PI3Kα inhibitors

Abstract

The present disclosure provides compounds, compositions, and methods useful for inhibiting PI3K alpha and / or treating a disease, disorder, or condition associated with PI3K alpha and / or treating cancer.

Description

[Technical Field]

[0001] The present disclosure provides compounds and pharmaceutical compositions thereof that modulate the activity of PI3K alpha and are useful in the treatment of various diseases associated with PI3K alpha, including cancer. [Background technology]

[0002] Over the past few decades, signal transduction events have been studied to demonstrate their crucial role in regulating almost every aspect of biological responses. Abnormal activation of signal transduction pathways that regulate cell survival and proliferation is commonly observed in many human cancers. The phosphoinositide 3-kinase (PI3K) signaling pathway has been reported to be one of the most highly mutated pathways in human cancers (Vogelstein et al., Science, 2013, 339(6127), 1546-1558). The PI3K signaling pathway regulates cell survival and proliferation. Increased activity of this pathway is associated with tumor progression and resistance to cancer therapy (Fusco et al., Front Oncol., 2021, 11, 644-737).

[0003] PI3Ks belong to the lipid kinase family, which catalyzes the phosphorylation of lipids contained in or associated with the cell membrane. The PI3K family includes 15 kinases with distinct substrates, expression patterns, and regulatory mechanisms. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine receptor kinases or G protein-coupled receptors to generate PIP3, which activates downstream effectors such as Akt, mTOR, or Rho GTPases (Fruman et al., Nat. Rev. Drug Discov., 2014, 13(2), 140-156).

[0004] Genetic mutations in the gene encoding PI3Kα include hotspot mutations within the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been observed to occur in many cancer types, including lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Because these gain-of-function mutations in PI3Kα are associated with tumor progression, targeting this pathway may offer valuable therapeutic opportunities (Courtney et al., J. Clin. Oncol., 2010, 28(6), 1075-1083). Several PI3K inhibitors (e.g., taselisib, alpelisib, bupallisib, etc.) have been developed, but these molecules inhibit multiple PI3K isoforms. These "pan-PI3K" inhibitors face major obstacles in clinical development due to their inability to achieve the required level of target inhibition in tumors while avoiding toxicity in cancer patients (Fruman et al., Nat. Rev. Drug Discov., 2014, 13(2), 140-156). The toxicity of PI3K inhibitors depends on their isoform selectivity profile. Inhibition of PI3Kα is associated with hyperglycemia and rash, whereas inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, myelosuppression, and hypertransaminasemia (Hanker et al., Cancer Discov., 2019, 9(4), 482-491). Therefore, selective inhibitors of PI3Kα may widen the therapeutic window, enabling sufficient target inhibition in tumors while avoiding dose-limiting toxicity in cancer patients. However, given the central role of PI3Kα in regulating glucose homeostasis and other important physiological processes, current PI3Kα-selective inhibitors that are equally effective against wild-type and mutant PI3Kα often cause hyperglycemia and / or hyperinsulinemia (Busaidy et al., J. Clin. Oncol., 2012, 30, 2919-2928). In summary, developing inhibitors with enhanced selectivity for mutant PI3Kα compared to wild-type PI3Kα may solve the problems of compensatory insulin production and hyperglycemia. Summary of the Invention

[0005] The present disclosure provides compounds and / or compositions useful for inhibiting PI3K α. In some embodiments, the provided compounds and / or compositions are useful for selectively inhibiting PI3K α over other PI3K isoforms. In some embodiments, the provided compounds and / or compositions are useful for selectively inhibiting mutant PI3K α over wide-type PI3K α. In some embodiments, the provided compounds and / or compositions are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with PI3K α. In some embodiments, the provided compounds and / or compositions are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with mutant PI3K α.

[0006] In some embodiments, the present disclosure provides certain compounds and / or compositions that are useful in medicine, and in particular for treating cancer.

[0007] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, U, ring A, L A , R A , R 1 , R 3 , R 5 , and n are each as defined herein.

[0008] In some embodiments, provided compounds have the structure of any of Formulas II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb described herein.

[0009] In some embodiments, provided compounds have the structure of any of Formulas II, III, IV, V, Va, VI, and VIa described herein.

[0010] In some embodiments, the present disclosure provides compositions comprising and / or delivering a provided compound. In some embodiments, such compositions are pharmaceutical compositions comprising a pharmaceutically acceptable carrier.

[0011] The present disclosure further provides a method of inhibiting PI3K alpha activity, comprising contacting PI3K alpha with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0012] The present disclosure further provides methods of treating a disease or disorder associated with PI3Kα in a patient by administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0014] The disclosure further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] Compounds and Definitions Compounds of the present invention include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thFurther, general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5 th Ed., Ed: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0016] Unless otherwise specified, a structure depicted herein is meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, both the R and S configurations of each stereocenter are contemplated as part of the present disclosure. As such, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the provided compounds, are within the scope of the present disclosure. For example, in some cases, Table 1 depicts one or more stereoisomers of a compound, representing each stereoisomer individually and / or as a mixture unless otherwise indicated. Unless otherwise indicated, all tautomeric forms of the provided compounds are within the scope of the present disclosure.

[0017] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Isotopically labeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number normally found in nature. Examples of isotopes present in compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 35 S, and 18In addition to being useful as therapeutic agents, certain isotopically labeled compounds of the present disclosure are also useful in drug and / or substrate tissue distribution assays, as analytical tools, or as probes in other biological assays. In one embodiment of the present disclosure, tritiated (e.g., 3 H) and carbon-14 (e.g., 14 C) isotopes are useful because they are easily detectable. In another embodiment of the invention, one or more hydrogen atoms are replaced with deuterium (e.g., 2 Substitution with heavier isotopes such as 1H can provide certain therapeutic advantages.

[0018] As used herein, unless otherwise specified, the suffix "-ene" is used to represent a divalent group. Thus, any of the above terms can be modified with the suffix "-ene" to represent a divalent version of that moiety. For example, a divalent carbocycle is "carbocyclylene," a divalent aryl ring is "arylene," a divalent benzene ring is "phenylene," a divalent heterocycle is "heterocyclylene," a divalent heteroaryl ring is "heteroarylene," a divalent alkyl chain is "alkylene," a divalent alkenyl chain is "alkenylene," a divalent alkynyl chain is "alkynylene," etc.

[0019] Aliphatic: As used herein, the term "aliphatic" refers to a linear (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic" or "alicyclic"), and has a single point of attachment to the rest of the molecule, unless otherwise specified. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4 In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof. In some embodiments, "aliphatic" refers to a linear (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, and has a single point of attachment to the rest of the molecule.

[0020] Alkyl: The term "alkyl," used alone or as part of a larger moiety, refers (unless otherwise specified) to an alkyl group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 ) refers to a saturated, optionally substituted, straight-chain or branched hydrocarbon group having the radical . Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0021] Alkenyl: The term “alkenyl,” used alone or as part of a larger moiety, refers to an alkyl group having at least one double bond and (unless otherwise specified) 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ) refers to an optionally substituted straight or branched hydrocarbon chain having an alkyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0022] Alkynyl: The term "alkynyl," used alone or as part of a larger moiety, refers to an alkynyl group having at least one triple bond and (unless otherwise specified) 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ) refers to an optionally substituted straight or branched chain hydrocarbon group having an alkynyl group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0023] Aryl: As used herein, the term "aryl" refers to an alkyl group having a total of 6 to 14 ring members (e.g., C 6-14 "aryl" refers to monocyclic, bicyclic, and polycyclic ring systems having a ring structure in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Unless otherwise specified, "aryl" groups are hydrocarbons.

[0024] Divalent: As used herein, the term "divalent" refers to a chemical moiety that has two points of attachment to the rest of the molecule. For example, a "divalent C 1-6 "Aliphatic" refers to a divalent aliphatic group, as defined herein, containing 1-6 aliphatic carbon atoms.

[0025] Carbocyclyl: As used herein, the terms "carbocyclyl," "carbocycle," and "carbocyclic ring" refer to a saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring system as described herein having 3 to 14 members (wherein the aliphatic ring system is optionally substituted as described herein). Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "alicyclic") refers to an optionally substituted monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation but is not aromatic, or an optionally substituted C5-C6 hydrocarbon. 10 "Cycloalkyl" refers to a bicyclic hydrocarbon having a single point of attachment to the rest of the molecule. The term "cycloalkyl" refers to an optionally substituted saturated ring system having from about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0026] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle used in administering a composition. In some embodiments, carriers include sterile liquids, such as water and oils (including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like). In some embodiments, a carrier is or includes one or more solid components.

[0027] Excipient: As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired viscosity or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.

[0028] Heteroaryl: As used herein, the terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to a monocyclic or bicyclic ring group having 5 to 10 ring atoms (e.g., a 5- or 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl), having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. Exemplary heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl. quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzisoxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include optionally substituted rings.

[0029] Heteroatom: As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0030] Heterocycle: As used herein, the terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more (e.g., 1-4) heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (e.g., in 3,4-dihydro-2H-pyrrolyl), NH (e.g., in pyrrolidinyl), or +It can be NR (e.g., in N-substituted pyrrolidinyl). The heterocyclic ring can be bonded to any heteroatom or carbon atom of its pendant group that results in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. The heterocyclyl group can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocyclic rings also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. The bicyclic heterocycle may also be a spirocyclic ring system (e.g., a 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) as defined above).

[0031] Partially unsaturated: As used herein, the term "partially unsaturated," when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl moieties) as defined herein.

[0032] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition is or can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals, such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0033] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen that exhibits a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to an appropriate population. In some embodiments, pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those adapted for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., buccal, sublingual, and those targeted for systemic absorption), boluses, powders, granules, pastes applied to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection (e.g., sterile solutions or suspensions, or sustained release formulations); topical application (e.g., creams, ointments, or sustained release patches or sprays applied to the skin, lungs, or oral cavity); vaginal or rectal administration (e.g., pessaries, creams, or foams); sublingual administration; ocular administration; transdermal administration; or administration to nasal, pulmonary, and other mucosal surfaces.

[0034] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the bounds of sound medical evaluation, and commensurate with a reasonable benefit / risk ratio.

[0035] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle (e.g., a liquid or solid filler, diluent, excipient, or solvent encapsulating material) that is involved in carrying or transporting a subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0036] Pharmaceutically acceptable salt: As used herein, the term "pharmaceutically acceptable salt" refers to a salt of such a compound that is suitable for use in a pharmaceutical context, i.e., a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0037] Prevent or Prophylaxis: As used herein, the terms "prevent" or "prevention," when used in reference to the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete when the onset of the disease, disorder, or condition has been delayed for a predefined period of time.

[0038] Substituted or optionally substituted: As described herein, compounds of the present disclosure can include "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). "Substituted" applies to one or more hydrogens that are explicit or implied from the structure (e.g., [ka] At least [ka] refers to, [ka] At least [ka] (refers to "optionally substituted"). Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the specified groups, the substituents can be the same or different at every position. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unaltered when subjected to conditions that permit its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes provided herein. Groups described as "substituted" preferably have one to four substituents, and more preferably one or two substituents. Groups described as "optionally substituted" can be unsubstituted or "substituted" as described above.

[0039] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 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) 0-4 SR°, -(CH2) 0-4 Ph (optionally substituted with R°), —(CH2) 0-4 O(CH2) 0-1 Ph (optionally substituted with R°), -CH=CHPh (optionally substituted with R°), -(CH2) 0-4 O(CH2) 0-1 -pyridyl (optionally 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) 0-4N(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) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)(=NR°)R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -(CH2) 0-4 -S(O)2NR°2, -(CH2) 0-4 S(O)(=NR°)NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(R°)S(O)(=NR°)R°, -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 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring (which may be substituted as defined below) having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -(CH2) 0-2 CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 C(O)NH2, -(CH2) 0-2 C(O)NHR ● , -(CH2) 0-2 C(O)NR ● 2, -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -(CH2) 0-2 NHC(O)R ● , -(CH2) 0-2 NR ● C(O)R ●, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of such R° include ═O and ═S.

[0041] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O ("oxo"), ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-(wherein each independent R * The presence of hydrogen, C 1-6 aliphatic (optionally substituted as defined below) or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3 O—, wherein each independent R * The presence of hydrogen, C 1-6Selected from aliphatic (optionally substituted as defined below) or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0042] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are independently hydrogen, C 1-6an aliphatic (optionally substituted as defined below) or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent R † The occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0044] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] Treat: As used herein, the term "treat" (and "treatment" or "treating") refers to any administration that partially or completely alleviates, ameliorates, relieves, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be treatment of a subject who does not exhibit symptoms of the relevant disease, disorder, and / or condition and / or a subject who exhibits only early symptoms of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be treatment of a subject who exhibits one or more established symptoms of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be treatment of a subject who has been diagnosed with the relevant disease, disorder, and / or condition.

[0046] Compounds provided In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] is a single or double bond; X is N or C; Y is N or C; Ring A is phenyl, a 5-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L A are independently a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic; Each R A are independently oxo, halogen, -CN, -ORA1 、-SR A1 、-N(R A1 )2、-C(O)R A1 、-C(O)OR A1 、-C(O)N(R A1 )2、-C(O)NR A1 (OR A1 )、-OC(O)R A1 -OC(O)N(R A1 )2、-OC(O)OR A1 、-OSO2R A1 、-OSO2N(R A1 )2、-N(R A1 )C(O)R A1 、-NR A1 C(O)OR A1 、-NR A1 C(O)N(R A1 )2、-N(R A1 )SO2R A1 、-NR A1 S(O)2N(R A1 )2、-NR A1 OR A1 、-NR A1 S(O)R A1 、-NR A1 S(O)N(R A1 )2、-S(O)R A1 、-SO2R A1 、-S(O)N(R A1 )2、-SO2N(R A1 )2、-SO3R A1 、-C(=NR m )R A1 、-C(=NR m )N(R A1 )2、-NR A1 C(=NR m )R A1 、-NR A1 C(=NR m )N(R A1 )2、-NR A1 S(O)(=NR m )R A1 、-NR A1 S(O)(=NR m )N(R A1 )2、-OS(O)(=NR m )R A1 、-S(O)(=NRm )R A1 , -S(O)(=NR m )N(R A1 )2, -P(O)(R A1 )2, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; Or two L's A -R Aare, together with the atoms to which they are attached, independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and sulfur; or an 8-10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3-7-membered monocyclic carbocyclyl, 5-10-membered bicyclic carbocyclyl, phenyl, 8-10-membered bicyclic aryl, 3-7-membered monocyclic heterocyclyl, 5-10-membered bicyclic heterocyclyl, 5-6-membered monocyclic heteroaryl, and 8-10-membered bicyclic heteroaryl independently selects 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; R 1 is hydrogen, or C 1-6 an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Or, R 1 and L A -R Aand one of, together with the atom to which it is attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic heterocyclyl and the 5- to 14-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; Z is N or CR 2 and; U is N or CR 4 and; R 2 and R 4 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR, -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 -L 5 -R 5A and; L 5 is a covalent bond or an optionally substituted divalent C 1-6It is aliphatic; Or, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 16-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 16-membered monocyclic carbocyclyl, the 5- to 16-membered bicyclic carbocyclyl, the 3- to 16-membered monocyclic heterocyclyl, and the 5- to 16-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; R 5A -OR 5A11 , -SR 5A1 , -NHR 5A12 , -N(R 5A12 )2, -C(O)R 5A1 , -C(O)N(R 5A1 )2, -C(O)NR 5A1 (OR 5A1 ), -OC(O)R 5A1 , -OC(O)N(R 5A1 )2, -OC(O)OR 5A1 , -OSO2R 5A1 , -OSO2N(R 5A1 )2, -N(R 5A1 )C(O)R 5A1 , -NR 5A1 C(O)OR 5A1 , -NR 5A1 C(O)N(R 5A1 )2, -N(R 5A1 )SO2R 5A1 , -NR 5A1 S(O)2N(R 5A1 )2, -NR 5A1 OR 5A1 , -NR 5A1 S(O)R 5A1 , -NR 5A1 S(O)N(R 5A1)2, -S(O)R 5A1 , -SO2R 5A1 , -S(O)N(R 5A1 )2, -SO2N(R 5A1 )2, -SO3R 5A1 , -C(=NR m )R 5A1 , -C(=NR m )N(R 5A1 )2, -NR 5A1 C(=NR m )R 5A1 , -NR 5A1 C(=NR m )N(R 5A1 )2, -NR 5A1 S(O)(=NR m )R 5A1 , -NR 5A1 S(O)(=NR m )N(R 5A1 )2, -OS(O)(=NR m )R 5A1 , -S(O)(=NR m )R 5A1 , -S(O)(=NR m )N(R 5A1 )2, -P(O)(R 5A1 )2, methyl, C 2-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A C 2-6Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R 5AG optionally substituted with a substituent; or R 5A The methyl group can be one, two, or three R 5AG substituted with a substituent; R A1 and R 5A1 are each independently hydrogen, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A1 or R 5A1 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's A1when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Or, two R's 5A1 when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5A11 is methyl, C 2-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A11 C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with a substituent; or R5A11 The methyl group can be one, two, or three R G1 substituted with a substituent; Each R 5A12 independently, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A12 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's 5A12 when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; R AG , R 5AG , and R G1are each independently a halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)OR, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSORN(R), -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R, when attached to the same nitrogen atom, combine to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R m are independently —OH, —CN, or R; and n is 0, 1, 2, 3, or 4.

[0047] In some embodiments of the preceding embodiments, L 5 and L A -R Aand one of, together with the atom to which it is attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic carbocyclyl, the 5- to 10-membered bicyclic carbocyclyl, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 10-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0048] In some embodiments, [ka] is a single or double bond; X is N or C; Y is N or C; Ring A is phenyl, a 5-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L A are independently a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6 Aliphatic groups are selected from 1, 2, 3, or 4 independently selected RNases. LA1 optionally substituted with substituents; Each R A are independently oxo, halogen, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)OR A1 , -C(O)N(R A1)2、-C(O)NR A1 (OR A1 )、-OC(O)R A1 -OC(O)N(R A1 )2、-OC(O)OR A1 、-OSO2R A1 、-OSO2N(R A1 )2、-N(R A1 )C(O)R A1 、-NR A1 C(O)OR A1 、-NR A1 C(O)N(R A1 )2、-N(R A1 )SO2R A1 、-NR A1 S(O)2N(R A1 )2、-NR A1 OR A1 、-NR A1 S(O)R A1 、-NR A1 S(O)N(R A1 )2、-S(O)R A1 、-SO2R A1 、-S(O)N(R A1 )2、-SO2N(R A1 )2、-SO3R A1 、-C(=NR m )R A1 、-C(=NR m )N(R A1 )2、-NR A1 C(=NR m )R A1 、-NR A1 C(=NR m )N(R A1 )2、-NR A1 S(O)(=NR m )R A1 、-NR A1 S(O)(=NR m )N(R A1 )2、-OS(O)(=NR m )R A1 、-S(O)(=NR m )R A1 、-S(O)(=NR m )N(R A1 )2、-P(O)(R A1 )2、C 1-6an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; Or two L's A -R Aare, together with the atoms to which they are attached, independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and sulfur; or an 8-10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3-7-membered monocyclic carbocyclyl, 5-10-membered bicyclic carbocyclyl, phenyl, 8-10-membered bicyclic aryl, 3-7-membered monocyclic heterocyclyl, 5-10-membered bicyclic heterocyclyl, 5-6-membered monocyclic heteroaryl, and 8-10-membered bicyclic heteroaryl independently selects 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; R 1 is hydrogen, or C 1-6 a group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R 1A optionally substituted with substituents; Or, R 1 and L A -R Aand one of, together with the atom to which it is attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic heterocyclyl and the 5- to 14-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; Z is N or CR 2 and; U is N or CR 4 and; R 2 and R 4 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR, -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R 2A optionally substituted with substituents; R 3 are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R 3A optionally substituted with substituents; R 5 -L 5 -R 5A and; L 5 is a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6 Aliphatic groups can be one, two, three, or four independently selected R L5A optionally substituted with substituents; Or, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 16-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 16-membered monocyclic carbocyclyl, the 5- to 16-membered bicyclic carbocyclyl, the 3- to 16-membered monocyclic heterocyclyl, and the 5- to 16-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; R 5A -OR 5A11 , -SR 5A1 , -NHR 5A12 , -N(R 5A12 )2, -C(O)R 5A1 , -C(O)N(R 5A1 )2, -C(O)NR 5A1 (OR 5A1 ), -OC(O)R 5A1 , -OC(O)N(R 5A1 )2, -OC(O)OR 5A1 , -OSO2R5A1 、-OSO2N(R 5A1 )2、-N(R 5A1 )C(O)R 5A1 、-NR 5A1 C(O)OR 5A1 、-NR 5A1 C(O)N(R 5A1 )2、-N(R 5A1 )SO2R 5A1 、-NR 5A1 S(O)2N(R 5A1 )2、-NR 5A1 OR 5A1 、-NR 5A1 S(O)R 5A1 、-NR 5A1 S(O)N(R 5A1 )2、-S(O)R 5A1 、-SO2R 5A1 、-S(O)N(R 5A1 )2、-SO2N(R 5A1 )2、-SO3R 5A1 、-C(=NR m )R 5A1 、-C(=NR m )N(R 5A1 )2、-NR 5A1 C(=NR m )R 5A1 、-NR 5A1 C(=NR m )N(R 5A1 )2、-NR 5A1 S(O)(=NR m )R 5A1 、-NR 5A1 S(O)(=NR m )N(R 5A1 )2、-OS(O)(=NR m )R 5A1 、-S(O)(=NR m )R 5A1 、-S(O)(=NR m )N(R 5A1 )2、-P(O)(R 5A1 )2、メチル、C 2-6an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R 5AG optionally substituted with a substituent; or R 5A The methyl group can be one, two, or three R 5AG substituted with a substituent; R A1 and R 5A1 are each independently hydrogen, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A1 or R 5A1 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's A1 when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R A11 optionally substituted with substituents; Or, two R's 5A1 when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R A11 optionally substituted with substituents; R 5A11 is methyl, C 2-6an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A11 C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with a substituent; or R 5A11 The methyl group can be one, two, or three R G1 substituted with a substituent; Each R 5A12 independently, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A12 C1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's 5A12 when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R 5B12 optionally substituted with substituents; R AG , R 5AG , and R G1 are each independently oxo, halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)OR, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR, -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m)R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each selected from 1, 2, 3, or 4 independently selected R AG1 optionally substituted with substituents; Each R is oxo, hydrogen, C 1-6 independently selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each selected from 1, 2, 3, or 4 independently selected R N optionally substituted with a substituent; or When two R's are attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R's. N optionally substituted with substituents; Each R LA1 , R 1A , R 2A , R 3A , R L5A , R A11 , R 5B12 , R AG1 , and R N is oxo, halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph, -(CH2) 0-4 O(CH2) 0-1 Ph, -CH=CHPh, -(CH2) 0-4 O(CH2) 0-1 -Pyridyl, -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) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)(=NR o )R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -(CH2) 0-4 -S(O)2NR°2, -(CH2) 0-4 S(O)(=NR o )NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(R°)S(O)(=NR o )R°, -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)O-N(R°)2, and -(C 1-4linear or branched alkylene)C(O)ON(R°)2; Each R° is independently oxo, hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R m is independently oxo, —OH, —CN, or R; and n is 0, 1, 2, 3, or 4.

[0049] In some embodiments of the preceding embodiment, R AG , R 5AG , and R G1 are each independently a halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)OR, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSORN(R), -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NRm )N(R)2, -P(O)(R)2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each selected from 1, 2, 3, or 4 independently selected R AG1 optionally substituted with substituents; Each R is hydrogen, C 1-6 independently selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each selected from 1, 2, 3, or 4 independently selected R N optionally substituted with a substituent; or When two R's are attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R's. N optionally substituted with substituents; Each R LA1 , R 1A , R 2A , R 3A , R L5A , R A11 , R 5B12 , R AG1 , and R N is a halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph, -(CH2) 0-4 O(CH2) 0-1 Ph, -CH=CHPh, -(CH2) 0-4 O(CH2) 0-1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0-4N(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) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)(=NR o )R°, -(CH2)<照 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -(CH2) 0-4 -S(O)2NR°2, -(CH2) 0-4 S(O)(=NR o )NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(R°)S(O)(=NR o )R°, -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)O-N(R°)2, and -(C 1-4linear or branched alkylene)C(O)ON(R°)2; Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Each R m are independently —OH, —CN, or R.

[0050] In some embodiments of the preceding embodiments, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic carbocyclyl, the 5- to 10-membered bicyclic carbocyclyl, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 10-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0051] In some embodiments, [ka] is a single or double bond; X is N or C; Y is N or C; Ring A is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L A are independently a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic; Each R A are independently oxo, halogen, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)OR A1 , -C(O)N(R A1 )2, -C(O)NR A1 (OR A1 ), -OC(O)R A1 -OC(O)N(R A1 )2, -OC(O)OR A1 , -OSO2R A1 , -OSO2N(R A1 )2, -N(R A1 )C(O)R A1 , -NR A1 C(O)OR A1 , -NR A1 C(O)N(R A1 )2, -N(R A1 )SO2R A1 , -NR A1 S(O)2N(R A1 )2, -NR A1 OR A1 , -NR A1 S(O)R A1 , -NR A1 S(O)N(R A1 )2, -S(O)R A1 , -SO2R A1 , -S(O)N(R A1 )2, -SO2N(R A1 )2, -SO3R A1 , -C(=NR m )R A1 , -C(=NR m )N(R A1 )2, -NR A1 C(=NR m )RA1 , -NR A1 C(=NR m )N(R A1 )2, -NR A1 S(O)(=NR m )R A1 , -NR A1 S(O)(=NR m )N(R A1 )2, -OS(O)(=NR m )R A1 , -S(O)(=NR m )R A1 , -S(O)(=NR m )N(R A1 )2, -P(O)(R A1 )2, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; R 1 is hydrogen, or C 1-6an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Z is N or CR 2 and; U is N or CR 4 and; R 2 and R 4 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR, -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 -L 5 -R 5A and; L 5 is a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic; R 5A -OR 5A11 , -SR 5A1 , -NHR 5A12 , -N(R 5A12 )2, -C(O)R 5A1 , -C(O)N(R 5A1 )2, -C(O)NR 5A1 (OR 5A1 ), -OC(O)R5A1 、-OC(O)N(R 5A1 )2、-OC(O)OR 5A1 、-OSO2R 5A1 、-OSO2N(R 5A1 )2、-N(R 5A1 )C(O)R 5A1 、-NR 5A1 C(O)OR 5A1 、-NR 5A1 C(O)N(R 5A1 )2、-N(R 5A1 )SO2R 5A1 、-NR 5A1 S(O)2N(R 5A1 )2、-NR 5A1 OR 5A1 、-NR 5A1 S(O)R 5A1 、-NR 5A1 S(O)N(R 5A1 )2、-S(O)R 5A1 、-SO2R 5A1 、-S(O)N(R 5A1 )2、-SO2N(R 5A1 )2、-SO3R 5A1 、-C(=NR m )R 5A1 、-C(=NR m )N(R 5A1 )2、-NR 5A1 C(=NR m )R 5A1 、-NR 5A1 C(=NR m )N(R 5A1 )2、-NR 5A1 S(O)(=NR m )R 5A1 、-NR 5A1 S(O)(=NR m )N(R 5A1 )2、-OS(O)(=NR m )R 5A1 、-S(O)(=NR m )R 5A1 、-S(O)(=NR m )N(R 5A1 )2、-P(O)(R 5A1 )2、メチル、C 2-6an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R 5AG optionally substituted with a substituent; or R 5A The methyl group can be one, two, or three R 5AG substituted with a substituent; R A1 and R 5A1 are each independently hydrogen, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A1 or R 5A1 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's A1 when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Or, two R's 5A1 when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5A11 is methyl, C 2-6an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A11 C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with a substituent; or R 5A11 The methyl group can be one, two, or three R G1 substituted with a substituent; Each R 5A12 independently, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A12 C1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's 5A12 when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; R AG , R 5AG , and R G1 are each independently a halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)OR, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSORN(R), -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R, when attached to the same nitrogen atom, combine to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R m are independently —OH, —CN, or R; and n is 0, 1, 2, 3, or 4.

[0052] In some embodiments, [ka] is a single or double bond; X is N or C; Y is N or C; Ring A is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L A are independently a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6 Aliphatic groups are selected from 1, 2, 3, or 4 independently selected RNases. LA1 optionally substituted with substituents; Each R A are independently oxo, halogen, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)OR A1 , -C(O)N(R A1 )2, -C(O)NR A1 (OR A1 ), -OC(O)R A1 -OC(O)N(R A1 )2, -OC(O)OR A1 , -OSO2R A1 , -OSO2N(R A1 )2, -N(R A1 )C(O)R A1 , -NR A1 C(O)OR A1 , -NR A1 C(O)N(R A1 )2, -N(R A1 )SO2R A1 , -NR A1 S(O)2N(R A1 )2, -NR A1 OR A1 , -NR A1 S(O)R A1 , -NR A1 S(O)N(RA1 )2, -S(O)R A1 , -SO2R A1 , -S(O)N(R A1 )2, -SO2N(R A1 )2, -SO3R A1 , -C(=NR m )R A1 , -C(=NR m )N(R A1 )2, -NR A1 C(=NR m )R A1 , -NR A1 C(=NR m )N(R A1 )2, -NR A1 S(O)(=NR m )R A1 , -NR A1 S(O)(=NR m )N(R A1 )2, -OS(O)(=NR m )R A1 , -S(O)(=NR m )R A1 , -S(O)(=NR m )N(R A1 )2, -P(O)(R A1 )2, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A C 1-6Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; R 1 is hydrogen, or C 1-6 a group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R 1A optionally substituted with substituents; Z is N or CR 2 and; U is N or CR 4 and; R 2 and R 4 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR, -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m)N(R)2, -NRS(O)(=NR m )R, -NR S (O) (=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R 2A optionally substituted with substituents; R 3 are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R 3A optionally substituted with substituents; R 5 -L 5 -R 5A and; L 5 is a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6 Aliphatic groups can be one, two, three, or four independently selected R L5A optionally substituted with substituents; R 5A -OR 5A11 , -SR 5A1 , -NHR 5A12 , -N(R 5A12 )2, -C(O)R 5A1 , -C(O)N(R 5A1 )2, -C(O)NR 5A1 (OR 5A1 ), -OC(O)R 5A1 , -OC(O)N(R 5A1 )2, -OC(O)OR 5A1 , -OSO2R 5A1 , -OSO2N(R 5A1 )2, -N(R 5A1 )C(O)R 5A1 , -NR 5A1 C(O)OR 5A1 , -NR 5A1 C(O)N(R 5A1 )2, -N(R 5A1 )SO2R 5A1 , -NR 5A1 S(O)2N(R 5A1 )2, -NR5A1 OR 5A1 , -NR 5A1 S(O)R 5A1 , -NR 5A1 S(O)N(R 5A1 )2, -S(O)R 5A1 , -SO2R 5A1 , -S(O)N(R 5A1 )2, -SO2N(R 5A1 )2, -SO3R 5A1 , -C(=NR m )R 5A1 , -C(=NR m )N(R 5A1 )2, -NR 5A1 C(=NR m )R 5A1 , -NR 5A1 C(=NR m )N(R 5A1 )2, -NR 5A1 S(O)(=NR m )R 5A1 , -NR 5A1 S(O)(=NR m )N(R 5A1 )2, -OS(O)(=NR m )R 5A1 , -S(O)(=NR m )R 5A1 , -S(O)(=NR m )N(R 5A1 )2, -P(O)(R 5A1 )2, methyl, C 2-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A C2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R 5AG optionally substituted with a substituent; or R 5A The methyl group can be one, two, or three R 5AG substituted with a substituent; R A1 and R 5A1 are each independently hydrogen, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R A1 or R 5A1 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's A1when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R A11 optionally substituted with substituents; Or, two R's 5A1 when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R A11 optionally substituted with substituents; R 5A11 is methyl, C 2-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A11C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with a substituent; or R 5A11 The methyl group can be one, two, or three R G1 substituted with a substituent; Each R 5A12 independently, C 1-6 an aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; where R 5A12 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 optionally substituted with substituents; Or, two R's 5A12when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R 5B12 optionally substituted with substituents; R AG , R 5AG , and R G1 are each independently a halogen, -CN, -OR, -SR, -N(R), -C(O)R, -C(O)OR, -C(O)N(R), -C(O)NR(OR), -OC(O)R, -OC(O)N(R), -OC(O)OR, -OSOR, -OSORN(R), -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R), -N(R)SOR, -NRS(O)N(R), -NROR, -NRS(O)R, -NRS(O)N(R), -S(O)R, -SOR, -S(O)N(R), -SON(R), -SOR, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each selected from 1, 2, 3, or 4 independently selected R AG1 optionally substituted with substituents; Each R is hydrogen, C 1-6 independently selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each selected from 1, 2, 3, or 4 independently selected R N optionally substituted with a substituent; or When two R's are attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R's. N optionally substituted with substituents; Each R LA1 , R 1A , R 2A , R 3A , R L5A , R A11 , R 5B12 , R AG1 , and R N is a halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph, -(CH2) 0-4 O(CH2) 0-1 Ph, -CH=CHPh, -(CH2) 0-4 O(CH2) 0-1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0-4N(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) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)(=NR o )R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -(CH2) 0-4 -S(O)2NR°2, -(CH2) 0-4 S(O)(=NR o )NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(R°)S(O)(=NR o )R°, -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)O-N(R°)2, and -(C 1-4linear or branched alkylene)C(O)ON(R°)2; Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R m are independently —OH, —CN, or R; and n is 0, 1, 2, 3, or 4.

[0053] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, U, ring A, L A , R A , R 1 , R 3 , L 5 , R 5A12 Each of n, and n, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0054] In some embodiments, the present disclosure provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein Z, U, ring A, L A , R A , R 1 , R 3 , L 5 , R 5A12Each of n, and n, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0055] As noted above, in some embodiments of either of Formulas I and II, [ka] is a single bond or a double bond. [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0056] As noted above, in some embodiments of either of Formulas I and II, X is N or C. In some embodiments, X is N. In some embodiments, X is C.

[0057] As noted above, in some embodiments of either of Formulas I and II, Y is N or C. In some embodiments, Y is N. In some embodiments, Y is C.

[0058] In some embodiments, X is C and Y is N. In some embodiments, X is N and Y is C. In some embodiments, X is C and Y is C.

[0059] As noted above, in some embodiments of any of Formulas I, II, and III, ring A is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, II, III, IV, V, and Va, ring A is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some embodiments, ring A is a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered monocyclic heteroaryl having 1 to 3 nitrogen atoms. In some embodiments, ring A is a 5-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms. In some embodiments, ring A is a 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered monocyclic heteroaryl having 1 to 3 nitrogen atoms. In some embodiments, ring A is a 6-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms. In some embodiments, ring A is a 6-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms. In some embodiments, ring A is selected from pyrazolyl, imidazolyl, triazolyl, and pyridyl. In some embodiments, ring A is pyrazolyl. In some embodiments, Ring A is imidazolyl. In some embodiments, Ring A is triazolyl. In some embodiments, Ring A is pyridyl.

[0061] As noted above, in some embodiments of any of Formulas I, II, and III, each L A are independently a covalent bond or an optionally substituted divalent C 1-6 In some embodiments of any of Formulas I, II, III, and IV, each L Aare independently a covalent bond or an optionally substituted divalent C 1-6 In some embodiments, L A is a covalent bond or a divalent C 1-2 In some embodiments, L is aliphatic (e.g., -CH- or -CHCH-). A is a covalent bond. In some embodiments, L A is a divalent C 1-6 In some embodiments, L A is a divalent C 1-3 In some embodiments, L A is a divalent C 1-2 In some embodiments, L is aliphatic (e.g., -CH- or -CHCH-). A is a divalent C1 aliphatic (e.g., -CH2-). In some embodiments, L A is a divalent C2 aliphatic (e.g., -CH2CH2-).

[0062] In some embodiments of any of Formulas I, II, III, and IV, each R A are independently oxo, halogen, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)OR A1 , -C(O)N(R A1 )2, -C(O)NR A1 (OR A1 ), -OC(O)R A1 -OC(O)N(R A1 )2, -OC(O)OR A1 , -OSO2R A1 , -OSO2N(R A1 )2, -N(R A1 )C(O)R A1 , -NR A1 C(O)OR A1 , -NR A1 C(O)N(R A1 )2, -N(R A1 )SO2R A1 , -NR A1S(O)2N(R A1 )2, -NR A1 OR A1 , -NR A1 S(O)R A1 , -NR A1 S(O)N(R A1 )2, -S(O)R A1 , -SO2R A1 , -S(O)N(R A1 )2, -SO2N(R A1 )2, -SO3R A1 , -C(=NR m )R A1 , -C(=NR m )N(R A1 )2, -NR A1 C(=NR m )R A1 , -NR A1 C(=NR m )N(R A1 )2, -NR A1 S(O)(=NR m )R A1 , -NR A1 S(O)(=NR m )N(R A1 )2, -OS(O)(=NR m )R A1 , -S(O)(=NR m )R A1 , -S(O)(=NR m )N(R A1 )2, -P(O)(R A1 )2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RA C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0063] As noted above, in some embodiments of any of Formulas I, II, and III, each R A are independently oxo, halogen, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)OR A1 , -C(O)N(R A1 )2, -C(O)NR A1 (OR A1 ), -OC(O)R A1 -OC(O)N(R A1 )2, -OC(O)OR A1 , -OSO2R A1 , -OSO2N(R A1 )2, -N(R A1 )C(O)R A1 , -NR A1 C(O)OR A1 , -NR A1 C(O)N(R A1 )2, -N(R A1 )SO2R A1 , -NR A1 S(O)2N(R A1 )2, -NR A1 OR A1 , -NR A1 S(O)R A1 , -NR A1 S(O)N(R A1 )2, -S(O)R A1 , -SO2R A1 , -S(O)N(R A1 )2, -SO2N(R A1 )2, -SO3R A1 , -C(=NR m)R A1 , -C(=NR m )N(R A1 )2, -NR A1 C(=NR m )R A1 , -NR A1 C(=NR m )N(R A1 )2, -NR A1 S(O)(=NR m )R A1 , -NR A1 S(O)(=NR m )N(R A1 )2, -OS(O)(=NR m )R A1 , -S(O)(=NR m )R A1 , -S(O)(=NR m )N(R A1 )2, -P(O)(R A1 )2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0064] In some embodiments, each R A independently, C 1-6 Aliphatic, -OR A1 , -N(R A1 2-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0065] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)N(R A1 2, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C2-6 Alkenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each independently have 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0066] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)N(R A1 2, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Alkenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each independently have 1, 2, 3, or 4 R AG It is optionally substituted with a substituent.

[0067] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 )2, -C(O)R A1 , -C(O)N(R A12, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Alkenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each independently represent one or two R AG It is optionally substituted with a substituent.

[0068] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 2, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Each of alkenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 RAG It is optionally substituted with a substituent.

[0069] In some embodiments, each R A independently, C 1-6 Aliphatic, -OR A1 , -N(R A1 2, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Each of the aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl may each be selected from 1, 2, 3, 4, 5, or 6 independently selected R AG It is optionally substituted with a substituent.

[0070] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A12, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Each of alkenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl may each be selected from 1, 2, 3, or 4 independently selected R AG It is optionally substituted with a substituent.

[0071] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A12, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Each of alkenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl may each be selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0072] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 2, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Alkenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each independently represent one or two RAG It is optionally substituted with a substituent.

[0073] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 )2, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Alkenyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each independently represent one or two R AG It is optionally substituted with a substituent.

[0074] In some embodiments, each R A independently, C 1-6 Alkyl, C 2-6 Alkenyl, -OR A1 , -N(R A1 )2, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A C 1-6 Alkyl, C 2-6 Alkenyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each independently represent one or two R AG It is optionally substituted with a substituent.

[0075] In some embodiments, each R Aare independently selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from 1, 2, 3, 4, 5, or 6 independently selected R AG It is optionally substituted with a substituent.

[0076] In some embodiments, each R A are independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is independently selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0077] In some embodiments, each R A are independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is independently selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0078] In some embodiments, each R A are independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0079] In some embodiments, each R Aare independently selected from 5-6 membered monocyclic heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0080] In some embodiments, R A is 1, 2, 3, 4, 5, or 6 R AG In some embodiments, R is phenyl optionally substituted with a substituent. A is phenyl.

[0081] In some embodiments, R A is 1, 2, 3, 4, 5, or 6 R AG C optionally substituted with a substituent 1-6 In some embodiments, R A is 1, 2, 3, 4, 5, or 6 R AG C optionally substituted with a substituent 1-3 In some embodiments, R A is 1, 2, 3, 4, or 5 R AG C optionally substituted with a substituent 1-2 In some embodiments, R A is 1, 2, 3, 4, or 5 R AG C optionally substituted with a substituent 1-2 In some embodiments, R A is one, two, or three R AG In some embodiments, R is a C alkenyl optionally substituted with a substituent. A is -CH=CH2.

[0082] In some embodiments, two L A -R Aare, together with the atoms to which they are attached, independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and sulfur; or an 8-10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3-7-membered monocyclic carbocyclyl, 5-10-membered bicyclic carbocyclyl, phenyl, 8-10-membered bicyclic aryl, 3-7-membered monocyclic heterocyclyl, 5-10-membered bicyclic heterocyclyl, 5-6-membered monocyclic heteroaryl, and 8-10-membered bicyclic heteroaryl independently selects 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0083] In some embodiments, each R A1 are independently hydrogen, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A1 C 1-6Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 Optionally substituted with a substituent or two R A1 when attached to the same nitrogen atom, they together form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0084] In some embodiments, each R A1 independently C 1-6 aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A1 Each C 1-6 Aliphatic and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl are selected from 1, 2, 3, 4, 5, or 6 independently selected R G1 It is optionally substituted with a substituent.

[0085] In some embodiments, each R A1 independently C 1-6 aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A1 Each C 1-6 Aliphatic and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl are each independently selected from one or two R G1 It is optionally substituted with a substituent.

[0086] In some embodiments, each RA1 independently C 1-6 alkyl, or 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R A1 Each C 1-6 Aliphatic and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl are selected from 1, 2, 3, 4, 5, or 6 independently selected R G1 It is optionally substituted with a substituent.

[0087] In some embodiments, each R A1 independently C 1-6 alkyl, or 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R A1 Each C 1-6 Aliphatic and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl are each independently selected from one or two R G1 It is optionally substituted with a substituent.

[0088] In some embodiments, each R A1 independently, C 1-6 aliphatic, where R A1 Each C 1-6 Aliphatic groups can be 1, 2, 3, 4, 5, or 6 independently selected R G1 It is optionally substituted with a substituent.

[0089] In some embodiments, each R A1 independently, C 1-6 alkyl, where R A1 Each C 1-6 Alkyl is one, two, three, four, five, or six independently selected R G1 In some embodiments, each R A1 independently, C 1-6 alkyl, where R A1 Each C 1-6 Alkyl is one, two, three, or four independently selected RG1 In some embodiments, each R A1 independently, C 1-6 alkyl, where R A1 Each C 1-6 Alkyl is one or two independently selected R G1 It is optionally substituted with a substituent.

[0090] In some embodiments, each R G1 is independently selected from OR, where each R is hydrogen or C 1-6 In some embodiments, each R G1 is independently selected from OR, where each R is hydrogen or C 1-6 In some embodiments, each R G1 are independently selected from OR, where each R is C 1-6 In some embodiments, each R G1 are independently selected from OR, where each R is C 1-3 In some embodiments, each R G1 is hydroxy or methoxy. In some embodiments, each R G1 is methoxy. In some embodiments, each R G1 is hydroxy.

[0091] In some embodiments, each R A1 independently, C 1-6 aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R A1 Each C 1-6 The alkyl and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl are optionally substituted with hydroxy or methoxy.

[0092] In some embodiments, each R A1 independently, C 1-6alkyl, or 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R A1 Each C 1-6 The alkyl and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl are optionally substituted with hydroxy or methoxy.

[0093] In some embodiments, each R A1 independently, C 1-6 alkyl, where R A1 Each C 1-6 The alkyl is optionally substituted with methoxy.

[0094] In some embodiments, each R AG are independently halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O )R, -NRC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, each R AG is halogen and C 1-6 In some embodiments, each R AG is an independently selected halogen. In some embodiments, each R AG are independently selected C 1-6 In some embodiments, each R AG are independently selected C 1-6 In some embodiments, each R AG are independently selected C 1-3 In some embodiments, each R AG is independently selected from fluoro and methyl. AG is fluoro. In some embodiments, each R AG is methyl.

[0096] In some embodiments, each R Ais methyl, ethyl, n-propyl, isopropyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, dimethylaminocarbonyl, azetidinylcarbonyl, (hydroxyazetidinyl)carbonyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, 5,6-dihydro-[1,2,4]triazolo[1,5-a]pi and 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, wherein methyl, ethyl, n-propyl, isopropyl, ethenyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, and 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl are each independently selected from one, two, three, or four independently selected R AG It is optionally substituted with a substituent.

[0097] In some embodiments, each R Ais methyl, ethyl, n-propyl, isopropyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, dimethylaminocarbonyl, azetidinylcarbonyl, (hydroxyazetidinyl)carbonyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, 5,6-dihydro-[1,2,4]triazolo[1,5- a]pyrazin-7(8H)-yl, wherein methyl, ethyl, n-propyl, isopropyl, ethenyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, and 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl are each independently selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0098] In some embodiments, each R A are independently selected from methyl, ethyl, n-propyl, isopropyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, cyclopropyl, cyclopentyl, phenyl, methylphenyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0099] In some embodiments, each R A are independently selected from methyl, ethyl, propyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, phenyl, methylphenyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, and tetrahydropyranyl.

[0100] In some embodiments, each L A is a covalent bond or C 1-3In some embodiments, each L A is a covalent bond or C 1-2 In some embodiments, each L A is a covalent bond. In some embodiments, each L A is C 1-3 In some embodiments, each L A is C 1-2 It is aliphatic.

[0101] In some embodiments, each L A is a covalent bond or C 1-2 aliphatic, and each R A is methyl, ethyl, n-propyl, isopropyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, dimethylaminocarbonyl, azetidinylcarbonyl, (hydroxyazetidinyl)carbonyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, 5,6-dihydro-[1,2,4]triazolo[1,5- a]pyrazin-7(8H)-yl, wherein methyl, ethyl, n-propyl, isopropyl, ethenyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, and 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl are each independently selected from one or two independently selected R AG It is optionally substituted with a substituent.

[0102] In some embodiments, each L A is a covalent bond or a C2 aliphatic, and each R Aare independently selected from methyl, ethyl, propyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, phenyl, methylphenyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, and tetrahydropyranyl.

[0103] In some embodiments, each L A is a covalent bond, and each R A are independently selected from methyl, ethyl, propyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, phenyl, methylphenyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, and tetrahydropyranyl.

[0104] In some embodiments, each L A is a C2 aliphatic, and each R A is independently selected from methyl, ethyl, propyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, phenyl, methylphenyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, and tetrahydropyranyl. A is a C2 aliphatic, and each R A is phenyl.

[0105] In some embodiments, [ka] teeth, [ka] [ka] [ka] [ka] is.

[0106] In some embodiments, [ka] teeth, [ka] is.

[0107] In some embodiments, [ka] teeth, [ka] is.

[0108] In some embodiments of any of Formulas I, II, III, IV, VI, and VIa, R 1 is hydrogen, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0109] As noted above, in some embodiments of any of Formulas I, II, and III, R 1 is hydrogen, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, R 1is an optionally substituted C 1-6 It is an aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0111] In some embodiments, R 1 is an optionally substituted C 1-6 alkyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, R 1 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. 1 is cyclopropyl.

[0113] In some embodiments, R 1 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is tetrahydrofuranyl.

[0114] In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted C 1-3 In some embodiments, R 1 is an optionally substituted C 1-2 It is aliphatic.

[0115] In some embodiments, R 1 is C 1-6 In some embodiments, R 1 is C 1-3In some embodiments, R 1 is C 1-2 In some embodiments, R 1 is an optionally substituted C 1-2 In some embodiments, R 1 is C 1-2 In some embodiments, R is an alkyl group that is optionally substituted with 1, 2, 3, or 4 halogen groups. 1 is an optionally substituted C 1-2 In some embodiments, R 1 is C 1-2 In some embodiments, R is an alkyl group, which is optionally substituted with one or two halogen groups. 1 is an optionally substituted C1 aliphatic. In some embodiments, R 1 is methyl, ethyl, or difluoroethyl. In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is difluoroethyl.

[0116] In some embodiments, R 1 is methyl, trideuteromethyl, ethyl, difluoroethyl, hydroxyethyl, cyclopropyl, or tetrahydrofuranyl.

[0117] In some embodiments, R 1 and L A -R AOne of them, together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic heterocyclyl and the 5- to 14-membered bicyclic heterocyclyl is independently substituted with 1, 2, 3, 4, 5, or 6 R AG substituents, optionally.

[0118] In some embodiments, R 1 and L A -R A One of them, together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, 3, 4, 5, or 6 R AG substituents).

[0119] In some embodiments, R 1 and L A -R A One of them, together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (optionally substituted with 1, 2, 3, or 4 R AG substituents).

[0120] In some embodiments, R 1 and L A -R A One of them, together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (optionally substituted with 1 or 2 R AG substituents).

[0121] In some embodiments, R1 and L A -R A One of them, together with the atom to which they are attached, forms a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (1, 2, 3, 4, 5, or 6 R AG substituents, optionally substituted).

[0122] In some embodiments, R 1 and L A -R A One of them, together with the atom to which they are attached, forms a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (1, 2, 3, or 4 R AG substituents, optionally substituted).

[0123] In some embodiments, R 1 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments of Formula IV, L 5 is a divalent C 1-3 aliphatic, which is selected from one, two, three, or four independently selected R L5A optionally substituted with substituents; Or, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 16-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 16-membered monocyclic carbocyclyl, the 5- to 16-membered bicyclic carbocyclyl, the 3- to 16-membered monocyclic heterocyclyl, and the 5- to 16-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; Ring B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, an 8-10 membered bicyclic aryl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 0, 1, 2, 3, 4, 5 or 6.

[0127] In some embodiments of Formula IV, L 5 is a divalent C 1-3 aliphatic, which is selected from one, two, three, or four independently selected R L5A optionally substituted with substituents; Or, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic carbocyclyl, the 5- to 10-membered bicyclic carbocyclyl, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 10-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG optionally substituted with substituents; Ring B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, an 8-10 membered bicyclic aryl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 0, 1, 2, 3, 4, 5 or 6.

[0128] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb, Z is N or CR2 In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, Z is N or CR 2 As noted above, in some embodiments of any of Formulas I, II, and III, Z is N or CR 2 In some embodiments, Z is CR 2 In some embodiments, Z is CH.

[0129] In some embodiments, R 2 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments, R 2 is hydrogen.

[0131] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb, R 3 are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0132] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, R 3are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0133] As noted above, in some embodiments of any of Formulas I, II, and III, R 3 are -F, -Cl, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NRm )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0134] In some embodiments, R 3 is -F, -Cl, -CN, or an optionally substituted C 1-6 In some embodiments, R 3 is -F, -Cl, or -CN. In some embodiments, R 3 is -F or -Cl. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted C 1-3 In some embodiments, R 3 is an optionally substituted C 1-3 In some embodiments, R 3 is an optionally substituted C 1-2 In some embodiments, R 3 is an optionally substituted C1-2 In some embodiments, R 3 is an optionally substituted C1 aliphatic. In some embodiments, R 3 is methyl, -CF, or -CFH. In some embodiments, R 3 is methyl. In some embodiments, R 3 is -Cl. In some embodiments, R 3 is methyl or -Cl. In some embodiments, R 3 is methyl or —CF. In some embodiments, R 3 is —CF 3 (i.e., trifluoromethyl).

[0135] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIb, and VIIb, U is N or CR 4 In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, U is N or CR 4 As noted above, in some embodiments of any of Formulas I, II, and III, U is N or CR 4 In some embodiments, U is CR 4 In some embodiments, U is CH.

[0136] In some embodiments, R 4 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R, -N RC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m)N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] In some embodiments, R 4 is hydrogen.

[0138] As noted above, in some embodiments of Formula I, R 5 -L 5 -R 5A is.

[0139] As noted above, in some embodiments of any of Formulas I, II, and III, L 5 is a covalent bond or an optionally substituted divalent C 1-6 In some embodiments, L 5 is an optionally substituted divalent C 1-6 In some embodiments, L 5 is a divalent C 1-6 In some embodiments, L is aliphatic and is optionally substituted with hydroxy. 5 is an optionally substituted divalent C 1-3 In some embodiments, L 5 is a divalent C 1-3In some embodiments, L is aliphatic and is optionally substituted with hydroxy. 5 is an optionally substituted divalent C 1-2 In some embodiments, L 5 is a divalent C 1-2 Being aliphatic, it is optionally substituted with hydroxy.

[0140] In some embodiments, L 5 is a divalent C 1-2 aliphatic, which is optionally substituted by hydroxy or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl is C 1-6 Optionally substituted with alkyl.

[0141] In some embodiments, L 5 is a divalent C 1-2 aliphatic, which is optionally substituted by hydroxy or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl is C 1-3 Optionally substituted with alkyl.

[0142] In some embodiments, L 5 is a divalent C 1-2 aliphatic, which is optionally substituted by hydroxy or piperazinyl, where piperazinyl is C 1-6 Optionally substituted with alkyl.

[0143] In some embodiments, L 5 is a divalent C 1-2 aliphatic, which is optionally substituted by hydroxy or piperazinyl, where piperazinyl is C 1-3Optionally substituted with alkyl.

[0144] In some embodiments, L 5 is a divalent C 1-2 It is aliphatic and is optionally substituted with hydroxy or methylpiperazinyl.

[0145] In some embodiments, L 5 is —CH(CH)—. In some embodiments, L 5 is —CH(CH)— or —CH(CHOH)—. In some embodiments, L 5 is —CH(CHOH)—. In some embodiments, L 5 is -CH2-, -CH(CH3)-, -CH(CH2OH)-, or [ka] In some embodiments, L 5 teeth, [ka] is.

[0146] In some embodiments, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 16-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 16-membered monocyclic carbocyclyl, the 5- to 16-membered bicyclic carbocyclyl, the 3- to 16-membered monocyclic heterocyclyl, and the 5- to 16-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AGIt is optionally substituted with a substituent.

[0147] In some embodiments, L 5 and L A -R A and one of, together with the atom to which it is attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 7-membered monocyclic carbocyclyl, the 5- to 10-membered bicyclic carbocyclyl, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 10-membered bicyclic heterocyclyl independently contains 1, 2, 3, 4, 5, or 6 R AG It is optionally substituted with a substituent.

[0148] As noted above, in some embodiments of Formula I, R 5A -OR 5A11 , -SR 5A1 , -NHR 5A12 , -N(R 5A12 )2, -C(O)R 5A1 , -C(O)N(R 5A1 )2, -C(O)NR 5A1 (OR 5A1 ), -OC(O)R 5A1 , -OC(O)N(R 5A1 )2, -OC(O)OR 5A1 , -OSO2R 5A1 , -OSO2N(R 5A1 )2, -N(R 5A1 )C(O)R 5A1 , -NR 5A1 C(O)OR 5A1 , -NR 5A1 C(O)N(R 5A1 )2, -N(R 5A1 )SO2R 5A1 , -NR 5A1 S(O)2N(R 5A1 )2, -NR 5A1OR 5A1 , -NR 5A1 S(O)R 5A1 , -NR 5A1 S(O)N(R 5A1 )2, -S(O)R 5A1 , -SO2R 5A1 , -S(O)N(R 5A1 )2, -SO2N(R 5A1 )2, -SO3R 5A1 , -C(=NR m )R 5A1 , -C(=NR m )N(R 5A1 )2, -NR 5A1 C(=NR m )R 5A1 , -NR 5A1 C(=NR m )N(R 5A1 )2, -NR 5A1 S(O)(=NR m )R 5A1 , -NR 5A1 S(O)(=NR m )N(R 5A1 )2, -OS(O)(=NR m )R 5A1 , -S(O)(=NR m )R 5A1 , -S(O)(=NR m )N(R 5A1 )2, -P(O)(R 5A1 )2, methyl, C 2-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A C 2-6Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R 5AG Optionally substituted with a substituent or R 5A The methyl group can be one, two, or three R 5AG It is substituted with a substituent.

[0149] In some embodiments, R 5A -NHR 5A12 -OR 5A11 is.

[0150] In some embodiments, R5A -OR 5A11 is.

[0151] In some embodiments, R 5A -NHR 5A12 is.

[0152] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, and VIIa, each R 5A12 independently, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A12 C 1-6Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 Optionally substituted with a substituent or two R 5A12 when attached to the same nitrogen atom, they together form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0153] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, each R 5A12 independently, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A12 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 RG1 Optionally substituted with a substituent or two R 5A12 when attached to the same nitrogen atom, they together form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0154] In some embodiments of any of Formulas I, II, and III, each R 5A12 independently, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A12 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 Optionally substituted with a substituent or two R 5A12when attached to the same nitrogen atom, they together form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0155] In some embodiments, each R 5A12 are independently a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5A12 Each of the 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 It is optionally substituted with a substituent.

[0156] In some embodiments, each R 5A12 are independently phenyl, an 8- to 10-membered bicyclic aryl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A12Each of the phenyl, 8- to 10-membered bicyclic aryl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 It is optionally substituted with a substituent.

[0157] In some embodiments, each R 5A12 is independently phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R 5A12 Each of the phenyl and 5- to 6-membered monocyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 It is optionally substituted with a substituent.

[0158] In some embodiments, each R 5A12 are independently phenyl or pyridinyl, each of which is selected from 1, 2, 3, 4, 5, or 6 independently selected R G1 In some embodiments, each R 5A12 independently, 1, 2, 3, 4, or 5 independently selected R G1 It is phenyl optionally substituted with a substituent.

[0159] In some embodiments, R 5A12 A single example of is phenyl or pyridinyl, each of which may be selected from one, two, or three independently selected R G1 In some embodiments, R 5A12 A single example of is phenyl or pyridinyl, each of which may be selected from one or two independently selected R G1 In some embodiments, R 5A12 A single example of is phenyl or pyridinyl, each of which may contain one R G1 It is optionally substituted with a substituent.

[0160] In some embodiments, each R 5A12independently, 1, 2, 3, 4, 5, or 6 independently selected R G1 In some embodiments, R is phenyl optionally substituted with a substituent. 5A12 A single example of 1, 2, or 3 independently selected R G1 In some embodiments, R is phenyl substituted with a substituent. 5A12 A single example of 1 or 2 independently selected R G1 In some embodiments, R is phenyl substituted with a substituent. 5A12 A single example of G1 It is a phenyl substituted with a substituent.

[0161] In some embodiments, each R 5A12 independently, 1, 2, 3, 4, 5, or 6 independently selected R G1 In some embodiments, R is pyridinyl optionally substituted with a substituent. 5A12 A single example of 1, 2, or 3 independently selected R G1 In some embodiments, R is a pyridinyl substituted with a substituent. 5A12 A single example of is pyridinyl, which can be selected from one or two independently selected R G1 In some embodiments, R 5A12 A single example of 1 or 2 independently selected R G1 In some embodiments, R is a pyridinyl substituted with a substituent. 5A12 A single example of G1 It is a pyridinyl substituted with a substituent.

[0162] In some embodiments of Formula I, each R 5A1 are independently hydrogen, C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A1 C 1-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 Optionally substituted with a substituent or two R 5A1 when attached to the same nitrogen atom, they together form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] As noted above, in some embodiments of Formula I, R 5A11 is methyl, C 2-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 5A11 C 2-6 Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R G1 Optionally substituted with a substituent or R 5A11 The methyl group can be one, two, or three R G1 It is substituted with a substituent.

[0164] In some embodiments, R 5A11 is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is independently selected from 1, 2, 3, 4, 5, or 6 R G1 It is optionally substituted with a substituent.

[0165] In some embodiments, R 5A11 is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is independently selected from one or two R G1 It is optionally substituted with a substituent.

[0166] In some embodiments, R 5A11is pyridyl, which is selected from one or two independently selected R G1 It is optionally substituted with a substituent.

[0167] In some embodiments of Formula I, each R 5AG are independently halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O )R, -NRC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb, each R G1 are independently halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O )R, -NRC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0169] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, each R G1 are independently halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O )R, -NRC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0170] In some embodiments of any of Formulas I, II, and III, each R G1are independently halogen, -CN, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)NR(OR), -OC(O)R, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O )R, -NRC(O)OR, -NRC(O)N(R)2, -N(R)SO2R, -NRS(O)2N(R)2, -NROR, -NRS(O)R, -NRS(O)N(R)2, -S(O)R, -SO2R, -S(O)N(R)2, -SO2N(R)2, -SO3R, -C(=NR m )R, -C(=NR m )N(R)2, -NRC(=NR m )R, -NRC(=NR m )N(R)2, -NRS(O)(=NR m )R, -NRS(O)(=NR m )N(R)2, -OS(O)(=NR m )R, -S(O)(=NR m )R, -S(O)(=NR m )N(R)2, -P(O)(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0171] In some embodiments, each R G1 is a halogen, C 1-6alkyl, phenyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -C(O)OR, -C(O)N(R), and -C(O)NR(OR), wherein each C 1-6 Alkyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl can be selected from 1, 2, 3, or 4 independently selected R AG1 It is optionally substituted by a substituent.

[0172] In some embodiments, each R G1 is a halogen, C 1-6 alkyl, phenyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; —C(O)OR, —C(O)N(R), and —C(O)NR(OR), wherein each C 1-6 Alkyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each independently selected from one or two R AG1 It is optionally substituted by a substituent.

[0173] In some embodiments, each R G1 is a halogen, C 1-6 alkyl, phenyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -C(O)OR, -C(O)N(R), and -C(O)NR(OR), wherein each C 1-6 Alkyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each independently selected from 1, 2, 3, or 4 R AG1 It is optionally substituted by a substituent.

[0174] In some embodiments, each R AG1 is a halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 C(O)NR°2, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)R°, -O(CH2) 0-4 R o , CN, -(CH2) 0-4 and —C(O)NR°, and —C(O)N(OR°)R°, where each R° is independently selected from hydrogen, C 1-6 It is an alkyl or a 3-6 membered saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0175] In some embodiments, each R AG1 is a halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 C(O)NR°2, -CH2)0-4 C(O)OR°, -(CH2) 0-4 and —C(O)R°, and —C(O)N(OR°)R°.

[0176] In some embodiments, each R° is independently hydrogen or C 1-6 In some embodiments, each R is independently hydrogen or C 1-3 In some embodiments, each R° is independently hydrogen or methyl.

[0177] In some embodiments, each R AG1 is a halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 C(O)NR°2, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 and —C(O)R°, and —C(O)N(OR°)R°, where each R° is independently hydrogen or C 1-6 It is alkyl.

[0178] In some embodiments, each R AG1 is independently selected from fluoro, methyl, ethyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, methoxyaminocarbonyl, cyano, cyclopropyl, hydroxy, methoxy, dimethylamino, dimethylaminomethyl, and tetrahydropyranyl.

[0179] In some embodiments, each R AG1 is independently selected from fluoro, methyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, and methoxyaminocarbonyl.

[0180] In some embodiments, each R G1 is a halogen, C 1-6aliphatic, and —C(O)OR. In some embodiments, each R G1 is a halogen, C 1-6 In some embodiments, each R G1 is a halogen, C 1-3 In some embodiments, each R G1 is a halogen, C 1-6 In some embodiments, each R G1 is a halogen, C 1-3 In some embodiments, each R G1 is independently selected from fluoro, chloro, methyl, and —C(O)OH.

[0181] In some embodiments, each R G1 is methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl, isoindolinonyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, -C(O)OR, -C(O)N(R), and -C( and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl are independently selected from pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl, isoindolinonyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, each independently selected from one or two RAG1 It is optionally substituted by a substituent.

[0182] In some embodiments, each R G1 is methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl , isoindolinyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, -C(O)OR, -C(O)N(R), and -C(O)NR(OR), wherein pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydropyrazolo[1,5-a]pyrazinyl, tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl, isoindolinonyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl each independently represent one or two R independently selected from fluoro, methyl, ethyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, methoxyaminocarbonyl, cyano, cyclopropyl, hydroxy, methoxy, dimethylamino, dimethylaminomethyl, and tetrahydropyranyl. AG1 It is optionally substituted by a substituent.

[0183] In some embodiments, each R G1is independently selected from methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, —C(O)OR, —C(O)N(R), and —C(O)NR(OR), wherein pyridinyl, pyridinonyl, phenyl, pyrazolyl, Zolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, and tetrazolyl each have one or two R independently selected from fluoro, methyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, and methoxyaminocarbonyl. AG1 It is optionally substituted by a substituent.

[0184] In some embodiments, R G1 is —C(O)OR. In some embodiments, R G1 is —C(O)OH. In some embodiments, one R G1 is -C(O)OR and another R G1 is a halogen, and C 1-6 In some embodiments, one R G1 is -C(O)OR and another R G1 is halogen and C 1-6 In some embodiments, one R G1 is -C(O)OR and another R G1 is halogen and C 1-3 In some embodiments, one R G1 is -C(O)OH, and another R G1 is halogen and C 1-6 In some embodiments, one R G1 is -C(O)OH, and another R G1 is halogen and C 1-3In some embodiments, one R G1 is -C(O)OH, and another R G1 is selected from fluoro, chloro, and methyl.

[0185] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb, each R is independently hydrogen, or C 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and sulfur. or two R's, when attached to the same nitrogen atom, combine to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0186] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, each R is independently hydrogen, or C 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and sulfur. or two R's, when attached to the same nitrogen atom, combine to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0187] As noted above, in some embodiments of any of Formulas I, II, and III, each R is independently hydrogen, or C 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and sulfur. or two R's, when attached to the same nitrogen atom, combine to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, each R is hydrogen, C 1-6 and independently selected from alkyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl is selected from C 1-6 Optionally substituted with alkyl.

[0189] In some embodiments, each R is independently selected from hydrogen, methyl, methylpiperidinyl, and pyridinyl.

[0190] In some embodiments, each R is independently selected from hydrogen, methyl, methylpiperidinyl, and pyridinyl. In some embodiments, R is hydrogen.

[0191] In some embodiments, Each R G1 is methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl , isoindolinyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, -C(O)OR, -C(O)N(R), and -C(O)NR(OR), wherein pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydropyrazolo[1,5-a]pyrazinyl, tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl, isoindolinonyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl each independently represent one or two R independently selected from fluoro, methyl, ethyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, methoxyaminocarbonyl, cyano, cyclopropyl, hydroxy, methoxy, dimethylamino, dimethylaminomethyl, and tetrahydropyranyl. AG1 optionally substituted by substituents; and Each R is independently selected from hydrogen, methyl, methylpiperidinyl, and pyridinyl.

[0192] In some embodiments, Each R G1is independently selected from methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, —C(O)OR, —C(O)N(R), and —C(O)NR(OR), wherein pyridinyl, pyridinonyl, phenyl, pyrazolyl, Zolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, and tetrazolyl each have one or two R independently selected from fluoro, methyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, and methoxyaminocarbonyl. AG1 optionally substituted by substituents; and Each R is hydrogen, C 1-6 and independently selected from alkyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl is selected from C 1-6 Optionally substituted with alkyl.

[0193] In some embodiments, Each R G1is independently selected from methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, —C(O)OR, —C(O)N(R), and —C(O)NR(OR), wherein pyridinyl, pyridinonyl, phenyl, pyrazolyl, Zolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, and tetrazolyl each have one or two R independently selected from fluoro, methyl, hydroxyethyl, —COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, and methoxyaminocarbonyl. AG1 optionally substituted by substituents; and Each R is independently selected from hydrogen, methyl, methylpiperidinyl, and pyridinyl.

[0194] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb, each R m is independently —OH, —CN, or R. In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, each R m is independently —OH, —CN, or R. As noted above, in some embodiments of any of Formulas I, II, and III, each R m are independently —OH, —CN, or R.

[0195] In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, VIa, VII, VIIa, and VIIb, each n is 0, 1, 2, 3, or 4. In some embodiments of any of Formulas I, II, III, IV, V, Va, VI, and VIa, each n is 0, 1, 2, 3, or 4. As noted above, in some embodiments of any of Formulas I, II, and III, each n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1.

[0196] In some embodiments, the compound of formula I is a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3, and U, Z, ring A, R 3 , R 5 , and R AG Each of the following, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0197] In some embodiments, the compound of Formula I is a compound of Formula Va: [ka] or a pharmaceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3, and U, Z, ring A, ring B, R 3 , L 5 , R G1 , R AG Each of , and m, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0198] In some embodiments, the compound of formula I is a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein U, Z, R 1 , R 3 , R 5A , and R AG Each of the following, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0199] In some embodiments, the compound of Formula I is a compound of Formula VIa: [ka] or a pharmaceutically acceptable salt thereof, wherein U, Z, R 1 , R 3 , R 5A12 , and R AG Each of the following, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0200] In some embodiments, the compound is a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3, and U, Z, R 3 , R 5 , and R AG Each of the following, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0201] In some embodiments, the compound is a compound of Formula VIIa: [ka] or a pharmaceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3, and U, Z, R 3 , L 5 , R5A12 , and R AG Each of the following, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0202] In some embodiments, the compound is a compound of formula VIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3, and U, Z, ring B, R 3 , L 5 , R G1 , R AG Each of , and m, both alone and in combination, is as defined above for Formula I and as described in classes and subclasses herein.

[0203] In some embodiments, the disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. [Table 1]

[0204] In some embodiments, the compound provided herein is a compound selected from the following: 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-3-phenyl-4,5-dihydropyrazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-3-vinyl-4,5-dihydropyrazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 6-methyl-3-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)picolinic acid; 2-((1-(7-chloro-3-ethyl-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-3,4-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-4-ethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-3,4-diethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,2-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 2-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpicolinic acid; 2-((1-(4-ethyl-3,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(4-ethyl-3,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 2-((1-(3,4-diethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,4-diethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-5-fluorobenzoic acid; 3-((1-(3,4-diethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpicolinic acid; 2-((1-(4,7-dimethyl-5-oxo-2-propyl-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-2-phenethyl-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-fluoropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-2-(pyrimidin-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(4-7-dimethyl-5-oxo-2-(o-tolyl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 2-[1-(3-methoxy-5,8-dimethyl-6-oxo-benzo[c][1,8]naphthyridin-10-yl)ethylamino]benzoic acid; 2-[1-[3-(dimethylamino)-5,8-dimethyl-6-oxo-benzo[c][1,8]naphthyridin-10-yl]ethylamino]benzoic acid; 2-[1-[3-(2-methoxyethoxy)-5,8-dimethyl-6-oxo-benzo[c][1,8]naphthyridin-10-yl]ethylamino]benzoic acid; 2-((1-(7-chloro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)benzoic acid; 6-methyl-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)picolinic acid; 2-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)picolinic acid; 2-Ethyl-3,6-dimethyl-8-((6-methyl-[2,4'-bipyridin]-3-yl)amino)-8,9-dihydrobenzo[de]pyrazolo[4,5,1-ij][1,7]naphthyridin-4(3H)-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(pyrimidin-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-N,N-dimethylbenzamide; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)benzoic acid; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpyridin-2-yl)-2-fluoro-N-methylbenzamide; 3-ethyl-9-(1-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((2-(4-acetylpiperazin-1-yl)phenyl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)phenyl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(4-(2,2-difluoroethyl)-3-ethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-cyclopentyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-isopropyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(7-chloro-3-ethyl-4-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(7-chloro-3-(cyclopropylmethyl)-4-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-propyl-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-(2-methoxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-(cyclopropylmethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-ethyl-4-methyl-5-oxo-7-(trifluoromethyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((2-(1H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-(1-methylpiperidin-4-yl)picolinamide; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-(pyridin-4-yl)picolinamide; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methoxypicolinamide; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)-2-hydroxyethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((2-(4-acetylpiperazin-1-yl)-6-chloropyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 5-(5-chloro-2-((1-(4,7-dimethyl-3-(1-methylazetidin-3-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)phenyl)-N-methylpicolinamide; 9-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-cyclopropylazetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)azetidin-1-yl)acetonitrile; 3-(3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)azetidin-1-yl)propanenitrile; 3-(1-acetylazetidin-3-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)azetidine-1-carboxylate; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)azetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylazetidin-3-yl)-9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-((1-(3-(1-acetylazetidin-3-yl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-chloro-N-methyl-[2,3'-bipyridine]-6'-carboxamide; 3-(1-acetylazetidin-3-yl)-9-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(dimethylglycyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-((S)-1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-((1-acetylpiperidin-4-yl)methyl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-((9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)methyl)-N,N-dimethylpiperidine-1-carboxamide; 4-((9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)methyl)-N-ethylpiperidine-1-carboxamide; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-3-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-hydroxyethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methylpyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrimidin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methylpyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methylpyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrimidin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-N-methylpicolinamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(Azetidine-1-carbonyl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(3-hydroxyazetidine-1-carbonyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-N,N,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(4-cyano-2-fluorophenyl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(4-cyanophenyl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-morpholinopyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; Ethyl 4-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)piperidine-1-carboxylate; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-ethylpyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-(1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d3)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-3-(1-isopropylpyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d3)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(3-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidin-1-yl)acetonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-3-(1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-3-(1-isopropylpyrrolidin-3-yl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylpyrrolidin-3-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidine-1-carboxylate; 3-(9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)-N,N-dimethylpyrrolidine-1-carboxamide; 3-(3-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidin-1-yl)propanenitrile; 3-(3-(9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidin-1-yl)propanenitrile; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d3)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(dimethylglycyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d3)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-(1-(1-methyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 1-(3-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidine-1-carbonyl)cyclopropane-1-carbonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpiperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-ethylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(2-methyltetrazol-5-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1,3,4-oxadiazol-2-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 5-[6-chloro-3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 3-[6-chloro-3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one; 9-[1-[[6-chloro-2-(1,3-dimethylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(4-hydroxy-1-piperidyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(3-fluoro-4-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(3-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 5-[3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-6-methyl-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 9-[1-[[6-chloro-2-(1-methyl-2-oxo-4-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-[(2R)-2-hydroxypropyl]-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-[(2S)-2-hydroxypropyl]-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyethyl)-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxetan-3-yl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-[4-[9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-3-yl]-1-piperidyl]propanenitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)piperidin-4-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methylsulfonyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 4-[9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-3-yl]piperidine-1-carboxylate methyl; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-(1-cyclopropylsulfonyl-4-piperidyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)-N,N-dimethylpiperidine-1-carboxamide; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(quinolin-6-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyacetyl)-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin5-one; 1-(4-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(1-methyl-1H-pyrazole-5-carbonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(dimethylglycyl)piperidin-4-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methyl-L-prolyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4-methyl-3-(1-methylpiperidin-4-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7-carbonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2-(1-methylpiperidin-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)-7-methyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(4-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-2-yl)piperidin-1-yl)propanenitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2-(1-methylazetidin-3-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-2-(1-methylpiperidin-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-2-(1-isopropylpiperidin-4-yl)-4,7-dimethyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-2-(1-methylpiperidin-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; Ethyl 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-2-yl)piperidine-1-carboxylate; 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-2-yl)-N,N-dimethylpiperidine-1-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-2-(1-(2,2-difluoroethyl)piperidin-4-yl)-4,7-dimethyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-[6-chloro-3-[1-[7-methyl-5-oxo-3-[(3S)-tetrahydrofuran-3-yl]-4-(trideuteriomethyl)pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(4-ethyl-7-methyl-5-oxo-3-((S)-tetrahydrofuran-3-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2'-methyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(4-ethyl-7-methyl-5-oxo-3-((S)-tetrahydrofuran-3-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methyl-[2,3'-bipyridine]-6'-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-cyclopropyl-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]amino]ethyl]-4-cyclopropyl-3-ethyl-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-ethyl-7-methyl-4-tetrahydrofuran-3-yl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-ethyl-4-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-(((3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)methyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(3-ethyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)benzoic acid; 4-(4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide; 3-(4-(4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propanenitrile; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2'-methyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(4-(2,2-difluoroethyl)-3-ethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methyl-[2,3'-bipyridine]-6'-carboxamide; 9-[1-[[2-(1-acetyl-4-piperidyl)-6-chloro-3-pyridyl]amino]ethyl]-3-ethyl-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-(2-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(4-hydroxypiperidin-1-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(quinolin-6-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(2-hydroxyethyl)-4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 5-[6-chloro-3-[1-[3-(2-hydroxyethyl)-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 9-[1-[[6-chloro-2-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-2-oxo-4-pyridyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(2-methoxy-4-pyridyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-4-piperidyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[2-(1-acetyl-4-piperidyl)-6-chloro-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-(2,2-difluoroethyl)-3-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 5-[6-chloro-3-[1-[4-(2,2-difluoroethyl)-3-(2-hydroxyethyl)-7-methyl-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-ethyl-3-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[(6-chloro-2-morpholino-3-pyridyl)amino]ethyl]-4-ethyl-3-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(2-morpholinoethyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-morpholinoethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(4,7-dimethyl-3-(2-morpholinoethyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 4-(6-chloro-3-((1-(4,7-dimethyl-3-(2-(4-methylpiperazin-1-yl)ethyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-(2-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethyl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-ethyl-7-methyl-3-(2-pyridyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-morpholinopyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-(pyridin-2-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(4-ethyl-7-methyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methyl-[2,3'-bipyridine]-6'-carboxamide; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-2-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-ethyl-7-methyl-3-(3-pyridyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(2-pyridylmethyl)pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-(pyridin-2-ylmethyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-3-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyethyl)-3-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-3-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyethyl)-3-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 3-[9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-3-yl]piperidine-1-carboxylate methyl ester; 5-[6-chloro-3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethoxy]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 5-[3-[1-[3-(1-acetyl-4-piperidyl)-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethoxy]-6-chloro-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-((dimethylamino)methyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(4-hydroxypiperidin-1-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 1-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-N-methylpiperidine-4-carboxamide; 10-(1-((2-(4-acetylpiperazin-1-yl)-6-chloropyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 3-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 4-(4-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide; 10-(1-((6-chloro-2'-methyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 4-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 6-chloro-N-methyl-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)-[2,3'-bipyridine]-6'-carboxamide; 10-(1-((6-chloro-6'-methoxy-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2'-methoxy-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2'-(dimethylamino)-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(quinolin-6-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 2-fluoro-N-methyl-4-(6-methyl-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)benzamide; 8-methyl-10-(1-((6-methyl-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-6-methylpyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((2',6-dimethyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylpyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 7-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one; 10-(1-((6-chloro-2-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-6'-((dimethylamino)methyl)-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 3-(3-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)-6-methylpyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 8-methyl-10-(1-((6-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 3-(3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; and 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-(4-methylpiperazin-1-yl)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the present disclosure encompasses the recognition that provided compounds exhibit certain desirable properties, e.g., compared to other known compounds. For example, in some embodiments, provided compounds are more potent in one or more biochemical or cellular assays described herein and / or have one or more other properties that make them more suitable for drug development, e.g., superior selectivity for mutant PI3Kα over wide-form (WT) PI3Kα, and / or superior ADME (absorption, distribution, metabolism, and excretion) properties (including, but not limited to, superior permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profile) than other known compounds. In some embodiments, provided compounds exhibit certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.

[0206] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a provided compound herein should be understood to include a reference to the salts thereof, unless otherwise indicated.

[0207] Unless otherwise specified or prohibited by the preceding definitions of any of Formulas I-VIIb, the variables X, Y, Z, U, ring A, L A , R A , RA1 , R AG , R 1 , R 2 , R 3 , R 4 , R 5 , L 5 , R 5A , R 5A1 , R 5A11 , R 5A12 , R 5AG , R G1 , R, R m It will be understood that the embodiments of, and n, both alone and in combination, apply to compounds of any of Formulas I-VIIb as defined above and described in classes and subclasses herein.

[0208] Unless otherwise specified or prohibited by any of the preceding definitions of Formulas I, II, and III, the variables X, Y, Z, U, ring A, L, A , R A , R A1 , R AG , R 1 , R 2 , R 3 , R 4 , R 5 , L 5 , R 5A , R 5A1 , R 5A11 , R 5A12 , R 5AG , R G1 , R, R m It will be understood that the embodiments of, and n, both alone and in combination, apply to compounds of any of Formulas I, II, and III as defined above and described in classes and subclasses herein.

[0209] Throughout this disclosure, unless otherwise indicated, references to compounds of Formula I are intended to include any of Formulas I, II, and III, as well as species of such formulas disclosed herein.

[0210] Preparation of the provided compounds The compounds of the present disclosure, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to many possible synthetic routes, such as the following schemes. The following schemes provide general guidance related to preparing the compounds of the present disclosure. Those skilled in the art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present disclosure. The compounds provided can generally be made by the processes described in the following schemes and examples.

[0211] In some embodiments, provided compounds are prepared according to the following schemes: [ka] During the ceremony, Hal 1 , Hal 2 , and Hal 3 are each independently a suitable halogen, and X, Y, Z, U, R 1 , R 3 , R 5 , ring A, L A , R A and n, both alone and in combination, are as defined above for Formula I and as described in classes and subclasses herein. Thus, in some embodiments, intermediate A-2 is prepared by a process comprising reacting a compound of formula A-1 with a suitable reagent (e.g., N-bromosuccinimide). In some embodiments, intermediate A-3 is prepared by a process comprising reacting intermediate A-2 under Sandmeyer reaction conditions. In some embodiments, intermediate A-4 is prepared by a process comprising reacting intermediate A-3 with a suitable reagent (e.g., oxalyl chloride or thionyl chloride). In some embodiments, intermediate A-6 is prepared by a process comprising contacting intermediate A-4 with a compound of formula A-5 under suitable conditions. In some embodiments, intermediate A-7 is prepared by reacting intermediate A-6 under suitable cyclization conditions (e.g., S NIn some embodiments, intermediate A-9 is prepared by a process comprising reacting intermediate A-7 with a compound of formula A-8 (e.g., a transition metal catalyzed cross-coupling reaction). In some embodiments, intermediate A-9 is prepared by a process comprising reacting intermediate A-7 with a compound of formula A-8. In some embodiments, a compound of formula I is prepared by a process comprising reacting intermediate A-9 under suitable conditions (e.g., a transition metal catalyzed cross-coupling reaction).

[0212] In some embodiments, provided compounds are prepared according to the following schemes: [ka] wherein Hal and Hal 1 each of X, Y, Z, U, R is a suitable halogen, M is a suitable reactive group (e.g., a pinacol boronic ester group or a tributyltin group), and 1 , R 3 , R 5A , ring A, L A , R A and n, both alone and in combination, are as defined above for Formula I and as described in classes and subclasses herein. Thus, in some embodiments, intermediate B-2 is prepared by a process comprising contacting compounds of formula A-7 and B-1 under suitable conditions (e.g., a metal-catalyzed cross-coupling reaction). In some embodiments, intermediate B-3 is prepared by a process comprising reacting intermediate B-2 under suitable reducing conditions. In some embodiments, intermediate B-4 is prepared by a process comprising reacting intermediate B-3 with a suitable reagent (e.g., PBr). In some embodiments, a compound of formula B-5 is prepared by a process comprising reacting intermediate B-4 with a suitable nucleophile.

[0213] composition The present disclosure also provides compositions comprising a compound provided herein and one or more other components. In some embodiments, the provided compositions comprise and / or deliver a compound described herein (e.g., a compound of any of Formulas I, II, and III).

[0214] In some embodiments, the compositions provided are pharmaceutical compositions that include and / or deliver a compound provided herein (e.g., a compound of any of Formulas I, II, and III) and further include a pharmaceutically acceptable carrier.

[0215] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve the desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions contain a compound described herein and one or more fillers, disintegrants, lubricants, anti-adhesive agents, flow agents, and / or antistatic agents. Provided pharmaceutical compositions can take a variety of forms, including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppositories, nasal sprays, and / or inhalers, eye drops, intraocular injection forms, depot forms, and injection and infusion solutions. Methods for preparing pharmaceutical compositions are well known in the art.

[0216] In some embodiments, provided compounds are formulated into unit dosage forms for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" refers to a physically discrete unit of active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, a unit dosage form contains an entire single dose of agent. In some embodiments, two or more unit dosage forms are administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is necessary or expected to be necessary to achieve the intended effect. The 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., tablet, capsule, etc.) containing a predetermined amount of one or more active agents, a sustained-release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents.

[0217] Provided compositions can be administered using any amount and any route of administration effective for treating or lessening the severity of any of the diseases or disorders described herein.

[0218] use The present disclosure provides uses for the compounds and compositions described herein. In some embodiments, the provided compounds and compositions are for use in medicine (e.g., as therapy). In some embodiments, the provided compounds and compositions are useful for treating diseases, disorders, or conditions, where the underlying pathology is mediated, in whole or in part, by PI3Kα. In some embodiments, the provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0219] In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject suffering from or susceptible to a disease, disorder, or condition associated with PI3K alpha. In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject suffering from or susceptible to a disease, disorder, or condition, wherein the underlying pathology is mediated in whole or in part by PI3K alpha.

[0220] In some embodiments, provided compounds are useful as PI3K alpha inhibitors. In some embodiments, the present disclosure provides a method for inhibiting PI3K alpha in a subject, the method comprising administering a provided compound or composition. In some embodiments, the present disclosure provides a method for inhibiting PI3K alpha in a biological sample, the method comprising contacting the sample with a provided compound or composition.

[0221] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with PI3K alpha in a subject in need thereof, the method comprising administering to the subject a provided compound or composition. In some embodiments, the disease, disorder, or condition is associated with a mutation in PI3K alpha. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition whose underlying pathology is mediated in whole or in part by PI3K alpha in a subject in need thereof, the method comprising administering to the subject a provided compound or composition.

[0222] In some embodiments, the disclosure provides methods of treating various PI3Kα-dependent diseases and disorders. In some embodiments, the disorder is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, PI3Kα-related diseases or disorders include CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal ... These include, but are not limited to, gastroesophageal carcinoma, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma.

[0223] Combination therapy For example, one or more other additional therapeutic agents can be used in combination with the compounds and salts provided herein, such as chemotherapeutic or other anti-cancer agents, anti-inflammatory agents, steroids, immunosuppressants, anesthetics (e.g., for use in conjunction with surgical procedures), or other agents useful in treating diseases associated with PI3Kα. These agents can be combined with the compounds in a single dosage form or can be administered as separate dosage forms, either simultaneously or sequentially.

[0224] The compounds described herein can be used in combination with one or more other kinase inhibitors for the treatment of diseases such as cancer that are affected by multiple signal transduction pathways.For example, the combination can include one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, CDK4 / 6, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Additionally, solid forms of the inhibitors described herein can be combined with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinases.

[0225] For the treatment of cancer and other proliferative disorders, the compounds described herein may be used in combination with other compounds, including JAK kinase inhibitors (ruxolitinib, the additional JAK1 / 2 and AK1-selective baricitinib or itacitinib), Pim kinase inhibitors (e.g., LGH447, INCB053914, and SGI-1776), PI3 kinase inhibitors, including PI3K-δ selective and broad-spectrum PI3K inhibitors (e.g., palsaclisib and INCB50797), and PI3K-γ inhibitors, such as PI3K-γ selective inhibitors. , MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin-dependent kinase inhibitors (e.g., palbociclib, ribociclib, and abemaciclib), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., OTX015, CPI-0610, INCB54329, or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), estrogen receptor modulators (e.g., fulvestrant), androgen receptor modulators (e.g., enzalutamide), BCL2 inhibitors (e.g., venetoclax) It can be used in combination with targeted therapies including hypoxia-inducible factor-2α inhibitors (e.g., velzutifan), exportin-1 (XPO-1) inhibitors (e.g., selinexor), KRAS inhibitors (e.g., sotorasib), arginase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919, or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and BTK inhibitors such as ibrutinib.

[0226] To treat cancer and other proliferative diseases, the compounds described herein can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds described herein can also be used in combination with medical therapies such as surgery or radiation therapy, e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioactive isotopes.

[0227] Examples of suitable chemotherapeutic agents include abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, bupallisib, intravenous busul Fan, oral busulfan, calsterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, Droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, ibritumomab mesylate Matinib, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafarnib, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab,Oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, piralalisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafen, Revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, Examples of the anti-cancer drug include nitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0228] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0229] Exemplary anti-inflammatory agents include, but are not limited to, aspirin, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0230] Exemplary steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[0231] Exemplary immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0232] Exemplary anesthetic agents include, but are not limited to, local anesthetics (e.g., lidocaine, procaine, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, mmobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

[0233] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered before administration of the compound or salt provided herein. In some embodiments, the compound or salt provided herein is administered during a surgical procedure. In some embodiments, the compound or salt provided herein is administered in combination with an additional therapeutic agent during a surgical procedure.

[0234] The additional compounds, inhibitors, agents, etc., as provided herein, can be combined with the compounds provided herein in a single or multiple dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0235] Labeled Compounds and Assay Methods Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal, or radiolabeled compounds of the present invention, which may be useful not only for imaging but also for both in vitro and in vivo assays for localizing and quantitating the PI3K alpha enzyme in tissue samples, including humans, and for identifying PI3K alpha enzyme ligands through inhibitory binding of the labeled compounds. Accordingly, the present invention also includes PI3K alpha enzyme assays comprising such labeled compounds.

[0236] The present invention further includes isotopically labeled compounds of the present invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the present invention in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into compounds of the present invention include, but are not limited to: 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C.13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 The radionuclide incorporated into the radiolabeled compound depends on the specific application of the radiolabeled compound. For example, in in vitro FGFR enzyme labeling and competition assays, 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S are most useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br is generally the most useful.

[0237] One or more constituent atoms of the compounds provided herein can be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, one or more atoms are replaced or substituted with deuterium. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms (e.g., C of Formula I). 1-6 One or more hydrogen atoms of an alkyl group can be optionally replaced with a deuterium atom, e.g., replacing -CD3 with -CH3. In some embodiments, an alkyl group of the disclosed formulas (e.g., a compound of any of Formulas I-VIIb) can be perdeuterated.

[0238] In some embodiments, a compound provided herein (eg, a compound of any of Formulas I-VIIb), or a pharmaceutically acceptable salt thereof, contains at least one deuterium atom.

[0239] In some embodiments, a compound provided herein (eg, a compound of any of Formulas I-VIIb), or a pharmaceutically acceptable salt thereof, contains two or more deuterium atoms.

[0240] In some embodiments, a compound provided herein (eg, a compound of any of Formulas I-VIIb), or a pharmaceutically acceptable salt thereof, contains three or more deuterium atoms.

[0241] In some embodiments, for a compound provided herein (e.g., a compound of any of Formulas I-VIIb), or a pharmaceutically acceptable salt thereof, all hydrogen atoms are replaced with deuterium atoms (i.e., the compound is "perdeuterated").

[0242] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0243] Synthetic methods for incorporating isotopes into organic compounds are known in the art (e.g., Deuterium Labeling in Organic Chemistry (Alan F. Thomas) (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange (Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann) Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling (James R. Hanson) Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0244] Substitution with a heavier isotope (e.g., deuterium) may confer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferable in some circumstances. (See, e.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312.) In particular, substitution at one or more metabolic sites may confer one or more therapeutic advantages.

[0245] The radiolabeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. Generally, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled compounds of the present invention to the PI3K alpha enzyme. Thus, the ability of the test compound to compete with the radiolabeled compound in binding to the PI3K alpha enzyme is directly correlated to its binding affinity.

[0246] kit The present invention also includes pharmaceutical kits useful, for example, for treating or preventing the PI3Kα-related diseases or disorders mentioned herein, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. Such kits can further include one or more of a variety of conventional pharmaceutical kit components (e.g., a container with one or more pharmaceutically acceptable carriers, additional containers, etc.) as desired, as would be readily apparent to one skilled in the art. Instructions (e.g., package inserts or labels) indicating the amounts of the components to be administered and / or guidelines for mixing the components can also be included in the kit.

[0247] The present invention will be described in more detail by specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way.Those skilled in the art will easily recognize that there are various non-critical parameters that can be changed or modified to achieve essentially the same results.The compounds in the examples have been found to be inhibitors of PI3Kα as described below. [Example]

[0248] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedure: While this general method illustrates the synthesis of certain specific compounds of the present disclosure, it will be understood that the following general method, and other methods known to those of skill in the art, can be applied to all compounds described herein and each subclass and species of those compounds.

[0249] Intermediate 1: 1-(3-amino-6-chloropyridin-2-yl)piperidin-4-ol [ka] To a solution of 6-chloro-2-fluoro-3-nitro-pyridine (100.00 mg, 0.57 mmol) in 3 mL of EtOH, piperidin-4-ol (57.30 mg, 0.57 mmol) was added and stirred at 45° C. for 1 hour. To this mixture, potassium 2-methylpropan-2-olate (127.13 mg, 1.13 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (431.54 mg, 1.70 mmol) were added, and after stirring at 80° C. overnight, the mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM and ethyl acetate to give the desired product as a yellow solid (90 mg, 70%). 10 H 15 ClNO (M+H) + LCMS calculated for m / z: 228.1; found: 228.1.

[0250] Intermediates 2-5. Intermediates 2-5 in Table I-1 were prepared similarly as described for Intermediate 1. [Table 2]

[0251] Intermediate 6: 6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-amine [ka] To a solution of 3-amino-6-chloropicolinic acid (100 mg, 0.58 mmol) in 2 mL of DCM was added (N-isocyanimino)triphenylphosphorane (175 mg, 0.58 mmol). After stirring overnight at room temperature, the mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and ethyl acetate to give the desired product as a yellow solid (84 mg, 74%). C7H6ClNO (M+H) + LCMS calculated for m / z: 197.0; found: 197.0.

[0252] Intermediate 7: 6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-amine [ka] Step 1: 3-Amino-6-chloro-N'-methylpicolinimide hydrazide [ka] To a solution of 3-amino-6-chloro-pyridine-2-carbonitrile (500 mg, 3.26 mmol) in 10 mL of EtOH, methylhydrazine (1.03 mL, 19.54 mml) was added at room temperature. After stirring at 100° C. for 24 hours, the solvent was removed under vacuum to give the desired product as a yellow solid (600 mg, 92%). 11 ClN5(M+H) + LCMS calculated for m / z: 200.1; found: 200.1.

[0253] Step 2: 6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-amine A solution of 3-amino-6-chloro-N'-methylpicolinimide hydrazide (600 mg, 3 mmol) was dissolved in 5 mL of formic acid. After stirring overnight at 105 °C, the solvent was removed under vacuum. Next, 5 mL of ammonium hydroxide solution in water and EtOH was added to the residue, and the mixture was stirred overnight at 100 °C. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was precipitated in ether, filtered, and washed with ether to give the desired product as a yellow solid (420 mg, 67%). C8H9ClN5 (M+H) + LCMS calculated for m / z: 210.1; found: 210.1.

[0254] Intermediate 8: 2-(3-(3-amino-6-chloropyridin-2-yl)-1H-1,2,4-triazol-1-yl)ethan-1-ol [ka] The title compound was prepared using a procedure similar to that described for Intermediate 7, except using 2-hydrazinylethan-1-ol instead of methylhydrazine in step 1. 11 ClNO (M+H) + LCMS calculated for m / z: 240.1; found: 240.1.

[0255] Intermediate 9: 6-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-amine [ka] 4-Methyl-1,2,4-triazole (120.16 mg, 1.45 mmol) was dissolved in 2 mL of THF and cooled to -78 °C. n-Butyllithium (578.44 uL, 1.45 mmol) was added via syringe. After stirring for 10 minutes, dichlorozinc (2 M in THF, 761.10 uL, 1.45 mmol) was added. The reaction mixture was stirred at -78 °C for 20 minutes and then warmed to room temperature. The resulting mixture was transferred via syringe to a pressure flask containing a mixture of 2-bromo-6-chloro-pyridin-3-amine (100.0 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (55.70 mg, 0.05 mmol), and 3 mL of dioxane. The reaction mixture was heated in a sealed flask at 120 °C for 15 hours and then cooled to room temperature. EtOAc was added to quench the reaction. The resulting mixture was washed with water. The organic layer was concentrated and purified on a silica gel column to give the product as a yellow solid (80 mg, 79%). C8H9ClN5 (M+H) + LCMS calculated for m / z: 210.1; found: 210.1.

[0256] Intermediate 10: 6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine [ka] To a solution of 3-amino-6-chloro-pyridine-2-carbonitrile (1.54 g, 10.00 mmol) in 20 mL of DMF, sodium azide (1.3 g, 20.00 mmol) and ammonium hydrochloride (1.7 g, 20.00 mmol) were added in one portion. After stirring at 120 °C for 12 h, the solvent was removed under vacuum. The residue was dissolved in water and the pH was adjusted to 2 by adding 10% HCl. The precipitate was collected by filtration to give the product as a white solid (1.8 g, 92%). C6H6ClN6 (M+H) + LCMS calculated for m / z: 197.0; found: 197.0.

[0257] Intermediate 11: 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine [ka] Step 1: 2-(6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione [ka] To a solution of 6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine (Intermediate 10) (1.8 g, 9.16 mmol) in 10 mL of acetic acid, isobenzofuran-1,3-dione (3.4 g, 22.89 mmol) was added at room temperature. After stirring at 120 °C overnight, the solvent was removed under vacuum to give the desired product as a yellow solid (2.9 g, 97%). 14 H8ClN6O2(M+H) + LCMS calculated for m / z: 327.0; found: 327.0.

[0258] Step 2: 2-(6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione [ka] To a solution of 2-[6-chloro-2-(1H-tetrazol-5-yl)-3-pyridyl]isoindoline-1,3-dione (3.00 g, 9.18 mmol) in 10 mL of DMF was added iodomethane (0.86 mL, 1.96 g, 13.77 mmol) and dipotassium carbonate (3.81 g, 27.55 mmol). After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography eluting with DCM and ethyl acetate to give the desired product as a yellow solid (540 mg, 17%) and the other regioisomer as a yellow solid (570 mg, 18%). 15 H10 ClN6O2(M+H) + LCMS calculated for m / z: 341.1; found: 341.1.

[0259] Step 3: 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine To a solution of 2-(6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione (540 mg, 1.58 mmol), 10 mL of hydrazine monohydrate was added. After stirring at 45° C. for 2 hours, the resulting mixture was diluted with water. The precipitate was filtered and washed with water to give the product as a white solid (330 mg, 100%). C7H8CN6 (M+H) + LCMS calculated for m / z: 211.0; found: 211.0.

[0260] Intermediate 12: 1-(1-methylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] Step 1: 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (500 mg, 1.43 mmol) was dissolved in 30% TFA in DCM. After stirring at room temperature for 1 hour, the solvent was removed in vacuo to give the product (360 mg, 100%). 12 H 21 BN3O2(M+H) + LCMS calculated for m / z: 250.2; found: 250.2.

[0261] Step 2: 1-(1-methylazetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 1-(azetidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (50.00 mg, 0.20 mmol) in 1 mL of ACN and 0.5 mL of AcOH, formaldehyde (73.94 μL, 60.26 mg, 2.01 mmol) and sodium triacetoxyborohydride (212.69 mg, 1.00 mmol) were added. After stirring at room temperature for 30 minutes, the mixture was quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluting with DCM and ethyl acetate, to give the desired product as a white solid (43 mg, 81%). 13 H 23 BN3O2(M+H) + LCMS calculated for m / z: 264.2; found: 264.2.

[0262] Intermediates 13-14 Intermediates 13-14 in Table I-2 were prepared similarly as described for Intermediate 12. [Table 3]

[0263] Intermediate 15: N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxamide [ka] To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (100 mg, 0.36 mmol) in 3 mL of ACN was added dimethylcarbamic chloride (77 mg, 0.72 mmol) and triethylamine (0.15 mL, 1.1 mmol). After stirring at room temperature for 30 minutes, the mixture was quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluting with DCM and ethyl acetate, to give the desired product as a white solid (102 mg, 81%). 17 H 30 BN4O3(M+H) + LCMS calculated for m / z: 349.2; found: 349.2.

[0264] Intermediate 16: 3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propanenitrile [ka] To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (50 mg, 0.18 mmol) in 1 mL of ACN was added acrylonitrile (47 mg, 0.2 mmol). After stirring at room temperature for 30 minutes, the mixture was quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluting with DCM and ethyl acetate, to give the desired product as a white solid (26 mg, 44%). 17 H 28 BN4O2(M+H) + LCMS calculated for m / z: 331.2; found: 331.2. 【0265...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutical acceptable salt thereof, wherein 【Chemistry 2】 is a single bond or a double bond; X is N or C; Y is N or C; Ring A is phenyl, a 5-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L Ａ each independently represent a covalent bond or an optionally substituted divalent C １－６ is aliphatic; Each R Ａ is independently oxo, halogen, -CN, -OR Ａ１ , -SR Ａ１ , -N(R Ａ１ ), -C(O)R ２ , -C(O)OR Ａ１ , -C(O)N(R Ａ１ ), -C(O)NR Ａ１ (OR ２ ), -OC(O)R Ａ１ -OC(O)N(R Ａ１ ), -OC(O)OR Ａ１ , -OSO Ａ１ R ２ , -OSO Ａ１ N(R ２ ), -N(R Ａ１ )C(O)R ２ , -NRC(O)OR Ａ１ , -NR ２ C(O)N(R Ａ１ ), -N(R Ａ１ )SO Ａ１ R Ａ１ , -NRS(O)N(R Ａ１ ), -NRO Ａ１ R ２ , -NRS(O)R Ａ１ , -NRS(O)N(R ２ ), -S(O)R Ａ１ , -SOR Ａ１ , -S(O)N(R ２ ), -SON(R Ａ１ ), -SON(R ２ ), -SOR Ａ１ , -SOR Ａ１ , -SOR Ａ１ , -S(O)N(R Ａ１ ), -SOR Ａ１ , -S(O)N(R Ａ１ ), -SOR ２ , -S(O)R Ａ１ , -SOR ２ , -SOR Ａ１ , -S(O)N(R Ａ１ ), -SON(R ２ , -SON(R ２ ), -SON(R Ａ１ ), -SON(R ２ , -SON(R ３ ), -C(=NR Ａ１ )R ｍ , -C(=NR Ａ１ )N(R ｍ ), -NR Ａ１ ), -NR ２ ), -NR Ａ１ C (=NR ｍ ) R Ａ１ , -NR Ａ１ C (=NR ｍ ) N (R Ａ１ ) ２ , -NR Ａ１ S(O)(=NR ｍ ) R Ａ１ , -NR Ａ１ S(O)(=NR ｍ ) N (R Ａ１ ) ２ , -OS(O)(=NR ｍ ) R Ａ１ , -S(O)(=NR ｍ ) R Ａ１ , -S(O)(=NR ｍ ) N (R Ａ１ ) ２ , -P(O)(R Ａ１ ) ２ , C １－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R Ａ C １－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; Or two L Ａ -R Ａ are, together with the atoms to which they are attached, independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and sulfur. and forming a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms, or an 8-10 membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3-7 membered monocyclic carbocyclyl, 5-10 membered bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered monocyclic heterocyclyl, 5-10 membered bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl independently selects from 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; R １ is hydrogen or C １－６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Or, R １ and L Ａ -R Ａ and one of R, taken together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of said 3- to 7-membered monocyclic heterocyclyl and 5- to 14-membered bicyclic heterocyclyl independently has 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; Z is N or CR ２ and U is N or CR ４ and R ２ and R ４ are each independently hydrogen, halogen, -CN, -OR, -SR, or -N(R) ２ , -C(O)R, -C(O)N(R) ２ , -C(O)NR(OR), -OC(O)R, -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N (R) ２ , -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R) ２ , -N(R)SO ２ R, -NRS(O) ２ N (R) ２ , -NROR, -NRS(O)R, -NRS(O)N(R) ２ , -S(O)R, -SO ２ R, -S(O)N(R) ２ , -SO ２ N (R) ２ , -SO ３ R, -C(=NR ｍ ) R, -C(=NR ｍ ) N (R) ２ , -NRC (=NR ｍ )R, -NRC(=NR ｍ ) N (R) ２ , -NRS(O)(=NR ｍ )R, -NRS(O)(=NR ｍ ) N (R) ２ , -OS(O)(=NR ｍ )R, -S(O)(=NR ｍ )R, -S(O)(=NR ｍ ) N (R) ２ , -P(O)(R) ２ , or C １－６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ３ -F, -Cl, -CN, -OR, -SR, -N(R) ２ , -C(O)R, -C(O)N(R) ２ , -C(O)NR(OR), -OC(O)R, -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N (R) ２ , -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R) ２ , -N(R)SO ２ R, -NRS(O) ２ N (R) ２ , -NROR, -NRS(O)R, -NRS(O)N(R) ２ , -S(O)R, -SO ２ R, -S(O)N(R) ２ , -SO ２ N (R) ２ , -SO ３ R, -C(=NR ｍ ) R, -C(=NR ｍ ) N (R) ２ , -NRC (=NR ｍ )R, -NRC(=NR ｍ ) N (R) ２ , -NRS(O)(=NR ｍ )R, -NRS(O)(=NR ｍ ) N (R) ２ , -OS(O)(=NR ｍ )R, -S(O)(=NR ｍ )R, -S(O)(=NR ｍ ) N (R) ２ , -P(O)(R) ２ , or C １－６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ５ Is, -L ５ -R ５Ａ and L ５ is a covalent bond or an optionally substituted divalent C １－６ is aliphatic; Or, L ５ and L Ａ -R Ａ and one of R, together with the atom to which they are attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 16-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of said 3- to 16-membered monocyclic carbocyclyl, 5- to 16-membered bicyclic carbocyclyl, 3- to 16-membered monocyclic heterocyclyl, and 5- to 16-membered bicyclic heterocyclyl independently selects 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; R ５Ａ は、-OR ５Ａ１１ 、-SR ５Ａ１ 、-NHR ５Ａ１２ 、-N(R ５Ａ１２ ) ２ 、-C(O)R ５Ａ１ 、-C(O)N(R ５Ａ１ ) ２ 、-C(O)NR ５Ａ１ (OR ５Ａ１ )、-OC(O)R ５Ａ１ 、-OC(O)N(R ５Ａ１ ) ２ 、-OC(O)OR ５Ａ１ 、-OSO ２ R ５Ａ１ 、-OSO ２ N(R ５Ａ１ ) ２ 、-N(R ５Ａ１ )C(O)R ５Ａ１ 、-NR ５Ａ１ C(O)OR ５Ａ１ 、-NR ５Ａ１ C(O)N(R ５Ａ１ ) ２ 、-N(R ５Ａ１ )SO ２ R ５Ａ１ 、-NR ５Ａ１ S(O) ２ N(R ５Ａ１ ) ２ 、-NR ５Ａ１ OR ５Ａ１ 、-NR ５Ａ１ S(O)R ５Ａ１ 、-NR ５Ａ１ S(O)N(R ５Ａ１ ) ２ 、-S(O)R ５Ａ１ 、-SO ２ R ５Ａ１ 、-S(O)N(R ５Ａ１ ) ２ 、-SO ２ N(R ５Ａ１ ) ２ 、-SO ３ R ５Ａ１ 、-C(=NR ｍ )R ５Ａ１ 、-C(=NR ｍ )N(R ５Ａ１ ) ２ 、-NR ５Ａ１ C(=NR ｍ )R ５Ａ１ , -NR ５Ａ１ C (=NR ｍ ) N (R ５Ａ１ ) ２ , -NR ５Ａ１ S(O)(=NR ｍ ) R ５Ａ１ , -NR ５Ａ１ S(O)(=NR ｍ ) N (R ５Ａ１ ) ２ , -OS(O)(=NR ｍ ) R ５Ａ１ , -S(O)(=NR ｍ ) R ５Ａ１ , -S(O)(=NR ｍ ) N (R ５Ａ１ ) ２ , -P(O)(R ５Ａ１ ) ２ , methyl, C ２－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R ５Ａ C ２－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R ５ＡＧ optionally substituted with a substituent; or The R ５Ａ The methyl group may have one, two, or three R ５ＡＧ substituted with a substituent; R Ａ１ and R ５Ａ１ are each independently hydrogen, C １－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R Ａ１ Or R ５Ａ１ C １－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R Ｇ１ optionally substituted with substituents; Or, two R's Ａ１ when attached to the same nitrogen atom, they are taken together to form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Or, two R's ５Ａ１ when attached to the same nitrogen atom, they are taken together to form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ５Ａ１１ is methyl, C ２－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R ５Ａ１１ C ２－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R Ｇ１ optionally substituted with a substituent; or The R ５Ａ１１ The methyl group may have one, two, or three R Ｇ１ substituted with a substituent; Each R ５Ａ１２ is independently １－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R ５Ａ１２ C １－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R Ｇ１ optionally substituted with substituents; Or, two R's ５Ａ１２ when attached to the same nitrogen atom, they are taken together to form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ＡＧ , R ５ＡＧ , and R Ｇ１ are each independently halogen, -CN, -OR, -SR, or -N(R) ２ , -C(O)R, -C(O)OR, -C(O)N(R) ２ , -C(O)NR(OR), -OC(O)R, -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N (R) ２ , -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R) ２ , -N(R)SO ２ R, -NRS(O) ２ N (R) ２ , -NROR, -NRS(O)R, -NRS(O)N(R) ２ , -S(O)R, -SO ２ R, -S(O)N(R) ２ , -SO ２ N (R) ２ , -SO ３ R, -C(=NR ｍ ) R, -C(=NR ｍ ) N (R) ２ , -NRC (=NR ｍ )R, -NRC(=NR ｍ ) N (R) ２ , -NRS(O)(=NR ｍ )R, -NRS(O)(=NR ｍ ) N (R) ２ , -OS(O)(=NR ｍ )R, -S(O)(=NR ｍ )R, -S(O)(=NR ｍ ) N (R) ２ , -P(O)(R) ２ , or C １－６ optionally substituted groups selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C １－６ an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R, when attached to the same nitrogen atom, together form an optionally substituted ring selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R ｍ is independently -OH, -CN, or R; and The compound, wherein n is 0, 1, 2, 3, or 4. 【Request 2】 【Chemistry 3】 is a single bond or a double bond; X is N or C; Y is N or C; Ring A is phenyl, a 5-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L Ａ are independently a covalent bond or a divalent C １－６ aliphatic, wherein the divalent C １－６ The aliphatic group may be one, two, three, or four independently selected RNs. ＬＡ１ optionally substituted with substituents; Each R Ａ is independently oxo, halogen, -CN, -OR Ａ１ , -SR Ａ１ , -N(R Ａ１ ), -C(O)R ２ , -C(O)OR Ａ１ , -C(O)N(R Ａ１ ), -C(O)NR Ａ１ ), -C(O)NR ２ (OR Ａ１ ), -OC(O)R Ａ１ -OC(O)N(R Ａ１ ), -OC(O)OR Ａ１ ), -OSO ２ R Ａ１ , -OSO ２ N(R Ａ１ ), -N(R ２ )(O)R Ａ１ ), -N(R ２ )(O)R Ａ１ ), -NR Ａ１ C(O)R Ａ１ , -NR Ａ１ C(O)OR Ａ１ , -NR Ａ１ C(O)N(R ２ ), -N(R Ａ１ )(O)SO ２ R Ａ１ , -NR Ａ１ S(O)R ２ , -NR Ａ１ S(O)N(R ２ ), -NR Ａ１ OR Ａ１ , -NR Ａ１ S(O)R Ａ１ , -NR Ａ１ S(O)N(R Ａ１ ), -S(O)R ２ , -SO Ａ１ R ２ , -S(O)N(R Ａ１ ), -SO Ａ１ N(R ２ ), -SO ２ R Ａ１ ), -C(=NR ２ )(O)R ３ , -C(=NR Ａ１ )(O)N(R ｍ ), -NR Ａ１ ), -C(=NR ｍ )(O)N(R Ａ１ ), -NR ２ Ａ１ ​C (=NR ｍ ) R Ａ１ , -NR Ａ１ C (=NR ｍ ) N (R Ａ１ ) ２ , -NR Ａ１ S(O)(=NR ｍ ) R Ａ１ , -NR Ａ１ S(O)(=NR ｍ ) N (R Ａ１ ) ２ , -OS(O)(=NR ｍ ) R Ａ１ , -S(O)(=NR ｍ ) R Ａ１ , -S(O)(=NR ｍ ) N (R Ａ１ ) ２ , -P(O)(R Ａ１ ) ２ , C １－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R Ａ C １－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; Or two L Ａ -R Ａ are, together with the atoms to which they are attached, independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and sulfur. and forming a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms, or an 8-10 membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3-7 membered monocyclic carbocyclyl, 5-10 membered bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered monocyclic heterocyclyl, 5-10 membered bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl independently selects from 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; R １ is hydrogen or C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein １－６ Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each have one, two, three, or four independently selected R １Ａ optionally substituted with substituents; Or, R １ and L Ａ -R Ａ and one of R, taken together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of said 3- to 7-membered monocyclic heterocyclyl and 5- to 14-membered bicyclic heterocyclyl independently has 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; Z is N or CR ２ and U is N or CR ４ and R ２ and R ４ are each independently hydrogen, halogen, -CN, -OR, -SR, or -N(R) ２ , -C(O)R, -C(O)N(R) ２ , -C(O)NR(OR), -OC(O)R, -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N (R) ２ , -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R) ２ , -N(R)SO ２ R, -NRS(O) ２ N (R) ２ , -NROR, -NRS(O)R, -NRS(O)N(R) ２ , -S(O)R, -SO ２ R, -S(O)N(R) ２ , -SO ２ N (R) ２ , -SO ３ R, -C(=NR ｍ ) R, -C(=NR ｍ ) N (R) ２ , -NRC (=NR ｍ )R, -NRC(=NR ｍ ) N (R) ２ , -NRS(O)(=NR ｍ )R, -NRS(O)(=NR ｍ ) N (R) ２ , -OS(O)(=NR ｍ )R, -S(O)(=NR ｍ )R, -S(O)(=NR ｍ ) N (R) ２ , -P(O)(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein １－６ Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each have one, two, three, or four independently selected R ２Ａ optionally substituted with substituents; R ３ -F, -Cl, -CN, -OR, -SR, -N(R) ２ , -C(O)R, -C(O)N(R) ２ , -C(O)NR(OR), -OC(O)R, -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N (R) ２ , -N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R) ２ , -N(R)SO ２ R, -NRS(O) ２ N (R) ２ , -NROR, -NRS(O)R, -NRS(O)N(R) ２ , -S(O)R, -SO ２ R, -S(O)N(R) ２ , -SO ２ N (R) ２ , -SO ３ R, -C(=NR ｍ ) R, -C(=NR ｍ ) N (R) ２ , -NRC (=NR ｍ )R, -NRC(=NR ｍ ) N (R) ２ , -NRS(O)(=NR ｍ )R, -NRS(O)(=NR ｍ ) N (R) ２ , -OS(O)(=NR ｍ )R, -S(O)(=NR ｍ )R, -S(O)(=NR ｍ ) N (R) ２ , -P(O)(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein １－６ Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each have one, two, three, or four independently selected R ３Ａ optionally substituted with substituents; R ５ Is, -L ５ -R ５Ａ and L ５ is a covalent bond or a divalent C １－６ aliphatic, wherein the divalent C １－６ Aliphatic groups are selected from 1, 2, 3, or 4 independently selected R Ｌ５Ａ optionally substituted with substituents; Or, L ５ and L Ａ -R Ａ and one of R, together with the atom to which they are attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of the 3- to 16-membered monocyclic carbocyclyl, 5- to 16-membered bicyclic carbocyclyl, 3- to 16-membered monocyclic heterocyclyl, and 5- to 16-membered bicyclic heterocyclyl independently selects 1, 2, 3, 4, 5, or 6 R ＡＧ optionally substituted with substituents; R ５Ａ は、-OR ５Ａ１１ 、-SR ５Ａ１ 、-NHR ５Ａ１２ 、-N(R ５Ａ１２ ) ２ 、-C(O)R ５Ａ１ 、-C(O)N(R ５Ａ１ ) ２ 、-C(O)NR ５Ａ１ (OR ５Ａ１ )、-OC(O)R ５Ａ１ 、-OC(O)N(R ５Ａ１ ) ２ 、-OC(O)OR ５Ａ１ 、-OSO ２ R ５Ａ１ 、-OSO ２ N(R ５Ａ１ ) ２ 、-N(R ５Ａ１ )C(O)R ５Ａ１ 、-NR ５Ａ１ C(O)OR ５Ａ１ 、-NR ５Ａ１ C(O)N(R ５Ａ１ ) ２ 、-N(R ５Ａ１ )SO ２ R ５Ａ１ 、-NR ５Ａ１ S(O) ２ N(R ５Ａ１ ) ２ 、-NR ５Ａ１ OR ５Ａ１ 、-NR ５Ａ１ S(O)R ５Ａ１ 、-NR ５Ａ１ S(O)N(R ５Ａ１ ) ２ 、-S(O)R ５Ａ１ 、-SO ２ R ５Ａ１ 、-S(O)N(R ５Ａ１ ) ２ 、-SO ２ N(R ５Ａ１ ) ２ 、-SO ３ R ５Ａ１ 、-C(=NR ｍ )R ５Ａ１ 、-C(=NR ｍ )N(R ５Ａ１ ) ２ 、-NR ５Ａ１ C(=NR ｍ )R ５Ａ１ , -NR ５Ａ１ C (=NR ｍ ) N (R ５Ａ１ ) ２ , -NR ５Ａ１ S(O)(=NR ｍ ) R ５Ａ１ , -NR ５Ａ１ S(O)(=NR ｍ ) N (R ５Ａ１ ) ２ , -OS(O)(=NR ｍ ) R ５Ａ１ , -S(O)(=NR ｍ ) R ５Ａ１ , -S(O)(=NR ｍ ) N (R ５Ａ１ ) ２ , -P(O)(R ５Ａ１ ) ２ , methyl, C ２－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R ５Ａ C ２－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R ５ＡＧ optionally substituted with a substituent; or The R ５Ａ The methyl group may have one, two, or three R ５ＡＧ substituted with a substituent; R Ａ１ and R ５Ａ１ are each independently hydrogen, C １－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R Ａ１ Or R ５Ａ１ C １－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R Ｇ１ optionally substituted with substituents; Or, two R's Ａ１ when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R Ａ１１ optionally substituted with substituents; Or, two R's ５Ａ１ when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R Ａ１１ optionally substituted with substituents; R ５Ａ１１ is methyl, C ２－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R ５Ａ１１ C ２－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R Ｇ１ optionally substituted with a substituent; or The R ５Ａ１１ The methyl group may have one, two, or three R Ｇ１ substituted with a substituent; Each R ５Ａ１２ is independently １－６ aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Here, the R ５Ａ１２ C １－６ Each of aliphatic, 3- to 7-membered monocyclic carbocyclyl, 5- to 10-membered bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered monocyclic heterocyclyl, 5- to 10-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl independently has 1, 2, 3, 4, 5, or 6 R Ｇ１ optionally substituted with substituents; Or, two R's ５Ａ１２ when attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R ５Ｂ１２ optionally substituted with substituents; R ＡＧ 、R ５ＡＧ 、and R Ｇ１ are each independently halogen, -CN, -OR, -SR, -N(R) ２ 、-C(O)R, -C(O)OR, -C(O)N(R) ２ 、-C(O)NR(OR), -OC(O)R, -OC(O)N(R) ２ 、-OC(O)OR, -OSO ２ R, -OSO ２ N(R) ２ 、-N(R)C(O)R, -NRC(O)OR, -NRC(O)N(R) ２ 、-N(R)SO ２ R, -NRS(O) ２ N(R) ２ 、-NROR, -NRSO(R), -NRSON(R) ２ 、-SO(R), -SO ２ R, -SON(R) ２ 、-SO ２ N(R) ２ 、-SO ３ R, -C(=NR ｍ )R, -C(=NR ｍ )N(R) ２ 、-NRC(=NR ｍ )R, -NRC(=NR ｍ )N(R) ２ 、-NRSO(=NR ｍ )R, -NRSO(=NR ｍ )N(R) ２ 、-OSO(=NR ｍ )R, -SO(=NR ｍ )R, -SO(=NR ｍ )N(R) ２ 、-P(O)(R) ２ 、C １－６ aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein １－６ Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R ＡＧ１ optionally substituted with substituents; Each R is hydrogen, C １－６ and 8-10 membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said C is independently selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein １－６ Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8- to 10-membered bicyclic aryl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl each may be selected from 1, 2, 3, or 4 independently selected R Ｎ optionally substituted with a substituent; or When two R are attached to the same nitrogen atom, they together form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and the 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each have 1, 2, 3, or 4 independently selected R Ｎ optionally substituted with substituents; Each R ＬＡ１ 、R １Ａ 、R ２Ａ 、R ３Ａ 、R Ｌ５Ａ 、R Ａ１１ 、R ５Ｂ１２ 、R ＡＧ１ 、and R Ｎ are halogen, -(CH ２ ) ０－４ R°, -(CH ２ ) ０－４ OR°, -O(CH ２ ) ０－４ R ｏ 、-O-(CH ２ ) ０－４ C(O)OR°, -(CH ２ ) ０－４ CH(OR°) ２ 、-(CH ２ ) ０－４ SR°, -(CH ２ ) ０－４ Ph, -(CH ２ ) ０－４ O(CH ２ ) ０－１ Ph, -CH=CHPh, -(CH ２ ) ０－４ O(CH ２ ) ０－１ -pyridyl, -NO ２ 、-CN, -N ３ 、-(CH ２ ) ０－４ N(R°) ２ 、-(CH ２ ) ０－４ N(R°)C(O)R°, -N(R°)C(S)R°, -(CH ２ ) ０－４ N(R°)C(O)NR° ２ 、-N(R°)C(S)NR° ２ 、-(CH ２ ) 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°, -(CH ２ ) ０－４ C(O)R°, -C(S)R°, -(CH ２ ) ０－４ C(O)OR°, -(CH ２ ) ０－４ C(O)SR°、-(CH ２ ) ０－４ C(O)OSiR° ３ 、-(CH ２ ) ０－４ OC(O)R°、-OC(O)(CH ２ ) ０－４ SR°、-(CH ２ ) ０－４ SC(O)R°、-(CH ２ ) ０－４ C(O)NR° ２ 、-C(S)NR° ２ 、-C(S)SR°、-SC(S)SR°、-(CH ２ ) ０－４ OC(O)NR° ２ 、-C(O)N(OR°)R°、-C(O)C(O)R°、-C(O)CH ２ C(O)R°、-C(NOR°)R°、-(CH ２ ) ０－４ SSR°、-(CH ２ ) ０－４ S(O) ２ R°、-(CH ２ ) ０－４ S(O)(=NR ｏ )R°、-(CH ２ ) ０－４ S(O) ２ OR°、-(CH ２ ) ０－４ OS(O) ２ R°、-(CH ２ ) ０－４ -S(O) ２ NR° ２ 、-(CH ２ ) ０－４ S(O)(=NR ｏ )NR° ２ 、-(CH ２ ) ０－４ S(O)R°、-N(R°)S(O) ２ NR° ２ 、-N(R°)S(O) ２ R°、-N(R°)S(O)(=NR ｏ )R°、-N(OR°)R°、-C(NH)NR° ２ 、-P(O) ２ R°、-P(O)R° ２ , -OP(O)R° ２ , -OP(O)(OR°) ２ , -SiR ° ３ , -(C １－４ Linear or branched alkylene)O-N(R°) ２ , and -(C １－４ Linear or branched alkylene)C(O)O-N(R°) ２ are independently selected from; Each R° is independently hydrogen, C １－６ Aliphatic, -CH ２ Ph, -O(CH ２ ) ０－１ Ph, -CH ２ -(5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R ｍ is independently -OH, -CN, or R; and 2. The compound of claim 1, wherein n is 0, 1, 2, 3, or 4, or a pharma- ceutically acceptable salt thereof.

3. The compound has formula II: 【Chemistry 4】 3. The compound of claim 1 or 2, which is, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

4. The compound has the formula III: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 3, which is:

5. 4. The compound according to any one of claims 1 to 3, wherein X is N and Y is C, or a pharma- ceutically acceptable salt thereof.

6. 4. The compound according to any one of claims 1 to 3, wherein X is C and Y is C, or a pharma- ceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, wherein Ring A is a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a pharma- ceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, imidazolyl, triazolyl, and pyridyl.

9. 8. The compound of claim 7, wherein Ring A is a 5-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms, or a pharma- ceutically acceptable salt thereof.

10. 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, wherein Ring A is pyrazolyl.

11. L Ａ is a covalent bond or a divalent C １－２ 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

12. L Ａ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein: is a covalent bond.

13. Each R Ａ is independently １－６ Alkyl, C ２－６ Alkenyl, -OR Ａ１ , -N(R Ａ１ ) ２ , -C(O)R Ａ１ , -C(O)N(R Ａ１ ) ２ , 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R Ａ C １－６ Alkyl, C ２－６ Alkenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each independently selected from one or two R ＡＧ 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

14. Each R Ａ１ is independently １－６ alkyl, or 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R Ａ１ Each C １－６ 14. The compound of any one of claims 1 to 13, wherein the alkyl and 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl are optionally substituted with hydroxy or methoxy, or a pharma- ceutically acceptable salt thereof.

15. Each R Ａ are independently selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from 1, 2, 3, 4, 5, or 6 R ＡＧ 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

16. Each R Ａ are independently selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is independently selected from one or two independently selected R ＡＧ 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

17. R Ａ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein is phenyl.

18. R Ａ is 1, 2, 3, 4, 5, or 6 R ＡＧ C optionally substituted with a substituent １－６ 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

19. R Ａ is 1, 2, 3, 4, or 5 R ＡＧ C optionally substituted with a substituent １－２ 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

20. R Ａ is -CH=CH ２ 20. The compound of claim 19, wherein:

21. Each R Ａ is methyl, ethyl, n-propyl, isopropyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, dimethylaminocarbonyl, azetidinylcarbonyl, (hydroxyazetidinyl)carbonyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyra and wherein said methyl, ethyl, n-propyl, isopropyl, ethenyl, cyclopropyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, tetrahydrofuranyl, piperazinyl, and 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl are each independently selected from one, two, three, or four independently selected R ＡＧ 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

22. Each R Ａ is independently selected from methyl, ethyl, n-propyl, isopropyl, ethenyl, methoxy, methoxyethoxy, dimethylamino, cyclopropyl, cyclopentyl, phenyl, methylphenyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, tetrahydrofuranyl, and tetrahydropyranyl, or a pharma- ceutically acceptable salt thereof.

23. 【Chemical 6】 teeth, 【Chemistry 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 【Chemistry 7-4】 5. The compound according to any one of claims 1 to 4, wherein:

24. 【Chemical 8】 teeth, 【Chemistry 9】 5. The compound according to any one of claims 1 to 4, wherein:

25. R １ is an optionally substituted C １－６ 25. The compound according to any one of claims 1 to 24, which is an aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a pharma- ceutically acceptable salt thereof.

26. R １ 25. The compound of any one of claims 1 to 24, wherein is methyl, trideuteromethyl, ethyl, difluoroethyl, hydroxyethyl, cyclopropyl, or tetrahydrofuranyl, or a pharma- ceutically acceptable salt thereof.

27. R １ is methyl, or a pharma- ceutically acceptable salt thereof.

28. R １ and L Ａ -R Ａ and one of R, taken together with the atom to which they are attached, forms a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of said 3- to 7-membered monocyclic heterocyclyl and 5- to 10-membered bicyclic heterocyclyl independently has 1, 2, 3, 4, 5, or 6 R ＡＧ The compound according to any one of claims 1 to 10, which is optionally substituted with a substituent.

29. R １ and L Ａ -R Ａ and one of R 1 and R 2 together with the atom to which they are attached is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (one or two R ＡＧ 11. The compound according to any one of claims 1 to 10, wherein the compound forms a substituted or unsubstituted heterocyclic ring.

30. Z is CR ２ 30. The compound according to any one of claims 1 to 29, wherein:

31. 31. The compound of claim 30, or a pharma- ceutically acceptable salt thereof, wherein Z is CH.

32. R ３ is -F, -Cl, -CN, or an optionally substituted C １－６ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

33. R ３ is an optionally substituted C １－６ 33. The compound of claim 32, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

34. R ３ is methyl or trifluoromethyl, or a pharma- ceutically acceptable salt thereof.

35. U is CR ４ 35. The compound according to any one of claims 1 to 34, which is: or a pharma- ceutically acceptable salt thereof.

36. 36. The compound of claim 35, or a pharma- ceutically acceptable salt thereof, wherein U is CH.

37. L ５ is an optionally substituted divalent C １－６ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

38. L ５ is an optionally substituted divalent C １－３ 40. The compound of claim 37, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

39. L ５ is -CH ２ -, -CH(CH ３ ) -, -CH(CH ２ OH)-, or 【Chemistry 10】 40. The compound of claim 38, wherein:

40. R ５Ａ is -NHR ５Ａ１２ Or -OR ５Ａ１１ 40. The compound of any one of claims 1 to 39, wherein:

41. Each R ５Ａ１２ are independently 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, 8-10 membered bicyclic aryl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from 1, 2, 3, 4, 5, or 6 independently selected R Ｇ１ 41. The compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

42. Each R ５Ａ１２ is independently phenyl or a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from 1, 2, 3, 4, 5, or 6 independently selected R Ｇ１ 41. The compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

43. Each R ５Ａ１２ are independently phenyl or pyridinyl, each of which is selected from 1, 2, 3, 4, 5, or 6 independently selected R Ｇ１ 41. The compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

44. Each R ５Ａ１２ is independently 1, 2, 3, 4, or 5 independently selected R Ｇ１ 42. The compound of claim 41, which is phenyl optionally substituted with substituents, or a pharma- ceutically acceptable salt thereof.

45. R ５Ａ１２ A single instance of is selected from one or two independently selected R Ｇ１ 41. The compound of any one of claims 1 to 40, which is phenyl substituted with a substituent, or a pharma- ceutically acceptable salt thereof.

46. R ５Ａ１２ A single example of is pyridinyl, which is represented by one or two independently selected R Ｇ１ 41. The compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

47. Each R Ｇ１ is halogen, C １－６ alkyl, phenyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -C(O)OR, -C(O)N(R) ２ and -C(O)NR(OR), where each C １－６ Alkyl, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each independently selected from 1, 2, 3, or 4 R ＡＧ１ 47. The compound of any one of claims 1 to 46, or a pharma- ceutically acceptable salt thereof, optionally substituted by a substituent.

48. Each R is independently selected from hydrogen, C alkyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl and 5-6 membered monocyclic heteroaryl is selected from C １－６ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

49. 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt thereof, wherein each R is independently selected from hydrogen, methyl, methylpiperidinyl, and pyridinyl.

50. Each R ＡＧ１ is a halogen, -(CH ２ ) ０－４ R°, -(CH ２ ) ０－４ OR°, -(CH ２ ) ０－４ C(O)NR° ２ , -(CH ２ ) ０－４ C(O)OR°, -(CH ２ ) ０－４ C(O)R°, -O(CH ２ ) ０－４ R ｏ , CN, -(CH ２ ) ０－４ C(O)NR° ２ and —C(O)N(OR°)R°, where each R° is independently selected from hydrogen, C １－６ 50. The compound of any one of claims 1 to 49, which is alkyl, or a 3-6 membered saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a pharma- ceutically acceptable salt thereof.

51. Each R ＡＧ１ is independently selected from fluoro, methyl, ethyl, hydroxyethyl, -COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, methoxyaminocarbonyl, cyano, cyclopropyl, hydroxy, methoxy, dimethylamino, dimethylaminomethyl, and tetrahydropyranyl, or a pharma- ceutically acceptable salt thereof.

52. Each R Ｇ１ is methyl, chloro, pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl, isoindolinonyl, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-onyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, -C(O)OR, -C(O)N(R) ２ and -C(O)NR(OR), wherein said pyridinyl, pyridinonyl, phenyl, pyrazolyl, pyrimidinyl, piperazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 1,2,4-oxadiazol-5(4H)-onyl, tetrazolyl, triazolyl, oxadiazolyl, indazolyl, quinolinyl, piperidinyl, piperazinyl, morpholinyl, isoindolinyl, hexahydro- 3H-oxazolo[3,4-a]pyrazin-3-onyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl are each one or two R independently selected from fluoro, methyl, ethyl, hydroxyethyl, -COOH, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonyl, methoxyaminocarbonyl, cyano, cyclopropyl, hydroxy, methoxy, dimethylamino, dimethylaminomethyl, and tetrahydropyranyl. ＡＧ１ is optionally substituted by a substituent; and 47. The compound of any one of claims 1 to 46, or a pharma- ceutically acceptable salt thereof, wherein each R is independently selected from hydrogen, methyl, methylpiperidinyl, and pyridinyl.

53. Each R Ｇ１ is halogen, C １－６ 47. The compound of any one of claims 1 to 46, or a pharma- ceutically acceptable salt thereof, wherein: - is independently selected from alkyl, and -C(O)OR.

54. Each R Ｇ１ is independently selected from fluoro, chloro, methyl, and -C(O)OH, or a pharma- ceutically acceptable salt thereof.

55. R ５Ａ１２ A single instance of Ｇ１ 45. The compound of claim 44, or a pharma- ceutically acceptable salt thereof, which is phenyl substituted with a substituent.

56. R Ｇ１ is -C(O)OR, or a pharma- ceutically acceptable salt thereof.

57. R Ｇ１ is -C(O)OH, or a pharma- ceutically acceptable salt thereof.

58. 58. The compound of any one of claims 1 to 57, or a pharma- ceutically acceptable salt thereof, wherein n is 0 or 1.

59. The compound of formula I is a compound of formula IV: 【Chemistry 11】 or a pharma- ceutical acceptable salt thereof, wherein: Ring B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-10 membered saturated or partially unsaturated bicyclic carbocyclyl, a phenyl, an 8-10 membered bicyclic aryl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and The compound according to any one of claims 1 to 3, 5 to 40, and 44 to 58, wherein m is 0, 1, 2, 3, 4, 5, or 6.

60. L ５ is a divalent C １－３ aliphatic, which is selected from 1, 2, 3, or 4 independently selected R Ｌ５Ａ optionally substituted with substituents; Or, L ５ and L Ａ -R Ａ and one of R, together with the atom to which they are attached, forms a 3- to 16-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 16-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 16-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 16-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of said 3- to 16-membered monocyclic carbocyclyl, 5- to 16-membered bicyclic carbocyclyl, 3- to 16-membered monocyclic heterocyclyl, and 5- to 16-membered bicyclic heterocyclyl independently selects 1, 2, 3, 4, 5, or 6 R ＡＧ 60. The compound of claim 59, or a pharma- ceutically acceptable salt thereof, optionally substituted with substituents.

61. The compound has formula V: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3. The compound of any one of claims 1-3, 7-10, and 30-58,

62. The compound has formula VI: 【Chemistry 13】 3. The compound of claim 1 or 2, which is:

63. The compound has formula VII: 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof, wherein z is 0, 1, 2, or 3. The compound of claim 1 or 2,

64. The compound is 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-3-phenyl-4,5-dihydropyrazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; and 2-((1-(4,7-dimethyl-5-oxo-3-vinyl-4,5-dihydropyrazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; or a pharma- ceutically acceptable salt thereof.

65. The compound is 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 6-methyl-3-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)picolinic acid; 2-((1-(7-chloro-3-ethyl-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-3,4-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-4-ethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-chloro-3,4-diethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,2-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinazolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3,4,7-trimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 2-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpicolinic acid; 2-((1-(4-ethyl-3,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(4-ethyl-3,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 2-((1-(3,4-diethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,4-diethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-5-fluorobenzoic acid; 3-((1-(3,4-diethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpicolinic acid; 2-((1-(4,7-dimethyl-5-oxo-2-propyl-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-2-phenethyl-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-fluoropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4,7-dimethyl-5-oxo-2-(pyrimidin-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(4-7-dimethyl-5-oxo-2-(o-tolyl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)picolinic acid; 2-[1-(3-methoxy-5,8-dimethyl-6-oxo-benzo[c][1,8]naphthyridin-10-yl)ethylamino]benzoic acid; 2-[1-[3-(dimethylamino)-5,8-dimethyl-6-oxo-benzo[c][1,8]naphthyridin-10-yl]ethylamino]benzoic acid; 2-[1-[3-(2-methoxyethoxy)-5,8-dimethyl-6-oxo-benzo[c][1,8]naphthyridin-10-yl]ethylamino]benzoic acid; and 2-((1-(7-chloro-3,4-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)benzoic acid; or a pharma- ceutically acceptable salt thereof.

66. The compound is 2-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)benzoic acid; 6-methyl-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)picolinic acid; 2-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)benzoic acid; and 6-chloro-3-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)picolinic acid; or a pharma- ceutically acceptable salt thereof.

67. The compound is 2-ethyl-3,6-dimethyl-8-((6-methyl-[2,4'-bipyridin]-3-yl)amino)-8,9-dihydrobenzo[de]pyrazolo[4,5,1-ij][1,7]naphthyridin-4(3H)-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(pyrimidin-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-N,N-dimethylbenzamide; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)benzoic acid; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpyridin-2-yl)-2-fluoro-N-methylbenzamide; 3-ethyl-9-(1-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((2-(4-acetylpiperazin-1-yl)phenyl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)phenyl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(4-(2,2-difluoroethyl)-3-ethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-cyclopentyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-isopropyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(7-chloro-3-ethyl-4-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(7-chloro-3-(cyclopropylmethyl)-4-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-propyl-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-(2-methoxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-(cyclopropylmethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-ethyl-4-methyl-5-oxo-7-(trifluoromethyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 3-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((2-(1H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-(1-methylpiperidin-4-yl)picolinamide; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-(pyridin-4-yl)picolinamide; 6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methoxypicolinamide; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)-2-hydroxyethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; and 9-(1-((2-(4-acetylpiperazin-1-yl)-6-chloropyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; or a pharma- ceutically acceptable salt thereof.

68. The compound is 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 5-(5-chloro-2-((1-(4,7-dimethyl-3-(1-methylazetidin-3-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)phenyl)-N-methylpicolinamide; 9-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylazetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-cyclopropylazetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)azetidin-1-yl)acetonitrile; 3-(3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)azetidin-1-yl)propanenitrile; 3-(1-acetylazetidin-3-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)azetidine-1-carboxylate methyl; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)azetidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylazetidin-3-yl)-9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-((1-(3-(1-acetylazetidin-3-yl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-chloro-N-methyl-[2,3′-bipyridine]-6′-carboxamide; 3-(1-acetylazetidin-3-yl)-9-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(dimethylglycyl)azetidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-((S)-1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-((1-acetylpiperidin-4-yl)methyl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-((9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)methyl)-N,N-dimethylpiperidine-1-carboxamide; 4-((9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)methyl)-N-ethylpiperidine-1-carboxamide; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-3-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-hydroxyethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methylpyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrimidin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methylpyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methylpyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrimidin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-N-methylpicolinamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(azetidine-1-carbonyl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(3-hydroxyazetidine-1-carbonyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-N,N,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(4-cyano-2-fluorophenyl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(4-cyanophenyl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-morpholinopyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; Ethyl 4-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)piperidine-1-carboxylate; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-ethylpyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-(1-methylpyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d3)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-3-(1-isopropylpyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d3)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(3-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d ３ )-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidin-1-yl)acetonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-3-(1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-3-(1-isopropylpyrrolidin-3-yl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylpyrrolidin-3-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidine-1-carboxylate methyl; 3-(9-(1-((6-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)-N,N-dimethylpyrrolidine-1-carboxamide; 3-(3-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidin-1-yl)propanenitrile; 3-(3-(9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidin-1-yl)propanenitrile; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d ３ )-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(dimethylglycyl)pyrrolidin-3-yl)-7-methyl-4-(methyl-d ３ )-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-(1-(1-methyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 1-(3-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)pyrrolidine-1-carbonyl)cyclopropane-1-carbonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methylpiperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-ethylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(2-methyltetrazol-5-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1,3,4-oxadiazol-2-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 5-[6-chloro-3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 3-[6-chloro-3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one; 9-[1-[[6-chloro-2-(1,3-dimethylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(4-hydroxy-1-piperidyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(3-fluoro-4-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(3-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 5-[3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-6-methyl-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 9-[1-[[6-chloro-2-(1-methyl-2-oxo-4-pyridyl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-[(2R)-2-hydroxypropyl]-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-[(2S)-2-hydroxypropyl]-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyethyl)-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxetan-3-yl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-[4-[9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-3-yl]-1-piperidyl]propanenitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2,2-difluoroethyl)piperidin-4-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methylsulfonyl-4-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 4-[9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-3-yl]piperidine-1-carboxylate methyl; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-(1-cyclopropylsulfonyl-4-piperidyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)-N,N-dimethylpiperidine-1-carboxamide; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(quinolin-6-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyacetyl)-4-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 1-(4-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(1-methyl-1H-pyrazole-5-carbonyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(1-(dimethylglycyl)piperidin-4-yl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methyl-L-prolyl)piperidin-4-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4-methyl-3-(1-methylpiperidin-4-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7-carbonitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2-(1-methylpiperidin-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-2-(1-(2-hydroxyethyl)piperidin-4-yl)-7-methyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(4-(9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-2-yl)piperidin-1-yl)propanenitrile; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-2-(1-methylazetidin-3-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-2-(1-methylpiperidin-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-2-(1-isopropylpiperidin-4-yl)-4,7-dimethyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-2-(1-methylpiperidin-4-yl)-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 2-(1-acetylpiperidin-4-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; Ethyl 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-2-yl)piperidine-1-carboxylate; 4-(9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]isoquinolin-2-yl)-N,N-dimethylpiperidine-1-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-2-(1-(2,2-difluoroethyl)piperidin-4-yl)-4,7-dimethyl-2,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-[6-chloro-3-[1-[7-methyl-5-oxo-3-[(3S)-tetrahydrofuran-3-yl]-4-(trideuteriomethyl)pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(4-ethyl-7-methyl-5-oxo-3-((S)-tetrahydrofuran-3-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2'-methyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-((S)-tetrahydrofuran-3-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(4-ethyl-7-methyl-5-oxo-3-((S)-tetrahydrofuran-3-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methyl-[2,3'-bipyridine]-6'-carboxamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-cyclopropyl-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]amino]ethyl]-4-cyclopropyl-3-ethyl-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-ethyl-7-methyl-4-tetrahydrofuran-3-yl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-ethyl-4-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-(((3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)methyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(3-ethyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)amino)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)benzoic acid; 3-ethyl-4,7-dimethyl-9-(1-((6-methyl-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2'-methyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-ethyl-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(4-(2,2-difluoroethyl)-3-ethyl-7-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methyl-[2,3'-bipyridine]-6'-carboxamide; 9-[1-[[2-(1-acetyl-4-piperidyl)-6-chloro-3-pyridyl]amino]ethyl]-3-ethyl-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(3-(2-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(4-hydroxypiperidin-1-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(quinolin-6-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 3-(2-hydroxyethyl)-4,7-dimethyl-9-(1-((6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-hydroxyethyl)-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 5-[6-chloro-3-[1-[3-(2-hydroxyethyl)-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 9-[1-[[6-chloro-2-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-2-oxo-4-pyridyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(2-methoxy-4-pyridyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-4-piperidyl)-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[2-(1-acetyl-4-piperidyl)-6-chloro-3-pyridyl]amino]ethyl]-3-(2-hydroxyethyl)-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-(2,2-difluoroethyl)-3-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 5-[6-chloro-3-[1-[4-(2,2-difluoroethyl)-3-(2-hydroxyethyl)-7-methyl-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethylamino]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-ethyl-3-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[(6-chloro-2-morpholino-3-pyridyl)amino]ethyl]-4-ethyl-3-(2-hydroxyethyl)-7-methyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(2-morpholinoethyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-morpholinoethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-3'-fluoro[2,4'-bipyridin]-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 4-(6-chloro-3-((1-(4,7-dimethyl-3-(2-morpholinoethyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 4-(6-chloro-3-((1-(4,7-dimethyl-3-(2-(4-methylpiperazin-1-yl)ethyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4-(2,2-difluoroethyl)-3-(2-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethyl)-7-methyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-ethyl-7-methyl-3-(2-pyridyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-(1-((6-chloro-2-morpholinopyridin-3-yl)amino)ethyl)-4-ethyl-7-methyl-3-(pyridin-2-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 6-chloro-3-((1-(4-ethyl-7-methyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-N-methyl-[2,3′-bipyridine]-6′-carboxamide; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-(pyridin-2-yl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-2-yl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4-ethyl-7-methyl-3-(3-pyridyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(2-pyridylmethyl)pyrazolo[3,4-c]isoquinolin-5-one; 3-(6-chloro-3-((1-(4,7-dimethyl-5-oxo-3-(pyridin-2-ylmethyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-3-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyethyl)-3-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-3-(1-methyl-3-piperidyl)pyrazolo[3,4-c]isoquinolin-5-one; 9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-3-[1-(2-hydroxyethyl)-3-piperidyl]-4,7-dimethyl-pyrazolo[3,4-c]isoquinolin-5-one; 3-[9-[1-[[6-chloro-2-(1-methylpyrazol-4-yl)-3-pyridyl]amino]ethyl]-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-3-yl]piperidine-1-carboxylate methyl; 5-[6-chloro-3-[1-[4,7-dimethyl-3-(1-methyl-4-piperidyl)-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethoxy]-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 5-[3-[1-[3-(1-acetyl-4-piperidyl)-4,7-dimethyl-5-oxo-pyrazolo[3,4-c]isoquinolin-9-yl]ethoxy]-6-chloro-2-pyridyl]-N-methyl-pyridine-2-carboxamide; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-3-(hydroxymethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-3-((dimethylamino)methyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(4-hydroxypiperidin-1-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 1-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-N-methylpiperidine-4-carboxamide; 10-(1-((2-(4-acetylpiperazin-1-yl)-6-chloropyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 3-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2'-methyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 4-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)-2-fluoro-N-methylbenzamide; 6-chloro-N-methyl-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)-[2,3'-bipyridine]-6'-carboxamide; 10-(1-((6-chloro-6'-methoxy-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2'-methoxy-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2'-(dimethylamino)-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(quinolin-6-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 2-fluoro-N-methyl-4-(6-methyl-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)benzamide; 8-methyl-10-(1-((6-methyl-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-6-methylpyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((2',6-dimethyl-[2,4'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylpyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 7-(6-chloro-3-((1-(8-methyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)pyridin-2-yl)hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one; 10-(1-((6-chloro-2-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-6'-((dimethylamino)methyl)-[2,3'-bipyridin]-3-yl)amino)ethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 3-(3-((1-(3,8-dimethyl-6-oxo-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-10-yl)ethyl)amino)-6-methylpyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 8-methyl-10-(1-((6-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 3-(3-((1-(3-ethyl-4,7-dimethyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-9-yl)ethyl)amino)-6-methylpyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 10-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; 10-(1-((6-chloro-2-(2-methyl-1-oxoisoindolin-5-yl)pyridin-3-yl)amino)-2-hydroxyethyl)-8-methyl-4,5-dihydro-3H,6H-2,2a,5a-triazaaceanthrylene-6-one; and 9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-(4-methylpiperazin-1-yl)ethyl)-3-ethyl-4,7-dimethyl-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one; or a pharma- ceutically acceptable salt thereof.

69. 69. A pharmaceutical composition comprising a compound according to any one of claims 1 to 68, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

70. A method for inhibiting PI3Kα, comprising administering to a subject a compound according to any one of claims 1 to 68, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 69.

71. 71. The method of claim 70, or a pharma- ceutically acceptable salt thereof, wherein the method selectively inhibits PI3Kα over other PI3K isoforms.

72. 72. The method of claim 70 or 71, or a pharma- ceutically acceptable salt thereof, wherein the method selectively inhibits mutant PI3Kα over wide PI3Kα.

73. A method for treating a disease, disorder, or condition associated with PI3Kα, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 68, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to claim 69.

74. 74. The method of claim 73, wherein the disease, disorder, or condition is associated with mutant PI3Kα.

75. 70. A method of treating cancer, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 68, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 69.

76. 76. The method of claim 75, wherein the cancer is selected from breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer.

77. 77. The method of claim 76, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome), or PIK3CA-associated overgrowth syndrome (PROS).

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