 159, wherein the cancer is associated with and / or characterized by abnormal activation of PI3Kα and / or mutations in PI3Kα.

[0379] 161. The compound used according to embodiment 160, 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.

[0380] 162. The compound used according to embodiment 161, wherein the PI3Kα protein comprises E542K, E545K, H1047R and / or H1047L mutations.

[0381] 163. The compound used according to any one of embodiments 159-162, wherein the cancer is characterized by a mutation in the RAS protein.

[0382] 164. The compound used according to embodiment 163, wherein the RAS protein contains a mutation in codons 12, 13 or 61.

[0383] 165. The compound used according to embodiment 163 or 164, wherein the RAS protein is KRAS.

[0384] 166. The compound used according to embodiment 165, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0385] 167. The compound used according to embodiment 166, wherein the KRAS protein contains a G12C or G12D mutation.

[0386] 168. The compound used according to embodiment 163 or 164, wherein the RAS protein is HRAS.

[0387] 169. The compound used according to embodiment 168, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0388] 170. The compound used according to embodiment 163 or 164, wherein the RAS protein is NRAS.

[0389] 171. The compound used according to embodiment 170, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

[0390] 172. The compound used according to any one of embodiments 159-171, wherein said cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancers; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancers; bone cancer; connective tissue cancers; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney and other urinary tissue cancers, including renal cell carcinoma (RCC). C); cancers of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

[0391] 173. The compound used according to embodiment 172, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

[0392] 174. The compound used in any of embodiments 159-173, wherein the cancer is characterized by a mutated, overexpressed and / or amplified receptor tyrosine kinase (e.g., HER family, Met, FGFR, Alk, PDGF, EGFR or ROS kinase).

[0393] 175. The compound used according to any one of embodiments 159-174, wherein the cancer is characterized by a mutation in the PTEN protein or a deficiency of the PTEN protein.

[0394] 176. The compound used according to embodiment 158 ​​is used to treat metabolic disorders, RASopathy, or vascular conditions.

[0395] 177. The compound used according to embodiment 176, wherein: (i) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) the RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome and Legius syndrome; and / or (iii) the vascular disease or disorder is selected from PIK3CA-associated overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Kertz syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibrolipovascular abnormality (FAVA)).

[0396] Example As described in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that although the general method describes the synthesis of certain compounds of this disclosure, the following general method and other methods known to those skilled in the art can be applied to all compounds as described herein and to the subclasses and species of each of these compounds.

[0397] The selected abbreviations used in the preceding sections and examples are summarized in the table below: Materials and methods The preparative thin-layer chromatography (Prep-TLC) separations described in this article are typically performed on 20 x 20 cm plates (500-μm thick silica gel).

[0398] Chromatographic purification is typically performed using Biotage Isolera. An automated system running Biotage Isolera One 2.0.6 software (Biotage LLC, Charlotte, NC) is used. Flow rates are the default values ​​specified for the column used. Reversed-phase chromatography is performed on KP-C18-HS Flash+ columns (Biotage LLC) of various sizes using an elution gradient of water and acetonitrile. Typical loadings are crude sample:RP SiO2 at ratios between 1:50 and 1:1000 by weight. Normal-phase chromatography is performed using elution gradients with various solvents (e.g., hexane, ethyl acetate, dichloromethane, methanol, acetone, chloroform, MTBE, etc.). The columns are SNAP columns containing KP-SIL or SNAP Ultra (25 pm spherical particles) of various sizes (Biotage LLC). Typical loadings are crude sample:SiO2 at ratios between 1:10 and 1:150 by weight. Alternatively, silica gel chromatography is performed on a Biotage Horizon rapid chromatography system.

[0399] Intermediates and exemplary compounds 1 1H NMR analysis is 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 spectrometer (operating at 400 MHz) according to the manufacturer's recommended standard operating procedures. A reference frequency is set for the internal standard using a TMS. Chemical shift values ​​(δ) are reported in parts per million (ppm), and splitting modes are abbreviated as: s (single), br.s (broad singlet), d (doublet), dd (doublet), t (triplet), and m (multiplet). Coupling constants ( J (Indicated in Hz. Typical deuterated solvents are used, as specified in individual examples.)

[0400] LCMS analysis is typically performed using one of the following conditions: (1) LC-MS spectra were acquired on an Agilent Technologies 6120B quadrupole spectrometer. The mobile phase for LC was acetonitrile (A) with 0.1% formic acid and water (B) with 0.1% formic acid, with elution gradients of 5%–95% A over 6.0 min, 5%–40% A over 6.0 min, and 80%–100% A over 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 were measured by electrospray ionization mass spectrometry (ESI). Unless otherwise specified, all temperatures are in degrees Celsius (°C).

[0401] (2) LCMS spectra were acquired on an Agilent Technologies 1290-6420 triple quadrupole spectrometer: the mobile phase for LC was acetonitrile (A) containing 0.05% formic acid and water (B) containing 0.05% formic acid, with an elution gradient of 5%–95% A over 5.0 min, using a ZORBAX SB-C18 50 mm x 2.1 mm x 1.8 μm capillary column; flow rate: 0.3 mL / min. Mass spectra were measured by electrospray ionization mass spectrometry (ESI).

[0402] (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 x 150 mm x 3.5 μm RapidResol column. The mobile phase was water (0.1% formic acid) / MeCN (0.1% formic acid), with a gradient of 5%–95% MeCN over 10 minutes, and a flow rate of 1 mL / min. Accurate mass data were obtained using a Thermo Fisher extractive plus EMR orbital trap LCMS system. Precise mass values ​​were calculated using ChemCalc.

[0403] (4) LC-MS spectra were acquired on an Alliance Waters 2695 spectrometer coupled with a dual absorbance detector (Waters 2487) and a Waters Micro Mass ZQ-2000 single quadrupole spectrometer. The mobile phase for LC was acetonitrile (A) and water (B) containing 0.01% formic acid, with an elution gradient of 5%–100% A over 10.0 min. A Kromasil 100-5-C18 150 mm x 4.6 mm x 5 μm column was used. Mass spectra were measured by electrospray ionization mass spectrometry (ESI).

[0404] (5) LC-MS spectra were acquired on a Waters Micromass-ZQ 2000 quadrupole spectrometer. The mobile phase for LC was (A) 0.1% formic acid in water; (B) 100% acetonitrile, with an elution gradient of 10%-90% B for 10.0 min, 90% B to 12 min, 90%-10% B for 12-13 min, and 90%-10% B for 13-15 min. A Phenomenex Gemini-C18 spectrometer (50 mm x 4.6 mm x 5 μm) was used; the flow rate was 0.5 mL / min. Mass spectra were measured by electrospray ionization mass spectrometry (ESI).

[0405] Typically, analytical HPLC spectral conditions are as follows: LC1: Agilent Technologies 1260 Infinity spectrometer, column: poroshell 120 EC-C18 150 mm x 4.6 mm x 4 μm; temperature: 40℃; eluent: 5:95 v / v acetonitrile / water + 0.02% trifluoroacetic acid over 20 min; flow rate: 1.2 mL / min; detection: VWD, 190-600 nm.

[0406] LC2: Shimadzu 2010 CHT, Waters X-select CSH C18 column (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 temperature ramp: time / B concentration: 0 / 5, 2 / 5, 20 / 50, 25 / 50, 30 / 90, 35 / 90, 37 / 05, 40 / 05.

[0407] Preparative HPLC was performed under one of the following conditions: 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 phase: 10% to 30%; Final organic phase: 60% to 80%; UV1: 240; UV2: 230; Flow rate: 15 mL / min.

[0408] Condition 2: C18 reversed-phase preparative HPLC was performed using a Waters purification system with a 2489 UV / Vis detector, a 2545 gradient module, and a fraction collector III controlled by a Waters Chromescope v1.6. The preparative HPLC column used was a Waters XBridge® Prep C18 5µM OBD. TM 19 x 250 mm column, mobile phase is water / MeCN or water (0.1% TFA) / MeCN (0.1% TFA).

[0409] Condition 3: Shimadzu preparative HPLC system; Column: Phenomenex Luna C18, 21.1 mm × 250 mm, 10 μm; Mobile phase: MP-A 10 mM ammonium acetate buffer, MP-B: methanol (100%), gradient elution for 35 minutes, UV: 254; Flow rate: 10 mL / min. Gradient temperature ramp: Time / B concentration: 0 / 50, 25 / 90, 30 / 90, 32 / 50, 35 / 50.

[0410] Compound names were generated using ChemDraw Professional.

[0411] Synthesis of the provided compounds The compounds provided herein, including various forms such as salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc., can be prepared by various methods, including those listed in the following examples.

[0412] Synthesis Example 1: N Synthesis of -[3-[[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1,2,3,4-tetrahydroisoquinoline-6-yl)thiopheno[3,2-c]pyridin-6-yl]amino]phenyl]prop-2-enamide (compound 1) Step A: Preparation of methyl 4-fluoro-2-(2-methoxyethoxy)benzoate: 1-bromo-2-methoxy-ethane (24.5 g, 176 mmol) and cesium carbonate (97.4 g, 220 mmol) were added to a solution of methyl 4-fluoro-2-hydroxybenzoate (25.0 g, 147 mmol) in MeCN (500 mL). The mixture was stirred at 70 °C under Ar for 16 h. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with saturated brine (100 mL), dried over Na2SO4, and concentrated under vacuum to give methyl 4-fluoro-2-(2-methoxyethoxy)benzoate (32.6 g, 97% yield) as a yellow oil. LCMS ESI (+) m / z 229.2(M+H).

[0413] Step B: Preparation of 4-fluoro-2-(2-methoxyethoxy)benzoic acid: Lithium hydroxide monohydrate (8.55 g, 357 mmol) was added to a solution of methyl 4-fluoro-2-(2-methoxyethoxy)benzoate (16.3 g, 71.4 mmol) in THF (82 mL), methanol (27 mL), and water (27 mL). The mixture was stirred at 25 °C for 6 h. The reactants were concentrated to remove THF and methanol, and then diluted with water (150 mL). An aqueous solution of HCl (3 N) was added to adjust the pH to 2. The mixture was extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with saturated brine (70 mL), dried over Na2SO4, and concentrated under vacuum to give 4-fluoro-2-(2-methoxyethoxy)benzoic acid (14.8 g, 97% yield) as a white solid. 1 HNMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.8, 6.8 Hz, 1H), 6.80-6.91 (m, 1H), 6.76 (dd, J = 10.0, 2.3 Hz, 1H), 4.34 (t, J = 4.6 Hz, 2H), 3.82 (t, J = 4.6Hz, 2H), 3.46 (s, 3H), 2.10 (s, 1H).

[0414] Step C: Preparation of 4-fluoro-N-methoxy-2-(2-methoxyethoxy)-N-methylbenzamide: 4-fluoro-2-(2-methoxyethoxy)benzoic acid (10.0 g, 46.7 mmol), N,OHATU (23.1 g, 60.7 mmol) was added to a solution of dimethyl hydroxylamine hydrochloride (5.47 g, 56.0 mmol) and triethylamine (20.0 mL, 140 mmol) in DCM (150 mL). The mixture was stirred at 25 °C for 6 h. The mixture was poured into water and the product was extracted with DCM. The organic fraction was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (EtOAc) to give 4-fluoro-N-methoxy-2-(2-methoxyethoxy)-N-methylbenzamide (10.8 g, yield 89.9%). 1 HNMR (400 MHz, CDCl3) δ 7.23 – 7.34 (m, 1H), 6.61 – 6.76 (m, 2H), 4.13 (t, J =4.8 Hz, 2H), 3.73 (t, J = 4.8 Hz, 2H), 3.41 (s, 3H), 2.80 (s, 6H).

[0415] Step D: Preparation of 2-[4-fluoro-2-(2-methoxyethoxy)benzoyl]thiophene-3-carboxylic acid: Thiophene (37.0 mL, 2.5 M solution in hexane, 92.4 mmol) was added dropwise to a solution of thiophene-3-carboxylic acid (5.92 g, 46.2 mmol) in THF (130 mL) at -60 °C under Ar. The mixture was stirred at -60 °C under Ar for 0.5 h, followed by the addition of 4-fluoro-N-methoxy-2-(2-methoxyethoxy)-N-methylbenzamide (10.8 g, 42.0 mmol) at -60 °C. The temperature was raised to 0 °C, and the resulting mixture was stirred at 0 °C for another 1 h. The mixture was poured into water. 1 NHCl aqueous solution was added to adjust the pH to 5. The mixture was concentrated to remove THF and diluted with water. The solid was filtered, washed with water, and dried under vacuum to give crude 2-[4-fluoro-2-(2-methoxyethoxy)benzoyl]thiophene-3-carboxylic acid (13.0 g, 57% yield). LCMS ESI (+) m / z 325.1 (M+H).

[0416] Step E: Preparation of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-thieno[3,2-c]pyran-6-carboxylate: Potassium carbonate (2.29 g, 16.6 mmol) was added to a solution of 2-[4-fluoro-2-(2-methoxyethoxy)benzoyl]thiophene-3-carboxylic acid (2.15 g, 6.63 mmol) and diethyl 2-bromomalonate (1.90 g, 7.96 mmol) in DMF (25 mL). The mixture was stirred at 25 °C for 76 h. The mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 3) to give ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-thieno[3,2-c]pyran-6-carboxylate (2.10 g, yield 81%). LCMS ESI (+) m / z 393.1 (M+H).

[0417] Step F: Preparation of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridine-6-carboxylate: Ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyran-6-carboxylate (1.80 g, 4.59 mmol) was added in portions to a mixture of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-thieno[3,2-c]pyran-6-carboxylate (50 mL) under argon atmosphere. The mixture was stirred at 95 °C for 14 h. The mixture was then cooled to ambient temperature, and the precipitate was collected by filtration. The filter cake was washed with water and MeOH and dried under vacuum to give ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridine-6-carboxylate (1.26 g, 70% yield). LCMS ESI (+) m / z 392.1 (M+H).

[0418] Step G: Preparation of ethyl 4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate: A suspension of ethyl 7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-oxo-5H-thieno[3,2-c]pyridine-6-carboxylate (3.00 g, 5.37 mmol) in phosphorus oxychloride (10.0 mL, 107 mmol) was stirred at 95 °C for 3 h. The mixture was concentrated under vacuum and diluted with DCM. The mixture was poured into an aqueous solution of NaHCO3 and the product was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 6) to give ethyl 4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate (1.09 g, yield 49%). LCMS ESI (+) m / z 410.1 (M+H).

[0419] Step H: Preparation of ethyl 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate: tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.48 g, 4.12 mmol), ethyl 4-chloro-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate (1.30 g, 3.17 mmol) and Na₂CO₃ (0.841 g, 7.93 mmol) were added to 1,4-dioxane (20 mL) and water (2 mL). Pd(dppf)Cl2 (220 mg, 0.300 mmol) was added to a solution in mL. The mixture was stirred at 95 °C under Ar for 16 h. The mixture was poured into water and the product was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (EtOAc / petroleum ether = 1 / 3) to give ethyl 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylate (1.20 g, yield 62%). LCMS ESI (+) m / z 607.3 (M+H).

[0420] Step I: Preparation of 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylic acid: LiOH·H₂O (554 mg, 13.2 mmol) was added to a solution of ethyl 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylic acid (800 mg, 1.32 mmol) in a 3:1:1 mixture of tetrahydrofuran, water, and methanol (20.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in water. The pH was adjusted to 3 with 1 N HCl. The mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridine-6-carboxylic acid (605 mg, yield 79%). LCMS ESI (+) m / z 579.2 (M+H).

[0421] Step J: Preparation of tert-butyl 6-[6-(benzyloxycarbonylamino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid: A solution of 4-(2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-6-carboxylic acid (40 mg, 0.069 mmol), benzyl alcohol (0.036 mL, 0.35 mmol), triethylamine (0.096 mL, 0.69 mmol) and [azido(phenoxy)phosphoryl]oxybenzene (96 mg, 0.35 mmol) in dry toluene (3 mL) was stirred at 25 °C for 30 min. The mixture was stirred at 90 °C for 4 h. The mixture was poured into water, and the product was extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by Prep-TLC (EtOAc / petroleum ether: 1 / 3) to give tert-butyl 6-[6-(benzyloxycarbonylamino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (38 mg, 80% yield).

[0422] Step K: Preparation of tert-butyl 6-[6-amino-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: Lithium hydroxide monohydrate (61 mg, 1.4 mmol) was added to a solution of tert-butyl 6-[6-(benzyloxycarbonylamino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 mg, 0.044 mmol) in 1,4-dioxane (1 mL) and water (1 mL). The mixture was stirred at 100 °C for 6 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄, concentrated, and purified by Prep-TLC (EtOAc / hexane = 1 / 2) to give tert-butyl 6-[6-amino-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (21 mg, yield 87%). LCMS ESI (+) m / z 550.2 (M+H).

[0423] Step L: Preparation of tert-butyl 6-[6-[3-(tert-butoxycarbonylamino)anilino]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: 1,1'-bis(diphenylphosphino)ferrocene (8.1 mg, 0.073 mmol), potassium tert-butoxy (16 mg, 0.15 mmol), and tert-butyl N-(3-iodophenyl)carbamate (35 mg, 0.11 mmol) were added to a suspension of 6-[6-amino-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (40 mg, 0.073 mmol), N-(3-iodophenyl)carbamate (35 mg, 0.11 mmol), and N-(3-iodophenyl)carbamate (35 mg, 0.11 mmol) in toluene (2 mL). 0.015 mmol). The mixture was stirred at 100 °C under Ar for 10 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-TLC (EtOAc / petroleum ether: 1 / 2) to give tert-butyl 6-[6-[3-(tert-butoxycarbonylamino)anilino]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (24 mg, 45% yield). LCMS ESI(+) m / z 741.3 (M+H).

[0424] Steps M to N: Preparation of tert-butyl 6-[6-(3-aminoanilino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: Trifluoroacetic acid (0.50 mL, 6.5 mmol) was added to a solution of tert-butyl 6-[6-[3-(tert-butoxycarbonylamino)anilino]-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (24 mg, 0.032 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to dryness to give N1-(7-(4-fluoro-2-(2-methoxyethoxy)phenyl)-4-(1,2,3,4-tetrahydroisoquinoline-6-yl)thieno[3,2-c]pyridin-6-yl)phenyl-1,3-diamine (30 mg). The crude product was dissolved in THF (2 mL). Aqueous solution of Na2CO3 (2 mL) and di-tert-butyl dicarbonate (7.1 mg, 0.032 mmol) in THF (1 mL) were added at 0 °C. The mixture was stirred at 0 °C for another 1 h. Aqueous solution of MeNH2 (1 mL) was added to quench the reaction. The product was extracted with EtOAc, dried over Na2SO4, concentrated, and purified by Prep-TLC (EtOAc / petroleum ether: 1 / 2) to give tert-butyl 6-[6-(3-aminoaniline)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (18 mg, yield 87%).

[0425] Step O: Preparation of tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-(propenylo-2-enoylamino)anilino]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate: At 0 °C, acryloyl chloride (1.9 mg, 0.020 mmol) was added to a solution of 6-[6-(3-aminoanilino)-7-[4-fluoro-2-(2-methoxyethoxy)phenyl]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (12 mg, 0.019 mmol) and triethylamine (0.013 mL, 0.094 mmol) in DCM (2 mL). The mixture was stirred at 0 °C for 1 h. The mixture was poured into water, and the product was extracted with EtOAc. The organic fraction was dried over anhydrous Na2SO4, concentrated, and purified by Prep-TLC (EtOAc / petroleum ether: 1 / 2) to give tert-butyl 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-(propenylo-2-enoylamino)anilino]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (9.6 mg, 74% yield). LCMS ESI (+) m / z 695.2 (M+H).

[0426] Step P: Preparation of N-[3-[[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1,2,3,4-tetrahydroisoquinoline-6-yl)thieno[3,2-c]pyridin-6-yl]amino]phenyl]prop-2-enamide: Trifluoroacetic acid (0.50 mL, 6.5 mmol) was added to a solution of 6-[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-6-[3-(prop-2-enylamino)anilino]thieno[3,2-c]pyridin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (9.6 mg, 0.014 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated and purified by Prep-HPLC to give N-[3-[[7-[4-fluoro-2-(2-methoxyethoxy)phenyl]-4-(1,2,3,4-tetrahydroisoquinoline-6-yl)thieno[3,2-c]pyridin-6-yl]amino]phenyl]prop-2-enamide (6.6 mg, yield 81%), as a trifluoroacetate. 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.99 (s, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.91(d, J = 10.7 Hz, 1H), 6.86 - 6.75 (m, 1H), 6.65 - 6.33 (m, 1H), 6.25 - 6.05(m, 2H), 5.71 - 5.52 (m, 1H), 4.34 - 4.10 (m, 3H), 4.10 - 3.86 (m, 6H), 3.85- 3.72 (m, 1H), 3.69 - 3.60 (m, 1H), 3.12 - 2.95 (m, 2H), 1.55 - 1.32 (m, 2H). LCMS ESI (+) m / z 595.2 (M+H).

[0427] Synthetic Example 2: Synthesis of 5-(6-(1-(1-acryloylazacyclobutane-3-yl)-1H-pyrazol-4-yl)-7-(phenylamino)thiopheno[3,2-c]pyridin-4-yl)-1-methylpyridin-2(1H)-one (Compound 2) Step A: Preparation of 6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine-4-ol: A solution of N,N-diethyl-2-methyl-thiophene-3-carboxamide (1.4 g, 7.1 mmol) in THF (15 mL) was cooled to -78 °C. n-BuLi (2.5 M) (0.68 g, 10.6 mmol) was slowly added at -78 °C, and stirring was continued for 2.0 h. Pure 1-(2-trimethylsilylethoxymethyl)pyrazol-4-carboxynitrile (1.9 g, 8.51 mmol) was added to the reaction mixture at -78 °C. The temperature was slowly raised to room temperature and stirred at room temperature for 5 h. After the reaction was complete, the reaction mixture was cooled to 0 °C and the pH was adjusted to 5 with 1.0 N HCl solution. The mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with EtOAc (100 mL), and the organic layer was washed with water (2 x 50 mL) followed by a saturated brine solution (50 mL). The organic layer was separated and dried over Na2SO4. The crude compound was purified by column chromatography eluting with 30% EtOAc in hexane. The desired fraction was concentrated to dryness under vacuum to give 6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol (1.1 g, 44.7%) as a solid. 1 HNMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.66-7.64(m, 1H), 7.26-7.25 (m, 1H), 6.97 (s, 1H), 5.52 (s, 2H), 3.64 (t, J = 8.4 Hz, 2H), 0.95 (t, J = 8.4 Hz, 2H), -0.00 to -0.02 (m, 9H).

[0428] Step B: Preparation of 7-iodo-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol: 6-[1-(2-trimethylsilyl)ethoxymethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-4-ol (1.70 g, 4.89 mmol) was added to a stirred solution of 6-[1-(2-trimethylsilyl)ethoxymethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-4-ol (1.70 g, 4.89 mmol) in DMF (17 mL) at 10 °C. N-iodosuccinimide (1.32 g, 5.87 mmol) was added at 10 °C. The reaction mixture was slowly heated to room temperature and stirred for 12 h. The reaction mixture was then slowly poured into ice-cold water (50 mL) and stirred for 10 min. The solid was filtered and dried under vacuum to give 7-iodo-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine-4-ol (1.2 g, 52%). 1 H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 5.2 Hz, 1H), 5.52 (s,2H), 3.66 (t, J = 8.4 Hz, 2H), 0.98-0.94 (m, 2H), -0.011 to -0.014 (m, 9H).

[0429] Step C: Preparation of 7-iodo-4-methoxy-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine: Ag₂CO₃ (90 mg, 0.33 mmol) and MeI (62 mg, 0.44 mmol) were added to a stirred solution of 7-iodo-6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]thieno[3,2-c]pyridine-4-ol (100 mg, 0.211 mmol) in toluene (2 mL). The reaction mixture was heated to 90 °C and stirred for 3 h. The reactants were diluted with EtOAc (10 mL), filtered through a Celite® pad, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give 7-iodo-4-methoxy-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine (67 mg, 65%) as a liquid. 1H NMR (400 MHz, CDCl3) δ 8.43(d, J = 0.4 Hz, 1H), 8.33 (d, J = 0.4 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.39(d, J = 5.6 Hz, 1H), 5.50 (s, 2H), 4.12 (s, 3H), 3.68-3.63 (m, 2H), 0.97-0.92 (m, 2H), -0.003 (m, 9H).

[0430] Step D: Preparation of 4-methoxy-N-phenyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine-7-amine: Aniline (0.94 mL, 10.3 mmol), Ruphos-Pd-G3 (0.086 g, 0.10 mmol), and t-BuOK (0.69 g, 6.2 mmol) were added to a stirred solution of 2-[[4-(7-iodo-4-methoxy-thieno[3,2-c]pyridine-6-yl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (2.5 g, 5.1 mmol) in THF (20 mL) under N2 purging at room temperature. The reaction mixture was then purged with N2 gas for 10 min. The contents were heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with EtOAc (50 mL) and stirred for 10 min. The solid was filtered off and the organic layer was evaporated under reduced pressure. The crude product was purified by column chromatography to give 4-methoxy-N-phenyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridine-7-amine (1.3 g, 53%) as a solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.28 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H),7.66 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.08-7.04 (m, 2H), 6.61(t, J = 7.2 Hz, 1H), 6.50-6.47 (m, 2H), 5.38 (s, 2H), 4.12 (s, 3H), 3.46 (t, J= 7.6 Hz, 2H), 0.78 (t, J = 8.4 Hz, 2H), -0.07 (m, 9H).

[0431] Step E: Preparation of 4-methoxy...

Claims

1. A compound of formula I'': I'' Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein: Ring A is a phenyl, pyridine, or 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl; The ring C is selected from phenyl; 9- to 10-membered bicyclic aryl ring; 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbon ring; 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 11-membered bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 12- to 13-membered polycyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring D is absent or selected from phenyl; 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered carbon rings; 5- to 10-membered bicyclic or polycyclic carbon rings; 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. L is a covalent bond, a divalent straight chain, or a branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-; Furthermore, if ring D does not exist, then L does not exist; Each R 1 C, independently selected from halogens, with optional substitution 1-6 Alkyl, cycloalkyl, -CN, -C(O)OR, -C(O)NR2, -CH2NR2, -N(R 7 )2、-N=S(R 7 )2、-SR 7 -(C 1-4 Alkylene) OR and -OR 7 , where R 1 The sulfur atoms in it can be oxidized; Each R 7 Independently selected from hydrogen, or optionally substituted C 1-6 Aliphatic, -(C 1-4 alkylene)OR, -(C 1-4 Alkylene)NR2, optionally substituted 3 to 6-membered carbon rings, optionally substituted 4 to 7-membered heteroaryl rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 4 to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Or two Rs 7 The groups, together with one or more atoms to which they are attached, form 4- to 6-membered heterocycles having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 C independently selected from halogens and optionally substituted C 1-6 Aliphatic, and -OR; Each R 3 Independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R)2, -(CH2) x C(O)OR, -(CH2) x C(O)N(R)2、-(CH2) x N(R)C(O)R、-(CH2) x Cy, -O(CH2) x Cy, -C(O)Cy, optionally substituted carbocyclic rings and optionally substituted C 1-6 aliphatic; Each R 4 C is independently optional substitution 1-6 aliphatic; R 5 C does not exist and is an optional substitution. 1-6 Aliphatic, -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; R 6 and R 6' With optional substitution of C 4-8 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 0 or 1; Each x is independently 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 aliphatic; Each Cy is independently selected from phenyl, a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbon ring, or a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each Cy is surrounded by 0-3 R... 8 The instance is replaced; and Each R 8 C independently selected from oxo, halogenated, and optionally substituted C 1-6 Aliphatic.

2. The compound of claim 1, wherein the compound has the formula IC': IC' Or its salts (e.g., pharmaceutically acceptable salts).

3. The compound of claim 1, wherein the compound has the formula ID': ID' Or its salts (e.g., pharmaceutically acceptable salts), wherein: L is a binary straight chain or branched chain. 1-6 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-.

4. The compound of claim 1, wherein the compound has the formula IE': IE' Or its salts (e.g., pharmaceutically acceptable salts).

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

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

7. The compound of claim 5, wherein ring B is a 5-membered carbon ring.

8. The compound according to any one of claims 1-4, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , and .

9. The compound of claim 8, wherein a portion thereof Selected from: , , and .

10. The compound of claim 9, wherein a portion thereof Selected from: and .

11. The compound of claim 1 or 2, wherein the compound has the formula IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, or IC3'-m: Or its salts (e.g., pharmaceutically acceptable salts).

12. The compound of claim 11, wherein the compound has the formula IC3'-a or a salt thereof (e.g., a pharmaceutically acceptable salt), and optionally wherein the compound is not selected from the compounds in Table P1.

13. The compound of claim 11, wherein the compound has the formula IC3'-b or a salt thereof (e.g., a pharmaceutically acceptable salt), and optionally wherein the compound is not selected from the compounds in Table P2.

14. The compound of claim 11, wherein the compound has the formula IC3'-c or a salt thereof (e.g., a pharmaceutically acceptable salt).

15. The compound of claim 11, wherein the compound has the formula IC3'-d or a salt thereof (e.g., a pharmaceutically acceptable salt), and optionally wherein the compound is not selected from the compounds in Table P3.

16. The compound of claim 11, wherein the compound has the formula IC3'-e or a salt thereof (e.g., a pharmaceutically acceptable salt), and optionally wherein the compound is not selected from the compounds in Table P4.

17. The compound of claim 11, wherein the compound has the formula IC3'-f or a salt thereof (e.g., a pharmaceutically acceptable salt).

18. The compound of claim 11, wherein the compound has the formula IC3'-g or a salt thereof (e.g., a pharmaceutically acceptable salt).

19. The compound of claim 11, wherein the compound has the formula IC3'-h or a salt thereof (e.g., a pharmaceutically acceptable salt).

20. The compound of claim 11, wherein the compound has the formula IC3'-i or a salt thereof (e.g., a pharmaceutically acceptable salt).

21. The compound of claim 11, wherein the compound has the formula IC3'-j or a salt thereof (e.g., a pharmaceutically acceptable salt).

22. The compound of claim 11, wherein the compound has the formula IC3'-k or a salt thereof (e.g., a pharmaceutically acceptable salt).

23. The compound of claim 11, wherein the compound has the formula IC3'-1 or a salt thereof (e.g., a pharmaceutically acceptable salt).

24. The compound of claim 11, wherein the compound has the formula IC3'-m or a salt thereof (e.g., a pharmaceutically acceptable salt).

25. The compound according to any one of claims 1-24, wherein each R 2 Independently selected from halogens and C 1-6 alkyl.

26. The compound of claim 25, wherein each R 2 It is F.

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

28. The compound according to any one of claims 1-27, wherein at least one R 1 Yes - OR 7 .

29. The compound of claim 28, wherein one of R... 1 Yes - OR 7 And any other R 1 The groups are all halogens.

30. The compound according to any one of claims 1-29, wherein a portion thereof yes .

31. The compound of claim 30, wherein a portion thereof yes or .

32. The compound according to any one of claims 1-31, wherein each R 7 Selected independently from C 1-6 Alkyl and -(C 1-4 (alkylene)OR.

33. The compound according to any one of claims 1-31, wherein each R 7 C-membered heteroaryl rings independently selected from those of 5- to 6-membered heteroaryl rings independently selected from nitrogen, oxygen, and sulfur, which are optionally substituted. 1-6 Aliphatic; C-shaped compounds with optional substitution of 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Aliphatic; and C-rings substituted with optional 3-7 membered carbon rings. 1-6 Aliphatic.

34. The compound of claim 33, wherein each R 7 Selected independently , , , , , , , , , and .

35. The compound according to any one of claims 1-31, wherein each R 7 The heterocycles are independently selected from 4- to 7-membered heterocycles with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 6-membered carbon rings with optional substitution.

36. The compound of claim 35, wherein each R 7 Independently selected from optionally substituted pyrrolidinyl and piperidinyl groups.

37. The compound of claim 35, wherein each R 7 Selected independently from: , , , , , , , , , , , , and .

38. The compound according to any one of claims 1-31, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

39. The compound according to any one of claims 1-31, wherein a portion thereof yes .

40. The compound according to any one of claims 1-37, wherein m is 2 or 3.

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

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

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

44. The compound according to any one of claims 1-40, wherein it is subjected to p R 3 The ring C with substituted groups is ,in: Ring C1 and ring C2 are fused together; The C1 ring is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and The ring C2 is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

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

48. The compound according to any one of claims 1-47, wherein each R 3 Independently selected from halogens, -C(O)N(R)2 and optionally substituted C 1-6 alkyl.

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

50. The compound according to any one of claims 1-49, wherein a portion thereof Selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , ,and .

51. The compound of claim 50, wherein a portion thereof Selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , ,and .

52. The compound of claim 51, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

53. The compound according to any one of claims 1-52, wherein ring D is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

56. The compound according to any one of claims 1-52, wherein a portion thereof yes ,in: Ring D1 and ring D2 are fused; Ring D1 is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Ring D2 is selected from phenyl; a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered carbon ring; and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

59. The compound according to any one of claims 1-52, wherein a portion thereof yes .

60. The compound according to any one of claims 1-59, wherein each R 4 Independently, C is optionally substituted with one or more -OH groups. 1-6 alkyl.

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

62. The compound according to any one of claims 1-61, wherein R 5 It is -C(O)R 9 Or -(CH2) x N(R)C(O)R 9 .

63. The compound according to any one of claims 1-62, wherein R 9 C is an optional substitute 2-6 alkenyl or optionally substituted C 2-6 Alkyne group.

64. The compound according to any one of claims 1-63, wherein R 5 yes , or .

65. The compound according to any one of claims 1-64, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

66. The compound of claim 59, wherein a portion thereof yes , where each R 4 It is methyl on its own.

67. The compound of claim 59, wherein a portion thereof Selected from: , , , , , , , , , , , , and .

68. The compound of claim 59, wherein a portion thereof Selected from: , , , , , , and .

69. The compound of claim 1 or 3, wherein L is a divalent straight-chain or branched C having at least one triple bond. 2-6 Hydrocarbon chain.

70. The compound of claim 1 or 3, wherein L is a divalent straight-chain or branched C. 1-2 A hydrocarbon chain in which one or more methylene units are optionally and independently replaced by -N(R)-, -N(R)C(O)-, -C(O)N(R)- or -C(O)-.

71. The compound of claim 1 or 4, wherein R 6 and R 6' With optional substitution of C 5-6 Hydrocarbon chain linkage, wherein one or more methylene units are optionally and independently replaced by -O- or -N(R)-.

72. The compound of claim 71, wherein R 6 and R 6' Connected to the following: -O(CH2)5-, -O(CH2)4-, -O(CH2)2OCH2- or -O(CH2)3OCH2-.

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

74. The compound of claim 1, wherein the compound is a compound of formula IF': IF' Or its salts (e.g., pharmaceutically acceptable salts), wherein: The ring C2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

75. The compound of claim 74, wherein the compound is a compound of formula IF1': IF1' Or its salts (e.g., pharmaceutically acceptable salts).

76. The compound of claim 74 or 75, wherein the compound is a compound of formula IF2': IF2' Or its salts (e.g., pharmaceutically acceptable salts).

77. The compound according to any one of claims 74-76, wherein the compound is a compound of formula IF3': IF3' Or its salts (e.g., pharmaceutically acceptable salts).

78. The compound according to any one of claims 74-76, wherein R 1 Yes - OR 7 .

79. The compound of claim 77 or 78, wherein R 7 Selected from C (optional substitution) 1-6 Aliphatic and -(C 1-4 (alkylene)OR.

80. The compound of claim 77 or 78, wherein R 7 C-membered heteroaryl rings selected from those of 5- to 6-membered heteroaryl rings that are optionally substituted, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Aliphatic; C-shaped compounds with optional substitution of 4- to 7-membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Aliphatic; and C-rings substituted with optional 3-7 membered carbon rings. 1-6 Aliphatic.

81. The compound of claim 78, wherein R 7 Selected from , , , , , , , , , and .

82. The compound of claim 77 or 78, wherein R 7 Selected from 4- to 7-membered heterocycles with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 6-membered carbon rings with optional substitution.

83. The compound of claim 82, wherein R 7 Selected from optionally substituted pyrrolidinyl and piperidinyl groups.

84. The compound of claim 83, wherein R 7 Selected from , , , , , , , , , , , , and .

85. The compound according to any one of claims 74-76, wherein a portion thereof yes .

86. The compound of claim 77, wherein a portion thereof yes .

87. The compound of claim 74 or 75, wherein n is 0 or 1.

88. The compound of claim 74, 75 or 87, wherein R 2 It is halogen.

89. The compound of claim 74, wherein Selected from: , , , , , , , , , , and .

90. The compound according to any one of claims 75-77, wherein Selected from: , , , , , and .

91. The compound according to any one of claims 74-90, wherein a portion thereof Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

92. The compound of claim 91, wherein a portion thereof Selected from: , , , , , , , , , , , , , , and .

93. A compound of formula II: II Or its salts (e.g., pharmaceutically acceptable salts), wherein: Ring A is a phenyl group and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered carbon rings; and phenyl rings; Ring D is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 9- to 10-membered bicyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 7-membered carbon rings, 5- to 10-membered bicyclic or polycyclic carbon rings, 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 6- to 11-membered bicyclic heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; J is a covalent bond, a divalent straight chain, or a branched chain. 1-4 hydrocarbon chain; X is -OR, -N(R)2, -C(O)N(R)2 or optionally substituted with a group selected from the following: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 1 Independently selected from halogens and -OR 7 ; Each R 7 Independently selected from the arbitrarily substituted C 1-6 Aliphatic and -(C 1-4 (alkylene)OR; Each R 2 C independently selected from halogens and optionally substituted C 1-6 aliphatic; Each R 4 Independently selected from the arbitrarily substituted C 1-6 aliphatic; R 5 It is -C(O)R 9 -(CH2) x N(R)C(O)R 9 Or -CN; R 9 C is an optional substitute 2-6 alkenyl, optionally substituted C 2-6 Alkyne group or 4-membered bicyclic carbon ring; m is 0, 1, 2, or 3; n is 0, 1, or 2; q is 0, 1, or 2; x is 0, 1, or 2; Each R is independently hydrogen or an optionally substituted C. 1-6 Aliphatic.

94. The compound of claim 93, wherein the compound has the formula IIF: IIF Or its salts (e.g., pharmaceutically acceptable salts), wherein: X is -C(O)N(R)2 or optionally substituted with a group selected from the following: phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, a 5- to 10-membered bicyclic carbon ring, a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 11-membered bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

95. The compound of claim 93, wherein the compound has the formula IIG: IIG Or its salts (e.g., pharmaceutically acceptable salts), wherein: J is a binary straight chain or a side chain. 1-4 hydrocarbon chain; and X is either -OR or -N(R)2.

96. The compound of claim 93 or 94, wherein X is a group selected from: a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein any ring is optionally C 1-6 Alkyl substitution.

97. The compound according to any one of claims 93-96, wherein a portion thereof Selected from: , , , , , and .

98. The compound according to any one of claims 93-97, wherein ring B is a 5-membered heteroaryl ring and a 5-membered carbon ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

101. The compound according to any one of claims 93-100, wherein ring B is selected from: , , , , , , , , , and .

102. The compound according to any one of claims 93-101, wherein each R 2 Independently selected from halogens and C 1-6 alkyl.

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

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

105. The compound according to any one of claims 93-104, wherein at least one R 1 Yes - OR 7 .

106. The compound of claim 105, wherein one of R... 1 Yes - OR 7 And any other R 1 The groups are all halogens.

107. The compound according to any one of claims 93-106, wherein a portion thereof yes .

108. The compound of claim 107, wherein a portion thereof yes or .

109. The compound according to any one of claims 93-108, wherein each R 7 Selected independently from C 1-6 Alkyl and -(C 1-4 (alkylene)OR.

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

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

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

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

114. The compound according to any one of claims 93-107, wherein a portion thereof yes ,in: Ring D1 is selected from phenyl, 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered carbon rings, and 4- to 7-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Among them, ring D1 and ring D2 are fused; and The ring D2 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered carbon ring, and a 4- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

117. The compound according to any one of claims 93-116, wherein a portion thereof yes .

118. The compound according to any one of claims 93-117, wherein each R 4 Independently, C is optionally substituted with one or more -OH groups. 1-6 alkyl.

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

120. The compound according to any one of claims 93-119, wherein R 5 It is -C(O)R 9 Or -(CH2) x N(R)C(O)R 9 .

121. The compound according to any one of claims 93-119, wherein R 9 C is an optional substitute 2-6 alkenyl or optionally substituted C 2-6 Alkyne group.

122. The compound according to any one of claims 93-121, wherein R 5 yes or .

123. The compound of any one of claims 93-122, wherein each R is hydrogen or C optionally substituted with one or more halogens. 1-6 alkyl.

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

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

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

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

128. The method of claim 127, wherein the subject suffers from a disease, condition, or disorder that can be improved by disrupting, inhibiting, and / or preventing the interaction between the small GTPase and the PI3Kα protein.

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

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

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

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

133. A method of treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

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

135. The method of claim 134, 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.

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

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

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

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

140. The method of claim 139, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

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

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

143. The method of claim 142, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

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

145. The method of claim 144, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

146. The method of any one of claims 132-145, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancer; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney and other urinary tissue cancers, including renal cell carcinoma (R... Cancer of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

147. The method of claim 146, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

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

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

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

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

152. A method for treating a metabolic disorder, the method comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

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

154. A method for treating RASopathy, the method comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

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

156. A method for treating vascular conditions or disorders, the method comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-125 or a pharmaceutically acceptable salt thereof.

157. The method of claim 156, wherein the vascular condition or disorder is selected from PIK3CA-associated overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Kertz syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibrolipovascular abnormality (FAVA)).

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

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

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

161. The method of claim 159 or 160, wherein the cells are contained within the subject.

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

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

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

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

166. The method of claim 165, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

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

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

169. The method of claim 168, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

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

171. The method of claim 170, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

172. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-125, used as a medicine.

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

174. The compound or use as described in claim 172 or 173, wherein the medicament is used to treat cancer.

175. The compound or use of claim 174, wherein the cancer is associated with and / or characterized by abnormal activation of PI3Kα and / or mutations in PI3Kα.

176. The compound or use of claim 175, 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.

177. The compound or use of claim 176, wherein the PI3Kα protein comprises E542K, E545K, H1047R and / or H1047L mutations.

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

179. The compound or use of claim 178, wherein the RAS protein contains a mutation in codons 12, 13 or 61.

180. The compound or use as claimed in claim 178 or 179, wherein the RAS protein is KRAS.

181. The compound or use of claim 179, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

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

183. The compound or use as described in claim 178 or 179, wherein the RAS protein is HRAS.

184. The compound of claim 183, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

185. The compound or use as described in claim 178 or 179, wherein the RAS protein is NRAS.

186. The compound or use of claim 184, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

187. The compound or use according to any one of claims 174-186, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancer; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney and other urinary tissue cancers, including renal cell carcinoma. (RCC); cancers of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

188. The compound or use of claim 187, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

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

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

191. The compound or use as claimed in claim 172 or 173, wherein the medicament is used to treat metabolic disorders, RASopathy, or vascular conditions.

192. The compound or use as described in claim 191, wherein: (i) The metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) The RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome and Legius syndrome; and / or (iii) The vascular disease or disorder is selected from PIK3CA-associated overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Kertz syndrome; PTEN hamartoma tumor syndrome (PHTS); or fibrolipovascular abnormality (FAVA)).

193. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-125, for the treatment of diseases, symptoms or ailments.

194. The compound used according to claim 193, which is used to treat cancer.

195. The compound used according to claim 192, wherein the cancer is associated with and / or characterized by abnormal activation of PI3Kα and / or mutations in PI3Kα.

196. The compound used in claim 195, 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.

197. The compound used according to claim 196, wherein the PI3Kα protein comprises E542K, E545K, H1047R and / or H1047L mutations.

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

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

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

201. The compound used in claim 200, wherein the KRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

202. The compound used in claim 201, wherein the KRAS protein comprises a G12C or G12D mutation.

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

204. The compound used in claim 203, wherein the HRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

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

206. The compound used in claim 204, wherein the NRAS protein comprises G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and / or Q61H mutations.

207. The compound used according to any one of claims 194-206, wherein the cancer is selected from pancreatic cancer; colon cancer; rectal cancer; colorectal cancer; bowel cancer; breast cancer; ovarian cancer; endometrial cancer; lung cancer; prostate cancer; oral and pharyngeal (lip, tongue, mouth, larynx, pharynx) cancers; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; liver and biliary tract cancers; bone cancer; connective tissue cancers; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney and other urinary tissue cancers, including renal cell carcinoma (…). RCC); cancers of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems, 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 leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)) and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas.

208. The compound used in claim 207, wherein the cancer is selected from breast cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, esophageal cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cell carcinoma, prostate cancer, and pancreatic cancer.

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

210. The compound used in any one of claims 194-209, wherein the cancer is characterized by a mutation in the PTEN protein or a deficiency of the PTEN protein.

211. The compound used according to claim 193, for the treatment of metabolic disorders, RASopathy, or vascular conditions.

212. The compound used according to claim 211, wherein: (i) The metabolic disorder is selected from hyperinsulinemia and type 2 diabetes; (ii) The RASopathy is selected from neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome and Legius syndrome; and / or (iii) The vascular disease or disorder is selected from PIK3CA-associated overgrowth syndrome (PROS) and vascular malformations (e.g., venous malformations; lymphatic malformations; congenital lipoma overgrowth with vascular, epidermal and skeletal abnormalities syndrome (CLOVES); Kertz syndrome; PTEN hamartoma tumor syndrome (PHTS); and fibrolipovascular abnormality (FAVA)).

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