PARP1 inhibitors

Abstract

The present disclosure provides compounds, compositions, and methods useful for inhibiting PARP1 and / or treating a disease, disorder, or condition associated with PARP1 and / or treating cancer.

Description

[Technical Field]

[0001] The present disclosure provides heterocyclic compounds and pharmaceutical compositions thereof that modulate the activity of PARP1 and are useful in the treatment of various PARP1-associated diseases (including cancer). [Background technology]

[0002] Poly (ADP-ribose) polymerase (PARP) is a superfamily of enzymes comprising at least 17 family members. Some of these PARP enzymes (including PARP1, PARP2, PARP5A, and PARP5B) catalyze the covalent attachment of NAD+ substrates to acceptor proteins, resulting in the linear or branched heteropolymer poly (ADP-ribose) (PAR), while other members attach mono (ADP-ribose) (MAR) to acceptor proteins. Accumulating evidence suggests that PARP enzymes have distinct functions. Among these identified PARPs, PARP1, PARP2, and PARP3 are DNA-dependent, and their enzymatic activity is strongly stimulated by endogenous and exogenous DNA damage (van Beek, L. et al. Int. J. Mol. Sci., 2021, 22, 5112). These first three PARP enzyme members are therefore important in regulating DNA damage repair through a mechanism called poly(ADP-ribosylation) (PARylation).

[0003] PARylation is a dynamic, short-lived post-translational modification that can occur within minutes. The polymers generated by PARylation can then be degraded by another enzyme called poly(ADP-ribose) glycohydrolase (PARG). These important enzymes protect cells from DNA damage-induced cellular dysfunction and cell death. Due to the large size and highly charged nature of PARs, PARylation dramatically alters the DNA damage response (DDR), cellular stress response, and regulation of RNA transcription / processing in various biological systems (Feng, X. et al. Int. Rev. Cell Mol. Biol., 2013, 304, 227; Kraus, WL, Mol. Cell, 2015, 58, 902; Cohen, MS, et al. Nat. Chem. Biol., 2018, 14, 236).

[0004] PARP1, a founding member of the PARP superfamily and responsible for over 90% of PARylation, has been extensively studied for its essential role in DNA damage response, particularly in the repair of DNA single-strand breaks (SSBs) (Durkacz, BW, et al. Nature, 1980, 283, 593). Basal levels of PARylation in quiescent cells are typically below detection. Upon exposure to genotoxic stress, PARP1 is rapidly activated by automodification (autoPARylation), thereby initiating the DNA damage response signaling pathway. This process involves a complex cascade of signaling events, beginning with the binding of PARP proteins to the damaged site, followed by PARylation, recruitment of repair factors, and ultimately dissociation from the damaged site (Bai, P., Mol. Cell, 2015, 58, 947). PARP2 is also involved in DNA damage repair. However, increasing evidence suggests that, independently of PARP1, PARP2 also plays an important role in the development and maintenance of hematopoietic cells and several other tissues.

[0005] Clinical data clearly demonstrate the efficacy of PARP inhibitors in treating various human cancers, particularly BRCA1 / 2-mutated homologous recombination-deficient (HRD) cancers. PARP inhibition impairs SSB repair by blocking PARylation. Meanwhile, PARP inhibitors also trap PARP proteins at DNA damage sites. PARP trapping blocks DNA replication, resulting in DNA double-strand breaks (DSBs) caused by replication fork collapse. Faithful repair of these breaks requires homologous recombination (HR). Without homologous recombination, these cells would die from accumulated DNA damage and genomic instability. PARP hyperactivation is frequently observed in cancer patients with HRD tumors. This correlation clearly indicates that these tumors are overly dependent on PARP-mediated DNA repair pathways (Helleday, T., Mol. Oncol., 2011, 5, 387). These mechanistic studies provide a rationale for targeting HRD cancers with PARP inhibitors.

[0006] Although PARP1 is the primary target for PARP inhibitor development, most, if not all, current PARP inhibitors also inhibit the enzymatic activity of other PARPs, particularly PARP2, a paralog of PARP1 (which shares 69% identity in the catalytic domain). In the presence of PARP1, PARP2 catalyzes only approximately 10% of intracellular PARylation (Ame, JC, et al. Bioessays, 2004, 26, 882; Ame, JC, et al. J. Biol. Chem., 1999, 274, 17860). Despite its functional overlap with PARP1, PARP2 also has unique functions in hematopoiesis, spermatogenesis, adipogenesis, and transcriptional regulation. Therefore, pharmacological inhibition of the PARP2 enzyme may have undesirable effects on the aforementioned tissues, resulting in adverse effects in clinical applications (Farres, J., et al. Blood, 2013, 122, 44; Chen, Q., et al. Nat. Commun., 2018, 9, 3233; Gui, B., et al. PNAS, 2019, 116, 14573). In summary, selective inhibition of PARP1 while preserving the essential functions of PARP2 and other PARP family members is expected to maximize the efficacy of PARP inhibitors in the treatment of human cancers while minimizing undesirable side effects. Summary of the Invention

[0007] The present disclosure provides compounds and / or compositions useful for inhibiting PARP 1. In some embodiments, the provided compounds and / or compositions are particularly useful for treating and / or preventing diseases, disorders, or conditions associated with PARP 1.

[0008] In some embodiments, the present disclosure provides certain compounds and / or compositions that are useful in medicine, particularly in the treatment of cancer.

[0009] In some embodiments, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein X, R 4 , R 5 , R 6 , R 7 , D 1 , D 2 , D 3 , ring B, ring C, R B , R C , n, and p are each as defined herein.

[0010] In some embodiments, provided compounds have the structure of any of Formulas II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d described herein.

[0011] 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.

[0012] The present disclosure further provides a method of inhibiting PARP1 activity, comprising contacting PARP1 with a compound described herein or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure further provides a method of treating a PARP1-associated disease or disorder 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.

[0014] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0015] 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

[0016] 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 th Further, 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.

[0017] 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.

[0018] Unless otherwise indicated, structures depicted herein are intended to include compounds which 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 18 In 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.

[0019] 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.

[0020] 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., C 1-4 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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 C6-C8 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.

[0027] 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.

[0028] 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.

[0029] 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" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include optionally substituted rings.

[0030] 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.

[0031] 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 6- 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).

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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).

[0038] 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.

[0039] 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.

[0040] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(CH2) 0-4 Ph(R O (which may be substituted with), -(CH2) 0-4 O(CH2) 0-1 Ph(R O -CH=CHPh(R O (which may be substituted with), -(CH2) 0-4 O(CH2) 0-1 -pyridyl (RO で may be substituted)、-NO2、-CN、-N3、-(CH2) 0-4 N(R O )2、-(CH2) 0-4 N(R O )C(O)R O ,-N(R O )C(S)R O ,-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、 -N(R O )N(R O )C(O)R O ,-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O ,-(CH2) 0-4 C(O)R O 、 -C(S)R O ,-(CH2) 0-4 C(O)OR O ,-(CH2) 0-4 C(O)SR O ,-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O ,-(CH2) 0-4 SC(O)R O ,-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O ,-SC(S)SR O ,-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)RO , -C(O)CHC(O)R O , -C(NOR O )R O , -(CH2) 0-4 SSR O , -(CH2) 0-4 S(O)2R O , -(CH2) 0-4 S(O)(=NR o )R O , -(CH2) 0-4 S(O)2OR O , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, or -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2, and each R O are optionally substituted as defined below and independently represent hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R O The occurrences of, taken 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.

[0041] R O (or two separate R O Suitable monovalent substituents on the ring formed by the occurrences of —(CH) 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) 0-2NR · 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 independently, 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. O Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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 -C(R 1 )=, -C(R 1 R 2 )-, or -N(R a )- and X is -C(R 1 )=, one of (i) to (iii) applies, (i)R 5 is absent, R 1 and R 4 together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Forming Ring A is a 5-membered partially unsaturated monocyclic carbocyclyl or a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; (ii)R 5 is absent, R 4 and L D1 -R 8 together with the carbon atoms to which they are attached form an optionally substituted ring selected from a 5- to 7-membered partially unsaturated carbocyclyl or a 5- to 7-membered partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (iii)R 5 is absent, D 1 is S or NR, and D 2 is absent, X is -C(R 1 R 2 )- or -N(R a )-, R 1 and R 2 are each independently hydrogen, halogen, —CN, —OR, —SR, —N(R), —NO, —C(O)R′, —C(O)OR, —C(O)N(R), —OC(O)R′, —OC(O)N(R), —OC(O)OR, —OSOR′, —OSOR(R), —N(R)C(O)R′, —N(R)SOR′, —S(O)R′, —SOR′, —SOR(R), —SOR′, —NHOR, —C(O)NR(OR), —NRC(O)OR, —NRC(O)N(R), —NRS(O)N(R), —NRS(O)R′, —NRS(O)N(R), —S(O)N(R), or C 1-6an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 and R 2 together with the carbon atoms to which they are attached form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 2 and R 4 together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Forming Ring A' is 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; R a is hydrogen or -L R3 -R 3 and L R3 is a covalent bond or an optionally substituted divalent C 1-6 is aliphatic, R 3 is hydrogen, or C 1-6an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; R 4 and R 5 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR', -OSOR(R), -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R), -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, -S(O)N(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 4 and R 5 together with the carbon atom *C to which they are attached, form *C=O, *C=S, *C=NR Lor forms an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 5 is absent, and R 4 and L D1 -R 8 taken together with the carbons to which they are attached form an optionally substituted ring selected from 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; R L is hydrogen, -CN, -OR L1 , or optionally substituted C 1-6 is alkyl, R L1 is hydrogen, C 1-6 Alkyl, or C 1-6 is haloalkyl, Each L is independently a covalent bond or an optionally substituted divalent C 1-6 is aliphatic, Each R A1 are independently halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m)R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -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, 6- 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, 6- to 10-membered saturated or partially unsaturated 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; R 6 and R 7は , each independently hydrogen, halogen, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 6 and R 7are taken together with the carbons to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; D 1 is CL D1 -R 8 , N, NR, or S; D 2 Is, absent, CL D2 -R 9 , or N and D 1 If is S or NR, D 2 is absent, D 3 is CR 10 or N, L D1 is a covalent bond or an optionally substituted divalent C 1-6 is aliphatic, L D2 is a covalent bond or an optionally substituted divalent C 1-6 is aliphatic, R 8 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NRm )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -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, 6- 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, 6- 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; R 9 and R 10 are each independently hydrogen, halogen, —CN, —OR, —SR, —N(R), —NO, —C(O)R′, —C(O)OR, —C(O)N(R), —OC(O)R′, —OC(O)N(R), —OC(O)OR, —OSOR′, —OSOR(R), —N(R)C(O)R′, —N(R)SOR′, —S(O)R′, —SOR′, —SOR(R), —SOR′, —NHOR, —C(O)NR(OR), —NRC(O)OR, —NRC(O)N(R), —NRS(O)N(R), —NRS(O)R′, —NRS(O)N(R), —S(O)N(R), or C 1-6 selected from optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 16-membered saturated or partially unsaturated polycyclic heterocyclylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is phenyl, an 8- to 10-membered bicyclic aryl, a 10- to 14-membered polycyclic aryl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R B independently, -L RB -R 11 and Each L RB are independently a covalent bond or an optionally substituted divalent C 1-6 is aliphatic, Each R C independently, -L RC -R 12 and Each L RC are independently a covalent bond or an optionally substituted divalent C 1-6 is aliphatic, R 11 and R 12 are each independently halogen, ═O, —CN, —OR, —SR, —N(R)2, —N +(R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -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, 6- 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, 6- 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; or R B and R C together with the intervening atoms to form ring D fused to one or both of ring B and ring C; Ring D is an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 8-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, a 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5- to 6-membered monocyclic heteroaryl having 1 to 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- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; or two R, when attached to the same nitrogen atom, combine to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R m are independently -OH, -CN, or R; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5.

[0048] In some embodiments, [ka] is a single or double bond, X is -C(R 1 )=, -C(R 1 R 2 )-, or -N(R a )- and X is -C(R 1 )=, one of (i) to (iii) applies, (i)R 5 is absent, R 1 and R 4together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Forming Ring A is a 5-membered partially unsaturated monocyclic carbocyclyl or a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; (ii)R 5 is absent, R 4 and L D1 -R 8 together with the carbon atoms to which they are attached form a 5- to 7-membered partially unsaturated carbocyclyl or a 5- to 7-membered partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 7-membered partially unsaturated carbocyclyl or the 5- to 7-membered partially unsaturated monocyclic heterocyclyl each optionally contains 1, 2, 3, or 4 independently selected R 4A substituted by a substituent, or (iii)R 5 is absent, D 1 is S or NR, and D 2 is absent, X is -C(R 1 R 2 )- or -N(R a )-, R 1 and R 2 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR', -OSOR(R), -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R), -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), -S(O)N(R), C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 1A substituted with a substituent, or R 1 and R 2 are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, the 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and the 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 1A substituted with a substituent, or R 2 and R 4 together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Forming Ring A' is 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; R a is hydrogen or -L R3 -R 3 and L R3 is a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, R 3 is hydrogen, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 3A substituted with a substituent, or R 4 and R 5are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR', -OSOR(R), -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R), -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), -S(O)N(R), C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 4A substituted with a substituent, or R 4 and R 5 together with the carbon atom *C to which they are attached, form *C=O, *C=S, *C=NR L, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, the 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and the 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally comprises 1, 2, 3, or 4 independently selected R 4A substituted with a substituent, or R 5 is absent, and R 4 and L D1 ~R 8 are taken together with the carbons to which they are attached to form a group selected from phenyl and a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is optionally joined to one, two, three, or four independently selected R 4A is substituted with a substituent, R L is hydrogen, -CN, -OR L1 , or C 1-6 alkyl, C 1-6 The alkyl optionally contains one, two, three, or four independently selected R N is substituted with a substituent, R L1 is hydrogen, C 1-6 Alkyl, or C 1-6 is haloalkyl, Each L is independently a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R A1 are independently halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R B1 is substituted with a substituent, R 6 and R 7 are each independently hydrogen, halogen, or C 1-6 forming an aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 8-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, and a 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 6A substituted with a substituent, or R 6 and R 7are taken together with the carbons to which they are attached to form a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, the 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and the 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 6A is substituted with a substituent, D 1 is CL D1 -R 8 , N, NR, or S; D 2 Is, absent, CL D2 -R 9 , or N and D 1 If is S or NR, D 2 is absent, D 3 is CR 10 or N, L D1 is a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, L D2 is a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, R 8 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N +(R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 8A is substituted with a substituent, R9 and R 10 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR', -OSOR(R), -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R), -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), -S(O)N(R), C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 9A is substituted with a substituent, Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 16-membered saturated or partially unsaturated polycyclic heterocyclylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is phenyl, an 8- to 10-membered bicyclic aryl, a 10- to 14-membered polycyclic aryl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R B independently, -L RB -R 11 and Each L RB are independently a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R C independently, -L RC -R 12 and Each L RC are independently a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, R 11 and R 12 are each independently halogen, ═O, —CN, —OR, —SR, —N(R)2, —N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m)N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 11A substituted with a substituent, or R B and R C together with the intervening atoms to form ring D fused to one or both of ring B and ring C; Ring D is selected from the group consisting of a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl, 6-8 membered saturated or partially unsaturated bicyclic heterocyclyl, phenyl, and 5-6 membered monocyclic heteroaryl, each optionally selected from 1, 2, 3, or 4 independently selected R D1 is substituted with a substituent, Each R is independently hydrogen, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R Nsubstituted with a substituent, or When two R are attached to the same nitrogen atom, they together form a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl optionally contains 1, 2, 3, or 4 independently selected R N is substituted with a substituent, Each R' is independently C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R N substituted with a substituent, or When two R' are attached to the same nitrogen atom, they together form a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl optionally contains 1, 2, 3, or 4 independently selected R N is substituted with a substituent, Each R 1A, R 3A , R 4A , R 6A , R 8A , R 9A , R 11A , R B1 , R D1 and R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NR O 2, -N(R O )N(R O )C(O)OR O , -(CH2) 0-4 C(O)R O , -C(S)R O、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O 、-N(ORO )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected, Each R O are 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 R O are taken together with their intervening atoms to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R m are independently -OH, -CN, or R; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5.

[0049] In some embodiments, the present disclosure provides a compound of formula II [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , D 1 , D 2 , D 3 , ring A, ring B, ring C, R A1 , R B , RC Each of L, m, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0050] In some embodiments, the present disclosure provides a compound of formula II-a [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , D 1 , D 2 , D 3 , ring A, ring C, R A1 , R B , R C Each of L, m, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0051] In some embodiments, the present disclosure provides a compound of formula II-ai [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , D 1 , ring A, ring C, R A1 , R B , R C Each of L, m, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0052] In some embodiments, the present disclosure provides a compound of formula III [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 5 , R 6 , R 7 , D 1, D 2 , D 3 , ring A', ring B, ring C, R A1 , R B , R C Each of L, m, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0053] In some embodiments, the present disclosure provides a compound of formula IV [ka] or a pharmaceutically acceptable salt thereof, wherein R a , R 6 , R 7 , D 1 , D 2 , D 3 , ring B, ring C, R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0054] In some embodiments, the present disclosure provides a compound of formula V [ka] or a pharmaceutically acceptable salt thereof, wherein R a , R 4 , R 5 , R 6 , R 7 , D 1 , D 2 , D 3 , ring B, ring C, R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0055] In some embodiments, the present disclosure provides a compound of formula VI [ka] or a pharmaceutically acceptable salt thereof, wherein X, R 4 , R 5 , R 6 , R 7 , D 1 , D 2 , D 3 , R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0056] In some embodiments, the present disclosure provides a compound of formula VI-a [ka] or a pharmaceutically acceptable salt thereof, wherein X, R 4 , R 5 , R 6 , R 7 , R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0057] In some embodiments, the present disclosure provides a compound of formula VI-b [ka] or a pharmaceutically acceptable salt thereof, wherein R a , R 6 , R 7 , D 1 , D 2 , D 3 , R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0058] In some embodiments, the present disclosure provides a compound of formula VII [ka] or a pharmaceutically acceptable salt thereof, wherein X, R 4 , R 5 , R 6 , R 7 , D 3 , ring B, ring C, R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0059] In some embodiments, the present disclosure provides a compound of formula VIII [ka] or a pharmaceutically acceptable salt thereof, wherein X, D 2 , D 3 , R 4A , R 6 , R 7 , ring B, ring C, R B , R C each of n and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein; X is -C(R 1 )=, then ring E is selected from 5-7 membered partially unsaturated carbocyclyl and 5-7 membered partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X is -C(R 1 R 2 )- or -N(R a )-, then Ring E is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; q is 0, 1, 2, 3, or 4.

[0060] In some embodiments, the compounds provided herein are compounds of formula VIII-a, VIII-b, VIII-c, or VIII-d [ka] or a pharmaceutically acceptable salt thereof, wherein: D 3 , R 3 , R 4A , R 6 , R 7 , ring B, ring C, R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0061] In some embodiments, the present disclosure provides a compound of formula IX [ka] or a pharmaceutically acceptable salt thereof, wherein X, D 2 , D 3 , R 4A , R 6 , R 7 , ring C, R C and p, both alone and in combination, are as defined above in Formula I and as described in classes and subclasses herein; X is -C(R 1 )=, then ring E is selected from 5-7 membered partially unsaturated carbocyclyl and 5-7 membered partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X is -C(R 1 R 2 )- or -N(R a )-, then Ring E is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; q is 0, 1, 2, 3, or 4.

[0062] In some embodiments of any of Formulas I, VIII, and IX, Ring E is a pyrimidine ring, a pyrimidinone ring, a pyridazine ring, or a pyridazinone ring.

[0063] In some embodiments of any of formulas I, VIII, and IX, ring E is a pyrimidine ring.

[0064] In some embodiments of any of Formulas I, VIII, and IX, q is 0, 1, or 2.

[0065] In some embodiments of any of Formulas I, VIII, and IX, q is 0.

[0066] In some embodiments of any of Formulas I, VIII, and IX, q is 1.

[0067] In some embodiments of any of Formulas I, VIII, and IX, q is 2.

[0068] In some embodiments, the compounds provided herein are compounds of formula IX-a, IX-b, IX-c, or IX-d [ka] or a pharmaceutically acceptable salt thereof, wherein: D 3 , R 3 , R 4A , R 6 , R 7 , ring C, R C Each of p, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein.

[0069] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, [ka] is a single bond or a double bond. [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0070] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X may be, where valence allows, —C(R 1 )=, -C(R 1 R 2 )-, or -N(R a In some embodiments, X is —C(R 1 )=. In some embodiments, X is -C(R 1 R 2 In some embodiments, X is —N(R a In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, X is —N(R a )-.

[0071] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 )=, then R 5 is absent.

[0072] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 )=, then R 1 and R 4 together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Form.

[0073] As noted above, in some embodiments of any of Formulas I, II, II-a, II-ai, VI, VI-a, and VII, ring A is a 5-membered partially unsaturated monocyclic carbocyclyl or a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0074] In some embodiments, ring A is a 5-membered partially unsaturated monocyclic carbocyclyl. 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 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms. In some embodiments, ring A is a 5-membered monocyclic heteroaryl having 1 nitrogen atom. In some embodiments, ring A is pyrrolyl or pyrazolyl. In some embodiments, ring A is pyrrolyl. In some embodiments, ring A is pyrazolyl.

[0075] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] is.

[0076] As noted above, in some embodiments of any of Formulas I, II, II-a, II-ai, VI, VI-a, and VII, R 4 and LD1 -R 8 are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from a 5- to 7-membered partially unsaturated carbocyclyl or a 5- to 7-membered partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 and L D1 -R 8 are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from a 6-membered partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 and L D1 -R 8 together with the carbon atoms to which they are attached form an optionally substituted ring selected from 6-membered partially unsaturated monocyclic heterocyclyl having one oxygen heteroatom.

[0077] In some embodiments, R 4 and L D1 -R 8 together with the carbon atoms to which they are attached form a 5- to 7-membered partially unsaturated carbocyclyl or a 5- to 7-membered partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 7-membered partially unsaturated carbocyclyl or the 5- to 7-membered partially unsaturated monocyclic heterocyclyl each optionally contains 1, 2, 3, or 4 independently selected R 4A is substituted by a substituent, Each R 4A are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O、-(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-CH=CHPh、-(CH2) 0-4 O(CH2) 0-1 -ピリジル、-NO2、-CN、-N3、-(CH2) 0-4 N(R O )2、-(CH2) 0-4 N(R O )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4OC(O)NR O 2. -C(O)N(OR O )R O , -C(O)C(O)R O , -C(O)CHC(O)R O , -C(NOR O )R O , -(CH2) 0-4 SSR O , -(CH2) 0-4 S(O)2R O , -(CH2) 0-4 S(O)(=NR o )R O , -(CH2) 0-4 S(O)2OR O , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0078] As noted above, in some embodiments of any of Formulas I, V, and VI, R 5is absent, and R 4 and L D1 -R 8 are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments, X is NR a and R 5 is absent, and R 4 and L D1 -R 8 are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0080] In some embodiments, R 5 is absent, and R 4 and L D1 -R 8 are taken together with the carbon atoms to which they are attached to form a ring selected from phenyl, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is optionally joined to one, two, three, or four independently selected R 4A It is substituted by a substituent.

[0081] In some embodiments, X is NR a and R 5 is absent, and R 4 and D1 -R 8 are taken together with the carbon atoms to which they are attached to form a ring selected from phenyl, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is optionally joined to one, two, three, or four independently selected R 4AIt is substituted by a substituent.

[0082] In some embodiments, R 4 and L D1 -R 8 together with the carbon atoms to which they are attached, [ka] and forming a ring selected from:

[0083] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 4 and L D1 -R 8 together with the carbon atoms to which they are attached, [ka] and forming a ring selected from:

[0084] In some embodiments, R 4 and L D1 -R 8 together with the carbon atoms to which they are attached, [ka] and forming a ring selected from:

[0085] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 R 2 )-, then R 1 and R 2are each independently hydrogen, halogen, —CN, —OR, —SR, —N(R), —NO, —C(O)R′, —C(O)OR, —C(O)N(R), —OC(O)R′, —OC(O)N(R), —OC(O)OR, —OSOR′, —OSOR(R), —N(R)C(O)R′, —N(R)SOR′, —S(O)R′, —SOR′, —SOR(R), —SOR′, —NHOR, —C(O)NR(OR), —NRC(O)OR, —NRC(O)N(R), —NRS(O)N(R), —NRS(O)R′, —NRS(O)N(R), —S(O)N(R), or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R 1 and R 2 are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl having 1 to 3 heteroatoms, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R 2 and R 4 together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Form.

[0086] In some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 R2 )-, or in some embodiments of Formula III, R 1 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSOR', -OSORN(R)2, -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R)2, -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)N(R)2, -S(O)N(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments, R 1 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R) SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, -S(O)N(R)2, C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4-S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0088] In some embodiments, R 1 is hydrogen.

[0089] In some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 R 2 )-, then R 2 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSOR', -OSORN(R)2, -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R)2, -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)N(R)2, -S(O)N(R)2, or C1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, R 2 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R) SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, -S(O)N(R)2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are independently halogen, -(CH2) 0-4 R O , -(CH2)0-4 OR O 、-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 CH(OR O )2、-(CH2) 0-4 SR O 、-(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-CH=CHPh、-(CH2) 0-4 O(CH2) 0-1 -ピリジル、-NO2、-CN、-N3、-(CH2) 0-4 N(R O )2、-(CH2) 0-4 N(R O )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SRO 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O 、-N(OR O )R O 、-C(NH)NR O 2、-P(O)2R O 、-P(O)R O 2、-OP(O)R O 2、-OP(O)(OR O )2、-SiR O 3、-(C 1-4Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0091] In some embodiments, R 1 and R 2 are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, the 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and the 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4N(R O )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2)0-4 S(O)2R O , -(CH2) 0-4 S(O)(=NR o )R O , -(CH2) 0-4 S(O)2OR O , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0092] In some embodiments, R 2 is hydrogen.

[0093] In some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 R 2 )-, then R 1 and R 2are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached form an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. 1 and R 2 together with the carbon atom to which they are attached form an optionally substituted cyclopropyl.

[0095] In some embodiments of any of Formulas I, VI, VI-a, and VII, X is —C(R 1 R 2 )-, then R 2 and R 4 together with the carbon atoms to which they are attached, are fused to the lactam ring shown [ka] Form.

[0096] As noted above, in some embodiments of any of Formulas I, III, VI, and VI-a, Ring A' is 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.

[0097] In some embodiments, ring A' is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A' is a 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A' is cyclopropyl.

[0098] In some embodiments, [ka] teeth [ka] is.

[0099] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X is —N(R a )-, or in some embodiments of Formula IV, V, or VI-b, R a is hydrogen or -L R3 -R 3 is.

[0100] In some embodiments, R a Ha-L R3 -R 3 In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R a Ha-L R3 -R 3 is.

[0101] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X is —N(R a )-, or in some embodiments of Formula IV, V, or VI-b, L R3 is a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic.

[0102] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, L R3 is a covalent bond.

[0103] In some embodiments, L R3 is a covalent bond. In some embodiments, L R3 is an optionally substituted divalent C 1-6 In some embodiments, L R3 is an optionally substituted divalent C 1-3 In some embodiments, L R3 is an optionally substituted divalent C 1-2 In some embodiments, L R3 is an optionally substituted divalent C2 aliphatic. In some embodiments, L R3 is an optionally substituted divalent C1 aliphatic.

[0104] In some embodiments, L R3 is a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2)0-4 C(O)OR O 、-(CH2) 0-4 CH(OR O )2、-(CH2) 0-4 SR O 、-(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-CH=CHPh、-(CH2) 0-4 O(CH2) 0-1 -ピリジル、-NO2、-CN、-N3、-(CH2) 0-4 N(R O )2、-(CH2) 0-4 N(R O )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4C(O)NR O 2. -C(S)NR O 2. -C(S)SR O , -SC(S)SR O , -(CH2) 0-4 OC(O)NR O 2. -C(O)N(OR O )R O , -C(O)C(O)R O , -C(O)CHC(O)R O , -C(NOR O )R O , -(CH2) 0-4 SSR O , -(CH2) 0-4 S(O)2R O , -(CH2) 0-4 S(O)(=NR o )R O , -(CH2) 0-4 S(O)2OR O , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(RO )2 is selected.

[0105] As noted above, in some embodiments of any of Formulas I, VI, VI-a, and VII, X is —N(R a )- or in some embodiments of Formula IV, V, or VI-b, R 3 is hydrogen, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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.

[0106] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 3 is hydrogen or optionally substituted C 1-6 It is aliphatic.

[0107] In some embodiments, R 3 is hydrogen or optionally substituted C 1-6 It is aliphatic.

[0108] In some embodiments, R 3 is hydrogen or C 1-6 Aliphatic, C 1-6 The aliphatic group optionally contains 1, 2, 3, or 4 independently selected R A It is substituted by a substituent.

[0109] In some embodiments, R 3 is hydrogen or C 1-6 Aliphatic, C 1-6 The aliphatic group optionally contains one, two, or three independently selected R 3A It is substituted by a substituent.

[0110] In some embodiments, R 3 is hydrogen or C 1-6 Aliphatic, C 1-6 The aliphatic group optionally includes one or two independently selected R 3A It is substituted by a substituent.

[0111] In some embodiments, R 3 is hydrogen. 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 1-2 In some embodiments, R 3 is an optionally substituted C2 aliphatic. In some embodiments, R 3 is optionally substituted ethyl. In some embodiments, R 3 is optionally substituted methyl.

[0112] In some embodiments, R 3 is C 1-6 aliphatic, which optionally contains 1, 2, 3, or 4 independently selected R 3A In some embodiments, R 3 is C 1-3 aliphatic, which optionally contains 1, 2, 3, or 4 independently selected R 3A In some embodiments, R 3 is C 1-2aliphatic, which optionally contains 1, 2, 3, or 4 independently selected R 3A In some embodiments, R 3 is an optionally substituted C2 aliphatic, which is optionally substituted with 1, 2, 3, or 4 independently selected R 3A In some embodiments, R 3 is ethyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 3A In some embodiments, R 3 is methyl, which is optionally substituted with one, two, or three independently selected R 3A It is substituted by a substituent.

[0113] In some embodiments, each R 3A is an independently selected halogen. In some embodiments, each R 3A is fluoro.

[0114] In some embodiments, R a is —CH2CH3 or —CH2CF2H. In some embodiments, R a teeth In some embodiments, R a is -CH3, -CH2CH3, or -CH2CF2H.

[0115] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R a is -CH2CH3.

[0116] In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S( O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, -S(O)N(R)2, or C 1-6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R 4 and R 5 together with the carbon atom *C to which they are attached, form *C=O, *C=S, *C=NR L or forms an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0117] In some embodiments, R 4 are hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -SO2R ', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, -S(O)N(R)2, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0118] In some embodiments, R 4 is hydrogen.

[0119] In some embodiments, R 5 are hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -SO2R ', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, -S(O)N(R)2, or C 1-6An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0120] In some embodiments, R 5 are independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSOR', -OSORN(R)2, -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R)2, -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)N(R)2, -S(O)N(R)2, C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 4A is substituted with a substituent, Each R 4A are independently halogen, -(CH2) 0-4 R O , -(CH2)0-4 OR O 、-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 CH(OR O )2、-(CH2) 0-4 SR O 、-(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-CH=CHPh、-(CH2) 0-4 O(CH2) 0-1 -ピリジル、-NO2、-CN、-N3、-(CH2) 0-4 N(R O )2、-(CH2) 0-4 N(R O )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SRO 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O 、-N(OR O )R O 、-C(NH)NR O 2、-P(O)2R O 、-P(O)R O 2、-OP(O)R O 2、-OP(O)(OR O )2、-SiR O 3、-(C 1-4Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0121] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each R 4A independently, C 1-6 Aliphatic and -OC 1-6 is selected from aliphatic.

[0122] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each R 4A is independently selected from methyl and methoxy.

[0123] In some embodiments, R 5 is hydrogen.

[0124] In some embodiments, R 4 and R 5 together with the carbon atom *C to which they are attached, form *C=O, *C=S, *C=NR L or forms an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0125] In some embodiments, R 4 and R 5together with the carbon atom *C to which they are attached to form *C=O or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl. 4 and R 5 together with the carbon atom *C to which they are attached to form *C=O. In some embodiments, R 4 and R 5 together with the carbon atom *C to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 4 and R 5 together with the carbon atom *C to which they are attached to form an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. 4 and R 5 taken together with the carbon atom *C to which they are attached form an optionally substituted cyclopropyl.

[0126] As noted above, in some embodiments of any of Formulas I, V, VI, VI-a, and VII, R 4 and L D1 -R 8 are taken together with the carbons to which they are attached to form an optionally substituted ring selected from 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur. 4 and L D1 -R 8 taken together with the carbons to which they are attached form an optionally substituted 6-membered monocyclic heteroaryl having 1-2 nitrogen heteroatoms. In some embodiments, R 4 and L D1 -R 8 together with the carbon to which they are attached form an optionally substituted pyrimidinyl.

[0127] In some embodiments, R L is hydrogen, -CN, -ORL1 , or optionally substituted C 1-6 It is alkyl.

[0128] In some embodiments, R L is hydrogen, -CN, -OR L1 , or C 1-6 alkyl, C 1-6 The alkyl optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NRO 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O)S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0129] In some embodiments, R L1 is hydrogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl.

[0130] In some embodiments, each L is independently a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic.

[0131] In some embodiments, each L is a covalent bond.

[0132] In some embodiments, each L is independently a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o、-O-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 CH(OR O )2、-(CH2) 0-4 SR O 、-(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-CH=CHPh、-(CH2) 0-4 O(CH2) 0-1 -ピリジル、-NO2、-CN、-N3、-(CH2) 0-4 N(R O )2、-(CH2) 0-4 N(R O )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2)0-4 C(O)NR O 2. -C(S)NR O 2. -C(S)SR O , -SC(S)SR O , -(CH2) 0-4 OC(O)NR O 2. -C(O)N(OR O )R O , -C(O)C(O)R O , -C(O)CHC(O)R O , -C(NOR O )R O , -(CH2) 0-4 SSR O , -(CH2) 0-4 S(O)2R O , -(CH2) 0-4 S(O)(=NR o )R O , -(CH2) 0-4 S(O)2OR O , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0133] In some embodiments, each R A1 are independently halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -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, 6- 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, 6- 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.

[0134] In some embodiments, each R A1are independently halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R B1 is substituted with a substituent, Each R B1 are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NR O2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NRO 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0135] In some embodiments, each R A1 are independently optionally substituted C 1-6 In some embodiments, each R A1 are independently optionally substituted C 1-3 In some embodiments, each R A1 are independently optionally substituted C 1-2 In some embodiments, each R A1 is independently optionally substituted methyl.

[0136] In some embodiments, R 6 and R 7 are each independently hydrogen, halogen, or C 1-6an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R 6 and R 7 are taken together with the carbons to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] In some embodiments, R 6 and R 7 are each independently hydrogen, halogen, or C 1-6 forming an aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 8-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, and a 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 6A substituted with a substituent, or R 6 and R 7are taken together with the carbons to which they are attached to form a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, the 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, the 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and the 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 6A is substituted with a substituent, Each R 6A are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4-S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0138] In some embodiments, R 6 is hydrogen, halogen, or C 1-6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0139] In some embodiments, R 6 is hydrogen, deuterium, or optionally substituted C 1-6 In some embodiments, R 6 is hydrogen or optionally substituted C1-6 In some embodiments, R 6 is hydrogen or deuterium. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is deuterium. In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is an optionally substituted C 1-3 In some embodiments, R 6 is an optionally substituted C 1-2 In some embodiments, R 6 is an optionally substituted C2 aliphatic. In some embodiments, R 6 is optionally substituted ethyl. In some embodiments, R 6 is -CH2CF3.

[0140] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 6 is hydrogen, deuterium, or optionally substituted C 1-6 It is aliphatic.

[0141] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 6 is hydrogen or deuterium.

[0142] In some embodiments, R 7 is hydrogen, halogen, or C 1-6An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In some embodiments, R 7 is hydrogen, deuterium, or optionally substituted C 1-6 In some embodiments, R 7 is hydrogen or optionally substituted C 1-6 In some embodiments, R 7 is hydrogen or deuterium. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is an optionally substituted C 1-6 In some embodiments, R 7 is an optionally substituted C 1-3 In some embodiments, R 7 is an optionally substituted C 1-2 In some embodiments, R 7 is an optionally substituted C2 aliphatic. In some embodiments, R 7 is optionally substituted ethyl. In some embodiments, R 7 is -CH2CF3.

[0144] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 7 is hydrogen, deuterium, or optionally substituted C 1-6 It is aliphatic.

[0145] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 7 is hydrogen or deuterium.

[0146] In some embodiments, R 6 and R 7 are taken together with the carbons to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0147] In some embodiments, R 6 and R 7 taken together with the carbons to which they are attached form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 6 and R 7 taken together with the carbons to which they are attached form an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 6 and R 7 taken together with the carbon to which they are attached form an optionally substituted cyclopropyl.

[0148] In some embodiments, R 6 and R 7 are each hydrogen.

[0149] In some embodiments, R 6 and R 7 are each deuterium.

[0150] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 6 and R 7 are each hydrogen.

[0151] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 6 and R 7 are each deuterium.

[0152] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 6 and R 7 are each hydrogen.

[0153] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 6 and R 7 are each deuterium.

[0154] As noted above, in some embodiments of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, and VI-b, D 1 is CL D1 -R 8 Or N.

[0155] In some embodiments, D 1 is CL D1 -R 8 In some embodiments, D 1 is N.

[0156] As noted above, in some embodiments of any of Formulas I, II, II-a, II-ai, VI, VI-b, and VII, D 1is S or NR, and D 2 In some embodiments, D 1 is S and D 2 is absent.

[0157] As noted above, in some embodiments of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, and VI-b, L D1 is a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic.

[0158] In some embodiments, L D1 is a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(RO )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2)0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0159] In some embodiments, L D1 is a covalent bond. In some embodiments, L D1 is an optionally substituted divalent C 1-6 In some embodiments, L D1 is an optionally substituted divalent C 1-3 In some embodiments, L D1 is an optionally substituted divalent C 1-2 In some embodiments, L D1 is an optionally substituted divalent C1 aliphatic. In some embodiments, L D1 is -CH2-.

[0160] In some embodiments, R8 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, or C 1-6 and optionally substituted groups selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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.

[0161] In some embodiments, R 8 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N +(R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 8A is substituted with a substituent, Each R8A is, independently, halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O , -N(R O )C(S)NR O , -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NR O , -N(R O )N(R O )C(O)OR[[ID=8​​​​​​​​​​​​​​​​​​3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O 、-N(OR O )R O 、-C(NH)NR O 2、-P(O)2R O 、-P(O)R O 2、-OP(O)R O2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0162] In some embodiments, R 8 is hydrogen, halogen, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. 8 is hydrogen or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. 8 is hydrogen. In some embodiments, R 8 is halogen. In some embodiments, R 8 is -F or -Cl. In some embodiments, R 8 is -F. In some embodiments, R 8 is —Cl. In some embodiments, R 8 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 8 is an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 8 is an optionally substituted cyclopropyl.

[0163] In some embodiments, CL D1 -R 8 is selected from —CH, —CF, —CCl, —CCHF, —COCH, —C-cyclopropyl, —C(hydroxymethyl), —C(cyanomethyl), and —C(methoxymethyl).

[0164] In some embodiments, D 2 Is, absent, CL D2 -R 9or N. In some embodiments, D 2 Is, absent, CL D2 -R 9 , or N and D 1 If is S or NR, D 2 is absent.

[0165] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, D 2 is CL D2 -R 9 In any embodiment of Formula I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, L D2 In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 9 In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, D 2 In any embodiment of Formula I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, D 2 is N.

[0166] In some embodiments, D 2 is CL D2 -R 9 In some embodiments, D 2 is N.

[0167] In some embodiments, L D2 is a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic.

[0168] In some embodiments, LD2 is a covalent bond or a divalent C 1-6 Aliphatic and divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NR O 2, -N(R O )N(R O )C(O)OR O , -(CH2) 0-4 C(O)R O , -C(S)RO 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O, -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0169] In some embodiments, L D2 is a covalent bond. In some embodiments, L D2 is an optionally substituted divalent C 1-6 In some embodiments, L D2 is an optionally substituted divalent C 1-3 In some embodiments, L D2 is an optionally substituted divalent C 1-2 In some embodiments, L D2 is an optionally substituted divalent C1 aliphatic. In some embodiments, L D2 is -CH2-.

[0170] In some embodiments, D 2 is CH.

[0171] In some embodiments, D 3 is CR 10 Or N.

[0172] In some embodiments, D 3 is CR 10 is.

[0173] In some embodiments, R 9 and R 10are each independently hydrogen, halogen, —CN, —OR, —SR, —N(R), —NO, —C(O)R′, —C(O)OR, —C(O)N(R), —OC(O)R′, —OC(O)N(R), —OC(O)OR, —OSOR′, —OSOR(R), —N(R)C(O)R′, —N(R)SOR′, —S(O)R′, —SOR′, —SOR(R), —SOR′, —NHOR, —C(O)NR(OR), —NRC(O)OR, —NRC(O)N(R), —NRS(O)N(R), —NRS(O)R′, —NRS(O)N(R), —S(O)N(R), or C 1-6 and optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0174] In some embodiments, R 9 and R 10 are each independently hydrogen, halogen, -CN, -OR, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR', -OSOR(R), -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R), -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), -S(O)N(R), C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-6 The aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contain 1, 2, 3, or 4 independently selected R 9A is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4-S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0175] In some embodiments, R 9 is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSOR', -OSORN(R)2, -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R)2, -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)N(R)2, -S(O)N(R)2, or C 1-6and optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0176] In some embodiments, R 9 is hydrogen or —CN. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -CN.

[0177] In some embodiments, R 10 is hydrogen, halogen, -CN, -OR, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR', -OSORN(R), -N(R)C(O)R', -N(R)SOR', -S(O)R', -SOR', -SOR(R), -SOR', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), and -S(O)N(R), or C 1-6 and optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0178] In some embodiments, R 10is hydrogen. In some embodiments, R 10 is halogen. In some embodiments, R 10 is -F.

[0179] In some embodiments, D 3 is —CH. In some embodiments, D 3 is -CF.

[0180] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, D 3 is CR 10 In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 10 is hydrogen or halogen. In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, R 10 In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, D 3 is CF.

[0181] In some embodiments, Ring B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-16 membered saturated or partially unsaturated polycyclic heterocyclylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0182] In some embodiments, ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 nitrogen atoms. In some embodiments, ring B is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 nitrogen atoms. In some embodiments, Ring B is piperazinylene (ie, a piperazinyl ring). In some embodiments, Ring B is piperidinylene (ie, piperidinyl).

[0183] In some embodiments, ring B is a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 7- to 9-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 7-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 7-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 nitrogen atoms. In some embodiments, ring B is a 7-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 2 nitrogen atoms. In some embodiments, ring B is an 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is an 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 nitrogen atoms. In some embodiments, ring B is an 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 3 nitrogen atoms. In some embodiments, ring B is an 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 2 nitrogen atoms. In some embodiments, ring B is a 9-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 9-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 nitrogen atoms. In some embodiments, ring B is a 9-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 2 nitrogen atoms.

[0184] In some embodiments, ring B is a 9-16-membered saturated or partially unsaturated polycyclic heterocyclylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 9-membered saturated or partially unsaturated polycyclic heterocyclylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 9-membered saturated or partially unsaturated polycyclic heterocyclylene having 1-5 nitrogen atoms. In some embodiments, ring B is a 9-membered saturated or partially unsaturated polycyclic heterocyclylene having 1-2 nitrogen atoms.

[0185] In some embodiments, [ka] teeth, [ka] is.

[0186] In some embodiments, [ka] teeth [ka] is.

[0187] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring B is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 nitrogen atoms.

[0189] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, n is 0 or 2. In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, n is 0.

[0190] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, [ka] teeth [ka] is.

[0191] In some embodiments, Ring C is phenyl, an 8- to 10-membered bicyclic aryl, a 10- to 14-membered polycyclic aryl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0192] In some embodiments, Ring C is phenyl.

[0193] In some embodiments, Ring C is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 6 membered monocyclic heteroaryl having 1-4 nitrogen atoms. In some embodiments, Ring C is a 6 membered monocyclic heteroaryl having 1-2 nitrogen atoms. In some embodiments, Ring C is pyridyl.

[0194] In some embodiments, ring C is a 6-10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring C is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 nitrogen atoms. In some embodiments, ring C is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-2 nitrogen atoms.

[0195] In some embodiments, [ka] teeth, [ka] is.

[0196] In some embodiments, ring C is [ka] is.

[0197] In some embodiments, ring C is [ka] is.

[0198] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, ring C is [ka] is.

[0199] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, ring C is [ka] is.

[0200] In some embodiments, ring C is [ka] is.

[0201] In some embodiments, ring C is [ka] is selected from.

[0202] In some embodiments, each R B independently, -L RB -R 11 is.

[0203] In some embodiments, each L RB are independently a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic.

[0204] In some embodiments, each L RB are independently a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6The aliphatic group optionally contains one, two, three, or four independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NR O 2, -N(R O )N(R O )C(O)OR O , -(CH2) 0-4 C(O)R O , -C(S)R O , -(CH2) 0-4 C(O)OR O , -(CH2)0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O 、-N(OR O )R O 、-C(NH)NR O2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0205] In some embodiments, L RB is a covalent bond. In some embodiments, L RB are independently an optionally substituted divalent C 1-6 In some embodiments, L RB are independently an optionally substituted divalent C 1-3 In some embodiments, L RB are independently an optionally substituted divalent C 1-2 In some embodiments, L RB is independently an optionally substituted divalent C1 aliphatic. In some embodiments, L RB is -CH2-.

[0206] In some embodiments, each R C independently, -L RC -R 12 is.

[0207] In some embodiments, each L RC are independently a covalent bond or an optionally substituted divalent C 1-6 It is aliphatic.

[0208] In some embodiments, each L RC are independently a covalent bond or a divalent C 1-6 aliphatic, where the divalent C 1-6 The aliphatic group optionally contains one, two, three, or four independently selected R Nis substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O )C(S)NR O 2, -(CH2) 0-4 N(R O )C(O)OR O , -N(R O )N(R O )C(O)R O , -N(R O )N(R O )C(O)NR O 2, -N(R O )N(R O )C(O)OR O , -(CH2) 0-4 C(O)R O , -C(S)R O , -(CH2) 0-4 C(O)OR O , -(CH2) 0-4 C(O)SR O , -(CH2) 0-4C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4 OS(O)2R O 、-(CH2) 0-4 -S(O)2NR O 2、-(CH2) 0-4 S(O)(=NR o )NR O 2、-(CH2) 0-4 S(O)R O 、-N(R O )S(O)2NR O 2、-N(R O )S(O)2R O 、-N(R O )S(O)(=NR o )R O 、-N(OR O )R O 、-C(NH)NR O 2、-P(O)2R O 、-P(O)R O 2、-OP(O)RO 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0209] In some embodiments, L RC is a covalent bond.

[0210] In some embodiments, R 11 and R 12 are each independently halogen, ═O, —CN, —OR, —SR, —N(R)2, —N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, or C 1-6an optionally substituted group selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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 R B and R C together with their intervening atoms to form ring D fused to one or both of ring B and ring C.

[0211] In some embodiments, R 11 and R 12 are each independently halogen, ═O, —CN, —OR, —SR, —N(R)2, —N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -P(O)(R)2, C 1-6selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6 Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 11A is substituted with a substituent, Each R 11A are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(RO )C(O)R O 、-N(R O )C(S)R O 、-(CH2) 0-4 N(R O )C(O)NR O 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2)0-4 S(O)2R O , -(CH2) 0-4 S(O)(=NR o )R O , -(CH2) 0-4 S(O)2OR O , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0212] In some embodiments, each R 11 are independently halogen, ═O, -CN, -OR, -SR, -N(R)2, -N +(R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -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, 6- 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, 6- 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.

[0213] In some embodiments, R 11 is halogen. In some embodiments, R 11 is -F. In some embodiments, R 11 is -OR. In some embodiments, R 11 is —OH. In some embodiments, R 11 is an optionally substituted C1-6 It is aliphatic.

[0214] In some embodiments, each R 12 are independently halogen, ═O, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O )R', -N(R)SO2R', -S(O)R', -SO2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )R', -C(=NR m )N(R)2, -NRC(=NR m )N(R)2, -NRC(=NR m )R', -NRS(O)N(R)2, -NRS(O)R', -NRS(O)(=NR m )R', -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=NR m )R', -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, 6- 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, 6- 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.

[0215] In some embodiments, R 12is —C(O)N(R). In some embodiments, R 12 is —C(O)N(Me)2. In some embodiments, R 12 is =O.

[0216] In some embodiments, R 12 is an optionally substituted C 1-6 In some embodiments, R 12 is an optionally substituted C 1-3 In some embodiments, R 12 is an optionally substituted C 1-2 In some embodiments, R 12 is optionally substituted methyl. In some embodiments, R 12 is methyl substituted with 1 to 3 halogen atoms. 12 is methyl substituted with 1 to 3 fluorine atoms. 12 is methyl. In some embodiments, R 12 is -CF3.

[0217] In some embodiments, R 12 is halogen. In some embodiments, R 12 is -F.

[0218] In some embodiments, each R 12 are independently -C(O)NHCH3, -C(O)NHCD3, C(O)NHCH2CH2, methyl, trifluoromethyl, fluoro, and trideuteromethyl ( -CD3).

[0219] In some embodiments, each R C are independently -C(O)NHCH3, -C(O)NHCD3, C(O)NHCH2CH2, methyl, trifluoromethyl, fluoro, and trideuteromethyl ( -CD3).

[0220] In some embodiments, ring C is one R selected from -C(O)NHCH3, -C(O)NHCD3, and C(O)NHCH2CH2; C Substituted by substituents, optionally including methyl, trifluoromethyl, fluoro, and trideuteromethyl ( -CD3) C It is substituted by a substituent.

[0221] In some embodiments, ring C is one R selected from -C(O)NHCH3, -C(O)NHCD3, and C(O)NHCH2CH2; C It is substituted by a substituent.

[0222] In some embodiments, ring C is one R selected from -C(O)NHCH3, -C(O)NHCD3, and C(O)NHCH2CH2; C a substituent, and a second R selected from methyl, trifluoromethyl, fluoro, and trideuteromethyl (-CD3). C It is substituted by a substituent.

[0223] In some embodiments, ring C contains one or two R selected from methyl and fluoro. Ca substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0224] In some embodiments, ring C has one R that is methyl. C a substituent and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0225] In some embodiments, ring C contains one R that is fluoro. Ca substituent and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0226] In some embodiments, ring C contains two R C a substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0227] In some embodiments, Ring C is phenyl or pyridinyl, each of which is selected from methyl and fluoro. Ca substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0228] In some embodiments, Ring C is phenyl or pyridinyl, each of which has one R that is methyl. C a substituent and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0229] In some embodiments, ring C is phenyl or pyridinyl, each of which contains one R that is fluoro. Ca substituent and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0230] In some embodiments, ring C is phenyl, which is substituted with two R C a substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0231] In some embodiments, [ka] teeth, [ka] is selected from.

[0232] In some embodiments of the preceding embodiment, Each R C is independently selected from methyl and fluoro; Each R is independently selected from methyl, cyclopropyl, methoxy, cyclopropylmethoxy, cyanocyclopropyl, cyanomethylcyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, cyclobutyl, cyanocyclobutyl, hydroxycyclobutyl, difluorocyclobutyl, cyanocyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, 3-oxabicyclo[3.1.0]hexanyl, methylpyrrolidinyl, and methylpiperidinyl.

[0233] In some embodiments, [ka] teeth, [ka] [ka] is selected from.

[0234] In some embodiments, [ka] teeth, [ka] [ka] is selected from.

[0235] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0236] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C is a 6-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms.

[0237] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C is phenyl.

[0238] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, ring C is [ka] is.

[0239] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, p is 1, 2, or 3. In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, p is 2. In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, p is 3. In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, [ka] teeth, [ka] is selected from.

[0240] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each L RC is a covalent bond.

[0241] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each R 12 are independently halogen, C 1-6 aliphatic, -C(O)N(R)2, and -C(O)NR(OR).

[0242] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each R 12is independently selected from fluoro, methyl, —C(O)NHR, and —C(O)NH(OR).

[0243] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each R is independently hydrogen, C 1-6 aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0244] Each R C is independently selected from methyl and fluoro; Each R is independently hydrogen, C 1-6 aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0245] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, each R is independently selected from methyl, cyclopropyl, methoxy, cyclopropylmethoxy, cyanocyclopropyl, cyanomethylcyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, cyclobutyl, cyanocyclobutyl, hydroxycyclobutyl, difluorocyclobutyl, cyanocyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, 3-oxabicyclo[3.1.0]hexanyl, methylpyrrolidinyl, and methylpiperidinyl.

[0246] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C contains one or two R selected from methyl and fluoro. C a substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0247] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C contains one R that is methyl. C a substituent and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0248] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C contains one R that is fluoro. C a substituent, and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl(hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0249] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, ring C contains two R C a substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. CIt is substituted by a substituent.

[0250] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C is phenyl or pyridinyl, each of which contains one or two R selected from methyl and fluoro. C a substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0251] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C is phenyl or pyridinyl, each of which contains one R that is methyl. Ca substituent and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0252] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, Ring C is phenyl or pyridinyl, which contains one R that is fluoro. C a substituent, and a second R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl(hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl C It is substituted by a substituent.

[0253] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, ring C is phenyl, which is substituted with two R C a substituent, and a third R selected from methylcarbamyl, cyclopropylcarbamyl, methoxycarbamyl, (cyclopropylmethoxy)carbamyl, (cyanocyclopropyl)carbamyl, (cyanomethylcyclopropyl)carbamyl, (hydroxymethylcyclopropyl)carbamyl, (methoxymethylcyclopropyl)carbamyl, cyclobutylcarbamyl, (cyanocyclobutyl)carbamyl, (hydroxycyclobutyl)carbamyl, (difluorocyclobutyl)carbamyl, (cyanocyclohexyl)carbamyl, tetrahydropyranylcarbamyl, tetrahydrofuranylcarbamyl, 3-oxabicyclo[3.1.0]hexanylcarbamyl, (methylpyrrolidinyl)carbamyl, and (methylpiperidinyl)carbamyl. C It is substituted by a substituent.

[0254] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, [ka] teeth, [ka] is selected from.

[0255] In some embodiments of the preceding embodiment, Each R C is independently selected from methyl and fluoro; Each R is independently selected from methyl, cyclopropyl, methoxy, cyclopropylmethoxy, cyanocyclopropyl, cyanomethylcyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, cyclobutyl, cyanocyclobutyl, hydroxycyclobutyl, difluorocyclobutyl, cyanocyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, 3-oxabicyclo[3.1.0]hexanyl, methylpyrrolidinyl, and methylpiperidinyl.

[0256] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, [ka] teeth, [ka] [ka] is selected from.

[0257] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, [ka] teeth, [ka] [ka] is selected from.

[0258] In some embodiments, ring C is [ka] is selected from R C is selected from methyl, trifluoromethyl, fluoro, and trideuteromethyl (-CD3).

[0259] In some embodiments, R B and R C together with their intervening atoms to form ring D fused to one or both of ring B and ring C.

[0260] In some embodiments, Ring D is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-8 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0261] In some embodiments, Ring D is selected from the group consisting of 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-8 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and nitrogen, oxygen, and sulfur. and sulfur, wherein the 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, the 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, the 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl, the 6-8 membered saturated or partially unsaturated bicyclic heterocyclyl, phenyl, and the 5-6 membered monocyclic heteroaryl each optionally contain 1, 2, 3, or 4 independently selected R D1 is substituted with a substituent, Each R D1 are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NRO 2、-N(R O )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2ORO , -(CH2) 0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0262] In some embodiments, Ring D is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring D is an optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring D is an optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl.

[0263] In some embodiments, Ring D is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0264] In some embodiments, Ring D is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is an optionally substituted 5 membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0265] In some embodiments, each R is independently hydrogen or C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 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 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0266] In some embodiments, each R is independently hydrogen, C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R N substituted with a substituent, or When two R are attached to the same nitrogen atom, they together form a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl optionally contains 1, 2, 3, or 4 independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(R O)C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2) 0-4OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0267] In some embodiments, each R is independently hydrogen or optionally substituted C 1-6 In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is an optionally substituted C 1-3 In some embodiments, R is an optionally substituted C 1-2 In some embodiments, R is an optionally substituted C1 aliphatic. In some embodiments, R is methyl.

[0268] In some embodiments, each R' is independently C 1-6aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 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 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0269] In some embodiments, each R' is independently C 1-6 selected from aliphatic, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 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, 6-10 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; 1-6Aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R N substituted with a substituent, or When two R' are attached to the same nitrogen atom, they together form a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl optionally contains 1, 2, 3, or 4 independently selected R N is substituted with a substituent, Each R N are independently halogen, -(CH2) 0-4 R O , -(CH2) 0-4 OR O , -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR O , -(CH2) 0-4 CH(OR O )2, -(CH2) 0-4 SR O , -(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 O )2, -(CH2) 0-4 N(R O )C(O)R O , -N(R O )C(S)R O , -(CH2) 0-4 N(R O )C(O)NR O 2, -N(RO )C(S)NR O 2、-(CH2) 0-4 N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O 2、-N(R O )N(R O )C(O)OR O 、-(CH2) 0-4 C(O)R O 、-C(S)R O 、-(CH2) 0-4 C(O)OR O 、-(CH2) 0-4 C(O)SR O 、-(CH2) 0-4 C(O)OSiR O 3、-(CH2) 0-4 OC(O)R O 、-OC(O)(CH2) 0-4 SR O 、-(CH2) 0-4 SC(O)R O 、-(CH2) 0-4 C(O)NR O 2、-C(S)NR O 2、-C(S)SR O 、-SC(S)SR O 、-(CH2) 0-4 OC(O)NR O 2、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH2C(O)R O 、-C(NOR O )R O 、-(CH2) 0-4 SSR O 、-(CH2) 0-4 S(O)2R O 、-(CH2) 0-4 S(O)(=NR o )R O 、-(CH2) 0-4 S(O)2OR O 、-(CH2)0-4 OS(O)2R O , -(CH2) 0-4 -S(O)2NR O 2, -(CH2) 0-4 S(O)(=NR o )NR O 2, -(CH2) 0-4 S(O)R O , -N(R O )S(O)NR O 2, -N(R O )S(O)2R O , -N(R O )S(O)(=NR o )R O , -N(OR O )R O , -C(NH)NR O 2. -P(O)2R O , -P(O)R O 2. -OP(O)R O 2. -OP(O)(OR O )2, -SiR O 3, -(C 1-4 Linear or branched alkylene)ON(R O )2, and -(C 1-4 Linear or branched alkylene)C(O)ON(R O )2 is selected.

[0270] In some embodiments, each R m are independently —OH, —CN, or R.

[0271] In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0;

[0272] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0273] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0274] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, X is -N(R a )- and R a Ha-L R3 -R 3 and L R3 is a covalent bond, R 3 is hydrogen or optionally substituted C 1-6 is aliphatic, Ring E is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4A independently, C 1-6 Aliphatic and -OC 1-6 selected from aliphatic R 6 is hydrogen, deuterium, or optionally substituted C 1-6 is aliphatic, R 7 is hydrogen, deuterium, or optionally substituted C 1-6 is aliphatic, D 2 is CH, D 3 is CR 10 and R 10 is hydrogen or halogen, Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L RC is a covalent bond, Each R 12 are independently halogen, C 1-6 selected from aliphatic, —C(O)N(R)2, and —C(O)NR(OR); Each R is independently hydrogen, C 1-6 selected from aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is 0 or 2, p is 1, 2, or 3; q is 0, 1, or 2.

[0275] In some embodiments of any of Formulas I, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, X is -N(R a )- and R a Ha-L R3 -R 3 and L R3 is a covalent bond, R 3 is hydrogen or optionally substituted C 1-6 is aliphatic, Ring E is a pyrimidine ring, a pyrimidinone ring, a pyridazine ring, or a pyridazinone ring; Each R 4A independently, C 1-6 Aliphatic and -OC 1-6 selected from aliphatic R 6 is hydrogen, deuterium, or optionally substituted C 1-6 is aliphatic, R7 is hydrogen, deuterium, or optionally substituted C 1-6 is aliphatic, D 2 is CH, D 3 is CR 10 and R 10 is hydrogen or halogen, Ring B is [ka] and Ring C is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L RC is a covalent bond, Each R 12 are independently halogen, C 1-6 selected from aliphatic, —C(O)N(R)2, and —C(O)NR(OR); Each R is independently hydrogen, C 1-6 selected from aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is 0, p is 1, 2, or 3; q is 0, 1, or 2.

[0276] In some embodiments, the disclosure provides a compound selected from Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the compounds provided herein are selected from the following: 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; N-methyl-5-(4-((2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-5-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-7'-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; N-methyl-5-(4-((3-methyl-4-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-(2,2-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((6-ethyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-2-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((4-ethyl-5-oxo-2,3,5,6-tetrahydropyrano[4,3,2-de]quinolin-8-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide; N,6-dimethyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; N-methyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(trifluoromethyl)picolinamide; 6-Fluoro-N-methyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 6-fluoro-5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide; N,6-dimethyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide; 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide; 5-(4-((3-ethyl-6-fluoro-1-methyl-4-oxo-1,3,4,5-tetrahydropyrazolo[3,4,5-de]quinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-bis(methyl-d3)picolinamide; 5-(4-((5-(difluoromethyl)-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((8-fluoro-5-methoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-chloro-3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-cyclopropyl-3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-8-fluoro-5-(hydroxymethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-(cyanomethyl)-3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-chloro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-bis(methyl-d3)picolinamide; 5-[4-[(12-ethyl-11-oxo-2,3,10,12-tetraazatricyclo[7.3.1.05,13]trideca-1,3,5,7,9(13)-pentaen-7-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide; 5-(4-((3-ethyl-8-fluoro-5-(methoxymethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-(difluoromethyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide; 5-(4-((5-cyclopropyl-8-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-5-methoxy-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-6-methyl-2,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-5-methyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl-d2)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((9-ethyl-6-fluoro-3-methyl-8-oxo-8,9-dihydro-7H-pyridazino[3,4,5-de]quinazolin-5-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; N-cyclopropyl-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-cyclopropyl-5-(4-((9-ethyl-6-fluoro-3-methyl-8-oxo-8,9-dihydro-7H-pyridazino[3,4,5-de]quinazolin-5-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methoxy-6-methylpicolinamide; N-(cyclopropylmethoxy)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)-6-methylpicolinamide; N-((1r,3r)-3-cyanocyclobutyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydro-2H-pyran-4-yl)picolinamide; N-(1-cyanocyclopropyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; (S)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide; N-(3,3-difluorocyclobutyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-((1s,3s)-3-cyanocyclobutyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-(1-(methoxymethyl)cyclopropyl)-6-methylpicolinamide; (R)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide; (R)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide; N-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylazetidin-3-yl)picolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)-6-methylpicolinamide; (S)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide; N-((1s,4s)-4-cyanocyclohexyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-((1r,4r)-4-cyanocyclohexyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylpiperidin-4-yl)picolinamide; (R)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylpyrrolidin-3-yl)picolinamide; (S)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylpyrrolidin-3-yl)picolinamide; N-(1-(cyanomethyl)cyclopropyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-cyclopropyl-5-(4-((9-ethyl-6-fluoro-2-methyl-3,8-dioxo-2,7,8,9-tetrahydro-3H-pyridazino[3,4,5-de]quinazolin-5-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 4-[4-[(6-ethyl-10-fluoro-7-oxo-2,4,6,8-tetraazatricyclo[7.3.1.05,13]trideca-1,3,5(13),9,11-pentaen-11-yl)methyl]piperazin-1-yl]-N,3-dimethyl-benzamide; N-cyclopropyl-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-methylbenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methoxy-3-methylbenzamide; N-(cyclopropylmethoxy)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-methylbenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide; N-cyclopropyl-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluorobenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluoro-N-methoxybenzamide; N-(cyclopropylmethoxy)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluorobenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluoro-N-methylbenzamide; N-cyclopropyl-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluorobenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluoro-N-methoxybenzamide; N-(cyclopropylmethoxy)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluorobenzamide; N-(1-(cyanomethyl)cyclopropyl)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-methylbenzamide; N-(1-(cyanomethyl)cyclopropyl)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluorobenzamide; N-(1-(cyanomethyl)cyclopropyl)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluorobenzamide; and N-cyclobutyl-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the compound provided herein is 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compound provided herein is N-cyclopropyl-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, or a pharmaceutically acceptable salt thereof.

[0280] 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 PARP1 over other PARP enzymes than other known compounds, and / or better ADME (absorption, distribution, metabolism, and excretion) properties (including, but not limited to, better permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profile). In some embodiments, provided compounds exhibit certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.

[0281] 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.

[0282] Unless otherwise specified or prohibited by any of the preceding definitions of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, the variables defined above and described in classes and subclasses herein [ka] , X, R 1 , R 2 , R a , R 4 , R 5 , ring A, ring A', L R3 , R 3 , R L , R L1 , L, R A1 , R 6 , R 7, D 1 , L D1 , R 8 , D 2 , L D2 , R 9 , D 3 , R 10 , ring B, ring C, R B , L RB , R 11 , R C , L RC , R 12 , ring D, R, R', R m ,m,n,p,R 1A , R 3A , R 4A , R 6A , R 8A , R 9A , R 11A , R B1 , R D1 , and R N applies to compounds of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, both alone and in combination.

[0283] Throughout this disclosure, unless otherwise indicated, it will be understood that references to compounds of Formula I are intended to include any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d, as well as the species of compounds of such formulas disclosed herein.

[0284] Preparation of the provided compounds The compounds provided can generally be made by the processes described in the following schemes and examples.

[0285] In some embodiments, a provided intermediate (eg, a compound of formula Int) is prepared according to the following scheme: [ka] wherein Z is N or C, PG is a suitable protecting group (e.g., -Boc, -Cbz, or -SEM), and X Int2 includes, but is not limited to, halogen, -B(OH)2, and -OTf; Z Int4 and X Int5 Each of the rings B, C, R includes, but is not limited to, halogen, -OTf, -Bpin, -Sn(Bu)3, and -ZnBr. B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein. Thus, in some embodiments, when Z is N, intermediate Int-3 is prepared by a process comprising contacting compounds of formula Int-1 and Int-2 under suitable conditions (e.g., nucleophilic aromatic substitution, Buchwald-Hartwig cross-coupling, Ullmann coupling, or Chan-Lam coupling). In some embodiments, when Z is C, intermediate Int-6 is prepared by a process comprising contacting compounds of formula Int-4 and Int-5 under suitable conditions (e.g., Suzuki, Stille, or Negishi coupling). In some embodiments, a compound of formula Int is prepared by reacting intermediate Int-1-3 or Int-1-6 under suitable conditions (e.g., removal of PG).

[0286] In some embodiments, provided compounds are prepared according to the following schemes: [ka] wherein LG is a suitable leaving group (e.g., a halogen, such as —Cl or —Br, or —OM), and X, R 4 , R 5 , R 6 , R 7 , D 1 , D 2 , D 3 , ring B, ring C, R B , RC Each of n, n, and p, both alone and in combination, is as defined above in Formula I and as described in classes and subclasses herein. Thus, in some embodiments, intermediate A-2 is prepared by a process comprising contacting a compound of Formula A-1 with a suitable reagent (e.g., a reducing agent such as LiAlH, DIBAL-H, and LiBHEt). In some embodiments, intermediate A-3 is prepared by a process comprising reacting intermediate A-2 under suitable conditions (e.g., HBr / AcOH, CBr / PPh, and MsCl / EtN). In some embodiments, a compound of Formula I is prepared by a process comprising contacting intermediate A-3 and Int under suitable conditions.

[0287] In some embodiments, provided compounds are prepared according to the following schemes: [ka] During the ceremony, L.G. B1 is a suitable leaving group (e.g., a halogen, such as —Cl or —Br, or —I, or —OTf), and Z B2 is -Bpin or -Sn(Bu)3, LG is a suitable leaving group (e.g., a halogen, such as -Cl or -Br, or -OM), and R 6 , R 7 , D 1 , D 2 , D 3 , ring A, ring B, ring C, R A1 , R B , R CEach of L, m, n, and p, both alone and in combination, is as defined above in Formula II and as described in classes and subclasses herein. Thus, in some embodiments, intermediate B-3 is prepared by a process comprising contacting compounds of formula B-1 and B-2 in the presence of a suitable metal complex (e.g., a palladium precatalyst complex, such as chloro(2-dicyclohexylphosphino-2',4',6'-triisoporpyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), and optionally in the presence of a suitable base (e.g., KPO, KCO, or CsCO). In some embodiments, intermediate B-4 is prepared by a process comprising reacting a compound of formula B-3 under suitable conditions (e.g., Fe / NHCl). In some embodiments, intermediate B-5 is prepared by a process comprising contacting a compound of formula B-4 with a suitable reagent (e.g., a reducing agent, such as LiAlH, DIBAL-H, and LiBHEt). In some embodiments, intermediate B-6 is prepared by a process comprising reacting a compound of formula B-5 under suitable conditions (e.g., HBr / AcOH, CBr / PPh, and MsCl / EtN). In some embodiments, a compound of formula II is prepared by a process comprising contacting intermediate B-6 and Int under suitable conditions.

[0288] In some embodiments, provided compounds are prepared according to the following schemes: [ka] where LG is a suitable leaving group (e.g., a halogen, such as —Cl or —Br, or —OM), and R a , R 6 , R 7 , D 1 , D 2 , D 3 , ring B, ring C, R B , R CEach of n, n, and p, both alone and in combination, is as defined above in Formula IV and as described in classes and subclasses herein. Thus, in some embodiments, intermediate C-2 is a compound of formula C-1 converted to a compound of formula R a In some embodiments, intermediate C-3 is prepared by a process comprising contacting a compound of formula C-2 with a suitable reagent (e.g., a reducing agent, such as LiAlH4, DIBAL-H, and LiBHEt3). In some embodiments, intermediate C-4 is prepared by a process comprising reacting a compound of formula C-3 under suitable conditions (e.g., HBr / AcOH, CBr4 / PPh3, and MsCl / Et3N). In some embodiments, a compound of formula IV is prepared by a process comprising contacting intermediate C-4 and Int under suitable conditions.

[0289] In some embodiments, provided compounds are prepared according to the following schemes: [ka] where LG is a suitable leaving group (e.g., a halogen, such as —Cl or —Br, or —OM), and R a , R 4 , R 5 , R 6 , R 7 , D 1 , D 2 , D 3 , ring B, ring C, R B , R C Each of n, n, and p, both alone and in combination, is as defined above in Formula V and as described in classes and subclasses herein. Thus, in some embodiments, intermediate D-2 is prepared by converting a compound of formula D-1 into a compound of formula R aIn some embodiments, intermediate D-3 is prepared by a process comprising contacting a compound of formula D-2 with a suitable reagent (e.g., a reducing agent, such as LiAlH4, DIBAL-H, and LiBHEt3). In some embodiments, intermediate D-4 is prepared by a process comprising reacting a compound of formula D-3 under suitable conditions (e.g., HBr / AcOH, CBr4 / PPh3, and MsCl / Et3N). In some embodiments, a compound of formula V is prepared by a process comprising contacting intermediate D-4 and Int under suitable conditions.

[0290] composition The present disclosure also provides compositions comprising the compounds 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, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d).

[0291] In some embodiments, provided compositions are pharmaceutical compositions that comprise and / or deliver a compound provided herein (e.g., a compound of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d) and further comprise a pharmaceutically acceptable carrier.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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 PARP1. In some embodiments, the provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0296] 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 PARP1. 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 PARP1.

[0297] In some embodiments, provided compounds are useful as PARP1 inhibitors. In some embodiments, the present disclosure provides a method for inhibiting PARP1 in a subject, comprising administering a provided compound or composition. In some embodiments, the present disclosure provides a method for inhibiting PARP1 in a biological sample, comprising contacting the sample with a provided compound or composition.

[0298] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with PARP1 in a subject in need thereof, the method comprising administering a provided compound or composition to the subject. In some embodiments, the disease, disorder, or condition is associated with overexpression of PARP1. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition whose underlying pathology is mediated in whole or in part by PARP1 in a subject in need thereof, the method comprising administering a provided compound or composition to the subject.

[0299] In some embodiments, the present disclosure provides a method of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a proliferative disease, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating metastatic cancer, comprising administering a provided compound or composition to a subject in need thereof. Exemplary cancers include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC)), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, neuroendocrine carcinoma, rhabdoid carcinoma, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma, ), bladder cancer, uterine serous carcinoma, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome, and promyelocytic leukemia), and lymphoid disorders (e.g., leukemia, multiple myeloma, mantle cell lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, hairy cell lymphoma).

[0300] When used as a single agent for monotherapy, the compounds and compositions of the present disclosure are expected to selectively kill tumor cells characterized by homologous recombination deficiency, while minimizing the impact on normal tissues.In some embodiments, the present disclosure provides a method for treating an aggressive cancer caused by or associated with a dysregulated DNA repair system, comprising administering a provided compound or composition to a subject in need thereof.In some embodiments, such aggressive cancers include, but are not limited to, breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.These malignant tumors are characterized by harmful or suspected harmful mutations in key genes involved in DNA damage repair pathways. In some embodiments, such important genes include, but are not limited to, ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, PALB2, NBS1, WRN, RAD51C, RAD51D, MRE11A, CHEK1, BLM, RAD51B, and BRIP1. Cancer patients with such mutations can be identified using companion diagnostics. Patients with advanced cancer who are homologous recombination deficiency positive are expected to benefit from monotherapy using the compounds and compositions of the present disclosure.

[0301] The compounds and compositions of the present disclosure are useful for the treatment of cancers characterized by dysregulation of DNA damage repair when used as cutting-edge maintenance therapy.Exemplary cancers include, but are not limited to, triple-negative breast cancer, high-grade serous ovarian cancer, platinum-sensitive advanced pancreatic cancer, and castration-resistant prostate cancer.These tumors are typically sensitive to platinum-based therapeutic agents and other DNA-damaging agents.As maintenance therapy, the compounds and compositions provided by the present disclosure can reduce the risk of recurrence or relapse and extend the progression-free survival of patients with advanced cancer.

[0302] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, for example, for preventing or reducing the risk of developing a disease, condition, or disorder in individuals who may have a predisposition to the disease, condition, or disorder but who have not yet experienced or exhibited the pathology or symptoms of the disease.

[0303] It will be understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (although the embodiments are intended to be combined as if written in multiple dependent form). Conversely, various features of the present disclosure, which are, for clarity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0304] Combination therapy The growth and survival of cancer cells can be affected by the dysfunction of multiple signaling pathways. To treat such conditions, it is useful to combine compounds that regulate different biological targets. In addition, targeting multiple signaling pathways or multiple biological molecules involved in a given signaling pathway can also reduce the possibility of drug resistance.

[0305] In some embodiments, provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents) simultaneously. In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any doses of a second regimen are administered); and in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy can involve administering one or more agent(s) or modality(s) to a subject receiving other agent(s) or modality(s) in the combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents, or active portions thereof, may be administered together in a combination composition.

[0306] For example, in some embodiments, provided compounds or compositions are administered to a subject who is undergoing or has undergone one or more additional therapies (e.g., anti-cancer therapies and / or therapies to address one or more side effects of such anti-cancer therapies or to otherwise provide palliative care).

[0307] Exemplary additional therapies include, but are not limited to, chemotherapy, radiation therapy, targeted therapies such as anti-inflammatory agents, steroids, immunosuppressants, immuno-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, phosphatase inhibitors, and kinase inhibitors.

[0308] In some embodiments, compounds or compositions provided herein can be used in combination with one or more agents targeting the following biological targets, including but not limited to: Wee1, ATR, ATM, DNA-PK, CDK4 / 6, CHK1 / 2, HER2, PI3K, mTOR, EGFR, VEGFR, FGFR, PDGFR, BTK, IGF-1R, BRAF, MEK, KRAS, EZH2, BCL2, HSP90, HDAC, topoisomerase, HIF-2a, androgen receptor, estrogen receptor, proteosome, RAD51, RAD52, POLQ, WRN, PD-1, and PD-L1. Hypoxia induced by HIF-2a inhibition leads to downregulation of BRCA gene expression, thereby making tumor cells more vulnerable to PARP1 inhibition. Exemplary cancers for the combination of PARP1 inhibitors and HIF-2a inhibitors include, but are not limited to, renal clear cell carcinoma, particularly in the subgroup with tumor suppressor von Hippel-Lindau (VHL) deficiency.

[0309] In some embodiments, the compounds or compositions provided herein can be used in combination with chemotherapy to treat cancer. In some embodiments, the compounds or compositions provided herein can be used in combination with chemotherapy to treat high-grade serous ovarian cancer. Exemplary chemotherapy regimens include, but are not limited to, platinum-based regimens, taxane-based regimens, and several other regimens, including albumin-bound paclitaxel, altretamine, capecitabine, cyclophosphamide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, and vinorelbine.

[0310] In some embodiments, the compounds or compositions provided herein can be used in combination with chemotherapy for the treatment of advanced metastatic breast cancer. Exemplary chemotherapy includes, but is not limited to, taxanes such as paclitaxel, docetaxel, and albumin-bound paclitaxel, anthracyclines, platinum-based drugs, vinorelbine, capecitabine, gemcitabine, ixabepilone, and eribulin. In some embodiments, such combination therapy can be used for malignant tumors of other histologies, including, but not limited to, brain tumors, lung cancers, kidney cancers, liver cancers, and blood cancers.

[0311] Radiation therapy is widely used clinically in the treatment of cancer. The compounds and compositions provided herein can improve the efficacy of radiation therapy through their potent activity in inhibiting DNA damage repair. In some embodiments, the compounds or compositions provided herein can be used in combination with radiation therapy to treat cancer. Exemplary cancers that can be treated with radiation therapy include, but are not limited to, small cell lung cancer, leukemia, lymphoma, germ cell tumors, non-melanoma skin cancer, head and neck cancer, breast cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer. In some embodiments, the compounds or compositions provided herein can overcome the resistance of certain cancers to radiation therapy (especially renal cell carcinoma and melanoma).

[0312] Immunotherapies involving antibodies to PD1, PD-L1, and CTLA4 have been successfully used to treat cancer. Despite this great success, resistance and relapse remain challenges for the majority of cancer patients. In some embodiments, the compounds or compositions provided herein can be used in combination with immunotherapy to improve the efficacy of conventional antibody-mediated immunotherapy by promoting DNA damage, increasing mutational burden, and modulating the STING innate immune pathway. In some embodiments, the compounds or compositions provided herein can be used in combination with immunotherapy to treat adult and pediatric patients with unresectable or metastatic tumors. In some embodiments, the compounds or compositions provided herein can be used in combination with immunotherapy to treat cancer. Exemplary cancers include, but are not limited to, non-small cell lung cancer, melanoma, squamous cell carcinoma of the head and neck, classical Hodgkin's lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, esophageal cancer, endometrial cancer, high tumor mutation burden cancer, cutaneous squamous cell carcinoma, microsatellite instability-high or mismatch repair-deficient colorectal cancer, and triple-negative breast cancer.

[0313] In some embodiments, the compounds or compositions provided herein can be used in combination with well-established targeted therapies for treating cancer, including, but not limited to, PI3K inhibitors, KRAS inhibitors, CDK4 / 6 inhibitors, BRAF inhibitors, MEK inhibitors, androgen receptor inhibitors, selective estrogen receptor modulators, proteosome inhibitors, mTOR inhibitors, EGFR inhibitors, FGFR inhibitors, MET inhibitors, PDGFR inhibitors, VEGFR inhibitors, EZH2 inhibitors, BTK inhibitors, and BCL2 inhibitors. Exemplary cancers include, but are not limited to, breast cancer, ovarian cancer, non-small cell lung cancer, hepatocellular carcinoma, renal clear cell carcinoma, melanoma, colorectal cancer, bladder cancer, prostate cancer, cholangiocarcinoma, and hematological cancers.

[0314] In some embodiments, compounds or compositions provided herein can be used in combination with inhibitors of other DNA damage repair proteins (including, but not limited to, CHEK1, CHEK2, ATM, ATR, DNA-PK, WEE1, RAD51, RAD52, POLQ, and WRN) to treat cancers sensitive to DNA damage. In some embodiments, compounds or compositions provided herein can be used in combination with WEE1 inhibitors to treat uterine serous carcinoma and cancers with TP53 gene mutations. In some embodiments, compounds or compositions provided herein can be used in combination with WRN inhibitors to treat microsatellite instability-high cancers, such as colon cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, and skin cancer.

[0315] 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 localizing and quantifying PARP1 enzyme in tissue samples, including human tissues, and for identifying PARP1 enzyme ligands through inhibitory binding of the labeled compounds, both in vitro and in vivo. Accordingly, the present invention also includes PARP1 enzyme assays comprising such labeled compounds.

[0316] 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.

[0317] 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). 1-6One 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, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d) can be perdeuterated.

[0318] In some embodiments, a compound provided herein (e.g., a compound of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom.

[0319] In some embodiments, a compound provided herein (e.g., a compound of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d), or a pharmaceutically acceptable salt thereof, contains two or more deuterium atoms.

[0320] In some embodiments, a compound provided herein (e.g., a compound of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d), or a pharmaceutically acceptable salt thereof, contains three or more deuterium atoms.

[0321] In some embodiments, for a compound provided herein (e.g., a compound of any of Formulas I, II, II-a, II-ai, III, IV, V, VI, VI-a, VI-b, VII, VIII, VIII-a, VIII-b, VIII-c, VIII-d, IX, IX-a, IX-b, IX-c, and IX-d), or a pharmaceutically acceptable salt thereof, all hydrogen atoms are replaced with deuterium atoms (i.e., the compound is "perdeuterated").

[0322] 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.

[0323] 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.

[0324] 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.

[0325] The radiolabeled compound of the present invention can be used in screening assays to identify / evaluate compounds.Generally speaking, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled compound of the present invention to PARP1 enzyme.Therefore, the ability of the test compound to compete with the radiolabeled compound in binding to PARP1 enzyme is directly correlated with its binding affinity.

[0326] kit The present invention also provides pharmaceutical kits useful, for example, for treating or preventing PARP1-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 comprise one or more of various 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.

[0327] The present invention will be further described in 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 parameters that are not critical and can be changed or modified to achieve essentially the same results.The compound of example is found to be an inhibitor of PARP1 as described below. [Example]

[0328] 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.

[0329] Materials and Methods Final compounds were purified by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0330] TFA conditions: Column: Waters XSelect CSH C 18 5 μm particle size, 30 × 150 mm; elution with mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min.

[0331] NH4HCO3 Conditions: Column: water XBridge BEH C 18 5 μm particle size, 30 × 150 mm; elution with mobile phase A: water (10 mM ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min.

[0332] HCOOH conditions: Column, Sunfire Prep C 18OBD 5 μm particle size, 30 × 150 mm; elution with mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min.

[0333] The separation gradient was optimized for each compound. The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) to confirm purity under the following conditions: Apparatus: Shimadzu LCMS-2020, Column: Halo C 18 2 μm particle size, 3 × 30 mm; Buffer: Mobile phase A: 0.05% TFA in water and Mobile phase B: Acetonitrile; Gradient: 0 → 60% B, 1.9 min, 60% → 100% B, 0.35 min, flow rate 1.5 mL / min.

[0334] Preparation of intermediates Intermediate 1: N-methyl-5-(piperazin-1-yl)picolinamide dihydrochloride Scheme I-1 [ka] Step 1: tert-Butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of methyl 5-bromopyridine-2-carboxylate (5 g, 23.1 mmol), tert-butyl piperazine-1-carboxylate (4.53 g, 24.3 mmol), cesium carbonate (22.62 g, 69.4 mmol), tris(dibenzylideneacetone)dipalladium (1.06 g, 1.2 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (1.08 g, 2.3 mmol) in toluene (200 mL) was heated at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether, to give the desired product as a yellow solid (4.7 g, 63%). 16 H 24 N3O4(M+H) + LCMS calculated m / z: 322.2; found: 322.1; 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.15 (dd, J = 8.7, 3.0 Hz, 1H), 3.95 (s, 3H), 3.62-3.58 (m, 4H), 3.35-3.32 (m, 4H), 1.47 (s, 9H).

[0335] Step 2: tert-Butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (4.7 g, 14.6 mmol) and methylamine (2 M in methanol, 100 mL) was stirred in a sealed tube at 50° C. for 16 hours. Upon cooling to room temperature, the mixture was concentrated under reduced pressure to give the desired product as a white solid (4.3 g, 92%). 16 H 25 N4O3(M+H) + LCMS calculated m / z: 321.2; found: 321.2; 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.00 (brs, 1H), 7.22 (dd, J = 8.8, 2.8 Hz, 1H), 3.62-3.60 (m, 4H), 3.30-3.28 (m, 4H), 3.01 (d, J = 5.2 Hz, 3H), 1.49 (s, 9H).

[0336] Step 3: N-methyl-5-(piperazin-1-yl)picolinamide dihydrochloride A mixture of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (4.3 g, 13.4 mmol) and hydrogen chloride (4 M in 1,4-dioxane, 30 mL) in methanol (10 mL) was stirred at 0° C. under a nitrogen atmosphere for 2 hours. The mixture was concentrated in vacuo, and the residue was diluted with a mixture of diethyl ether and hexane (1 / 1, 30 mL). The solid was collected by filtration, washed with hexane, and dried in vacuo to give the desired product as a white solid (3.9 g, 99%). 11 H 17 NO(M+H) + LCMS calculated m / z: 221.1; found: 221.3; 1 H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 2H), 9.15 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H), 7.84 (dd, J = 9.0, 3.0 Hz, 1H), 3.74-3.71 (m, 4H), 3.21-3.18 (m, 4H), 2.81 (s, 3H).

[0337] Intermediate 2: N,6-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride Scheme I-2 [ka] Step 1: 5-Bromo-N,6-dimethylpicolinamide A mixture of 5-bromo-6-methylpyridine-2-carboxylic acid (5 g, 23.1 mmol) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (10.56 g, 27.8 mmol) in N,N-dimethylformamide (80 mL) at room temperature for 30 minutes, followed by the addition of N-ethyl-N-isopropylpropan-2-amine (14.96 g, 115.7 mmol) and methylamine hydrochloride (2.34 g, 34.7 mmol). The resulting mixture was stirred at the same temperature for 2 hours and then diluted with ethyl acetate (500 mL). The resulting mixture was washed with water (3 × 100 mL) and brine (3 × 100 mL). The combined organics were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether to give the desired product as a white solid (4.53 g, 85%). 10 BrNO(M+H) + LCMS calculated m / z: 229.0; found: 228.9, 230.9; 1 H NMR (300 MHz, CD3OD) δ 8.11 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 2.97 (s, 3H), 2.72 (s, 3H).

[0338] Step 2: tert-Butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of 5-bromo-N,6-dimethylpyridine-2-carboxamide (700 mg, 3.1 mmol), tert-butyl piperazine-1-carboxylate (854 mg, 4.6 mmol), palladium(II) acetate (69 mg, 0.31 mmol), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (285 mg, 0.46 mmol), and cesium carbonate (1.99 g, 6.1 mmol) in toluene (12 mL) was stirred at 80°C for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 60% ethyl acetate in petroleum ether to give the desired product as a yellow solid (800 mg, 78%). 17 H 27 N4O3(M+H) + LCMS calculated m / z: 335.2; found: 335.3; 1 H NMR (300 MHz, CDCl3) δ 8.12 (brs, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 3.64-3.61 (m, 4H), 3.04 (d, J = 5.1 Hz, 3H), 2.95-2.92 (m, 4H), 2.58 (s, 3H), 1.51 (s, 9H).

[0339] Step 3: N,6-Dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride A mixture of tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (150 mg, 0.45 mmol) in dichloromethane (6 mL) was treated with hydrogen chloride (4 mL, 4 M in dioxane). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give the desired product as a pale yellow solid (130 mg, crude), which was used in the next step without further purification. 12 H 19 NO(M+H) + LCMS calculated m / z: 235.2; found: 235.1.

[0340] Intermediate 3: N-methyl-5-(piperazin-1-yl)-6-(trifluoromethyl)picolinamide hydrochloride Scheme I-3 [ka] Step 1: Methyl 6-bromo-5-fluoropicolinate A mixture of 6-bromo-5-fluoropicolinic acid (5 g, 22.73 mmol) in dichloromethane (50 mL) and methanol (50 mL) was combined with (trimethylsilyl)diazomethane (2 M in hexanes, 45.46 mL, 90.91 mmol) under a nitrogen atmosphere at room temperature for 16 hours, then quenched with saturated aqueous sodium carbonate (100 mL), extracted with ethyl acetate (2 × 100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 30% ethyl acetate in petroleum, to give the desired product as a white solid (4.6 g, 86%). C7H6BrFNO2 (M+H) + LCMS calculated m / z: 234.0; found: 234.0.

[0341] Step 2: tert-Butyl 4-(2-bromo-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of methyl 6-bromo-5-fluoropicolinate (1.71 g, 7.31 mmol), potassium carbonate (2.02 g, 14.61 mmol), and tert-butyl piperazine-1-carboxylate (1.43 g, 7.67 mmol) in N,N-dimethylformamide (20 mL) was stirred at 110 °C for 5 hours. After cooling to room temperature, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% ethyl acetate in dichloromethane to give the desired product as a yellow solid (1.83 g, 63%). 16 H 23 BrN3O4(M+H) +LCMS calculated m / z: 400.1; found: 400.1; 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.66-3.63 (m, 4H), 3.13-3.10 (m, 4H), 1.49 (s, 9H).

[0342] Step 3: tert-Butyl 4-(2-bromo-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(2-bromo-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (1.83 g, 4.57 mmol) and methylamine (30 mL, 31% in methanol) was combined at room temperature and stirred at the same temperature for 16 hours. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 25% ethyl acetate in dichloromethane to give the desired product as a yellow solid (1.6 g, 88%). 16 H 24 BrN4O3(M+H) + LCMS calculated m / z: 399.1; found: 399.1; 1 H NMR (300 MHz, CDCl3) δ 8.12 (dd, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 3.68-3.64 (m, 4H), 3.11-3.08 (m, 4H), 3.04 (d, J = 5.0 Hz, 3H), 1.51 (s, 9H).

[0343] Step 4: tert-Butyl 4-(6-(methylcarbamoyl)-2-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(2-bromo-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (1.6 g, 4.01 mmol), silver fluoride (1.83 g, 14.43 mmol), and copper powder (1.40 g, 22.04 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hours, and then trifluoromethyltrimethylsilane (2.51 g, 17.63 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 90 °C for 18 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 30% dichloromethane in ethyl acetate to give the desired product as a pale yellow solid (880 mg, 57%). 17 H 24 F3N4O3(M+H) + LCMS calculated m / z: 389.2; found: 389.3; 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 3.61-3.59 (m, 4H), 3.04 (d, J = 5.0 Hz, 3H), 3.00-2.97 (m, 4H), 1.49 (s, 9H).

[0344] Step 5: N-methyl-5-(piperazin-1-yl)-6-(trifluoromethyl)picolinamide hydrochloride A mixture of tert-butyl 4-(6-(methylcarbamoyl)-2-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylate (30 mg, 0.08 mmol) in hydrochloride (4 M in 1,4-dioxane, 0.5 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure to give the desired product as a yellow solid (20 mg, crude), which was used in the next step without further purification. 12 H 16 F3N4O(M+H) +LCMS calculated: 289.1; found: 289.3.

[0345] Intermediate 4: 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride Scheme I-4 [ka] Step 1: Methyl 5-bromo-6-fluoropicolinate A mixture of methyl 5-bromopicolinate (5 g, 23.15 mmol) and difluorosilver (11.82 g, 81.01 mmol) in acetonitrile (50 mL) was stirred at room temperature for 16 hours. The mixture was filtered, and the filter cake was washed with dichloromethane (2 × 100 mL). The filtrate was washed with saturated aqueous ammonium chloride solution (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to give the desired product as a white solid (4.52 g, 83%). C7H6BrFNO2 (M+H) + LCMS calculated m / z: 234.0; observed: 233.9; 1 H NMR (300 MHz, CDCl3) δ 8.14 (dd, J = 10.8, 10.8 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H), 4.00 (s, 3H); 19 F NMR (377 MHz, CDCl3) δ -61.98.

[0346] Step 2: tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of methyl 5-bromo-6-fluoropicolinate (3.3 g, 14.1 mmol), tert-butyl piperazine-1-carboxylate (3.94 g, 21.15 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.99 g, 2.12 mmol), tris(dibenzylideneacetone)dipalladium (1.29 g, 1.41 mmol), and cesium carbonate (9.19 g, 28.2 mmol) in toluene (40 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether, to give the desired product as a yellow solid (2.7 g, 56%). 16 H 23 FN3O4(M+H) + LCMS calculated m / z: 340.2; found: 340.1; 1 H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.28-7.23 (m, 1H), 3.96 (s, 3H), 3.63-3.60 (m, 4H), 3.22-3.19 (m, 4H), 1.49 (s, 9H); 19 F NMR (282 MHz, CDCl3) δ -69.20.

[0347] Step 3: tert-Butyl 4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (2.7 g, 7.96 mmol) and methylamine (30 mL, 31% in methanol) was combined at room temperature and stirred at the same temperature for 16 hours. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 30% ethyl acetate in dichloromethane to give the desired product as a yellow solid (2.3 g, 85%). 16 H 24 FN4O3(M+H) +LCMS calculated m / z: 339.2; found: 339.3; 1 H NMR (300 MHz, CDCl3) δ 8.02 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (s, 1H), 7.37-7.30 (m, 1H), 3.65-3.61 (m, 4H), 3.18-3.15 (m, 4H), 3.02 (d, J = 5.0 Hz, 3H), 1.51 (s, 9H); 19 F NMR (282 MHz, CDCl3) δ -72.71.

[0348] Step 4: 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride A mixture of tert-butyl 4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (28 mg, 0.08 mmol) in hydrochloride (4 M in 1,4-dioxane, 0.9 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the desired product as a yellow solid (20 mg, crude), which was used in the next step without further purification. 11 H 16 FN4O(M+H) + LCMS calculated m / z: 239.1; found: 239.2.

[0349] Intermediate 5: N-ethyl-6-methyl-5-(piperazin-1-yl)picolinamide hydrochloride Scheme I-5 [ka] Step 1: 5-Bromo-N-ethyl-6-methylpicolinamide A mixture of 5-bromo-6-methylpicolinic acid (2 g, 9.26 mmol) in N,N-dimethylformamide (30 mL) was treated with 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.22 g, 11.11 mmol) at room temperature for 30 minutes, followed by the addition of ethanolamine hydrochloride (1.13 g, 13.89 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.98 g, 46.29 mmol). The resulting mixture was stirred at the same temperature for 16 hours and then diluted with ethyl acetate (300 mL). The resulting mixture was washed with water (3 × 100 mL) and brine (3 × 100 mL). The combined organics were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether to give the desired product as a white solid (1.5 g, 67%). 12 BrNO(M+H) + LCMS calculated m / z: 243.0; observed: 242.9; 1 H NMR (300 MHz, CDCl3) δ 7.97-7.88 (m, 3H), 3.55-3.46 (m, 2H), 2.69 (s, 3H), 1.28 (t, J = 7.2Hz, 3H).

[0350] Step 2: tert-Butyl 4-(6-(ethylcarbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate A mixture of 5-bromo-N-ethyl-6-methylpicolinamide (320 mg, 1.32 mmol), tert-butyl piperazine-1-carboxylate (294 mg, 1.58 mmol), palladium acetate (30 mg, 0.13 mmol), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (123 mg, 0.2 mmol), and cesium carbonate (858 mg, 2.63 mmol) in dry toluene (8 mL) was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 40% ethyl acetate in petroleum ether, to give the desired product as a white solid (360 mg, 78%). 18 H 29 N4O3(M+H) + LCMS calculated: 349.2; Found: 349.3; 1 H NMR (300 MHz, CDCl3) δ 8.07 (brs, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 3.62-3.59 (m, 4H), 3.55-3.46 (m, 2H), 2.93-2.89 (m, 4H), 2.57 (s, 3H), 1.49 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H).

[0351] Step 3: N-Ethyl-6-methyl-5-(piperazin-1-yl)picolinamide hydrochloride A mixture of tert-butyl 4-(6-(ethylcarbamoyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate (50 mg, 0.14 mmol) in dichloromethane (1 mL) was treated with hydrogen chloride (4 M in 1,4-dioxane, 1.0 mL). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the desired product as a pale yellow solid, which was used in the next step without further purification. 13 H 21 NO(M+H) + LCMS calculated m / z: 249.2; found: 249.1.

[0352] Intermediate 6: N,6-bis(methyl-d3)-5-(piperazin-1-yl)picolinamide Scheme I-6 [ka] Step 1: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-(methyl-d3)picolinic acid A mixture of zinc (1.63 g, 24.98 mmol), [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (339 mg, 0.63 mmol), sodium iodide (1.4 g, 9.37 mmol), tert-butyl 4-(2-bromo-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 3, Step 2: 2.5 g, 6.25 mmol), and iodomethane-d3 (4.53 g, 31.23 mmol) in dry tetrahydrofuran (30 mL) was stirred under a nitrogen atmosphere at room temperature for 24 hours. The mixture was then concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: acetonitrile in water; elution: 5% to 70% gradient, 30 min; detector: UV 254 nm). The fractions were collected, combined, and lyophilized to give the desired product (1.0 g, 39%). 16 H 21 D3N3O4(M+H) + LCMS calculated m / z: 325.2; found: 325.1.

[0353] Step 2: tert-butyl 4-(2-(methyl-d3)-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate A mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-(methyl-d3)picolinic acid (450 mg, 1.39 mmol) in N,N-dimethylformamide (5 mL) was treated with 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (633 mg, 1.66 mmol) at room temperature for 30 minutes, followed by the addition of methane-d3-amine hydrochloride (117 mg, 1.66 mmol) and N-ethyl-N-isopropylpropan-2-amine (538 mg, 4.16 mmol). The resulting mixture was stirred at the same temperature for 2 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed with water (3 × 30 mL) and brine (3 × 30 mL). The combined organics were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in dichloromethane, to give the desired product as a yellow solid (227 mg, 48%). 17 H 21 D6N4O3(M+H) + LCMS calculated m / z: 341.2; found: 341.2.

[0354] Step 3: N,6-bis(methyl-d3)-5-(piperazin-1-yl)picolinamide A solution of tert-butyl 4-(2-(methyl-d3)-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (227 mg, 0.67 mmol) in dichloromethane (3 mL) was treated with hydrogen chloride (4 M in 1,4-dioxane, 3 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with dichloromethane (4 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the desired product as a brown solid (150 mg), which was used directly without further purification. C 12 H 13 D6N4O(M+H) + LCMS calculated m / z: 241.2; found: 241.1.

[0355] Intermediate 7: Methyl 6-methyl-5-(piperazin-1-yl)picolinate Scheme I-7 [ka] Step 1: Methyl 5-bromo-6-methylpicolinate To a stirred mixture of 5-bromo-6-methylpicolinic acid (5 g, 23.15 mmol) in dichloromethane (40 mL) was added N,N-dimethylpyridin-4-amine (4.24 g, 34.71 mmol) at 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (4.67 g, 24.36 mmol) was added portionwise. Methanol (10 mL, 246.96 mmol) was then added. The resulting mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to give the desired product as a white solid (3.7 g, 69%). CHBrNO (M+H) + LCMS calculated m / z: 230.0; found: 229.9; 1 H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 4.00 (s, 3H), 2.77 (s, 3H).

[0356] Step 2: tert-Butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate To a round-bottom flask equipped with a magnetic stir bar was added methyl 5-bromo-6-methylpicolinate (3.6 g, 15.65 mmol), cesium carbonate (15.295 g, 46.94 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (1.46 g, 3.13 mmol), tris(dibenzylideneacetone)dipalladium (1.43 g, 1.57 mmol), and tert-butylpiperazine-1-carboxylate (3.21 g, 17.21 mmol). The flask was sealed with a rubber septum, evacuated, and back-filled with nitrogen (this process was repeated a total of three times). Toluene (100 mL) was added. The reaction was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether to give the desired product as a brown solid (5 g, 96%). 17 H 26 N3O4(M+H) + LCMS calculated m / z: 336.2; found: 336.1; 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 3.63-3.61 (m, 4H), 2.96-2.94 (m, 4H), 2.67 (s, 3H), 1.49 (s, 9H).

[0357] Step 3: Methyl 6-methyl-5-(piperazin-1-yl)picolinate A solution of tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate (5 g, 14.91 mmol) in hydrogen chloride (4 M in 1,4-dioxane, 50 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with 25% isopropanol in chloroform (3 × 200 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give the desired product as a brown oil (3.3 g, 94%). 12 H 18 N3O2(M+H) + LCMS calculated m / z: 236.1; found: 236.1; 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.09-3.06 (m, 4H), 2.99-2.96 (m, 4H), 2.62 (s, 3H).

[0358] Preparation of the provided compounds Example 1: 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (I-1) Scheme 1 [ka] Step 1: Methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate To a mixture of dimethyl 2-aminoterephthalate (5 g, 23.9 mmol) in toluene (50 mL) was added isocyanatoethane (1.70 g, 23.9 mmol) and triethylamine (3.63 g, 35.9 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 120° C. for 16 hours. Upon cooling to room temperature, the crude product precipitated. It was collected by filtration, washed with ethyl acetate (2×10 mL), and dried at room temperature to give the desired product as a white solid (4.8 g, 80%). 12 H 13 N2O4(M+H) + LCMS calculated m / z: 249.1; found: 249.2. 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0359] Step 2: 3-Ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione To a mixture of methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (100 mg, 0.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added lithium triethylborohydride (1.0 M in THF, 1.0 mL, 1.0 mmol) dropwise under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at the same temperature for 30 minutes and then quenched by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted with dichloromethane (2 x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: acetonitrile in water; elution: 5% to 50% gradient, 30 minutes; detector: UV 254 nm). The fractions were collected, combined, and lyophilized to give the desired product as a white solid (70 mg, 78%). 11 H13 N2O3(M+H) + LCMS calculated m / z: 221.1; found: 221.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J = 8.0 Hz, 1H), 5.45 (t, J = 5.2 Hz, 1H), 4.56 (d, J = 5.2 Hz, 2H), 3.92 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H).

[0360] Step 3: 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (I-1) A mixture of 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione (50 mg, 0.24 mmol) was combined with hydrogen bromide (2 mL of a 33 wt.% solution in glacial acetic acid) at room temperature, and the reaction was then heated at 80° C. for 2 hours under a nitrogen atmosphere. Upon cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was taken up in acetonitrile (3 mL), and then N-methyl-5-(piperazin-1-yl)picolinamide dihydrochloride (75 mg, 0.3 mmol) and N-ethyl-N-isopropylpropan-2-amine (235 mg, 1.8 mmol) were added. The resulting mixture was then heated at 70° C. for an additional 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 8% B → 29% B, 7 min). The eluted fractions were collected and lyophilized to give the desired product as a pale yellow solid (33.8 mg). 22 H 27 N6O3(M+H) + LCMS calculated m / z: 423.2; found: 423.0. 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.41-8.38 (m, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 7.19-7.17 (m, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.60 (s, 2H), 3.38-3.45 (m, 4H), 2.78 (d, J = 5.2 Hz, 3H), 2.56-2.53 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H).

[0361] Example 2: 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (I-2) Scheme 2 [ka] Step 1: 3-Ethyl-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one To a mixture of methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (2 g, 8.1 mmol) in anhydrous tetrahydrofuran (100 mL) was added diisobutylaluminum hydride solution (1.0 M in THF, 40.3 mL, 40.3 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 30 minutes. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with dichloromethane (2×300 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate, to give the desired product as a white solid (800 mg, 48%). 11 H 15 N2O2(M+H) + LCMS calculated m / z: 207.1; found: 207.1.1 H NMR (400 MHz, CDCl3) δ 7.03-7.01 (m, 2H), 6.93-6.91 (m, 1H), 6.69 (s, 1H), 4.63 (s, 2H), 4.43 (s, 2H), 3.52-3.46 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H). Step 2: 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (I-2) A mixture of 3-ethyl-7-(hydroxymethyl)-1,4-dihydroquinazolin-2-one (50 mg, 0.2 mmol) was combined with hydrogen bromide (33 wt.% solution in glacial acetic acid, 2 mL) at room temperature, and the reaction was then heated at 80° C. for 2 hours under a nitrogen atmosphere. Upon cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was taken up in acetonitrile (3 mL), and then N-methyl-5-(piperazin-1-yl)picolinamide dihydrochloride (70 mg, 0.2 mmol) and N-ethyl-N-isopropylpropan-2-amine (235 mg, 1.8 mmol) were added. The resulting mixture was then heated at 70° C. for an additional 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B → 55% B, 7 min). The eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid (14.3 mg). 22 H 29 N6O2(M+H) + LCMS calculated m / z: 409.2; found: 409.0. 1H NMR (400 MHz, DMSO-d6+ D2O) δ 8.34 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.8 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.06 (dd, J = 8.0, 1.6 Hz, 1H), 6.90 (s, 1H), 4.74 (s, 2H), 4.30 (s, 2H), 3.52-3.13 (m, 10H), 2.82 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H).

[0362] Example 3: N-methyl-5-(4-((2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-5-yl)methyl)piperazin-1-yl)picolinamide (I-3) Scheme 3 [ka] Step 1: 7-Bromo-1-(4-methoxybenzyl)quinolin-2(1H)-one To a mixture of 7-bromoquinolin-2(1H)-one (2 g, 8.9 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 0.43 g, 10.7 mmol) portionwise under a nitrogen atmosphere at 0 °C. The mixture was stirred at the same temperature for 30 minutes, and then 1-(chloromethyl)-4-methoxybenzene (2.1 g, 13.39 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 hours, then quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organics were washed with brine (3 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate in petroleum ether, to give the desired product as a white solid (1.6 g, 52%). 17 H 15 BrNO2(M+H) + LCMS calculated m / z: 344.0; found: 344.0. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 9.2 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.31-7.28 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.87- 6.84 (m, 2H), 6.79 (d, J = 9.6 Hz, 1H), 5.43 (s, 2H), 3.77 (s, 3H).

[0363] Step 2: 5-Bromo-3-(4-methoxybenzyl)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]quinolin-2-one To a mixture of iodotrimethyl-lambda-6-sulfanone (5.11 g, 23.2 mmol) in anhydrous tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexane, 9.30 mL, 23.2 mmol) dropwise under a nitrogen atmosphere at 0° C., followed by the dropwise addition of 7-bromo-1-[(4-methoxyphenyl)methyl]quinolin-2-one (1.6 g, 4.6 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 hours, then quenched with water at 0° C., and the mixture was extracted with ethyl acetate (2×100 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether, to give the desired product as an off-white solid (1.1 g, 66%). 18 H 17 BrNO2(M+H) + LCMS calculated m / z: 358.0; found: 358.0. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.0 Hz, 1H), 7.13-7.07 (m, 3H), 7.01 (d, J = 2.0 Hz, 1H), 6.86-6.83 (m, 2H), 5.21-5.17 (m, 1H), 4.96-4.92 (m, 1H), 3.77 (s, 3H), 2.55-2.50 (m, 1H), 2.43-2.38 (m, 1H), 1.67-1.62 (m, 1H), 0.68-0.64 (m, 1H).

[0364] Step 3: 5-Bromo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]quinolin-2-one To a mixture of 5-bromo-3-(4-methoxybenzyl)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]quinolin-2-one (1 g, 2.8 mmol) in acetonitrile (4.5 mL) and water (0.5 mL) was added diammonium cerium(IV) nitrate (5.38 g, 9.8 mmol) in portions. The resulting mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (2 × 100 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate in petroleum ether, to give the desired product as a brown solid (400 mg, 60%). 10 H9BrNO(M+H) + LCMS calculated m / z: 238.0; found: 238.0. 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 8.0, 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 2.53-2.48 (m, 1H), 2.21-2.15 (m, 1H), 1.70-1.64 (m, 1H), 0.84-0.70 (m, 1H).

[0365] Step 4: 2-Oxo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline-5-carbaldehyde To a mixture of 5-bromo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]quinolin-2-one (20 mg, 0.08 mmol) in anhydrous tetrahydrofuran (0.2 mL) was added n-butyllithium (2.5 M in hexanes, 0.12 mL, 0.3 mmol) under a nitrogen atmosphere at −78° C., followed by N,N-dimethylformamide (0.1 mL) at −78° C. The resulting mixture was warmed to room temperature, quenched with water, and extracted with ethyl acetate (2×10 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate in petroleum ether, to give the desired product as a white solid (10 mg, 63%). 11 H 10 NO2(M+H) + LCMS calculated m / z: 188.1; found: 188.0. 1 H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.69 (s, 1H), 7.53 (s, 2H), 7.29 (s, 1H), 2.64-2.59 (m, 1H), 2.30-2.24 (m, 1H), 1.80-1.75 (m, 1H), 0.89-0.79 (m, 1H).

[0366] Step 5: N-methyl-5-(4-((2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-5-yl)methyl)piperazin-1-yl)picolinamide (I-3) A mixture of 2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline-5-carbaldehyde (30 mg, 0.2 mmol), N-methyl-5-(piperazin-1-yl)picolinamide dihydrochloride (47 mg, 0.2 mmol), and sodium acetate (26 mg, 0.3 mmol) in ethanol (3 mL) was stirred at room temperature for 20 minutes, followed by the addition of sodium cyanoborohydride (20 mg, 0.3 mmol) and acetic acid (19 mg, 0.3 mmol). The resulting mixture was stirred at room temperature for an additional 4 hours, then concentrated in vacuo, and the residue was purified by reverse flash chromatography (column: C18 silica gel; mobile phase: acetonitrile in water, 5% to 95% gradient, 30 minutes). The fractions were collected, combined, and lyophilized to give the desired product as a white solid (9 mg). 22 H 26 NO2(M+H) + LCMS calculated m / z: 392.2; found: 392.3. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.41-8.38 (m, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.8, 2.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.89-6.85 (m, 2H), 3.43 (s, 2H), 3.33-3.30 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 2.54-2.52 (m, 4H), 2.50-2.43 (m, 1H), 2.08-1.95 (m, 1H), 1.59-1.54 (m, 1H), 0.52-0.49 (m, 1H).

[0367] Example 4: N-methyl-5-(4-((4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide (I-4) Scheme 4 [ka] Step 1: Methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate To a mixture of methyl 2-oxocyclopentane-1-carboxylate (5 g, 35.2 mmol) in dichloromethane (50 mL) was added sodium hydride (60%, 1.69 g, 42.2 mmol) portionwise under a nitrogen atmosphere at 0 °C. The mixture was stirred at the same temperature for 30 minutes, and then trifluoromethanesulfonic anhydride (11.91 g, 42.2 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 hours, then quenched with water, and the mixture was extracted with dichloromethane (3 × 200 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate in petroleum ether, to give the desired product as a colorless oil (8 g, 83%). 1 H NMR (300 MHz, CDCl3) δ 3.81 (s, 3H), 2.81-2.69 (m, 4H), 2.09-1.99 (m, 2H).

[0368] Step 2: Methyl 4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-3-nitrobenzoate A mixture of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (500 mg, 1.8 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (492 mg, 2.188 mmol), cesium carbonate (1188 mg, 3.6 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (143 mg, 0.2 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate in petroleum ether, to give the desired product as a white solid (500 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 1.6 Hz, 1H), 8.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.50 (s, 3H), 2.91-2.79 (m, 4H), 2.17-2.09 (m, 2H).

[0369] Step 3: Methyl 4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate To a mixture of methyl 4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-3-nitrobenzoate (500 mg, 1.6 mmol) in ethanol (15 mL) and water (2.5 mL) was added iron (457 mg, 8.2 mmol) and ammonium chloride (263 mg, 4.9 mmol). The resulting mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate, to give the desired product as a white solid (250 mg, 63%). 14 H 14 NO3(M+H) + LCMS calculated m / z: 244.1; found: 244.1. 1 H NMR (400 MHz, CDCl3) δ 9.41 (brs, 1H), 8.87-7.80 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.25-3.13 (m, 4H), 2.29-2.23 (m, 2H).

[0370] Step 4: 7-(hydroxyme...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof. [In the formula, 【Chemistry 2】 is a single or double bond, X is -C(R １ ) = , -C(R １ R ２ ) - or -N(R ａ ) - and X is -C(R １ )=, then one of (i) to (iii) is true; (i) R ５ is absent, R １ and R ４ together with the carbon atoms to which they are attached, are fused to the lactam ring shown 【Transformation 3】 Forming Ring A is a 5-membered partially unsaturated monocyclic carbocyclyl or a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; (ii) R ５ is absent, R ４ and L Ｄ１ -R ８ together with the carbon atoms to which they are attached form an optionally substituted ring selected from a 5- to 7-membered partially unsaturated carbocyclyl or a 5- to 7-membered partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (iii) R ５ is absent, D １ is S or NR, and D ２ is absent, X is -C(R １ R ２ )- or -N(R ａ ) - if R １ and R ２ are each independently hydrogen, halogen, —CN, —OR, —SR, or —N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , or C １－６ optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R １ and R ２ are taken together with the carbon atoms to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ２ and R ４ together with the carbon atoms to which they are attached, are fused to the lactam ring shown 【Chemistry 4】 Forming Ring A' is 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; R ａ is hydrogen or -L Ｒ３ -R ３ and L Ｒ３ is a covalent bond or an optionally substituted divalent C １－６ is aliphatic, R ３ is hydrogen or C １－６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; R ４ and R ５ are each independently hydrogen, halogen, —CN, —OR, —SR, or —N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , or C １－６ optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ４ and R ５ together with the carbon atom *C to which they are attached, *C=O, *C=S, *C=NR Ｌ or forms an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ５ is absent, and R ４ and L Ｄ１ -R ８ taken together with the carbons to which they are attached form an optionally substituted ring selected from 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; R Ｌ represents hydrogen, -CN, -OR Ｌ１ or optionally substituted C １－６ is alkyl, R Ｌ１ is hydrogen, C １－６ Alkyl, or C １－６ is haloalkyl, Each L is independently a covalent bond or an optionally substituted divalent C １－６ is aliphatic, Each R Ａ１ is independently halogen, -CN, -OR, -SR, -N(R) ２ , -N ＋ (R) ３ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -C(=NR ｍ )(R'), -C(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(R'), -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O)(=NR ｍ )(R'), -NRS(O) ２ N(R) ２ , -S(O)N(R) ２ , -OS(O)(=R ｍ )(R'), -S(O)(=NR ｍ )(R'), -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, 6- 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, 6- 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; R ６ and R ７は , each independently hydrogen, halogen, or C １－６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ６ and R ７ are taken together with the carbons to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; D １ is C-L Ｄ１ -R ８ , N, NR, or S; D ２ Is absent, C-L Ｄ２ -R ９ , or N, and D １ is S or NR, D ２ is absent, D ３ is CR １０ or N, L Ｄ１ is a covalent bond or an optionally substituted divalent C １－６ is aliphatic, L Ｄ２ is a covalent bond or an optionally substituted divalent C １－６ is aliphatic, R ８ is hydrogen, halogen, -CN, -OR, -SR, -N(R) ２ , -N ＋ (R) ３ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -C(=NR ｍ )(R', -C(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(R', -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O)(=NR ｍ )(R', -NRS(O) ２ N(R) ２ , -S(O)N(R) ２ , -OS(O)(=R ｍ )(R', -S(O)(=NR ｍ )(R', -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, 6- 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, 6- 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; R ９ and R １０ are each independently hydrogen, halogen, —CN, —OR, —SR, or —N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , or C １－６ selected from optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 16-membered saturated or partially unsaturated polycyclic heterocyclylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is phenyl, an 8- to 10-membered bicyclic aryl, a 10- to 14-membered polycyclic aryl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R Ｂ are independently -L ＲＢ -R １１ and Each L ＲＢ are independently a covalent bond or an optionally substituted divalent C １－６ is aliphatic, Each R Ｃ are independently -L ＲＣ -R １２ and Each L ＲＣ are independently a covalent bond or an optionally substituted divalent C １－６ is aliphatic, R １１ and R １２ are each independently a halogen, ═O, —CN, —OR, —SR, or —N(R) ２ , -N ＋ (R) ３ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -C(=NR ｍ )R', -C(=NR ｍ ) N (R) ２ , -NRC (=NR ｍ ) N (R) ２ , -NRC (=NR ｍ )R', -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O)(=NR ｍ )R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , -OS(O)(=R ｍ )R', -S(O)(=NR ｍ )R', -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, 6- 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, 6- 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; or R Ｂ and R Ｃ together with the intervening atoms to form ring D fused with one or both of ring B and ring C; Ring D is an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5- to 6-membered monocyclic 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- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; or two R, when attached to the same nitrogen atom, combine to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C １－６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; or two R', when attached to the same nitrogen atom, combine to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R ｍ are independently —OH, —CN, or R; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5. 【Request Item 2】 【Chemistry 5】 is a single bond or a double bond, X is -C(R １ ) = , -C(R １ R ２ ) - or -N(R ａ ) - and X is -C(R １ )=, then one of (i) to (iii) is true; (i) R ５ is absent, R １ and R ４ together with the carbon atoms to which they are attached, form a fused lactam ring as shown. 【Transformation 6】 Forming Ring A is a 5-membered partially unsaturated monocyclic carbocyclyl or a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; (ii) R ５ is absent, R ４ and L Ｄ１ -R ８ together with the carbon atoms to which they are attached form a 5- to 7-membered partially unsaturated carbocyclyl or a 5- to 7-membered partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said 5- to 7-membered partially unsaturated carbocyclyl or said 5- to 7-membered partially unsaturated monocyclic heterocyclyl each optionally containing 1, 2, 3, or 4 independently selected R ４Ａ substituted by a substituent, or (iii) R ５ is absent, D １ is S or NR, and D ２ is absent, X is -C(R １ R ２ )- or -N(R ａ ) - if R １ and R ２ are each independently hydrogen, halogen, —CN, —OR, —SR, or —N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally selected from 1, 2, 3, or 4 independently selected R １Ａ substituted with a substituent, or R １ and R ２ together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contains 1, 2, 3, or 4 independently selected R １Ａ substituted with a substituent, or R ２ and R ４ together with the carbon atoms to which they are attached, form a fused lactam ring as shown. 【Transformation 7】 Forming Ring A' is 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; R ａ is hydrogen or -L Ｒ３ -R ３ and L Ｒ３ is a covalent bond or a divalent C １－６ aliphatic, and the divalent C １－６ The aliphatic group optionally includes 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, R ３ But hydrogen, C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said phenyl, said 8- to 10-membered bicyclic aryl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, said 5- to 6-membered monocyclic heteroaryl, and said 8- to 10-membered bicyclic heteroaryl each optionally comprises 1, 2, 3, or 4 independently selected R ３Ａ is substituted with a substituent, R ４ and R ５ are each independently hydrogen, halogen, —CN, —OR, —SR, or —N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally selected from 1, 2, 3, or 4 independently selected R ４Ａ substituted with a substituent, or R ４ and R ５ together with the carbon atom *C to which they are attached, *C=O, *C=S, *C=NR Ｌ , a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally comprises 1, 2, 3, or 4 independently selected R ４Ａ substituted with a substituent, or R ５ is absent, and R ４ and L Ｄ１ ~R ８ together with the carbon to which they are attached form a group selected from phenyl and 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said phenyl and said 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each optionally being bound to 1, 2, 3, or 4 independently selected R ４Ａ is substituted with a substituent, R Ｌ is hydrogen, -CN, -OR Ｌ１ , or C １－６ alkyl, １－６ The alkyl is optionally selected from 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, R Ｌ１ But hydrogen, C １－６ Alkyl, or C １－６ is haloalkyl, Each L is independently a covalent bond or a divalent C １－６ aliphatic, and the divalent C １－６ The aliphatic group optionally includes one, two, three, or four independently selected R Ｎ is substituted with a substituent, Each R Ａ１ is independently halogen, -CN, -OR, -SR, -N(R) ２ , -N ＋ (R) ３ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -C(=NR ｍ )(R)', -C(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(R)', -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O)(=NR ｍ )(R)', -NRS(O) ２ N(R) ２ , -S(O)N(R) ２ , -OS(O)(=R ｍ )(R)', -S(O)(=NR ｍ )(R)', -P(O)(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said phenyl, said 8- to 10-membered bicyclic aryl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, said 5- to 6-membered monocyclic heteroaryl, and said 8- to 10-membered bicyclic heteroaryl each optionally comprises 1, 2, 3, or 4 independently selected R Ｂ１ is substituted with a substituent, R ６ and R ７ are each independently hydrogen, halogen, C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally selected from 1, 2, 3, or 4 independently selected R ６Ａ substituted with a substituent, or R ６ and R ７ together with the carbons to which they are attached form a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 6- 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 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally contains 1, 2, 3, or 4 independently selected R ６Ａ is substituted with a substituent, D １ But C-L Ｄ１ -R ８ , N, NR, or S; D ２ But, absent, C-L Ｄ２ -R ９ , or N, and D １ is S or NR, D ２ is absent, D ３ But, CR １０ or N, L Ｄ１ is a covalent bond or a divalent C １－６ aliphatic, and the divalent C １－６ The aliphatic group optionally includes 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, L Ｄ２ is a covalent bond or a divalent C １－６ aliphatic, and the divalent C １－６ The aliphatic group optionally includes 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, R ８ is hydrogen, halogen, -CN, -OR, -SR, -N(R) ２ , -N ＋ (R) ３ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -C(=NR ｍ )(R)', -C(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(R)', -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O)(=NR ｍ )(R)', -NRS(O) ２ N(R) ２ , -S(O)N(R) ２ , -OS(O)(=R ｍ )(R)', -S(O)(=NR ｍ )(R)', -P(O)(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said phenyl, said 8- to 10-membered bicyclic aryl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, said 5- to 6-membered monocyclic heteroaryl, and said 8- to 10-membered bicyclic heteroaryl each optionally comprises 1, 2, 3, or 4 independently selected R ８Ａ is substituted with a substituent, R ９ and R １０ are each independently hydrogen, halogen, —CN, —OR, —SR, or —N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N (R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N (R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O) ２ N (R) ２ , -S(O)N(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and said 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl each optionally selected from 1, 2, 3, or 4 independently selected R ９Ａ is substituted with a substituent, Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 16-membered saturated or partially unsaturated polycyclic heterocyclylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is phenyl, an 8- to 10-membered bicyclic aryl, a 10- to 14-membered polycyclic aryl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R Ｂ But independently, -L ＲＢ -R １１ and Each L ＲＢ are independently a covalent bond or a divalent C １－６ aliphatic, and the divalent C １－６ The aliphatic group optionally includes 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, Each R Ｃ But independently, -L ＲＣ -R １２ and Each L ＲＣ are independently a covalent bond or a divalent C １－６ aliphatic, and the divalent C １－６ The aliphatic group optionally includes 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, R １１ and R １２ are each independently halogen, =O, -CN, -OR, -SR, -N(R) ２ , -N ＋ (R) ３ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R', -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)SO ２ R', -S(O)R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) ２ , -C(=NR ｍ )(R'), -C(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(N(R) ２ , -NRC(=NR ｍ )(R'), -NRS(O)N(R) ２ , -NRS(O)R', -NRS(O)(=NR ｍ )(R'), -NRS(O) ２ N(R) ２ , -S(O)N(R) ２ , -OS(O)(=R ｍ )(R'), -S(O)(=NR ｍ )(R'), -P(O)(R) ２ , C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said phenyl, said 8- to 10-membered bicyclic aryl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, said 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl each optionally selected from 1, 2, 3, or 4 independently selected R １１Ａ substituted with a substituent, or R Ｂ and R Ｃ together with the intervening atoms to form a ring D fused with one or both of ring B and ring C; Ring D is independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and nitrogen, oxygen, and sulfur; and 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms, wherein said 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, said 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, said 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl, said 6-8 membered saturated or partially unsaturated bicyclic heterocyclyl, said phenyl, and said 5-6 membered monocyclic heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R Ｄ１ is substituted with a substituent, Each R is independently hydrogen, C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said phenyl, said 8- to 10-membered bicyclic aryl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, said 5- to 6-membered monocyclic heteroaryl, and said 8- to 10-membered bicyclic heteroaryl each optionally comprises 1, 2, 3, or 4 independently selected R Ｎ substituted with a substituent, or When two R are attached to the same nitrogen atom, they together form a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl optionally has 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, Each R' is independently C １－６ aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 6- 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, 6- 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; １－６ aliphatic, said 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, said phenyl, said 8- to 10-membered bicyclic aryl, said 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, said 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, said 5- to 6-membered monocyclic heteroaryl, and said 8- to 10-membered bicyclic heteroaryl each optionally comprises 1, 2, 3, or 4 independently selected R Ｎ substituted with a substituent, or When two R' are attached to the same nitrogen atom, they combine to form a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl optionally contains 1, 2, 3, or 4 independently selected R Ｎ is substituted with a substituent, Each R １Ａ , R ３Ａ , R ４Ａ , R ６Ａ , R ８Ａ , R ９Ａ , R １１Ａ , R Ｂ１ , R Ｄ１ and R Ｎ are independently halogen, -(CH ２ ) ０－４ R O , -(CH ２ ) ０－４ OR O , -O(CH ２ ) ０－４ R ｏ , —O—(CH ２ ) ０－４ C(O)OR O , -(CH ２ ) ０－４ CH (OR O ) ２ , -(CH ２ ) ０－４ SR O , -(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 O ) ２ , -(CH ２ ) ０－４ N (R O ) C(O)R O , -N(R O ) C(S)R O , -(CH ２ ) ０－４ N (R O )C(O)NR O ２ , -N(R O ) C(S)NR O ２ , -(CH ２ ) ０－４ N(R O )C(O)OR O 、-N(R O )N(R O )C(O)R O 、-N(R O )N(R O )C(O)NR O ２ 、-N(R O )N(R O )C(O)OR O 、-(CH ２ ) ０－４ C(O)R O 、-C(S)R O 、-(CH ２ ) ０－４ C(O)OR O 、-(CH ２ ) ０－４ C(O)SR O 、-(CH ２ ) ０－４ C(O)OSiR O ３ 、-(CH ２ ) ０－４ OC(O)R O 、-OC(O)(CH ２ ) ０－４ SR O 、-(CH ２ ) ０－４ SC(O)R O 、-(CH ２ ) ０－４ C(O)NR O ２ 、-C(S)NR O ２ 、-C(S)SR O 、-SC(S)SR O 、-(CH ２ ) ０－４ OC(O)NR O ２ 、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH ２ C(O)R O 、-C(NOR O )R O 、-(CH ２ ) ０－４ SSR O , -(CH ２ ) ０－４ S (O) ２ R O , -(CH ２ ) ０－４ S(O) (=NR ｏ ) R O , -(CH ２ ) ０－４ S (O) ２ OR O , -(CH ２ ) ０－４ OS (O) ２ R O , -(CH ２ ) ０－４ -S(O) ２ NR O ２ , -(CH ２ ) ０－４ S(O) (=NR ｏ ) NR O ２ , -(CH ２ ) ０－４ S(O)R O , -N(R O ) S (O) ２ NR O ２ , -N(R O ) S (O) ２ R O , -N(R O )S(O)(=NR ｏ ) R O , -N(OR O ) R O , —C(NH)NR O ２ , -P(O) ２ R O , -P(O)R O ２ , -OP(O)R O ２ , -OP(O)(OR O ) ２ , -SiR O ３ , -(C １－４ Linear or branched alkylene)O-N(R O ) ２ , and -(C １－４ linear or branched alkylene)C(O)O—N(R O ) ２ is selected from Each R O are 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 R O occurrences 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, and sulfur; Each R ｍ is independently —OH, —CN, or R; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

3. 10. The compound of claim 1, wherein the compound is a compound of formula VIII 【Transformation 8】 or a pharmaceutically acceptable salt thereof. [In the formula, X is -C(R １ )=, then Ring E is selected from 5-7 membered partially unsaturated carbocyclyl and 5-7 membered partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X is -C(R １ R ２ )- or -N(R ａ )-, then Ring E is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; q is 0, 1, 2, 3, or 4; Each R ４Ａ are independently halogen, -(CH ２ ) ０－４ R O , -(CH ２ ) ０－４ OR O , -O(CH ２ ) ０－４ R ｏ , —O—(CH ２ ) ０－４ C(O)OR O , -(CH ２ ) ０－４ CH (OR O ) ２ , -(CH ２ ) ０－４ SR O , -(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 O ) ２ , -(CH ２ ) ０－４ N (R O ) C(O)R O , -N(R O ) C(S)R O , -(CH ２ ) ０－４ N (R O )C(O)NR O ２ , -N(R O ) C(S)NR O ２ , -(CH ２ ) ０－４ N (R O )C(O)OR O , -N(R O ) N (R O ) C(O)R O , -N(R O ) N (R O )C(O)NR O ２ 、-N(R O )N(R O )C(O)OR O 、-(CH ２ ) ０－４ C(O)R O 、-C(S)R O 、-(CH ２ ) ０－４ C(O)OR O 、-(CH ２ ) ０－４ C(O)SR O 、-(CH ２ ) ０－４ C(O)OSiR O ３ 、-(CH ２ ) ０－４ OC(O)R O 、-OC(O)(CH ２ ) ０－４ SR O 、-(CH ２ ) ０－４ SC(O)R O 、-(CH ２ ) ０－４ C(O)NR O ２ 、-C(S)NR O ２ 、-C(S)SR O 、-SC(S)SR O 、-(CH ２ ) ０－４ OC(O)NR O ２ 、-C(O)N(OR O )R O 、-C(O)C(O)R O 、-C(O)CH ２ C(O)R O 、-C(NOR O )R O 、-(CH ２ ) ０－４ SSR O 、-(CH ２ ) ０－４ S(O) ２ R O 、-(CH ２ ) ０－４ S(O)(=NR ｏ )R O , -(CH ２ ) ０－４ S (O) ２ OR O , -(CH ２ ) ０－４ OS (O) ２ R O , -(CH ２ ) ０－４ -S(O) ２ NR O ２ , -(CH ２ ) ０－４ S(O) (=NR ｏ ) NR O ２ , -(CH ２ ) ０－４ S(O)R O , -N(R O ) S (O) ２ NR O ２ , -N(R O ) S (O) ２ R O , -N(R O )S(O)(=NR ｏ ) R O , -N(OR O ) R O , —C(NH)NR O ２ , -P(O) ２ R O , -P(O)R O ２ , -OP(O)R O ２ , -OP(O)(OR O ) ２ , -SiR O ３ , -(C １－４ Linear or branched alkylene)O-N(R O ) ２ , and -(C １－４ linear or branched alkylene)C(O)O—N(R O ) ２ is selected from Each R O are 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 R O and the occurrences of are taken together with their intervening atoms to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. X is -N(R ａ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

5. R ａ Ga-L Ｒ３ -R ３ 2. The compound of claim 1, wherein:

6. L Ｒ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is a covalent bond.

7. R ３ is hydrogen or optionally substituted C １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is aliphatic.

8. R ａ Ga-CH ２ CH ３ 2. The compound of claim 1, wherein:

9. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein ring E is a pyrimidine ring, a pyrimidinone ring, a pyridazine ring, or a pyridazinone ring.

10. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein ring E is a pyrimidine ring.

11. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

12. Each R ４Ａ But independently, C １－６ Aliphatic and -OC １－６ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, selected from aliphatic.

13. Each R ４Ａ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein is independently selected from methyl and methoxy.

14. R ６ is hydrogen, deuterium, or optionally substituted C １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is aliphatic.

15. R ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or deuterium.

16. R ７ is hydrogen, deuterium, or optionally substituted C １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is aliphatic.

17. R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or deuterium.

18. R ６ and R ７ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is hydrogen.

19. R ６ and R ７ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is deuterium.

20. D ２ is C-L Ｄ２ -R ９ 2. The compound of claim 1, wherein:

21. L Ｄ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is a covalent bond.

22. R ９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

23. D ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is CH.

24. D ２ 2. The compound of claim 1, wherein is N, or a pharmaceutically acceptable salt thereof.

25. D ３ is CR １０ 2. The compound of claim 1, wherein:

26. R １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halogen.

27. R １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

28. D ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

29. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

30. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 nitrogen atoms.

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

32. 2. The compound of claim 1, wherein n is 0, or a pharmaceutically acceptable salt thereof. 【Request Item 33】 【Chemistry 9】 but 【Chemistry 10】 2. The compound of claim 1, wherein:

34. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

35. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 6-membered monocyclic heteroaryl having 1 to 2 nitrogen atoms.

36. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl.

37. Ring C 【Chemistry 11】 2. The compound of claim 1, wherein:

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

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

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

41. 【Chemistry 12】 but, 【Chemistry 13】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

42. Each L ＲＣ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is a covalent bond.

43. Each R １２ are independently halogen, C １－６ Aliphatic, -C(O)N(R) ２ 2. The compound of claim 1, wherein the compound is selected from:

44. Each R １２ is independently selected from fluoro, methyl, —C(O)NHR, and —C(O)NH(OR), or a pharmaceutically acceptable salt thereof.

45. Each R is independently hydrogen, C １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

46. 【Chemistry 14】 but, 【Chemistry 15】 is selected from Each R Ｃ is independently selected from methyl and fluoro; Each R is independently hydrogen, C １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

47. 2. The compound of claim 1, wherein each R is independently selected from methyl, cyclopropyl, methoxy, cyclopropylmethoxy, cyanocyclopropyl, cyanomethylcyclopropyl, hydroxymethylcyclopropyl, methoxymethylcyclopropyl, cyclobutyl, cyanocyclobutyl, hydroxycyclobutyl, difluorocyclobutyl, cyanocyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, 3-oxabicyclo[3.1.0]hexanyl, methylpyrrolidinyl, and methylpiperidinyl, or a pharmaceutically acceptable salt thereof.

48. 【Chemistry 16】 but, 【Chemistry 17-1】 【Chemistry 17-2】 2. The compound of claim 1, wherein:

49. X is -N(R ａ ) - and R ａ Ga-L Ｒ３ -R ３ and L Ｒ３ is a covalent bond, R ３ is hydrogen or optionally substituted C １－６ is aliphatic, Ring E is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R ４Ａ But independently, C １－６ Aliphatic and -OC １－６ selected from aliphatic R ６ is hydrogen, deuterium, or optionally substituted C １－６ is aliphatic, R ７ is hydrogen, deuterium, or optionally substituted C １－６ is aliphatic, D ２ is CH, D ３ is CR １０ and R １０ is hydrogen or halogen, Ring B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L ＲＣ is a covalent bond, Each R １２ are independently halogen, C １－６ Aliphatic, -C(O)N(R) ２ and —C(O)NR(OR); Each R is independently hydrogen, C １－６ selected from aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is 0 or 2; p is 1, 2, or 3; 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

50. X is -N(R ａ ) - and R ａ Ga-L Ｒ３ -R ３ and L Ｒ３ is a covalent bond, R ３ is hydrogen or optionally substituted C １－６ is aliphatic, Ring E is a pyrimidine ring, a pyrimidinone ring, a pyridazine ring, or a pyridazinone ring; Each R ４Ａ But independently, C １－６ Aliphatic and -OC １－６ selected from aliphatic R ６ is hydrogen, deuterium, or optionally substituted C １－６ is aliphatic, R ７ is hydrogen, deuterium, or optionally substituted C １－６ is aliphatic, D ２ is CH, D ３ is CR １０ and R １０ is hydrogen or halogen, Ring B [Chemistry 18] and Ring C is phenyl or a 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each L ＲＣ is a covalent bond, Each R １２ are independently halogen, C １－６ Aliphatic, -C(O)N(R) ２ and —C(O)NR(OR); Each R is independently hydrogen, C １－６ selected from aliphatic, 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, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is 0, p is 1, 2, or 3; 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

51. The compound of claim 1, wherein the compound is a compound of formula IX-a 【Chemistry 19】 or a pharmaceutically acceptable salt thereof.

52. The compound of claim 1, wherein the compound is selected from the following: 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; N-methyl-5-(4-((2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-5-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-7'-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; N-methyl-5-(4-((1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; N-methyl-5-(4-((3-methyl-4-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]quinolin-7-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-(2,2-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((6-ethyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-2-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((4-ethyl-5-oxo-2,3,5,6-tetrahydropyrano[4,3,2-de]quinolin-8-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide; 5-(4-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide; N,6-dimethyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; N-methyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)-6-(trifluoromethyl)picolinamide; 6-fluoro-N-methyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 6-fluoro-5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide; 5-(4-((4-fluoro-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide; N,6-dimethyl-5-(4-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide; 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; and 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide; or a pharmaceutically acceptable salt thereof.

53. The compound of claim 1, wherein the compound is selected from the following: 5-(4-((3-ethyl-6-fluoro-1-methyl-4-oxo-1,3,4,5-tetrahydropyrazolo[3,4,5-de]quinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-bis(methyl-d3)picolinamide; 5-(4-((5-(difluoromethyl)-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((8-fluoro-5-methoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-chloro-3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-cyclopropyl-3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-8-fluoro-5-(hydroxymethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-(cyanomethyl)-3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-chloro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide; 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-bis(methyl-d3)picolinamide; 5-[4-[(12-ethyl-11-oxo-2,3,10,12-tetraazatricyclo[7.3.1.05,13]trideca-1,3,5,7,9(13)-pentaen-7-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide; 5-(4-((3-ethyl-8-fluoro-5-(methoxymethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-(difluoromethyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide; and 5-(4-((5-cyclopropyl-8-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1, wherein the compound is selected from the following: 5-(4-((3-ethyl-9-fluoro-5-methoxy-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-6-methyl-2,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-5-methyl-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl-d2)piperazin-1-yl)-N,6-dimethylpicolinamide; 5-(4-((9-ethyl-6-fluoro-3-methyl-8-oxo-8,9-dihydro-7H-pyridazino[3,4,5-de]quinazolin-5-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide; N-cyclopropyl-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-cyclopropyl-5-(4-((9-ethyl-6-fluoro-3-methyl-8-oxo-8,9-dihydro-7H-pyridazino[3,4,5-de]quinazolin-5-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methoxy-6-methylpicolinamide; N-(cyclopropylmethoxy)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)-6-methylpicolinamide; N-((1r,3r)-3-cyanocyclobutyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydro-2H-pyran-4-yl)picolinamide; N-(1-cyanocyclopropyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; (S)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide; N-(3,3-difluorocyclobutyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-((1s,3s)-3-cyanocyclobutyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-(1-(methoxymethyl)cyclopropyl)-6-methylpicolinamide; (R)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide; (R)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide; N-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylazetidin-3-yl)picolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)-6-methylpicolinamide; (S)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide; N-((1s,4s)-4-cyanocyclohexyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-((1r,4r)-4-cyanocyclohexyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylpiperidin-4-yl)picolinamide; (R)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylpyrrolidin-3-yl)picolinamide; (S)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methyl-N-(1-methylpyrrolidin-3-yl)picolinamide; N-(1-(cyanomethyl)cyclopropyl)-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; N-cyclopropyl-5-(4-((9-ethyl-6-fluoro-2-methyl-3,8-dioxo-2,7,8,9-tetrahydro-3H-pyridazino[3,4,5-de]quinazolin-5-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; 4-[4-[(6-ethyl-10-fluoro-7-oxo-2,4,6,8-tetraazatricyclo[7.3.1.05,13]trideca-1,3,5(13),9,11-pentaen-11-yl)methyl]piperazin-1-yl]-N,3-dimethyl-benzamide; N-cyclopropyl-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-methylbenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-N-methoxy-3-methylbenzamide; N-(cyclopropylmethoxy)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-methylbenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide; N-cyclopropyl-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluorobenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluoro-N-methoxybenzamide; N-(cyclopropylmethoxy)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluorobenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluoro-N-methylbenzamide; N-cyclopropyl-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluorobenzamide; 4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluoro-N-methoxybenzamide; N-(cyclopropylmethoxy)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluorobenzamide; N-(1-(cyanomethyl)cyclopropyl)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-methylbenzamide; N-(1-(cyanomethyl)cyclopropyl)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-3-fluorobenzamide; N-(1-(cyanomethyl)cyclopropyl)-4-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-2,3-difluorobenzamide; and N-cyclobutyl-5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]quinazolin-8-yl)methyl)piperazin-1-yl)-6-methylpicolinamide; or a pharmaceutically acceptable salt thereof.

55. 55. A pharmaceutical composition comprising a compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

56. An agent for inhibiting PARP1, comprising a compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof.

57. 56. The pharmaceutical composition of claim 55 for treating a disease, disorder, or condition associated with PARP1.

58. 56. The pharmaceutical composition of claim 55 for treating cancer.

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