Compositions and methods for degrading the aromatic hydrocarbon receptor nuclear translocation protein

Abstract

The present application provides compounds having ARNT degradation activity (e.g., compounds of Formula (A)) and pharmaceutically acceptable derivatives thereof. In addition, pharmaceutical compositions comprising the above-mentioned compounds, and methods of using these compounds to treat subjects having a disease or disorder mediated by ARNT are also provided.

Description

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 617,634, filed January 4, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This application provides compounds for compositions and methods of degrading aryl hydrocarbon receptor nuclear translocases (ARNTs). It also provides methods for treating, preventing, or improving diseases and conditions in which ARNT activity is undesirable. Background Technology

[0003] ARNT (HIF-1β) is an approximately 86 kDa protein encoded by the ARNT gene. ARNT contains a basic helical-loop-helical domain, two characteristic Per-Arnt-Sim (PAS) domains, and a PAC domain. This protein binds to a ligand-binding aryl hydrocarbon receptor (AhR) and assists in the translocation of this complex to the nucleus, thereby promoting the expression of genes involved in the metabolism of exogenous substances. ARNT is also a cofactor in the transcriptional regulation of hypoxia-inducible factors (HIFs), such as through the formation of heterodimers with HIF-1α, HIF-2α, and HIF-3α. In leukemia, a chromosomal translocation of this locus to the ETV6 gene (ets variant 6) on chromosome 12 has been described. Alternative splicing produces various transcript variants. ARNT can also form biologically significant heterodimers with AHRR, NPAS1, NPAS3, NPAS4, SIM1, and SIM2. See, for example, Wu and Rastinejad et al. Curr. Opin. Struct. Biol. 2017 43、1-9 .

[0004] AhR is a ligand-activated transcription factor that mediates numerous responses to toxic environmental chemicals such as TCDD or dioxin-like polychlorinated biphenyls (PCBs). AhR must form a heterodimer with ARNT to function as a transcription factor. Upon dimerization, the AhR:ARNT heterodimer induces transcription of genes containing exogenous substance response element (XRE) sequences in their promoters. Studies have also shown that the AhR pathway is selectively active in tumors overexpressing indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO / TDO) and is associated with resistance to immune checkpoint inhibitors. Selective blockade of AhR delays the progression of IDO / TDO-overexpressing tumors, and its efficacy is improved when used in combination with PD-1 blockers. See, for example, Campesato et al. Nat. Commun. 2020 11 4011.

[0005] HIFs are a class of proteins that bind to ARNTs to initiate hypoxia-induced gene expression. Elevated levels of two subtypes, HIF-1α and HIF-2α, are commonly found in malignant tumors and are frequently thought to play a role in tumorigenesis and poor patient prognosis. See, for example, Mandl et al. Cell Death Dis. 2016, 7, e2284. HIF-2α is a tumor-promoting factor in clear cell renal cell carcinoma and breast cancer. See, for example, Mazumder et al. Cancers (Basel) 2023, 15, 1316; de Heer et al., J. Clin. Invest. 2020, 130, 5074-87; Chen et al. Nature 2016, 539, 112-7; Kaelin, J. Clin. Invest. 2022, 132, e162480. HIF-1 is also a key mediator in pathogenic immune responses, such as lymphoid and myeloid immune regulation in autoimmune diseases, controlling the activation of macrophages, neutrophils, and dendritic cells. See, for example, Islam et al. Immunology 2021, 164, 31-42; Taylor and Scholz, Nat. Rev. Nephrol. 2022, 18, 573-87. HIF-2α / ARNT is also associated with the pathogenesis of ischemic heart disease (IHD). See, for example, Ullah et al. Biology (Basel) 2023, 12, 995.

[0006] Therefore, ARNT plays a central role in AhR and HIF signal transduction. See, for example, Vorrink and Domann. Chem. Biol. Interact. 2014, 218, 82-8. Therefore, there is a need for compounds and compositions used in methods for degrading ARNT, thereby mediating AhR and HIF signaling. Summary of the Invention

[0007] This application provides compounds having the structure of formula (A): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or its pharmaceutically acceptable derivatives; wherein: R 1 C1-C, whether substituted or not 10 Alkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl; R 2 and R 3 Each is independently H, deuterium, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C3-C 10 cycloalkyl; or R 2 and R 3 Together with the carbon atom it is attached to, it forms C(O) or substituted or unsubstituted C3-C. 10 cycloalkyl; R 13 It can be H, deuterium, or hydroxyl; X is CR 4 R 5 Or C(O), where R 4 and R 5 Each is independently H, deuterium, or substituted or unsubstituted C1-C 10 Alkyl; and c and d are each an independent integer, either 0, 1, or 2.

[0008] This application also provides compounds and compositions for degrading ARNT, wherein the compounds have the structure of formula (I): ; Its pharmaceutically acceptable derivatives, among which: R 1 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R 2 and R 3 Each is independently H, alkyl or cycloalkyl, or R 2 and R 3 Together they form spirocycloalkyl groups; a and b are each independently selected from integers from 1 to 3; and X is CR 4 R 5 Or C(O), where R 4 and R 5 Each is independently H, alkyl, or arylalkyl.

[0009] This application also provides a pharmaceutical composition comprising the above-described compounds provided in this application (e.g., compounds of formula (A) or (I)), or their enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; or their pharmaceutically acceptable derivatives; and pharmaceutically acceptable excipients.

[0010] Furthermore, this application also provides a method for treating, preventing, or improving one or more ARNT-mediated disease or symptom symptoms in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound provided in this application (e.g., compound of formula (A) or compound of formula (I), or an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug; or a pharmaceutically acceptable derivative thereof.

[0011] This application also provides a method for treating, preventing, or improving symptoms of one or more cancers in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound provided in this application (e.g., a compound of formula (A) or formula (I), or an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug; or a pharmaceutically acceptable derivative thereof.

[0012] This application also provides a method for inhibiting cell growth, comprising contacting the cells with an effective amount of a compound provided in this application (e.g., a compound of formula (A) or formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug; or a pharmaceutically acceptable derivative thereof.

[0013] This application also provides a method for inducing ARNT degradation, comprising contacting the ARNT with an effective amount of a compound provided in this application (e.g., a compound of formula (A) or formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug; or a pharmaceutically acceptable derivative thereof. Attached Figure Description

[0014] Figure 1 The dose-response curves for ARNT degradation induced by compound A001 in NCI-H929 cells are shown.

[0015] Figure 2The dose-response curves of ARNT degradation induced by (3-(5-(1-benzyl-4-hydroxypiperidin-4-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione) are shown.

[0016] Figure 3 The dose-response curves of Helios degradation induced by compound A001 in a 24-hour HiBiT assay are shown.

[0017] Figure 4 Two dose-response plots are shown for the induction of Helios degradation using (3-(5-(1-benzyl-4-hydroxypiperidin-4-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione) in a 24-hour HiBiT assay.

[0018] Figure 5 The dose-response curves of Helios degradation induced by compound A001 in the 6-hour Jurkat cell line are shown.

[0019] Figure 6 The dose-response curves of Helios degradation induced by (3-(5-(1-benzyl-4-hydroxypiperidin-4-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione) in the 6-hour Jurkat cell line are shown.

[0020] Figure 7 The dose-response curve of VEGF inhibition using compound A001 is shown. Detailed Implementation

[0021] I. Definition: To facilitate understanding of the content disclosed in this application, some terms are defined below.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. If multiple definitions exist for a term in this application, the definition in this section shall prevail unless otherwise stated.

[0023] Unless the context clearly indicates otherwise, the singular forms “a”, “an”, and “the” include plural references.

[0024] As used in this application, "subject" means animal, such as a mammal, including humans, such as patients.

[0025] As used herein, "biological activity" refers to the activity of a compound in vivo, or the physiological response produced after administration of a compound, composition, or other mixture to the body. Therefore, biological activity encompasses both the therapeutic effects and pharmacokinetic behavior of such compounds, compositions, and mixtures. Biological activity can be observed in in vitro systems designed to test such activity.

[0026] As used in this application, "pharmaceutically acceptable derivatives" of compounds include, but are not limited to, their salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, inclusion compounds, solvates, or hydrates. Such derivatives can be readily prepared by those skilled in the art using known derivatization methods. The resulting compounds can be administered to animals or humans without substantial toxicity, and the compounds are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as, but not limited to, amine salts. N,N' -Dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N methylglucosamine, procaine, N -Benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidone-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as, but not limited to, lithium, potassium and sodium salts; alkaline earth metal salts, such as, but not limited to, barium, calcium and magnesium salts; transition metal salts, such as, but not limited to, zinc salts; and inorganic salts, such as, but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as, but not limited to, hydrochlorides and sulfates; and salts of organic acids, such as, but not limited to, acetates, lactates, malates, tartrates, citrates, ascorbic acid salts, succinates, butyrates, valerates, methanesulfonates and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl esters, alkenyl esters, alkynyl esters, aryl esters, arylalkyl esters and cycloalkyl esters with acidic groups, said acidic groups including, but not limited to, carboxylic acids, phosphoric acids, phosphonic acids, sulfonic acids, sulfinic acids and boric acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the formula -C=C(OR), wherein R is alkyl, alkenyl, alkynyl, aryl, arylalkyl, and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula -C=C(OC(O)R), wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of compounds with one or more solvent molecules or water molecules, or with 1 to about 100, 1 to about 10, or 1 to about 2, 3, or 4 solvent molecules or water molecules.

[0027] As used in this application, "treatment" means any manner that alleviates or otherwise beneficially alters one or more symptoms of a disease or condition. "Treatment" also covers any pharmaceutical use of the composition of the application, such as for treating a disease or condition involving ARNT activity.

[0028] As used in this application, “improvement” of symptoms of a particular condition by applying a particular compound or pharmaceutical composition means any relief attributable to or related to the application of the compound or pharmaceutical composition, whether permanent or temporary, lasting or transient.

[0029] As used herein, unless otherwise stated, the terms “manage,” “managing,” and “management” include preventing the recurrence of a particular disease or condition in a subject who already has that disease or condition, and / or prolonging the time a subject with that disease or condition remains in remission. These terms include modulating the threshold, occurrence, and / or duration of the disease or condition, or altering how a subject responds to the disease or condition.

[0030] When groups are specified by their conventional chemical formula (written from left to right), they also cover chemically identical groups that would result from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0031] Unless otherwise stated, the term "alkyl" (whether used alone or as part of another substituent) refers to an alkyl group having a specified number of carbon atoms (i.e., C1-C2). 10 A straight-chain (i.e., unbranched) or branched saturated hydrocarbon group (representing 1 to 10 carbon atoms) may include divalent and polyvalent groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0032] Unless otherwise stated, the term "alkenyl" (whether used alone or as part of another substituent) refers to an alkenyl group having a specified number of carbon atoms (i.e., C1-C2). 10 Alkenes are straight-chain (i.e., unbranched) or branched hydrocarbon groups having one or more carbon-carbon double bonds (representing 1 to 10 carbon atoms), and may include divalent and polyvalent groups. Examples of alkenes include, but are not limited to, vinyl (i.e., methinel), 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and more advanced homologues and isomers.

[0033] Unless otherwise stated, the term "alkynyl" (whether used alone or as part of another substituent) refers to a group having a specified number of carbon atoms (i.e., C1-C2).10 A straight-chain (i.e., unbranched) or branched hydrocarbon group (representing 1 to 10 carbon atoms) having one or more carbon-carbon triple bonds, which may include divalent and polyvalent groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologues and isomers.

[0034] The term "alkylene" (whether used alone or as part of another substituent) refers to a divalent group derived from an alkyl group, examples of which include, but are not limited to, -CH. 2c H 2c H 2c H2-. Typically, alkyl (or alkylene) groups will have 1 to 24 carbon atoms, including groups with 10 or fewer carbon atoms. “Lower alkyl” or “lower alkylene” refers to shorter-chain alkyl or alkylene groups, typically having six or fewer carbon atoms.

[0035] The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups that are attached to the rest of the molecule by an oxygen, amino, or sulfur atom, respectively.

[0036] Unless otherwise stated, the term "heteroalkyl" (whether used alone or in combination with other terms) refers to a straight-chain or branched hydrocarbon group containing a heteroatom selected from O, N, P, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, the nitrogen atom may have alkyl substituents to satisfy a valence, and / or may optionally be quaternized. The heteroatoms O, N, P, Si, and S may be located at any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. A maximum of two heteroatoms can be adjacent, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" (whether used alone or as part of another substituent) refers to a divalent group derived from a heteroalkylene group, examples of which include, but are not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For alkylene and heteroalkylene linking groups, the direction in which the linking group is written does not imply its orientation. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-.

[0037] Unless otherwise stated, the terms “cycloalkyl” and “heterocycloalkyl” (whether used alone or in combination with other terms) refer to the cyclic form of “alkyl” and “heteroalkyl”, respectively, including bicyclic, tricyclic, and bridged bicyclic groups. Furthermore, for heterocycloalkyl groups, the heteroatom may occupy a position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and bicyclic [2.2.2]octyl. Examples of heterocyclic alkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, 1-azabicyclo[2.2.2]octyl and 2-azabicyclo[2.2.2]octyl.

[0038] Unless otherwise stated, the term "halogen" (whether used alone or as part of another substituent) refers to a fluorine, chlorine, bromine, or iodine atom. Furthermore, terms such as "haloalkyl" include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0039] Unless otherwise stated, the term "aryl" refers to an aromatic hydrocarbon substituent comprising multiple unsaturated bonds, which may be monocyclic or polycyclic (one to three rings in one embodiment) fused or covalently linked together. The term "heteroaryl" refers to an aryl group containing one to four heteroatoms selected from N, O, and S in a ring, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via carbon atoms or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrole, 2-pyrrole, 3-pyrrole, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxolinyl, 5-quinoxolinyl, 3-quinolinyl, and 6-quinolinyl. The substituents in the aryl and heteroaryl ring systems may be selected from the acceptable substituents described in this application. The term "heteroarylium" refers to a heteroaryl group with a positive charge on one or more heteroatoms.

[0040] As used in this application, the term "oxo" refers to an oxygen atom that is double-bonded to a carbon atom.

[0041] The terms above (e.g., "alkyl", "heteroalkyl", "aryl", and "heteroaryl") are intended to include both substituted and unsubstituted forms of the group. Non-limiting examples of substituted groups for each type of group are provided below.

[0042] In one embodiment, the substituents of alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are selected from: deuterium, -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R"', -OC(O)NR'R"', -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R'")=NR"', -NR-C(NR'R")=NR', -S(O)R', -S(O)2R', -S(O)2NR'R"', -NRSO2R', -NRSO2NR The substitutions for 'R'', -CN, and -NO2 range from zero to the number of hydrogen atoms in the group. In one embodiment, the substituents of the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups further include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl groups. In one embodiment, R', R", R"', and R"" are each independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy, or arylalkyl. When the compounds provided in this application include more than one R group, for example, each R group is independently selected; similarly, when more than one R', R", R"' is present... When R' and R" are attached to the same nitrogen atom, each of these groups is also independently chosen. When R' and R" are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituent groups, those skilled in the art will understand that the term "alkyl" is intended to include groups in which a carbon atom is bonded to a non-hydrogen group, such as haloalkyl groups (e.g., -CF3 and -CH). 2c F3) and acyl groups (e.g., -C(O)CH3, -C(O)CF3 and -C(O)CH2OCH3).

[0043] The substituted groups of aryl and heteroaryl groups, in one embodiment, are selected from: deuterium, halogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R R', R"', R"', -NR-C(NR'R")=NR"", -NR-C(NR'R")=NR', -S(O)R', -S(O)2R', -S(O)2NR'R"", -NRSO2R', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, wherein the number of substitutions ranges from zero to the total number of hydrogen atoms on the aromatic ring system; and in one embodiment, R', R"', R"' R and R"" are each independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds provided in this application include more than one R group, for example, each R group is independently selected; similarly, when more than one R', R", R"', and R"" group is present, each of these groups is also independently selected.

[0044] Two substituent groups on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula -Q'-C(O)-(CRR'). q A ring of the formula -Q''-, wherein Q' and Q'' are independently -NR-, -O-, -CRR'-, or single bonds, and q is an integer from 0 to 3. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH2). r The substituents -b- are replaced by -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. The single bonds of the newly formed ring may optionally be replaced by double bonds. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -(CRR'-). s -X'-(CR''R''') tThe substituents are replaced by -, wherein s and t are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. In one embodiment, the substituents R, R', R" and R'" are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0045] As used in this application, the term "heteroatom" or "cyclic heteroatom" includes oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0046] As used in this application, a prodrug refers to a compound that, after administration in vivo, is metabolized through one or more steps or processes, undergoes chemical changes under physiological conditions, or is otherwise converted into a biologically, pharmaceutically, or therapeutically active form of the compound. Furthermore, a prodrug can be converted into a biologically, pharmaceutically, or therapeutically active form of the compound in an in vitro environment via chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, it can be converted into the compound provided in this application.

[0047] Some of the compounds provided in this application may exist in both solvated and hydrated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of this disclosure. Some of the compounds provided in this application may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent to the intended use herein and are intended to be included within the scope of this disclosure.

[0048] Some of the compounds provided in this application have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, tautomers, geometric isomers, and single isomers are all included within the scope of this disclosure. The compounds provided in this application do not include those known in the art that are too unstable to be synthesized and / or isolated.

[0049] The compounds provided in this application may also contain atomic isotopes in non-natural proportions on one or more atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variants of the compounds provided in this application, whether or not they are radioactive, are included within the scope of this disclosure.

[0050] II. Compounds used in compositions and methods: In one embodiment, this application provides a compound having the structure of formula (A): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or its pharmaceutically acceptable derivatives; wherein: R 1 C1-C, whether substituted or not 10 Alkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl; R 2 and R 3 Each is independently H, deuterium, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl; or R2 and R3 together with the carbon atom they are attached to form a C(O) or a substituted or unsubstituted C3-C. 10 cycloalkyl; R 13 It can be H, deuterium, or hydroxyl; X is CR 4 R 5 Or C(O), where R 4 and R 5 Each is independently H, deuterium, or substituted or unsubstituted C1-C 10 Alkyl; and c and d are each an independent integer, either 0, 1, or 2.

[0051] In another embodiment, this application provides compounds having the structure of formula (I) for use in the compositions and methods provided in this application: ; or pharmaceutically acceptable derivatives thereof, wherein: R 1 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R 2 and R 3 Each is independently H, alkyl or cycloalkyl, or R 2 and R 3 Together they form spirocycloalkyl groups; a and b are each independent integers from 1 to 3; and X is CR4 R 5 Or C(O), where R 4 and R 5 Each is independently H, alkyl, or arylalkyl.

[0052] In yet another embodiment, this application provides a compound having the structure of formula (Ia) for use in the compositions and methods provided in this application: ; or pharmaceutically acceptable derivatives thereof, wherein: R 1 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R 2 It is H, alkyl, or cycloalkyl; and X is CR 4 R 5 Or C(O), where R 4 and R 5 Each is independently H, alkyl, or arylalkyl.

[0053] In some implementations, X is CR 4 R 5 , where R 4 and R 5 Each is as defined herein. In some implementations, X is C(O).

[0054] In yet another embodiment, this application provides compounds having the structure of formula (II): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 1 R 2 R 3 R 4 R 5 R 13 c and d are each defined as in this article.

[0055] In yet another embodiment, this application provides a compound having the structure of formula (III): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 1 R 2 R 3 R 4 R 5 and R 13 Each as defined in this article.

[0056] In some implementations, R 1 It is either aryl or heteroaryl, each optionally converted to -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)-(CH2) m -R 10 or -S(O) p -(CH2) q -R 11 Replace; where R 6 H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 7 and R 8 Each is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 7 and R 8 Together with the atoms it is attached to, it forms a heterocyclic alkyl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl or a fused, bridged, or spirofused bicyclic cycloalkyl, or a monocyclic heterocyclic alkyl or a fused, bridged, or spirofused bicyclic heterocyclic alkyl; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and m, n, p, and q are each independently an integer from 0 to 2; or R 1 It is aryl or heteroaryl, each optionally fused with a cycloalkyl or heterocycloalkyl ring.

[0057] In some implementations, R 1It is either aryl or heteroaryl, each optionally converted to -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)-(CH2) m -R 10 or -S(O) p -(CH2) q -R 11 Replace; where R 6 H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 7 and R 8 Each is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 7 and R 8 Together with the atoms it is attached to, it forms a heterocyclic alkyl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl or a fused, bridged, or spirofused bicyclic cycloalkyl, or a monocyclic heterocyclic alkyl or a fused, bridged, or spirofused bicyclic heterocyclic alkyl; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and m, n, p, and q are each independently an integer from 0 to 2.

[0058] In some implementations, R 1 For aryl, optionally -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)-R 10 or -S(O)2-R 11Replace; where R 6 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R 7 and R 8 Each is independently H, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 7 and R 8 Together with the atoms it is attached to, it forms a heterocyclic alkyl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl or a fused, bridged, or spirofused bicyclic cycloalkyl, or a monocyclic heterocyclic alkyl or a fused, bridged, or spirofused bicyclic heterocyclic alkyl; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and n and p are each an independent integer from 0 to 2.

[0059] In some implementations, R 1 For aryl, optionally -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)-R 10 or -S(O)2-R 11 Replace; where R 6 It is a heterocyclic alkyl or aryl group; R 7 For H; R 8 It is a heterocyclic alkyl or aryl group; R 9 R 10 and R 11 Each is independently a monocyclic heterocyclic alkyl group or a fused, bridged, or spirofused bicyclic heterocyclic alkyl group; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; n is an integer of 0 or 1; and p is an integer from 0 to 2 independently.

[0060] In some implementations, R 1 For aryl, optionally -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)-R 10or -S(O)2-R 11 Replace; where R 6 It is a heterocyclic alkyl or aryl group; R 7 For H; R 8 It is a heterocyclic alkyl or aryl group; R 9 R 10 and R 11 Each is independently a monocyclic heterocyclic alkyl or a fused, bridged or spirofused bicyclic heterocyclic alkyl; and n is an integer of 0 or 1.

[0061] In some implementations, R 1 It is phenyl, optionally substituted as described herein.

[0062] In some implementations, R 1 For phenyl, optionally with -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 8 -C(O)-R 10 or -S(O)2-R 11 Replace; where R 6 It is a heterocyclic alkyl or aryl group; R 7 For H; R 8 It is a heterocyclic alkyl or aryl group; R 9 R 10 and R 11 Each is independently a monocyclic heterocyclic alkyl or a fused, bridged or spirofused bicyclic heterocyclic alkyl; and n is an integer of 0 or 1.

[0063] In some implementations, R 1 It is an unsubstituted phenyl group.

[0064] In some implementations, R 1 It is aryl, optionally fused with a cycloalkyl or heterocycloalkyl ring. In some embodiments, R 1 It is a phenyl group, optionally fused with a heterocyclic alkyl ring.

[0065] In some implementations, R 1 C 1- C 10 Alkyl, C3-C 10 cycloalkyl, C6-C 14 Aryl, C7-C 15The arylalkyl, heteroaryl, or heterocyclic alkyl groups are each optionally substituted with one, two, three, or four substituents, each substituent being independently deuterium, cyano, halogen, nitro, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CO2R', -CONR'R", -OR', -OC(O)R', -OC(O)NR'R", -NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'C(O)NR"R"', -NRSO2R', -NRSO2NR'R"', -SR', -S(O)R', -S(O)2R' or -S(O)2NR'R"; wherein each R', R" and R"' is independently hydrogen, substituted or unsubstituted C 1- C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl; or R' and R" together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C 10 Cycloalkyl, or substituted or unsubstituted heterocyclic alkyl.

[0066] In some implementations, R 1 For C1-C 10 烷基 C3-C 10 cycloalkyl, C6-C 14 Aryl, C7-C 15 Arylalkyl, heteroaryl, or heterocyclic alkyl groups, each optionally substituted with one or more substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C 1- C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0067] In some implementations, R 1 C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 1 For C1-C 10 Alkyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C 1- C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 Aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 It is isopropyl.

[0068] In some implementations, R 1 C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R1 is C3-C. 10Cycloalkyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0069] In some implementations, R 1 For substituted or unsubstituted monocyclic C3-C 10 Cycloalkyl. In some embodiments, R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, which may optionally be substituted. In some embodiments, R 1 Cyclohexyl group, whether substituted or unsubstituted.

[0070] In some implementations, R 1 For substituted or unsubstituted bicyclic C3-C 10 Cycloalkyl. In some embodiments, R1 is bridged, fused, or spirocyclic C4-C. 10 Cycloalkyl groups, which are optionally substituted. In some embodiments, R 1 For replacement or non-replacement of bridge connection C5-C 10 Cycloalkyl. In some embodiments, R 1 It is a substituted or unsubstituted bicyclic [1.1.1]pentyl group. In some embodiments, R 1 For substituted or unsubstituted bicyclic [1.1.1]pentane-1-yl. In some embodiments, R 1 For substituted or unsubstituted fused C4-C 10 Cycloalkyl. In some embodiments, R 1 For substituted or unsubstituted spirorings C4-C 10 Cycloalkyl. In some embodiments, R1 It is cyclohexyl, 4-aminocyclohexyl, or 3-fluorobicyclo[1.1.1]pentan-1-yl.

[0071] In some implementations, R 1 C6-C, whether substituted or not 14 Aryl. In some embodiments, R 1 For C6-C 14 The aryl group is optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0072] In some implementations, R 1 The phenyl group may be substituted or unsubstituted. In some embodiments, R... 1 It is a phenyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14芳基 C7-C, substituted or unsubstituted 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 It is a phenyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10杂 Alkyl, substituted or unsubstituted C6-C 14 Aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, or -OR'; wherein R' is a substituted or unsubstituted C1-C. 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl.

[0073] In some implementations, R 1 It is a phenyl group, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methyl-sulfonyl, or aminosulfonyl. In some embodiments, R 1 It is phenyl, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, morpholinylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methylpyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0074] In some implementations, R 1It is a phenyl group, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H- -pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1 It is phenyl, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoro-methyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, morpholinomethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, or phenoxy.

[0075] In some implementations, R 1为Phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 4-(tetrahydro-2H-pyran-4-ylmethyl)phenyl, 4-(morpholinylmethyl)phenyl, 4-hydroxy Methylphenyl, 4-methoxymethyl-phenyl, 4-phenoxymethylphenyl, 4-((dimethylamino)methyl)phenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-methylphenyl, 3,4-di(trifluoromethyl)phenyl, 3-cyclobutylphenyl, 4-cyclobutylphenyl, 4-cyclohexylphenyl, 4-phenylphenyl, 4-(pyrazol-1-yl)phenyl, 4-(1-methylpyrazol-3-yl)phenyl, 4-(1-methylpyrazol-4-yl)phenyl, 4-(2-methylpyrazol-3-yl)phenyl, 3-(oxetane-3-yl)phenyl, 4-(oxetane-3-yl)phenyl, 3-(tetrahydro-2H-pyran) -4-yl)phenyl, 4-(tetrahydro-2H-pyran-4-yl)phenyl, 3-(piperidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(4,4-difluoropiperidin-1-yl)phenyl, 4-(4-(hydroxymethyl)piperidin-1-yl)phenyl, 4-(4-hydroxypiperidin-1-yl)phenyl, 3-morpholinylphenyl, 4-morpholinylphenyl, 3-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 4-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4 -Methoxyphenyl, 4-trifluoromethoxyphenyl, 4-(2-hydroxyethoxy)phenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzylmethoxyphenyl, 4-(piperidin-4-yloxy)-phenyl, 4-(tetrahydro-2H-pyran-4-yl)oxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 4-phenylaminophenyl, 3-amino-carbonylphenyl, 4-aminocarbonylphenyl, 3-methylaminocarbonylphenyl, 4-methylamino-carbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-(methanesulfonyl)phenyl, or 4-aminosulfonylphenyl.

[0076] In some implementations, R 1The following are listed: phenyl, 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 3-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-(tetrahydro-2H-pyran-4-ylmethyl)phenyl, 4-methoxymethyl Phenyl, 4-phenylphenyl, 4-(pyrazol-1-yl)phenyl, 4-(1-methylpyrazol-3-yl)phenyl, 4-(1-methylpyrazol-4-yl)-phenyl, 4-(piperidin-1-yl)phenyl, 3-morpholinylphenyl, 3-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 4-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 3-phenoxyphenyl, or 4-phenoxyphenyl.

[0077] In some implementations, R 1 For substituted or unsubstituted bicyclic C8-C 14 Aryl. In some embodiments, R1 is a bicyclic C8-C 14 Aryl, optionally substituted with one, two or three substituents, each independently being deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 The 2,3-dihydroindenyl group may be substituted or unsubstituted. In some embodiments, R... 1 It is substituted or unsubstituted 2,3-dihydroinden-2-yl.

[0078] In some implementations, R 1 C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R1 C7-C 15 Arylalkyl, optionally substituted with one, two or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 The benzyl group may be substituted or unsubstituted. In some embodiments, R 1 It is benzyl or 3-fluorobenzyl.

[0079] In some implementations, R 1 For substituted or unsubstituted heteroaryl groups. In some embodiments, R 1 It is a heteroaryl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0080] In some implementations, R 1 It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 1为 The 5- or 6-membered heteroaryl group is optionally substituted. In some embodiments, R 1为 Substituted or unsubstituted 5-membered heteroaryl group. In some embodiments, R 1 It is a 5-membered heteroaryl group. Each substituent is independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 The group is isoxazolyl, oxazolyl, pyrazolyl, thiazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, or tetrazolyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1 The derivative is isoxazol-4-yl, oxazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, thiazolyl-2-yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, or tetrazol-5-yl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1为Isoxazol-4-yl, oxazol-2-yl, pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 3-methylpyrazol-4-yl, 1-(trifluoromethyl)pyrazol-4-yl, 1-(isopropyl)pyrazol-3-yl, 1-(isopropyl)pyrazol-4-yl, 1-phenyl-pyrazol-4-yl, thiazole-2-yl, 5-methylthiazole-2-yl, 1,2,4-triazole-3-yl, 5-methyl-1,3,4-thiadiazole-2-yl, or tetrazol-5-yl.

[0081] In some implementations, R 1 For substituted or unsubstituted 6-membered heteroaryl groups. In some embodiments, R 1 It is a 6-membered heteroaryl group. Each substituent can be independently deuterated, cyano, halogenated, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 It is pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoro-methyl, isopropyl, or phenyl. In some embodiments, R 1为 Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-hydroxypyridin-4-yl, or 1-methyl-2-oxo-1,2-dihydropyridin-4-yl.

[0082] In some implementations, R 1 For substituted or unsubstituted bicyclic heteroaryl groups. In some embodiments, R 1 It is a 5,5-fused, 5,6-fused, or 6,6-fused heteroaryl group, each optionally substituted. In some embodiments, R 1For substituted or unsubstituted 5,5-fused heteroaryl groups. In some embodiments, R 1 It is a 5,5-fused heteroaryl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1为 5,6-Dihydro-cyclopentano[d]thiazolyl or 6,7-dihydropyrrolo[1,2-]imidazolyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1 It is 5,6-dihydrocyclopenten[d]-thiazolyl-2-yl or 6,7-dihydropyrrolo[1,2-]imidazolyl-2-yl.

[0083] In some implementations, R 1为 Substituted or unsubstituted 5,6-fused heteroaryl groups. In some embodiments, R 1为 5,6-fused heteroaryl, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 The derivative is benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzo[d][1,2,3]triazolyl, imidazo[1,2-]pyridyl, indolyl, indazolyl, pyrazolo[1,5-]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-b]pyridyl, or [1,2,4]triazolo[1,5-]pyridyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1为 Benzofuran-6-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzothiazol-2-yl, benzo[d]-[1,2,3]triazol-5-yl, imidazo[1,2-]pyridin-2-yl, indole-5-yl, indole-6-yl, indazole-4-yl, indazole-5-yl, indazole-6-yl, pyrazolo[1,5-]pyridin-6-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrrolo[3,2-b]pyridin-2-yl, pyrrolo[3,2-b]pyridin-6-yl, or [1,2,4]triazolo[1,5-]pyridin-7-yl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl.

[0084] In some implementations, R 1为 2,3-Dihydroisoindolyl, 2,3-Dihydrobenzofuranyl, 1,3-Dihydroisobenzofuranyl, benzo[d][1,3]dioxane, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1It is 2,3-dihydroisoindol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 1,3-dihydroisobenzofuran-5-yl, benzo[d]-[1,3]dioxane-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl.

[0085] In some implementations, R 1为 Benzofuran-6-yl, 1-methylbenzimidazol-5-yl, 3-methylbenzimidazol-5-yl, benzoxazol-2-yl, benzothiazol-2-yl, 1-methylbenzo[d][1,2,3]triazol-5-yl, imidazo[1,2-a]pyridin-2-yl, 1-methylindole-5-yl, 1-methylindole-6-yl, indazole-5-yl, 1-methyl-indazole-4-yl, 1-methylindazole-5-yl, 1-methylindazole-6-yl, pyrazolo[1,5-a]pyridin-6-yl, 2,2-difluorobenzo[d][1,3]dioxazol-5-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrrolo[3,2-b]pyridin-2-yl, pyrrolo[3,2-b]pyridin-6-yl 2,2-Dimethylbenzo[d][1,3]dioxazol-5-yl, 2,2-dimethyl-2,3-dihydro-benzofuran-6-yl, [1,2,4]triazol[1,5-a]pyridin-7-yl, 1,3-dihydroisobenzofuran-5-yl, 2,3-dihydro-benzofuran-5-yl, 3-oxo-3,4-dihydro-1,4-benzo Oxazin-6-yl, 2,3-dihydroindene-2-yl, 2,3-dihydroisoindole-5-yl, 3-oxo-2,3-dihydroisoindole-5-yl, 2,3-dihydrobenzofuran-6-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl.

[0086] In some implementations, R 1 For substituted or unsubstituted 6,6-fused heteroaryl groups. In some embodiments, R 1 It is a 6,6-fused heteroaryl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10环 Alkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl. In some embodiments, R 1 The molecule is quinolinyl, chromanyl, 3,4-dihydropyrido[3,2-b][1,4]oxazinyl, or 3,4-dihydro-1,4-benzoxazinyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1为 Quinolin-2-yl, quinolin-3-yl, quinolin-6-yl, chroman-6-yl, chroman-7-yl, 3,4-dihydropyrido-[3,2-b][1,4]oxazin-7-yl, or 3,4-dihydro-1,4-benzoxazin-6-yl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl. In some embodiments, R 1 It is quinoline-2-yl, quinoline-3-yl, quinoline-6-yl, chroman-6-yl, chroman-7-yl, 4-methyl-3,4-dihydropyrido[3,2-b][1,4]oxazin-7-yl, or 3-oxo-3,4-dihydro-1,4-benzoxazin-6-yl.

[0087] In some implementations, R 1 It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 1 It is a heterocyclic alkyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0088] In some implementations, R 1 It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 1 It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1 It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0089] In some implementations, R 1为 Substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 1为 A 6-membered heterocyclic alkyl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterated, cyano, halogenated, oxo, substituted, or unsubstituted C1-C. 10Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0090] In some implementations, R 1 It is an azacyclobutane, tetrahydropyranyl, piperidinyl, tetrahydrothiapyranyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 3-azaspiro[5.5]undecyl, or 8-azabicyclo[3.2.1]octyl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, phenyl, or pyridyl. In some embodiments, R 1 It is azacyclobutane-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydropyran-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiapyran-4-yl, 2-azaspiro[3.3]heptane-6-yl, 2-azaspiro[3.5]nonane-7-yl, 3-azaspiro[5.5]undecane-9-yl, or 8-azabicyclo[3.2.1]octane-3-yl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In some embodiments, R 1为1-Phenyrazine-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydropyran-3-yl, piperidin-4-yl, 1-(isopropyl)-piperidin-4-yl, 1-phenylpiperidin-3-yl, 1-phenylpiperidin-4-yl, 1-(2-chlorophenyl)piperidin-4-yl, 1-(3-chlorophenyl)piperidin-4-yl, 1-(4-chlorophenyl)piperidin-4-yl, 1-benzylpiperidin-4-yl, 1 -(pyridin-3-yl)piperidin-4-yl, 1-(pyridin-2-yl)piperidin-4-yl, 1-acetylpiperidin-4-yl, 1,1-tetrahydrothiapyran-4-yl, 2-azaspiro[3.3]heptane-6-yl, 2-azaspiro[3.5]nonane-7-yl, 8-phenyl-8-azabicyclo[3.2.1]octane-3-yl, or 3-azaspiro[5.5]undecane-9-yl. In some embodiments, R 1为 1-Phenylopirin-3-yl, 1-Phenylopirin-4-yl, 1-(3-chlorophenyl)piperidin-4-yl, or 1-(4-chlorophenyl)piperidin-4-yl.

[0091] In yet another embodiment, this application provides compounds having the structure of formula (IV): ; A mixture of two or more diastereomers, tautomers, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a pharmaceutically acceptable derivative thereof; wherein: R 1a R 1b R 1c R 1d and R 1e Each is independently H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl; or R 1a and R 1b Together with the carbon atom it is attached to, it forms a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic alkyl group; or R 1b and R 1c Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic alkyl group; and R 2 R 3 R 4 R 5 R 13 c, and d are each as defined in this article.

[0092] In yet another embodiment, this application provides compounds having the structure of formula (V): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 2 R 3 R 4 R 5 R 13 R 1a R 1b R 1c R 1d and R 1e Each as defined in this article.

[0093] In yet another embodiment, this application provides compounds having the structure of formula (VI): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 2 R 3 R 4 R 5 R 13 R 1a R 1b R 1c R 1d and R 1e Each as defined in this article.

[0094] In yet another embodiment, this application provides compounds having the structure of formula (VII): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 2 R 3 R 4 R 5 R 13 R 1a R 1b R 1c R 1d and R 1e Each as defined in this article.

[0095] In some implementations, R 1a R 1b R 1c R 1d and R 1e Each is independently H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0096] In some implementations, R 1a H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0097] In some implementations, R 1a 为 H. In some implementations, R 1a For deuterium. In some implementations, R 1a It is cyano. In some embodiments, R 1a It is a halogen. In some embodiments, R 1a It is fluorine or chlorine. In some embodiments, R 1a It is fluorine. In some embodiments, R 1a It is chlorine. In some implementations, R 1a C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 1a It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 1a It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1a It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1a C1-C, whether substituted or not 10 Heteroalkyl groups.

[0098] In some implementations, R 1a C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 1a It is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R1a C6-C, whether substituted or not 14 Aryl. In some embodiments, R 1a The phenyl group may be substituted or unsubstituted. In some embodiments, R... 1a C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 1a For substituted or unsubstituted heteroaryl groups. In some embodiments, R 1a It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 1a It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 1a For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1a The pyrazol group may be substituted or unsubstituted. In some embodiments, R 1a It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 1a为 Pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted, C1-C 10 Alkyl substitution. In some embodiments, R 1a It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 1a It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 1a It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0099] In some implementations, R 1a It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 1a It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1a It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 1aIt is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 1a It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 1a It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 1a It is either piperidin-1-yl or morpholino.

[0100] In some implementations, R 1a It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 1a It is a bridged, fused, or spirofused heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1a It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 1a The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 1a It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 1a It is a substituted or unsubstituted heterocyclic alkyl group.

[0101] In some implementations, R 1a For -COR', where R' is as defined herein. In some implementations, R 1a It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1a For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 1a The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1a For -OR', where R' is as defined herein. In some implementations, R 1a =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 1a为 -NR'R", where R' and R" are each as defined herein. In some implementations, R1a The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1a Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 1a The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1a For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 1a The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0102] In some implementations, R 1a The following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1a It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0103] In some implementations, R 1aThe following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1a It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0104] In some implementations, R 1b H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0105] In some implementations, R 1b For H. In some implementations, R 1bFor deuterium. In some implementations, R 1b It is cyano. In some embodiments, R 1b It is a halogen. In some embodiments, R 1b It is fluorine or chlorine. In some embodiments, R 1b It is fluorine. In some embodiments, R 1b为 Chlorine. In some implementations, R 1b C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 1b It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 1b It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1b It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 1b C1-C, whether substituted or not 10 Heteroalkyl groups.

[0106] In some implementations, R 1b C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 1b It is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 1b C6-C, whether substituted or not 14 Aryl. In some embodiments, R 1b The phenyl group may be substituted or unsubstituted. In some embodiments, R... 1b C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 1b For substituted or unsubstituted heteroaryl groups. In some embodiments, R 1b It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 1b为 The 5- or 6-membered heteroaryl group is optionally substituted. In some embodiments, R 1b For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1b The pyrazol group may be substituted or unsubstituted. In some embodiments, R 1b It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 1bC1-C is a C1-C structure in which pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl groups are optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 1b It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 1b It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 1b It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0107] In some implementations, R 1b It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 1b It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 1b It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1b It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 1b为 Substituted or unsubstituted 4-membered heterocyclic alkyl group. In some embodiments, R 1b It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 1b It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 1b It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 1b It is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 1b为 Oxycyclic butane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholinoyl, each optionally substituted. In some embodiments, R 1b It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 1b It is either piperidin-1-yl or morpholino.

[0108] In some implementations, R 1b It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 1b It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1b It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 1bIt is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 1b The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 1b It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 1b It is a substituted or unsubstituted heterocyclic alkyl group.

[0109] In some implementations, R 1b For -COR', where R' is as defined herein. In some implementations, R 1b It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1b For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 1b The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1b For -OR', where R' is as defined herein. In some implementations, R 1b =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 1b For -NR'R", where R' and R" are each as defined herein. In some implementations, R 1b The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1b Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 1b The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1b For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 1b The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0110] In some implementations, R 1bThe following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1b It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0111] In some implementations, R 1b The following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1b It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0112] In some implementations, R 1c为 H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0113] In some implementations, R 1c For H. In some implementations, R 1c For deuterium. In some implementations, R 1c It is cyano. In some embodiments, R 1c It is a halogen. In some embodiments, R 1c为 Fluorine or chlorine. In some implementations, R 1c It is fluorine. In some embodiments, R 1c It is chlorine. In some implementations, R 1c C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 1c为 Methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 1c It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1c为 Methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 1c为 Substituted or unsubstituted C1-C 10 Heteroalkyl groups.

[0114] In some implementations, R 1c C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 1cIt is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 1c为 Substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 1c The phenyl group may be substituted or unsubstituted. In some embodiments, R... 1c C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 1c For substituted or unsubstituted heteroaryl groups. In some embodiments, R 1c It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 1c It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 1c For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1c The pyrazol group may be substituted or unsubstituted. In some embodiments, R 1c It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 1c The C1-C group is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 1c为 1-Pyrazol-1-yl, 1-methylpyrazol-3-yl, 2-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 1c It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 1c It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0115] In some implementations, R 1c It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 1c为 Substituted or unsubstituted monocyclic heterocyclic alkyl groups. In some embodiments, R 1c为 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl groups are optionally substituted. In some embodiments, R 1c It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 1c It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 1c It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 1c It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 1c为 Substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 1cIt is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 1c It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 1c为 Oxycyclic butane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 1c为 Piperidin-1-yl or morpholino.

[0116] In some implementations, R 1c It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 1c It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1c It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 1c It is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 1c The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 1c It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 1c It is a substituted or unsubstituted heterocyclic alkyl group.

[0117] In some implementations, R 1c为 -COR', where R' is as defined herein. In some implementations, R 1c It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1c For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 1c The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1c为 -OR', where R' is as defined herein. In some implementations, R 1c =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 1c For -NR'R", where R' and R" are each as defined herein. In some implementations, R1c The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1c Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 1 c is -S(O)2R', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1c为 -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 1c The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0118] In some implementations, R 1c The following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methylpyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1c It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0119] In some implementations, R 1c为H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl 4,4-Difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1c It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0120] In some implementations, R 1d H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0121] In some implementations, R 1d For H. In some implementations, R 1dFor deuterium. In some implementations, R 1d It is cyano. In some embodiments, R 1d It is a halogen. In some embodiments, R 1d It is fluorine or chlorine. In some embodiments, R 1d It is fluorine. In some embodiments, R 1d It is chlorine. In some implementations, R 1d为 Substituted or unsubstituted C1-C 10 Alkyl group. In some embodiments, R 1d It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 1d It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1d It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 1d C1-C, whether substituted or not 10 Heteroalkyl groups.

[0122] In some implementations, R 1d C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 1d It is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 1d C6-C, whether substituted or not 14 Aryl. In some embodiments, R 1d The phenyl group may be substituted or unsubstituted. In some embodiments, R... 1d为 Substituted or unsubstituted C7-C 15 Arylalkyl. In some embodiments, R 1d For substituted or unsubstituted heteroaryl groups. In some embodiments, R 1d为 Substituted or unsubstituted monocyclic heteroaryl groups. In some embodiments, R 1d It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 1d For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1d The pyrazol group may be substituted or unsubstituted. In some embodiments, R 1d It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 1d为Pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted, C1-C 10 Alkyl substitution. In some embodiments, R 1d It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 1d It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 1d It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0123] In some implementations, R 1d It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 1d It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 1d It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1d It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 1d为 Substituted or unsubstituted 4-membered heterocyclic alkyl group. In some embodiments, R 1d为 Substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 1d It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 1d为 Substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 1d为 Oxyhexacyclic butylene, tetrahydropyranyl, piperidinyl, or morpholinyl, each optionally substituted. In some embodiments, R 1d It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 1d It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 1d It is either piperidin-1-yl or morpholino.

[0124] In some implementations, R 1d It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 1d It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1d It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 1dIt is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 1d The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 1d It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 1d It is a substituted or unsubstituted heterocyclic alkyl group.

[0125] In some implementations, R 1d For -COR', where R' is as defined herein. In some implementations, R 1d It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1d For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 1d The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1d For -OR', where R' is as defined herein. In some implementations, R 1d =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 1d For -NR'R", where R' and R" are each as defined herein. In some implementations, R 1d The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1d Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 1d The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1d For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 1d为 -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C 10 alkyl.

[0126] In some implementations, R 1dThe following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1d It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0127] In some implementations, R 1d The following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1d It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0128] In some implementations, R 1e H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0129] In some implementations, R 1e For H. In some implementations, R 1e For deuterium. In some implementations, R 1e It is cyano. In some embodiments, R 1e It is a halogen. In some embodiments, R 1e It is fluorine or chlorine. In some embodiments, R 1e It is fluorine. In some embodiments, R 1e It is chlorine. In some implementations, R 1e C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 1e It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 1e It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1e It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 1e为 Substituted or unsubstituted C1-C 10 Heteroalkyl groups.

[0130] In some implementations, R 1e C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 1eIt is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 1e C6-C, whether substituted or not 14 Aryl. In some embodiments, R 1e The phenyl group may be substituted or unsubstituted. In some embodiments, R... 1e C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 1e For substituted or unsubstituted heteroaryl groups. In some embodiments, R 1e It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 1e It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 1e For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1e为 Substituted or unsubstituted pyrazolyl group. In some embodiments, R 1e It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 1e The C1-C group is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 1e It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 1e It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 1e It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0131] In some implementations, R 1e It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 1e It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 1e It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 1eIt is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 1e It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 1e It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 1e It is either piperidin-1-yl or morpholino.

[0132] In some implementations, R 1e It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 1e为 Bridged, fused, or spirocyclic heterocyclic alkyl groups are optionally substituted. In some embodiments, R 1e It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 1e The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 1e It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 1e It is a substituted or unsubstituted heterocyclic alkyl group.

[0133] In some implementations, R 1e For -COR', where R' is as defined herein. In some implementations, R 1e It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1e For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 1e The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1e For -OR', where R' is as defined herein. In some implementations, R 1e为 -OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 1e For -NR'R", where R' and R" are each as defined herein. In some implementations, R1e The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1e Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 1e The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1e For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 1e The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0134] In some implementations, R 1e The following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1e It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0135] In some implementations, R 1eThe following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 1e It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0136] In some implementations, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form heteroaryl groups, which may optionally be substituted by one, two, or three substituents, each independently deuterated, cyano, halogenated, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10Alkyl, substituted or unsubstituted C1-C 10杂 Alkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0137] In some implementations, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heteroaryl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heteroaryl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted 6-membered heteroaryl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form furanyl, imidazoleyl, pyrroleyl, pyrazoleyl, 1,2,3-triazoleyl, or pyridinyl groups, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, halogen, or a substituted or unsubstituted C1-C group. 10 Alkyl group. In some embodiments, R 1a and R 1b Together with the carbon atoms attached thereto, they form furan-2,3-diyl, imidazole-4,5-diyl, pyrrole-2,3-diyl, pyrazole-4,5-diyl, 1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, fluorine, or methyl. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form furan-2,3-diyl, 1-methylimidazol-4,5-diyl, pyrrole-2,3-diyl, 1-methylpyrrole-2,3-diyl, pyrazole-4,5-diyl, 1-methylpyrazole-4,5-diyl, 1-methyl-1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl.

[0138] In some implementations, R 1a and R 1bTogether with the carbon atoms attached to them, they form substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form heterocyclic alkyl groups, which may optionally be substituted with one, two, or three substituents, each substituent being independently deuterium, oxo, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0139] In some implementations, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heterocyclic alkyl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heterocyclic alkyl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted six-membered heterocyclic alkyl groups. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form tetrahydrofurandiyl, pyrrolidinediyl, 1,3-m-dioxanediyl, oxodiyl, or morpholindiyl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, halogen, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R1a and R 1b Together with the carbon atoms attached thereto, they form tetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 1,3-dioxolane-4,5-diyl, tetrahydropyran-2,3-diyl, or morpholine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently oxo, fluorine, or methyl. In some embodiments, R 1a and R 1b Together with the carbon atoms attached to them, they form tetrahydrofuran-2,3-diyl, 5,5-dimethyltetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 2-oxopyrrolidine-3,4-diyl, 2,2-difluoro-1,3-dioxolane-4,5-diyl, 2,2-dimethyl-1,3-dioxolane-4,5-diyl, tetrahydropyran-2,3-diyl, 4-methylmorpholine-2,3-diyl, or 5-oxopyolane-2,3-diyl.

[0140] In some implementations, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 1b and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups. In some embodiments, R 1b and R 1b Together with the carbon atoms attached to them, they form heteroaryl groups, which may optionally be substituted by one, two, or three substituents, each of which is independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0141] In some implementations, R 1b and R 1b Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heteroaryl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heteroaryl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted 6-membered heteroaryl groups. In some embodiments, R 1b and R 1bc Together with the carbon atoms attached to them, they form furanyl, imidazoleyl, pyrroleyl, pyrazoleyl, 1,2,3-triazoleyl, or pyridinyl groups, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, halogen, or a substituted or unsubstituted C1-C group. 10 Alkyl group. In some embodiments, R 1b and R 1c Together with the carbon atoms attached thereto, they form furan-2,3-diyl, imidazole-4,5-diyl, pyrrole-2,3-diyl, pyrazole-4,5-diyl, 1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, fluorine, or methyl. In some embodiments, R 1b and R 1b Together with the carbon atoms attached to them, they form furan-2,3-diyl, 1-methylimidazol-4,5-diyl, pyrrole-2,3-diyl, 1-methylpyrrole-2,3-diyl, pyrazole-4,5-diyl, 1-methylpyrazole-4,5-diyl, 1-methyl-1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl.

[0142] In some implementations, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 1b and R 1cTogether with the carbon atoms attached to them, they form heterocyclic alkyl groups, optionally substituted with one, two, or three substituents, each independently being deuterium, oxo, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 Aryl, substituted or unsubstituted C7-C15 arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14芳基 C7-C, substituted or unsubstituted 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0143] In some implementations, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heterocyclic alkyl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heterocyclic alkyl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form substituted or unsubstituted six-membered heterocyclic alkyl groups. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form tetrahydrofurandiyl, pyrrolidinediyl, 1,3-m-dioxanediyl, oxodiyl, or morpholindiyl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, halogenated, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 1b and R 1cTogether with the carbon atoms attached thereto, they form tetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 1,3-dioxolane-4,5-diyl, tetrahydropyran-2,3-diyl, or morpholine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently oxo, fluorine, or methyl. In some embodiments, R 1b and R 1c Together with the carbon atoms attached to them, they form tetrahydrofuran-2,3-diyl, 5,5-dimethyltetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 2-oxopyrrolidine-3,4-diyl, 2,2-difluoro-1,3-dioxopentane-4,5-diyl, 2,2-dimethyl-1,3-dioxopentane-4,5-diyl, tetrahydropyran-2,3-diyl, 4-methylmorpholine-2,3-diyl, or 5-oxopyrroline-2,3-diyl.

[0144] In yet another embodiment, this application provides compounds having the structure of formula (VIII): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or its pharmaceutically acceptable derivatives; wherein: R 2a R 2b R 2c R 2d and R 2e Each is independently H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C 1- C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C15 arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl; or R 2a and R 2b and together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups; or R 2b and R 2c and together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups; and R 2 R 3 R 4 R 5 R 13 c and d are each defined as in this article.

[0145] In yet another embodiment, this application provides compounds having the structure of formula (IX): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 2 R 3 R 4 R 5 R 13 R 2a R 2b R 2c R 2d and R 2e Each as defined in this article.

[0146] In yet another embodiment, this application provides a compound having the structure of formula (X): ; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 2 R 3 R 4 R 5 R 13 R 2a R 2b R 2c R 2d and R 2e Each as defined in this article.

[0147] In another embodiment, this application provides compounds having the structure of formula (XI): Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof; wherein R 2 R 3 R 4 R 5 R 1 3. R 2a R 2b R 2c R 2d and R 2e Each as defined in this article.

[0148] ; In some implementations, R 2a R 2b R 2c R 2d and R 2e Each is independently H, deuterium, cyano, or halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0149] In some implementations, R 2a H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O )2 NR'R"; where each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10环 Alkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0150] In some implementations, R 2a For H. In some implementations, R 2a For deuterium. In some implementations, R 2a It is cyano. In some embodiments, R 2a It is a halogen. In some embodiments, R 2a It is fluorine or chlorine. In some embodiments, R 2a It is fluorine. In some embodiments, R 2a It is chlorine. In some implementations, R 2a C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 2a It can be methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 2a It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 2a It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 2a C1-C, whether substituted or not 10 Heteroalkyl groups.

[0151] In some implementations, R 2a C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 2aIt is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 2a为 Substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 2a The phenyl group may be substituted or unsubstituted. In some embodiments, R... 2a C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 2a For substituted or unsubstituted heteroaryl groups. In some embodiments, R 2a It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 2a It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 2a For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2a The pyrazole group may be substituted or unsubstituted. In some embodiments, R 2a It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 2a The C1-C group is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 2a It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 2a It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 2a It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0152] In some implementations, R 2a It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 2a It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2a It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 2aIt is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 2a为 Oxycyclic butane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholinoyl, each optionally substituted. In some embodiments, R 2a It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 2a It is either piperidin-1-yl or morpholino.

[0153] In some implementations, R 2a It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 2a It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2a It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 2a The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 2a It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 2a It is a substituted or unsubstituted heterocyclic alkyl group.

[0154] In some implementations, R 2a For -COR', where R' is as defined herein. In some implementations, R 2a It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2a For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 2a For -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2a For -OR', where R' is as defined herein. In some implementations, R 2a =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 2a For -NR'R", where R' and R" are each as defined herein. In some implementations, R2a The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2a Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 2a The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2a For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 2a The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0155] In some implementation schemes, R 2a The following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2a It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0156] In some implementations, R 2aThe following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2a It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0157] In some implementations, R 2b H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0158] In some implementations, R 2b For H. In some implementations, R 2bFor deuterium. In some implementations, R 2b It is cyano. In some embodiments, R 2b It is a halogen. In some embodiments, R 2b It is fluorine or chlorine. In some embodiments, R 2b It is fluorine. In some embodiments, R 2b It is chlorine. In some implementations, R 2b For substituted or unsubstituted C 1- C 10 Alkyl group. In some embodiments, R 2b It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 2b It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 2b It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 2b C1-C, whether substituted or not 10 Heteroalkyl groups.

[0159] In some implementations, R 2b C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 2b It is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 2b C6-C, whether substituted or not 14 Aryl. In some embodiments, R 2b为 Substituted or unsubstituted phenyl groups. In some embodiments, R 2b C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 2b For substituted or unsubstituted heteroaryl groups. In some embodiments, R 2b It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 2b It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 2b For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2b The pyrazol group may be substituted or unsubstituted. In some embodiments, R 2b It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 2bThe C1-C is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 2b It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 2b It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 2b It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0160] In some implementations, R 2b It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 2b It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 2b It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2b It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 2b It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 2b It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 2b It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 2b It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 2b It is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 2b It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 2b It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 2b It is either piperidin-1-yl or morpholino.

[0161] In some implementations, R 2b It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 2b It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2b It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 2bIt is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 2b The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 2b It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 2b It is a substituted or unsubstituted heterocyclic alkyl group.

[0162] In some implementations, R 2b For -COR', where R' is as defined herein. In some implementations, R 2b It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2b For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 2b The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2b For -OR', where R' is as defined herein. In some implementations, R 2b =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 2b For -NR'R", where R' and R" are each as defined herein. In some implementations, R 2b The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2b Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 2b为 -S(O)2R', where R' is a substituted or unsubstituted C1-C 10 Alkyl group. In some embodiments, R 2b For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 2b The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0163] In some implementations, R 2bThe following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2b It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0164] In some implementations, R 2b The following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2b It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0165] In some implementations, R 2c H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10Heteroalkyl, substituted or unsubstituted Cc-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0166] In some implementations, R 2c For H. In some implementations, R 2c For deuterium. In some implementations, R 2c It is cyano. In some embodiments, R 2c It is a halogen. In some embodiments, R 2c It is fluorine or chlorine. In some embodiments, R 2c It is fluorine. In some embodiments, R 2c It is chlorine. In some implementations, R 2c C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 2c It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 2c It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 2c It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 2c C1-C, whether substituted or not 10 Heteroalkyl groups.

[0167] In some implementations, R 2c C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 2cIt is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 2c C6-C, whether substituted or not 14 Aryl. In some embodiments, R 2c The phenyl group may be substituted or unsubstituted. In some embodiments, R... 2c C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 2c For substituted or unsubstituted heteroaryl groups. In some embodiments, R 2c It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 2c It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 2c For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2c The pyrazol group may be substituted or unsubstituted. In some embodiments, R 2c It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 2c The C1-C group is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 2c It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 2c It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 2c It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0168] In some implementations, R 2c It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 2c It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2c It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 2cIt is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 2c It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 2c It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 2c It is either piperidin-1-yl or morpholino.

[0169] In some implementations, R 2c It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 2c It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2c It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 2c The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 2c It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 2c It is a substituted or unsubstituted heterocyclic alkyl group.

[0170] In some implementations, R 2c For -COR', where R' is as defined herein. In some implementations, R 2c It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2c For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 2c The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2c For -OR', where R' is as defined herein. In some implementations, R 2c =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 2c For -NR'R", where R' and R" are each as defined herein. In some implementations, R2c The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2c Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 2c The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2c For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 2c The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0171] In some implementations, R 2c The following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2c It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0172] In some implementations, R 2cThe following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2c It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0173] In some implementations, R 2d H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0174] In some implementations, R 2d For H. In some implementations, R 2dFor deuterium. In some implementations, R 2d It is cyano. In some embodiments, R 2d It is a halogen. In some embodiments, R 2d It is fluorine or chlorine. In some embodiments, R 2d It is fluorine. In some embodiments, R 2d It is chlorine. In some implementations, R 2d C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 2d It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 2d It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 2d It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 2d C1-C, whether substituted or not 10 Heteroalkyl groups.

[0175] In some implementations, R 2d C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 2d It is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 2d C6-C, whether substituted or not 14 Aryl. In some embodiments, R 2d The phenyl group may be substituted or unsubstituted. In some embodiments, R... 2d C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 2d For substituted or unsubstituted heteroaryl groups. In some embodiments, R 2d It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 2d It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 2d For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2d The pyrazol group may be substituted or unsubstituted. In some embodiments, R 2d It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 2dThe C1-C is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 2d It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 2d It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 2d It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0176] In some implementations, R 2d It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 2d It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 2d It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2d It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 2d It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 2d It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 2d It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 2d It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 2d It is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 2d It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 2d It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 2d It is either piperidin-1-yl or morpholino.

[0177] In some implementations, R 2d It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 2d It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2d It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 2dIt is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 2d The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 2d It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 2d It is a substituted or unsubstituted heterocyclic alkyl group.

[0178] In some implementations, R 2d For -COR', where R' is as defined herein. In some implementations, R 2d It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2d For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 2d The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2d For -OR', where R' is as defined herein. In some implementations, R 2d =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 2d For -NR'R", where R' and R" are each as defined herein. In some implementations, R 2d The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2d Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 2d The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2d For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 2d The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0179] In some implementations, R 2dThe following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2d It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0180] In some implementations, R 2d The following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2d It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0181] In some implementations, R 2e H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0182] In some implementations, R 2e For H. In some implementations, R 2e For deuterium. In some implementations, R 2e It is cyano. In some embodiments, R 2e It is a halogen. In some embodiments, R 2e It is fluorine or chlorine. In some embodiments, R 2e It is fluorine. In some embodiments, R 2e It is chlorine. In some implementations, R 2e C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 2e It is methyl, ethyl, propyl, or butyl, each optionally substituted. In some embodiments, R 2e It is methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, or dimethylaminomethyl. In some embodiments, R 2e It can be methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxy-methyl, or dimethylaminomethyl. In some embodiments, R 2e C1-C, whether substituted or not 10 Heteroalkyl groups.

[0183] In some implementations, R 2e C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 2eIt is either cyclobutyl or cyclohexyl, each optionally substituted. In some embodiments, R 2e C6-C, whether substituted or not 14 Aryl. In some embodiments, R 2e The phenyl group may be substituted or unsubstituted. In some embodiments, R... 2e C7-C, whether substituted or not 15 Arylalkyl. In some embodiments, R 2e For substituted or unsubstituted heteroaryl groups. In some embodiments, R 2e It is a substituted or unsubstituted monocyclic heteroaryl group. In some embodiments, R 2e It is a 5- or 6-membered heteroaryl group, each optionally substituted. In some embodiments, R 2e For substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2e The pyrazol group may be substituted or unsubstituted. In some embodiments, R 2e It is pyrazole-1-yl, pyrazole-3-yl, or pyrazole-4-yl, each optionally substituted. In some embodiments, R 2e The C1-C is pyrazol-1-yl, pyrazol-3-yl, or pyrazol-4-yl, each optionally substituted or unsubstituted. 10 Alkyl substitution. In some embodiments, R 2e It is pyrazole-1-yl, 1-methylpyrazole-3-yl, 2-methylpyrazole-3-yl, or 1-methylpyrazole-4-yl. In some embodiments, R 2e It is pyrazol-1-yl, 1-methylpyrazol-3-yl, or 1-methylpyrazol-4-yl. In some embodiments, R 2e It is a 6-membered heteroaryl group, either substituted or unsubstituted.

[0184] In some implementations, R 2e It is a substituted or unsubstituted heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted monocyclic heterocyclic alkyl group. In some embodiments, R 2e It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2e It is a substituted or unsubstituted 3-membered heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted four-membered heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted 5-membered heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted 6-membered heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted 7-membered heterocyclic alkyl group. In some embodiments, R 2eIt is an oxetane-butyl, tetrahydropyranyl, piperidinyl, or morpholinyl group, each optionally substituted. In some embodiments, R 2e It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, or morpholino, each optionally substituted. In some embodiments, R 2e It is an oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, or morpholino. In some embodiments, R 2e It is either piperidin-1-yl or morpholino.

[0185] In some implementations, R 2e It is a substituted or unsubstituted bicyclic heterocyclic alkyl group. In some embodiments, R 2e It is a bridged, fused, or spirocyclic heterocyclic alkyl group, each optionally substituted. In some embodiments, R 2e It is a substituted or unsubstituted bridged heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted 8-azabicyclo[3.2.1]octyl group. In some embodiments, R 2e The substituted or unsubstituted 8-azabicyclo[3.2.1]octane-8-yl. In some embodiments, R 2e It is a substituted or unsubstituted fused heterocyclic alkyl group. In some embodiments, R 2e It is a substituted or unsubstituted heterocyclic alkyl group.

[0186] In some implementations, R 2e For -COR', where R' is as defined herein. In some implementations, R 2e It is -COR', where R' is substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2e For -CONR'R", where R' and R" are each as defined herein. In some implementations, R 2e The form is -CONR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2e For -OR', where R' is as defined herein. In some implementations, R 2e =-OR', where R' is independently H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl. In some embodiments, R 2e For -NR'R", where R' and R" are each as defined herein. In some implementations, R2e The form is -NR'R", where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2e Let R' be -S(O)2R', where R' is as defined herein. In some implementations, R 2e The expression is -S(O)2R', where R' is a substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2e For -S(O)2NR'R"; where R' and R" are each as defined herein. In some implementations, R 2e The expression is -S(O)2NR'R"; where R' and R" are each independently H, or substituted or unsubstituted C1-C. 10 alkyl.

[0187] In some implementations, R 2e The following are not part of the group: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methyl-pyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, tetrahydropyranyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, tetrahydropyranyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2e It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, tetrahydropyranylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methyl-pyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl, or phenoxy.

[0188] In some implementations, R 2eThe following are compounds: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, morpholinylmethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxetane-3-yl, tetrahydro-2H-pyran-4-yl, piperidine-1-yl 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, tetrahydro-2H-pyran-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl. In some embodiments, R 2e It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, tetrahydro-2H-pyran-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl, or phenoxy.

[0189] In some implementations, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form heteroaryl groups, which may optionally be substituted by one, two, or three substituents, each of which is independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0190] In some implementations, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heteroaryl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heteroaryl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted 6-membered heteroaryl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form furanyl, imidazoleyl, pyrroleyl, pyrazoleyl, 1,2,3-triazoleyl, or pyridinyl groups, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, halogen, or a substituted or unsubstituted C1-C group. 10 Alkyl group. In some embodiments, R 2a and R 2b Together with the carbon atoms attached thereto, they form furan-2,3-diyl, imidazole-4,5-diyl, pyrrole-2,3-diyl, pyrazole-4,5-diyl, 1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, fluorine, or methyl. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form furan-2,3-diyl, 1-methylimidazol-4,5-diyl, pyrrole-2,3-diyl, 1-methylpyrrole-2,3-diyl, pyrazole-4,5-diyl, 1-methylpyrazole-4,5-diyl, 1-methyl-1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl.

[0191] In some implementations, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 2a and R2b Together with the carbon atoms attached to them, they form heterocyclic alkyl groups, which may optionally be substituted with one, two, or three substituents, each substituent being independently deuterium, oxo, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0192] In some implementations, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heterocyclic alkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heterocyclic alkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form substituted or unsubstituted six-membered heterocyclic alkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form tetrahydrofurandiyl, pyrrolidinediyl, 1,3-m-dioxanediyl, oxodiyl, or morpholindiyl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, halogen, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2a and R 2bTogether with the carbon atoms attached thereto, they form tetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 1,3-dioxolane-4,5-diyl, tetrahydropyran-2,3-diyl, or morpholine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently oxo, fluorine, or methyl. In some embodiments, R 2a and R 2b Together with the carbon atoms attached to them, they form tetrahydrofuran-2,3-diyl, 5,5-dimethyltetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 2-oxopyrrolidine-3,4-diyl, 2,2-difluoro-1,3-dioxopentane-4,5-diyl, 2,2-dimethyl-1,3-dioxopentane-4,5-diyl, tetrahydropyran-2,3-diyl, 4-methylmorpholine-2,3-diyl, or 5-oxopyrroline-2,3-diyl.

[0193] In some implementations, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted heteroaryl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form heteroaryl groups, which may optionally be substituted by one, two, or three substituents, each of which is independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0194] In some implementations, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heteroaryl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heteroaryl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted 6-membered heteroaryl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form furanyl, imidazoleyl, pyrroleyl, pyrazoleyl, 1,2,3-triazoleyl, or pyridinyl groups, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, halogen, or a substituted or unsubstituted C1-C group. 10 Alkyl group. In some embodiments, R 2b and R 2c Together with the carbon atoms attached thereto, they form furan-2,3-diyl, imidazole-4,5-diyl, pyrrole-2,3-diyl, pyrazole-4,5-diyl, 1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, fluorine, or methyl. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form furan-2,3-diyl, 1-methylimidazol-4,5-diyl, pyrrole-2,3-diyl, 1-methylpyrrole-2,3-diyl, pyrazole-4,5-diyl, 1-methylpyrazole-4,5-diyl, 1-methyl-1,2,3-triazole-4,5-diyl, or pyridine-2,3-diyl.

[0195] In some implementations, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted heterocyclic alkyl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form heterocyclic alkyl groups, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, oxo, cyano, or halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0196] In some implementations, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted monocyclic heterocyclic alkyl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted 5-membered heterocyclic alkyl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form substituted or unsubstituted six-membered heterocyclic alkyl groups. In some embodiments, R 2b and R 2c Together with the carbon atoms attached to them, they form tetrahydrofurandiyl, pyrrolidinediyl, 1,3-m-dioxanediyl, oxodiyl, or morpholindiyl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, halogen, or substituted or unsubstituted C1-C. 10 Alkyl group. In some embodiments, R 2b and R 2c Together with the carbon atoms attached thereto, they form tetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 1,3-dioxolane-4,5-diyl, tetrahydropyran-2,3-diyl, or morpholine-2,3-diyl, each optionally substituted with one or two substituents, each substituent being independently oxo, fluorine, or methyl. In some embodiments, R 2b and R 2cTogether with the carbon atoms attached to them, they form tetrahydrofuran-2,3-diyl, 5,5-dimethyltetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 2-oxopyrrolidine-3,4-diyl, 2,2-difluoro-1,3-dioxopentane-4,5-diyl, 2,2-dimethyl-1,3-dioxopentane-4,5-diyl, tetrahydropyran-2,3-diyl, 4-methylmorpholine-2,3-diyl, or 5-oxopyrroline-2,3-diyl.

[0197] In some implementations, R 2 H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl. In some embodiments, R 2 H, or substituted or unsubstituted C1-C 10 Alkyl group. In some embodiments, R 2 For H. In some implementations, R 2 C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 2 C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 2 For substituted or unsubstituted monocyclic C3-C 10 Cycloalkyl.

[0198] In some implementations, R 3 H, substituted or unsubstituted C1-C 10 Alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl. In some embodiments, R 3 H, or substituted or unsubstituted C1-C 10 Alkyl group. In some embodiments, R 3 For H. In some implementations, R 3 C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 3 C3-C, whether substituted or not 10 Cycloalkyl. In some embodiments, R 3 For substituted or unsubstituted monocyclic C3-C 10 Cycloalkyl.

[0199] In some implementations, R 2 and R 3 Each is independently H, alkyl, or cycloalkyl. In some embodiments, R 2 and R 3Each is independently H or alkyl. In some embodiments, R 2 and R 3 Each is independently H or methyl. In some embodiments, R 2 Methyl, and R 3 For H. In some implementations, R 2 and R 3 Each is H. In some implementations, R 2 and R 3 Together in the form of spirocyclopropyl.

[0200] In some implementations, R 2 and R 3 Together with the carbon atom it is attached to, it forms C(O) or substituted or unsubstituted C3-C. 10 Cycloalkyl. In some embodiments, R 2 and R 3 Together with the carbon atom it is attached to, it forms C(O). In some embodiments, R 2 and R 3 Together with the carbon atom it is attached to, they form substituted or unsubstituted C3-C atoms. 10 Cycloalkyl. In some embodiments, R 2 and R 3 Together with the carbon atom it is attached to, they form substituted or unsubstituted monocyclic C3-C rings. 10 Cycloalkyl.

[0201] In some implementations, R 4 H, substituted or unsubstituted C1-C 10 Alkyl group. In some embodiments, R 4 For H. In some implementations, R 4 C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 4 For unsubstituted C1-C 10 Alkyl group. In some embodiments, R 4 It is a methyl group.

[0202] In some implementations, R 5 H, substituted or unsubstituted C1-C 10 Alkyl group. In some embodiments, R 5 For H. In some implementations, R 5 C1-C, whether substituted or not 10 Alkyl group. In some embodiments, R 5 For unsubstituted C1-C 10 Alkyl group. In some embodiments, R 5 It is a methyl group.

[0203] In some implementations, R 4 and R 5 Each is independently H or alkyl. In some embodiments, R 4 and R 5 Each is independently H or methyl. In some embodiments, R 4 For H and R 5 It is methyl. In some embodiments, R 4 For methyl and R 5 For H. In some implementations, R 4 and R 5 Each is represented by H.

[0204] In some implementations, R 6 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In some embodiments, R 6 It is a heterocyclic alkyl or aryl group.

[0205] In some implementations, R 7 and R 8 Each is independently H, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, R 7 For H; and R 8 It is a heterocyclic alkyl or aryl group.

[0206] In some implementations, R 9 R 10 and R 11 Each is independently a monocyclic, bridged, or spirocyclic bicyclic cycloalkyl or a monocyclic, bridged, or spirocyclic bicyclic heterocyclic alkyl. In some embodiments, R 9 R 10 and R 11 Each is an independent bicyclic heterocyclic alkyl group that is monocyclic, bridged, or spirocyclic.

[0207] In some implementations, R 12 It is alkyl, aryl, or heteroaryl. In some embodiments, R 12 It is alkyl or aryl. In some embodiments, R 12 It is an alkyl group. In some embodiments, R 12 It is an aryl group.

[0208] In some implementations, R 13 For H. In some implementations, R 13 It is a hydroxyl group.

[0209] In some implementations, a is an integer 1. In some implementations, a is an integer 2. In some implementations, a is an integer 3.

[0210] In some implementations, b is an integer 1. In some implementations, b is an integer 2. In some implementations, b is an integer 3.

[0211] In some implementations, c is an integer 0. In some implementations, c is an integer 1. In some implementations, c is an integer 2.

[0212] In some implementations, d is an integer 0. In some implementations, d is an integer 1. In some implementations, d is an integer 2.

[0213] In some implementations, m, n, and q are each independently an integer, either 0 or 1. In some implementations, m is an integer 0. In some implementations, n is an integer 1. In some implementations, p is an integer 2. In some implementations, q is an integer 0.

[0214] In some embodiments, the various alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, alkoxy, alkylamino, and alkylthio groups described herein are optionally substituted with one, two, three, or four substituents, each substituent being independently deuterium, cyano, halogen, oxo, nitro, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CO2R', -CONR'R", -OR', -OC(O)R', -OC(O)NR'R", -NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'C(O)NR"R"', -NRSO2R', -NRSO2NR'R'', -SR', -S(O)R', -S(O)2R', or -S(O)2NR'R"; wherein R', R" and R"' are independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0215] In some embodiments, each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, alkoxy, and alkylamino group is optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, -COR', -CONR'R", -OR', -NR'R", -S(O)2R', or -S(O)2NR'R"; wherein each R' and R" is independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic alkyl.

[0216] The groups in the formulas described herein (including formulas (I) to (XI) and (Ia)), R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 1a R 1b R 1c R 1d R 1e R 2a R 2b R 2c R 2d R 2e R', R", R'", R"", R"", X, a, b, c, d, m, n, p, q, s, and t are defined in the embodiments described herein. All combinations of embodiments of such groups provided in this application are within the scope of this disclosure.

[0217] In some embodiments, the compound provided in this application is neither tert-butyl4-(6-(2,6-dioxoperidin-3-yl)-5-oxo-6,7-dihydro-5-yl) H -pyrrolo[3,4- b Pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate is not 3-[2-[1-[[4-[4-[6-[(6-acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyridino[2,3-d]pyrimidin-2-yl)amino]-3-pyridyl]-1-piperidinyl]phenyl]methyl]-4-hydroxy-4-piperidinyl]-5,7-dihydro-5-oxo-6 H -pyrrolo[3,4-b]pyrido-6-yl]-2,6-piperidindione

[0218] In some embodiments, the compound provided in this application is not 3-[2-[1-[[4-[4-[6-[(6-acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyridino[2,3-d]pyrimidin-2-yl)amino]-3-pyridyl]-1-piperidinyl]phenyl]methyl]-4-hydroxy-4-piperidinyl]-5,7-dihydro-5-oxo-6H-pyrrolo[3,4-b]pyridino-6-yl]-2,6-piperidinedione trifluoroacetate.

[0219] In some embodiments, this application provides 3-(2-(1-benzyl-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6-yl) for compounds used in compositions and methods. H -pyrrolo[3,4-b]-pyridin-6-yl)piperidine-2,6-dioneA001.

[0220] In some embodiments, this application provides, for compounds used in compositions and methods: 3-(2-(1-benzyl-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A001; 3-(2-(4-hydroxy-1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A002; 3-(2-(4-hydroxy-1-(2-methylbenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b]pyrido-6-yl)piperidine-2,6-dione A003; 3-(2-(4-hydroxy-1-(4-methylbenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A004; 3-(2-(4-hydroxy-1-phenylethylpiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A005; 3-(2-(4-hydroxy-1-(2-hydroxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A006; 3-(2-(4-hydroxy-1-(3-hydroxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] - b ]Pyridin-6-yl)piperidine-2,6-dione A007; 3-(2-(4-hydroxy-1-(2-cyanobenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] - b ]Pyrido-6-yl)piperidine-2,6-dione A008; 3-(2-(4-hydroxy-1-(4-cyanobenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] - b ]Pyrido-6-yl)piperidine-2,6-dione A009; 3-(2-(4-hydroxy-1-(3-cyanobenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] - b ]pyrido-6-yl)piperidine-2,6-dione A010; 3-(2-(4-hydroxy-1-(4-(hydroxymethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A011; 3-(2-(1-(4-chlorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A012; 3-(2-(1-(2,4-difluorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A013; 3-(2-(1-(4-(dimethylamino)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A014; 3-(2-(1-([1,1'-biphenyl]-4-ylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A015; 3-(2-(4-hydroxy-1-(4-(methanesulfonyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A016; 3-(2-(4-hydroxy-1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A017; 3-(2-(4-hydroxy-1-(3-phenoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A018; 3-(2-(1-(cyclohexylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A019; 3-(2-(4-hydroxy-1-(3-methylbenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4-b ]pyrido-6-yl)piperidin-2,6-dione A020; 3-(2-(1-(3-aminobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A021; 3-(2-(4-hydroxy-1-((2-oxo-1,2-dihydropyridin-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A022; 3-(2-(4-hydroxy-1-(2-methoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A023; 3-(2-(4-hydroxy-1-(3-methoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A024; 3-(2-(4-hydroxy-1-(4-methoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A025; 3-(2-(1-(3-chlorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A026; 3-(2-(1-(benzofuran-6-ylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A027; 3-(2-(1-((1H-indazol-5-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A028; 3-(2-(4-hydroxy-1-(pyrazolo[1,5-a]pyridin-6-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A029; 3-(2-(1-((2,3-dihydro-1H-inden-2-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A030; 3-(2-(4-hydroxy-1-(4-aminocarbonylphenylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A031; 3-(2-(4-hydroxy-1-(3-aminocarbonylphenylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A032; 3-(2-(1-(3-(dimethylamino)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A033; 3-(2-(4-hydroxy-1-(4-(methoxymethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A034; 3-(2-(4-hydroxy-1-(quinolin-6-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A035; 3-(2-(4-hydroxy-1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A036; 3-(2-(1-((1,1-dioxotetrahydro-2H-thiaran-4-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A037; 3-(2-(4-hydroxy-1-((1-phenyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A038; 3-(2-(4-hydroxy-1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A039; 4-((4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5-yl) H -pyrrolo[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)-N,N-dimethylbenzamide A040; 3-(2-(1-((2,2-difluorobenzo[ d [1,3]m-dioxacyclopentan-5-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A041; 3-(2-(4-hydroxy-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A042; 3-(2-(1-(4-(benzyloxy)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A043; 3-(2-(4-hydroxy-1-((1-methyl-1) H -Indazol-5-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b]Pyrido-6-yl)piperidine-2,6-dione A044; 3-(2-(4-hydroxy-1-((1-methyl-1) H -pyrazol-3-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A045; 4-((4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5-yl) H -pyrrolo[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)-N-methylbenzamide A046; 3-(2-(4-hydroxy-1-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A047; 3-(2-(4-hydroxy-1-(4-(1-methyl-1-hydroxy ... H -pyrazol-4-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A048; 3-(2-(4-hydroxy-1-((1-phenylpiperidin-4-yl)methyl)piperidin-4-yl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A049; 3-(2-(4-hydroxy-1-(4-(phenylamino)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A050; 3-(2-(4-hydroxy-1-(4-(4-hydroxypiperidin-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A051; 3-(2-(1-((1 H-pyrrolo[3,2-b]pyrido-6-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H- Pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A052; 3-(2-(1-((2,2-dimethylbenzo[ d [1,3]m-dioxacyclopentan-5-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A053; 3-(2-(1-((2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A054; 3-(2-(4-hydroxy-1-(isoxazo-4-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A055; 3-(2-(4-hydroxy-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A056; 3-(2-(4-hydroxy-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridino-6-yl)piperidin-2,6-dione A057; 3-(2-(1-(4-((dimethylamino)methyl)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A058; 3-(2-(4-hydroxy-1-(4-phenoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A059; 3-(2-(4-hydroxy-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A060; 3-(2-(4-hydroxy-1-(4-(4-(hydroxymethyl)piperidin-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A061; 3-(2-(4-hydroxy-1-(4-(phenoxymethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A062; 3-(2-(1-((1-(3-chlorophenyl)-4-piperidinyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A063; 3-(2-(1-((1-(2-chlorophenyl)-4-piperidinyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A064; 3-(2-(1-((1-(4-chlorophenyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A065; 3-(2-(4-hydroxy-1-((4-(1-methylpyrazol-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A066; 3-(2-(4-hydroxy-1-((4-(2-methylpyrazol-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A067; 3-(2-(4-hydroxy-1-((4-pyrazol-1-ylphenyl)methyl)-4-piperidinyl)-5-oxo-7H-pyrrolo[3,4-b]pyridino-6-yl)piperidin-2,6-dione A068; 3-(2-(4-hydroxy-1-((1-(2-pyridyl)-4-piperidinyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A069; 3-(2-(4-hydroxy-1-(((R)-1-phenylpiperidin-3-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A070; 3-(2-(4-hydroxy-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A071; 3-(2-(4-hydroxy-1-((8-phenyl-8-azabicyclo[3.2.1]octane-3-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A072; 3-(2-(4-hydroxy-1-((1-phenylazacyclobutane-3-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A073; 3-(2-(1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A074; 3-(2-(1-(3,4-dimethoxybenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A075; 3-(2-(4-hydroxy-1-((1-methylindol-5-yl)methyl)-4-piperidinyl)-5-oxo-7H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A076; 3-(2-(4-hydroxy-1-((1-methylindazol-4-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A077; 3-(2-(4-hydroxy-1-((4-(oxecyclobutane-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A078; 3-(2-(4-hydroxy-1-((3-(1-piperidinyl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A079; 3-(2-(1-((4-(4,4-difluoro-1-piperidinyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A080; 3-(2-(4-hydroxy-1-(4-(piperidin-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A081; 3-(2-(4-hydroxy-1-((4-tetrahydropyran-4-ylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A082; 3-(2-(4-hydroxy-1-(3-(tetrahydro-2H-pyran-4-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A083; 3-(2-(1-((3-fluorophenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b]-pyridin-6-yl)piperidine-2,6-dione A084; 3-(2-(4-hydroxy-1-((4-morpholinylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A085; 3-(2-(4-hydroxy-1-((3-morpholinylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A086; 3-(2-(4-hydroxy-1-((3-(oxecyclobutane-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A087; 3-(2-(4-hydroxy-1-((4-(tetrahydropyran-4-ylmethyl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A088; 3-(2-(1-((2-fluorophenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A089; 3-(2-(4-hydroxy-1-isobutyl-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)-piperidine-2,6-dione A090; 3-(2-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A091; 3-(2-(4-hydroxy-1-((1-methylbenzimidazol-5-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A092; 3-(2-(4-hydroxy-1-((3-methylbenzimidazol-5-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A093; 3-(2-(4-hydroxy-1-((1-methylindole-6-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A094; 3-(2-(4-hydroxy-1-((4-(morpholinylmethyl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A095; 3-(2-(1-((4-fluorophenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-Pyridin-6-yl)piperidine-2,6-dione A096; (3 S )-3-((7 S )-2-(1-Benzyl-4-hydroxy-4-piperidinyl)-7-methyl-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A097; ( S )-3-(( R )-2-(4-hydroxy-1-((1-phenylpiperidin-4-yl)methyl)piperidin-4-yl)-7-methyl-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A098; 3-(2-(1-(2-(3-fluorophenyl)ethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A099; 3-(2-(1-(chroman-7-ylmethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-Pyridin-6-yl)piperidine-2,6-dione A100; 3-(2-(1-(chroman-6-ylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A101; 3-(2-(1-((2,3-dihydrobenzofuran-6-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A102; 3-(2-(1-(2,3-dihydrobenzofuran-5-ylmethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A103; 3-(2-(1-(1,3-dihydroisobenzofuran-5-ylmethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A104; 3-(2-((3 S 4 S )-1-Benzyl-3,4-dihydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A105; 3-(2-((3 R 4 R )-1-Benzyl-3,4-dihydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A106; 3-(2-(1-((3,4-bis(trifluoromethyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A107; 3-(2-(1-((4-tert-butylphenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A108; 3-(2-(1-((3-tert-butylphenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A109; 3-(2-(4-hydroxy-1-((4-isopropylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A110; 3-(2-(4-hydroxy-1-((3-isopropylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A111; 3-(2-(1-((3-(1,1-difluoroethyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A112; 3-(2-(1-((4-(1,1-difluoroethyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A113; 3-(2-(1-(4-ethylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A114; 3-(2-(1-(4-chloro-3-methylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A115; 3-(2-(1-(4-((1 R 5 S )-8-azabicyclo[3.2.1]octane-8-yl)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A116; 3-(2-(1-(4-cyclobutylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A117; 3-(2-(1-(3-ethylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A118; 3-(2-(1-(4-chloro-3-fluorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A119; 3-(2-(1-(3-cyclobutylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b Pyrido-6-yl)piperidin-2,6-dione A120; 3-(2-(1-((3-((1 R 5 S )-8-azabicyclo[3.2.1]octane-8-yl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A121; 3-(2-(1-(4-cyclohexylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A122; 4-((4-(6-(( S )-2,6-dioxopiperidin-3-yl)-7-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)benzylnitrile A123; 4-((4-(( R )-6-(( S )-2,6-dioxopiperidin-3-yl)-7-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo-[3,4- b]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)benzylnitrile A124; 3-(2-{4-hydroxy-1-[(1 H [-pyrazol-4-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A125; 3-(2-{4-hydroxy-1-[(1,3-oxazol-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A126; 3-(2-{4-hydroxy-1-[(1 H -1,2,4-triazol-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A127; 3-(2-{4-hydroxy-1-[(pyridin-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A128; 3-(2-{4-hydroxy-1-[(pyridin-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A129; 3-(2-{4-hydroxy-1-[(1-methyl-1-hydroxy ... H [-pyrazol-4-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A130; 3-(2-{4-hydroxy-1-[(1,3-thiazolyl-2-yl)methyl]piperidin-4-yl}-5-oxo-5H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A131; 3-(2-{4-hydroxy-1-[(piperidin-4-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A132; 3-(2-{4-hydroxy-1-[(tetrahydro-2-)- H [-pyran-2-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A133; 3-(2-{4-hydroxy-1-[(tetrahydropyran-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A134; 3-(2-{4-hydroxy-1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A135; 3-{2-[1-({2-azaspiro[3.3]heptane-6-yl}methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A136; 3-(2-{4-hydroxy-1-[(5-methyl-1,3-thiazo-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A137; 3-[2-(4-hydroxy-1-{[(1 r 4 r [4-Aminocyclohexyl]methyl[piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A138; 3-{2-[4-hydroxy-1-({5-hydroxy-1-(4 ... H 6 H 7 H -pyrrolo[1,2- a [imidazol-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4-b]pyrido-6-yl}piperidin-2,6-dione A139; 3-(2-{4-hydroxy-1-[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A140; 3-[2-(4-hydroxy-1-{[1-(propyl-2-yl)-1-] H -pyrazol-4-yl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A141; 3-{2-[4-hydroxy-1-({imidazo[1,2- a [pyridin-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A142; 3-{2-[4-hydroxy-1-({1 H -pyrrolo[2,3- b [pyridin-5-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- bPyrido-6-ylpiperidine-2,6-dione A143; 3-(2-{1-[(1,3-benzoxazol-2-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A144; 3-{2-[4-hydroxy-1-({[1,2,4]triazolo[1,5- a [pyridin-7-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A145; 3-(2-{1-[(2,3-dihydro-1 ... H [-isoindol-5-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A146; 3-{2-[4-hydroxy-1-({4-hydroxy-1-( ... H 5 H 6 H 7 H -pyrazolo[1,5- a [pyridin-3-yl]methyl)-piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A147; 3-{2-[1-({4 H 5 H 6 H -Cyclopenta[ d [1,3]thiazolyl-2-yl]methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A148; 3-{2-[1-({2-azaspiro[3.5]nonane-7-yl}methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A149; 3-(2-{1-[(1-acetylpiperidin-4-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A150; 3-[2-(4-hydroxy-1-{[1-(propyl-2-yl)piperidin-4-yl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A151; 3-(2-{4-hydroxy-1-[(quinolin-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo-[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A152; 3-(2-{4-hydroxy-1-[(3-oxo-2,3-dihydro-1-]) H -isoindol-5-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A153; 3-[(4-{6-[2,6-dioxopiperidin-3-yl]-5-oxo-5-yl] H 6 H 7 H -pyrrolo[3,4- b [Pyridin-2-yl]-4-hydroxypiperidin-1-yl)methyl]-N-methylbenzamide A154; 3-(2-{1-[(1,3-benzothiazol-2-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A155; 3-[2-(4-hydroxy-1-{[4-(2-hydroxyethoxy)phenyl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidin-2,6-dione A156; 3-[2-(4-hydroxy-1-{[4-(2 ... H -1,2,3,4-Tetrazol-5-yl)phenyl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A157; 3-(2-{4-hydroxy-1-[(3-oxo-3,4-dihydro-2- H -1,4-Benzoxazine-6-yl)methyl]-piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A158; 3-{2-[4-hydroxy-1-({4-methyl-2-hydroxy-1-( ...(4-hydroxy- H ,3 H 4 H -pyrido[3,2- b [1,4]oxazine-7-yl]methyl)-piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4-b]pyrido-6-yl}piperidin-2,6-dione A159; 3-{2-[1-({3-azaspiro[5.5]undecane-9-yl}methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A160; 4-[(4-{6-[2,6-dioxopiperidin-3-yl]-5-oxo-5-yl] H 6 H 7 H -pyrrolo[3,4- b [Pyridin-2-yl]-4-hydroxypiperidin-1-yl)methyl]benzene-1-sulfonamide A161; 3-(2-{4-hydroxy-1-[(5-methyl-1-]) H [-pyrazol-4-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A162; 3-(2-{4-hydroxy-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A163; 3-[2-(4-hydroxy-1-{[1-(propyl-2-yl)-1H-pyrazol-3-yl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A164; 3-{2-[4-hydroxy-1-({1 H -pyrrolo[3,2- b [pyridin-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A165; 3-{2-[4-hydroxy-1-({5-hydroxy-1-(4 ... H 6 H 7 H 8 H -imidazo[1,2- a [pyridin-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A166; 3-[2-(4-hydroxy-1-{[4-(piperidin-4-yloxy)phenyl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b[Pyrido-6-yl]piperidine-2,6-dione A167; 3-(2-{1-[(1-benzylpiperidin-4-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A168; or 3-(2-{4-hydroxy-1-[(quinolin-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A169; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

[0221] III. Synthesis of Compounds: The compounds provided in this application can be synthesized using methods well known to those skilled in the art. In one embodiment, the compounds provided in this application are prepared as shown in Scheme I, wherein R 1 R 2 R 3 X, a, b, c, and d are each as defined herein; and LG is a leaving group, such as chlorine, bromine, iodine, or toluenesulfonyloxy. .

[0222] In another embodiment, the compound provided in this application is prepared as shown in Scheme II, wherein R 1 R 2 R 3 X, LG, a, b, c, and d are each defined as follows: .

[0223] IV. Pharmaceutical Composition: The pharmaceutical composition provided in this application comprises a therapeutically effective amount of one or more of the compounds provided in this application, as well as a pharmaceutically acceptable carrier, diluent, or excipient.

[0224] The compounds can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or elixirs for oral administration, or sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch formulations and dry powder inhalers. Typically, the above-mentioned compounds are formulated into pharmaceutical compositions using techniques and procedures known to those skilled in the art. See, for example, [link to relevant documentation]. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed; Ansel et al. , Ed.; Lippincott Williams & Williams, 1999.

[0225] In the composition, an effective concentration of one or more compounds or pharmaceutically acceptable salts is mixed with a suitable drug carrier or excipient. In some embodiments, the concentration of the compound in the composition is sufficient to effectively deliver, upon administration, one or more symptoms and / or progression of the disease or condition disclosed herein.

[0226] Typically, the composition is formulated into a single-dose administration form. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected carrier to an effective concentration that relieves or improves the condition to be treated. Suitable drug carriers or delivery systems for the compounds provided in this application include any such carriers known to those skilled in the art as suitable for a particular route of administration.

[0227] Furthermore, compounds can be formulated as the sole pharmaceutically active ingredient in a composition, or in combination with other active ingredients. Liposome suspensions, including tissue-targeting liposomes (such as tumor-targeting liposomes), can also serve as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared according to methods known in the art. Briefly, liposomes known in the art (such as multilayer vesicles (MLVs)) can be formed by drying lecithin and cephalinylserine (7:3 molar ratio) into a thin film. This film is then hydrated with a buffer (such as 10 mM sodium phosphate buffer (PBS) containing 150 mM NaCl, pH 7.0). The mixture is sonicated and eluted to produce a vesicle suspension of suitable size. The vesicle suspension is mixed with the compounds provided in this application to obtain a pharmaceutical formulation.

[0228] The active compound is contained in a pharmaceutically acceptable carrier in an amount sufficient to produce a therapeutically beneficial effect when used to treat a subject without undesirable side effects. Therapeutic effective concentrations are determined by testing the compound using the in vitro and in vivo systems described herein, and then extrapolated to the human dose. In some embodiments, the active compound is administered by a method to achieve a therapeutically effective concentration of the drug. In some embodiments, companion diagnostics are used to determine the therapeutic concentration and safety profile of the active compound in a specific subject or subject population. Olsen and Jorgensen, Front. Oncol. 2014, 4, 105. The concentration of the active compound in a pharmaceutical composition will depend on the absorption, tissue distribution, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the dosing regimen and dosage, and other factors known to those skilled in the art. For example, the amount delivered may be sufficient to improve one or more symptoms of the disease or condition disclosed herein.

[0229] In some embodiments, the therapeutically effective dose should produce a serum concentration of the active ingredient of about 0.1 ng / mL to about 50-100 μg / mL. In one embodiment, the pharmaceutical composition provides a dose of about 0.001 mg to about 2000 mg of the compound per kilogram of body weight per day. Pharmaceutical dosage units are prepared to provide about 1 mg to about 1,000 mg, and in some embodiments about 10 to about 500 mg of the essential active ingredient.

[0230] The active ingredient can be administered once or divided into multiple smaller doses administered at intervals. It should be understood that the precise dosage and duration of treatment are functions of the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​can also vary depending on the severity of the symptom being alleviated. Furthermore, it should be understood that for any given subject, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition; and the concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed compositions.

[0231] Therefore, an effective concentration or amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, is mixed with a suitable drug carrier or excipient to form a pharmaceutical composition for systemic, local, or topical administration. The amount of the compound contained in the composition should be sufficient to improve one or more symptoms, or for the treatment, delay of progression, or prevention (of an associated disease). The concentration of the active compound in the composition will depend on the absorption rate, tissue distribution, inactivation rate, excretion rate of the active compound, dosing regimen, dosage, specific dosage form, and other factors known to those skilled in the art.

[0232] The composition is intended for administration via a suitable route, including but not limited to oral, enteric, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, dermal, transdermal, buccal, rectal, topical, intranasal, or inhalation. For oral administration, it may be formulated into capsules and tablets. The composition is in liquid, semi-liquid, or solid form and is formulated in a manner suitable for each route of administration.

[0233] Solutions or suspensions intended for parenteral, intradermal, subcutaneous, or topical application may include any of the following components: sterile diluents, such as water for injection, physiological saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol and methylparaben; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates, and phosphates; and agents for adjusting tension, such as sodium chloride or glucose. Parenteral formulations may be packaged in ampoules, injection pens, disposable syringes, or single- or multi-dose vials made of glass, plastic, or other suitable materials.

[0234] When the solubility of a compound is insufficient, solubilization methods can be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as TWEEN®, or dissolution in an aqueous solution of sodium bicarbonate.

[0235] After mixing or adding the compound, the resulting mixture can be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on many factors, including the intended route of administration and the solubility of the compound in the chosen carrier or support. The effective concentration is sufficient to improve the symptoms of the treated disease, condition, or symptom and can be determined experimentally.

[0236] Pharmaceutical compositions are provided for administration to humans and animals in unit doses, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions containing suitable amounts of the compound or its pharmaceutically acceptable salts. Pharmaceutically therapeutically active compounds and their salts are formulated and administered in unit dose or multiple dose forms. As used herein, a unit dose form refers to an individual physical unit suitable for human and animal subjects and individually packaged as is known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect when combined with a desired drug carrier, excipient, or diluent. Examples of unit dose forms include ampoules, syringes, and individually packaged tablets or capsules. Unit dose forms can be administered in fractions or multiples thereof. Multiple dose forms refer to multiple identical unit dose forms packaged in a single container and administered in separate unit dose forms. Examples of multiple dose forms include vials, bottles containing tablets or capsules, or bottles containing pints or gallons (liquid). Therefore, multi-dose formulations are multiple unit doses that are not separated in the packaging.

[0237] Sustained-release formulations can also be prepared. Examples of suitable sustained-release formulations include semi-permeable matrices containing solid hydrophobic polymers of the compounds provided herein, said matrices being in the form of molded articles, such as films or microcapsules. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or polyvinyl alcohol), polylactides, copolymers of L-glutamic acid and L-glutamic acid ethyl ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (e.g., LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for more than 100 days, some hydrogels release proteins for shorter periods. When encapsulated compounds remain in vivo for extended periods, they may denature or aggregate due to exposure to moisture at 37°C, leading to loss of biological activity and potential structural changes. A reasonable stabilization strategy can be designed based on the mechanism involved. For example, if the aggregation mechanism is found to be the formation of intermolecular SS bonds through thiol-disulfide exchange, stabilization can be achieved by modifying thiol residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0238] Dosage forms or compositions containing 0.005% to 100% of the active ingredient, with the balance being a non-toxic carrier, can be prepared. For oral administration, pharmaceutically acceptable non-toxic compositions can be formed by incorporating any conventionally used excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained-release formulations, such as (but not limited to) implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers (such as collagen, ethylene-vinyl acetate, polyanhydride, polyglycolic acid, polyorthoesters, polylactic acid, etc.). Methods for preparing these compositions are well known to those skilled in the art. The intended compositions may contain about 0.001% to 100% of the active ingredient, in some embodiments about 0.1% to 85% of the active ingredient, or in other embodiments about 75% to 95% of the active ingredient.

[0239] An active compound or a pharmaceutically acceptable salt thereof may be prepared together with a carrier that protects the compound from rapid elimination from the body, such as a sustained-release formulation or a coating.

[0240] The composition may include other active compounds to achieve the desired combination of properties. The compounds provided in this application, or their pharmaceutically acceptable salts as described herein, may also be advantageously combined with another pharmacological agent known in the art to be valuable for treating one or more of the aforementioned diseases or medical conditions (e.g., diseases related to oxidative stress). It should be understood that such combination therapies constitute a further aspect of the compositions and treatment methods provided herein.

[0241] The lactose-free compositions provided in this application may contain excipients well known in the art, such as those listed in the United States Pharmacopeia (USP) SP (XXI) / NF (XVI). Typically, lactose-free compositions contain a pharmaceutically compatible and pharmaceutically acceptable amount of an active ingredient, a binder / filler, and a lubricant. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0242] This further includes anhydrous pharmaceutical compositions and dosage forms containing the compounds provided in this application. For example, in the pharmaceutical industry, adding water (e.g., 5%) is widely accepted as a method to simulate long-term storage in order to determine properties such as shelf life or the stability of the formulation over time. In reality, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of moisture on formulations can be critical, as moisture and / or humidity are commonly encountered during the production, handling, packaging, storage, transportation, and use of formulations.

[0243] The anhydrous pharmaceutical compositions and dosage forms provided in this application can be prepared using anhydrous or low-moisture components and under low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms containing lactose and at least one active ingredient containing a primary or secondary amine should be anhydrous if significant exposure to moisture and / or humidity is anticipated during manufacturing, packaging, and / or storage.

[0244] The preparation and storage of anhydrous pharmaceutical compositions should maintain their anhydrous properties. Therefore, anhydrous compositions should be packaged using materials known to prevent contact with water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to: sealed aluminum foil, plastic, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0245] A. Oral dosage form: Oral drug dosage forms can be solid, gel, or liquid. Solid dosage forms include tablets, capsules, granules, and powders. Types of oral tablets include compressed tablets, chewable tablets, and tablets that can be enteric-coated, sugar-coated, or film-coated. Capsules can be hard capsules or soft capsules, while granules and powders can be combined with other ingredients known to those skilled in the art and delivered in non-effervescent or effervescent forms.

[0246] In some embodiments, the formulation is a solid dosage form, such as capsules or tablets. The tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients, or compounds with similar properties: binders; diluents; disintegrants; lubricants; gliding agents; flavoring agents (sweeteners); and flavoring agents.

[0247] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, gum arabic paste, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium stearate or calcium stearate, lycopodium powder, and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Gliders include, but are not limited to, colloidal silica. Disintegrants include croscarmellose sodium, hydroxyacetic acid starch sodium, crospovidone, alginate, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Colorants include, for example, any approved water-soluble FD&C dyes and mixtures thereof; and water-insoluble FD&C dyes suspended on hydrated alumina. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners (such as saccharin), as well as a variety of spray-dried flavorings. Fragrances include natural flavorings extracted from plants (such as fruits) and synthetic blends of compounds that produce a pleasant sensory experience (including, but not limited to, peppermint and methyl salicylate). Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Enteric coating materials include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coating materials include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0248] If oral administration is required, the compound can be formulated into a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated with an enteric coating to keep it intact in the stomach while releasing the active compound in the intestines. The composition can also be formulated in combination with antacids or other such ingredients.

[0249] When the dosage unit is in capsule form, in addition to the substances of the types mentioned above, it may also contain a liquid carrier (such as fatty oil). Furthermore, the dosage unit form may contain various other substances that alter the physical form of the dosage unit, such as sugar coatings and other enteric-coated substances. This compound can also be administered as an ingredient in elixirs, suspensions, syrups, rice paper capsules, dispensing agents, chewing gum, etc. Syrups, in addition to the active compound, may also contain sucrose as a sweetener, as well as certain preservatives, dyes, coloring agents, and flavorings.

[0250] The active ingredient may also be mixed with other active ingredients that do not impair the intended effect, or with substances that complement the intended effect, such as antacids, H2 receptor antagonists, and diuretics. The active ingredient is the compound described herein or a pharmaceutically acceptable salt thereof. High concentrations of the active ingredient may be contained, with the active ingredient content reaching up to approximately 98% (by weight).

[0251] Pharmaceutically acceptable carriers contained in tablets include binders, lubricants, diluents, disintegrants, colorants, flavorings, and wetting agents. Enteric-coated tablets, due to their enteric coating, resist the action of gastric acid and dissolve or disintegrate in the neutral or alkaline environment of the intestine. Sugar-coated tablets are compression tablets with different layers of pharmaceutically acceptable substances on the outer surface. Film-coated tablets are compression tablets coated with polymers or other suitable coating materials. Multilayer compression tablets are compression tablets made using the aforementioned pharmaceutically acceptable substances through multiple compression cycles. Colorants may also be used in the above dosage forms. Flavorings and sweeteners are used in compression tablets, sugar-coated tablets, multilayer compression tablets, and chewable tablets. Flavorings and sweeteners are particularly useful in the preparation of chewable tablets and lozenges.

[0252] Oral liquid dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles. Aqueous solutions include, for example, elixirs and syrups. Emulsions may be oil-in-water or water-in-oil. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles.

[0253] Elisms are clear, sweetened aqueous solutions of alcohol. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in another as tiny droplets. Pharmaceutically acceptable carriers used in emulsions include non-aqueous liquids, emulsifiers, and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules reconstituted into oral liquid dosage forms include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules reconstituted into oral liquid dosage forms include organic acids and carbon dioxide sources. Coloring agents and flavoring agents are used in all of the above dosage forms.

[0254] Solvents include glycerol, sorbitol, ethanol, and syrups. Examples of preservatives include glycerol, methylparaben and propylparaben, benzoic acid, sodium benzoate, and alcohols. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, tragacanth gum, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethyl cellulose, pectin, tragacanth gum, Veegum (magnesium aluminum silicate), and gum arabic. Diluents include lactose and sucrose. Sweeteners include sucrose, syrups, glycerol, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include any approved, certified water-soluble FD&C dyes and mixtures thereof. Fragrances include natural flavorings extracted from plants (such as fruits) and synthetic mixtures of compounds that produce a pleasant taste experience.

[0255] For solid dosage forms, solutions or suspensions (e.g., in propylene carbonate, vegetable oil, or triglycerides) can be encapsulated in gelatin capsules. Such solutions and methods for their preparation and encapsulation are disclosed in U.S. Patents 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, solutions (e.g., solutions in polyethylene glycol) can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate accurate dosing.

[0256] Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or its salt in vegetable oils, glycols, triglycerides, propylene glycol esters (such as propylene carbonate) and other such carriers, and then encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, formulations containing the compounds provided herein, dialkylated mono- or polyalkylene glycols (including, but not limited to, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol), and one or more antioxidants (such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates).

[0257] Other formulations include, but are not limited to, aqueous alcoholic solutions containing pharmaceutically acceptable acetals. The alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes (such as acetaldehyde diethyl acetal).

[0258] In all embodiments, the tablet and capsule formulations may be coated as known to those skilled in the art to modify or maintain the solubility of the active ingredient. Thus, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, waxes, and cellulose acetate phthalate.

[0259] B. Injectables, solutions, and emulsions: This article also considers parenteral administration, typically by injection, which can be administered subcutaneously, intramuscularly, or intravenously. Injectable formulations can be prepared in conventional forms, as liquid solutions or suspensions, or in solid forms suitable for dissolving or suspending in a liquid prior to injection, or as emulsions. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. Suitable excipients include, for example, water, saline, glucose, glycerol, or ethanol. Furthermore, if desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubilizers, and other such agents, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrin. This article also considers protocols involving the implantation of sustained-release or continuous-release systems to maintain a constant dose level. In short, the compounds provided in this application are dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, siloxane carbonate copolymer, hydrophilic polymers such as acrylic acid and methacrylate hydrogels, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate. The outer membrane is surrounded by a polymer membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionic polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / ethyleneoxyethanol copolymer. These membrane materials are insoluble in body fluids. The compound diffuses through the external polymer membrane in a controlled-release step. The percentage of active compound contained in such parenteral compositions is highly dependent on their specific properties, the activity of the compound, and the needs of the subject.

[0260] The parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Parenteral formulations include injectable sterile solutions, sterile dried soluble products (such as lyophilized powders mixed with a solvent prior to use), including subcutaneous tablets, injectable sterile suspensions, sterile dried insoluble products mixed with a carrier prior to use, and sterile emulsions. The solutions may be aqueous or non-aqueous.

[0261] If administered intravenously, suitable carriers include physiological saline or phosphate-buffered saline (PBS), as well as solutions containing thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0262] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, chelating agents, and other pharmaceutically acceptable substances.

[0263] Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water for injection, and gluconate-lactated Ringer's injection. Non-aqueous enteric carriers include plant-derived fixed oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents added at bacteriostatic or bactericidal concentrations must be added to multi-dose container-packaged enteric preparations, including phenol or cresol, mercury compounds, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride, and benzalkonium chloride. Isotonic agents include sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfite. Local anesthetics include procaine hydrochloride. Suspension and dispersing agents include sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 (TWEEN® 80). Metal ion chelating agents include EDTA. Drug carriers also include ethanol, polyethylene glycol, and propylene glycol for water-miscible carriers, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0264] The concentration of the pharmaceutically active compound is adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dosage depends on the age, weight, and condition of the subject or animal, as is known in the art.

[0265] Unit doses of parenteral formulations are packaged in ampoules, capped vials, or syringes with needles. All formulations intended for parenteral administration must be sterile, as is known and practiced in the art.

[0266] For example, intravenous or intra-arterial infusion of a sterile aqueous solution containing the active compound is an effective route of administration. Another approach is to inject a sterile aqueous or oily solution or suspension containing the active substance as needed to produce the desired pharmacological effect.

[0267] Injectable formulations are designed for both local and systemic administration. Typically, a therapeutically effective dose is formulated containing at least about 0.1% w / w to about 90% w / w or more, for example, more than 1% w / w relative to the treated tissue. The active ingredient can be administered once or divided into several smaller doses administered at intervals. It should be understood that the precise dose and duration of treatment are functions of the tissue to be treated and can be determined using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dose values ​​may also vary with the age of the individual being treated. It should also be understood that for any particular subject, the specific dosing regimen should be adjusted at any time based on individual needs and the professional judgment of the person administering or supervising the administration. The concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed formulations.

[0268] The compound may be suspended in a micronized or other suitable form, or may be derivatized to produce a more soluble active product or a prodrug. The form of the resulting mixture depends on a variety of factors, including the intended route of administration and the solubility of the compound in the selected carrier or excipient. An effective concentration sufficient to improve the symptoms of the condition can be determined empirically.

[0269] C. Freeze-dried powder: This application also relates to lyophilized powders, which can be reconstituted and administered in the form of solutions, emulsions, and other mixtures. They can also be reconstituted and formulated into solids or gels.

[0270] Aseptic lyophilized powders are prepared by dissolving the compounds provided in this application or their pharmaceutically acceptable salts in a suitable solvent. The solvent may contain excipients that enhance the stability of the powder or other pharmacological components or the stability of a reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, dextran, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, or other suitable agents. The solvent may also contain buffers such as citrate, sodium phosphate, or potassium phosphate, or other such buffers known to those skilled in the art, at approximately a neutral pH in one embodiment. The solution is then aseptically filtered and lyophilized under standard conditions known to those skilled in the art to obtain the desired formulation. Typically, the resulting solution is dispensed into vials for lyophilization. Each vial will contain a single dose (including, but not limited to, 10-1,000 mg or 100-500 mg) or multiple doses of the compound. The lyophilized powder may be stored under appropriate conditions, such as from about 4°C to room temperature.

[0271] Reconstitute the lyophilized powder with water for injection to provide a formulation for parenteral administration. For reconstitution, add approximately 1–50 mg, 5–35 mg, or 9–30 mg of the lyophilized powder per mL of sterile water or other suitable carrier. The exact amount depends on the compound selected. This amount can be determined empirically.

[0272] D. Topical administration: Topical mixtures are prepared according to the descriptions for local and systemic administration. The resulting mixtures may be solutions, suspensions, emulsions, etc., and are formulated into creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, rinses, sprays, suppositories, bandages, skin patches, or any other formulation suitable for local administration.

[0273] The compound or a pharmaceutically acceptable salt thereof may be formulated into an aerosol form for topical application, such as by inhalation (see, for example, U.S. Patents 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids that can be used to treat inflammatory diseases, particularly asthma). These formulations for the respiratory tract may be in aerosol form or nebulizer solution, or as a fine powder for inhalation, used alone or in combination with an inert carrier (such as lactose). In this case, the diameter of the particles in the formulation will be less than 50 micrometers or less than 10 micrometers.

[0274] The compound can be formulated for topical or external use, such as topically applied to the skin and mucous membranes (e.g., the eyes), in the form of gels, creams, and lotions, as well as for ocular, intrathecal, or intraspinal administration. Topical administration is considered for transdermal delivery and ocular or mucous membrane administration, or for inhalation therapy. Nasal solutions containing the active compound can also be administered, alone or in combination with other pharmaceutically acceptable excipients.

[0275] These solutions, especially those for ophthalmic use, can be prepared as isotonic solutions of 0.01%–10%, with a pH of approximately 5–7, and containing appropriate salts.

[0276] E. Compositions administered via other routes: This application also considers other routes of administration, such as topical application, transdermal patches, and rectal administration.

[0277] For example, drug dosage forms for rectal administration include rectal suppositories, capsules, and tablets for systemic effects. As used herein, a rectal suppository is a solid substance that, upon insertion into the rectum, melts or softens at body temperature to release one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances used in rectal suppositories include a matrix or carrier and agents that raise the melting point. Examples of matrices include cocoa butter (cocoa soybean oil), glycerin gelatin, polywax (polyoxyethylene glycol), and suitable mixtures of mono-, di-, and triglycerides of fatty acids. Various combinations of matrices can be used. Agents that raise the melting point of suppositories include cetylene and waxes. Rectal suppositories can be prepared by compression or molding. A typical weight of a rectal suppository is approximately 2 to 3 grams.

[0278] Tablets and capsules for rectal administration are prepared using the same pharmaceutically acceptable substances and the same methods as oral formulations.

[0279] F. Sustained-release composition: The active ingredients provided in this application can be administered via controlled-release methods or delivery devices well known to those skilled in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, and 3,598,123; and U.S. Patent Nos. 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, and 5,891,470. 4, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500, and 6,740,634. Such dosage forms can be used with, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeable systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide slow or controlled release of one or more active ingredients, providing desired release profiles in varying proportions. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for the active ingredient provided in this application.

[0280] All controlled-release pharmaceutical formulations share a common goal: to improve the therapeutic effects achieved by their non-controlled-release counterparts. In one implementation, the use of a best-designed controlled-release formulation in medical treatment is characterized by curing or controlling the condition with the least amount of pharmaceutical substance in the shortest possible time. In some implementations, the advantages of controlled-release formulations include sustained drug activity, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release formulations can be used to influence onset time or other properties, such as drug blood levels, thereby affecting the occurrence of side effects (e.g., adverse reactions).

[0281] Most controlled-release formulations are designed to initially release a certain amount of the drug (active ingredient) to rapidly produce the desired therapeutic effect, followed by a gradual and sustained release of additional amounts of the drug to maintain that therapeutic or preventative level over an extended period. To maintain this constant drug level in the body, the drug must be released from the dosage form at a rate sufficient to replenish the amount metabolized and excreted. Controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0282] In some embodiments, the agent may be administered via intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other administration methods. In one embodiment, a pump may be used. See, for example, Buchwald. et al. Surgery 1980, 88 , 507-16; Sefton, Crit. Ref. Biomed. Eng 1987, 14, 201-40; Saudek et al., N. Engl. J. Med 1989, 321, 574-9. In another embodiment, a polymer material may be used. In yet another embodiment, the controlled-release system may be placed near the therapeutic target, i.e., thus requiring only a fraction of the systemic dose.

[0283] In some implementations, the controlled-release device is introduced into the subject at sites of inappropriate immune activation or near tumors. Other controlled-release systems are discussed in Langer's review (Science 1990, 249, 1527-33). The active ingredient can be dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as acrylic and methacrylate hydrogels, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which are insoluble in body fluids. The product is surrounded by an outer polymer membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / ethyleneoxyethanol copolymer. The active ingredient then diffuses through the outer polymer membrane in a release rate control step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on their specific properties and the needs of the subject.

[0284] G. Targeted formulations: The compounds provided in this application, or their pharmaceutically acceptable salts, can also be formulated to target specific tissues, receptors, or other regions of the body in a subject to be treated, including delivery systems based on liposomes, resealed red blood cells, and antibodies. Many such targeting methods are well known to those skilled in the art. All such targeting methods are intended for use in point-of-care compositions. For non-limiting examples of targeting methods, see, for example, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0285] In one embodiment, liposome suspensions, including tissue-targeting liposomes such as tumor-targeting liposomes, can serve as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes, such as multilayer vesicles (MLVs), can be formed by drying lecithin and cephalinositol serine (molar ratio 7:3) on the inner wall of a flask. A solution of the compound provided in this application is added to phosphate-buffered saline (PBS) free of divalent cations, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, precipitated by centrifugation, and then resuspended in PBS.

[0286] H. Manufactured Products: The compound or pharmaceutically acceptable salt may be packaged as an article comprising packaging material, the compound or pharmaceutically acceptable salt provided in this application for treating, preventing or improving one or more symptoms or progressions of the disease or condition disclosed herein, and a label indicating that the compound or pharmaceutically acceptable salt is used for treating, preventing or improving one or more symptoms or progressions of the disease or condition disclosed herein.

[0287] The articles of manufacture provided in this application include packaging materials. Packaging materials used for packaging pharmaceutical products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging materials suitable for the selected formulation and the intended method of administration and treatment. Various formulations of the compounds and compositions provided in this application are contemplated.

[0288] In some embodiments, this document also provides a kit that simplifies the administration of an appropriate amount of the active ingredient to a subject when used by a medical practitioner. In some embodiments, the kit provided herein comprises a container and a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0289] In some embodiments, the kit includes a container containing a dosage form of the compound provided in this application, including a single enantiomer or a mixture of its diastereomers; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in combination with a container containing one or more other therapeutic agents described herein.

[0290] The kit provided in this application may also include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needle-free injectors, infusion bags, patches, and inhalers. The kit provided in this application may also include a condom for administering the active ingredient.

[0291] The kits provided in this application may also include pharmaceutically acceptable excipients for the administration of one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container of a suitable excipient, wherein the active ingredient is dissolved to form a particle-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable excipients include, but are not limited to: aqueous excipients, including but not limited to USP water for injection, sodium chloride injection, Ringer's solution, glucose injection, glucose and sodium chloride injection, and lactated Ringer's solution; water-miscible excipients, including but not limited to ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous excipients, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0292] V. Administration: The compounds and pharmaceutical compositions provided in this application may be administered in the specific therapeutic or preventative effective amounts, at specific time intervals, in specific dosage forms, and in specific methods of administration as described herein.

[0293] In some embodiments, the therapeutic or preventative effective amount of the compound provided in this application is about 0.005 to about 1,000 mg per day, about 0.01 to about 500 mg per day, about 0.01 to about 250 mg per day, about 0.01 to about 100 mg per day, about 0.1 to about 100 mg per day, about 0.5 to about 100 mg per day, about 1 to about 100 mg per day, about 0.01 to about 50 mg per day, about 0.1 to about 50 mg per day, about 0.5 to about 50 mg per day, about 1 to about 50 mg per day, about 0.02 to about 25 mg per day, about 0.05 to about 10 mg per day, about 0.05 to about 5 mg per day, about 0.1 to about 5 mg per day, or about 0.5 to about 5 mg per day.

[0294] In some embodiments, the therapeutic or preventative effective amount of the compound provided in this application is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.

[0295] In some embodiments, the recommended daily dose range for the compound or its derivatives provided in this application for the conditions described herein is from about 0.5 mg to about 50 mg / day, administered as a single dose once daily or divided into several doses throughout the day. In some embodiments, the daily dose range is from about 1 mg to about 50 mg / day. In some embodiments, the daily dose range is from about 0.5 mg to about 5 mg / day. Specific daily doses include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / day.

[0296] In some embodiments, the recommended starting dose is 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, or 50 mg / day. In some embodiments, the recommended starting dose may be 0.5, 1, 2, 3, 4, or 5 mg / day. In some embodiments, the dose is increased to 15, 20, 25, 30, 35, 40, 45, and 50 mg / day. In some embodiments, the compound provided in this application is administered at an amount of about 25 mg / day. In some embodiments, the compound provided in this application is administered at an amount of about 10 mg / day. In some embodiments, the compound provided in this application is administered at an amount of about 5 mg / day. In some embodiments, the compound provided in this application is administered at an amount of about 4 mg / day. In some embodiments, the compound provided in this application is administered at an amount of about 3 mg / day.

[0297] In some embodiments, the effective dose for treatment or prevention is about 0.001 to about 100 mg / kg / day, about 0.01 to about 50 mg / kg / day, about 0.01 to about 25 mg / kg / day, about 0.01 to about 10 mg / kg / day, about 0.01 to about 9 mg / kg / day, about 0.01 to about 8 mg / kg / day, about 0.01 to about 7 mg / kg / day, about 0.01 to about 6 mg / kg / day, about 0.01 to about 5 mg / kg / day, about 0.01 to about 4 mg / kg / day, about 0.01 to about 3 mg / kg / day, about 0.01 to about 2 mg / kg / day, about 0.01 to about 1 mg / kg / day, or about 0.01 to about 0.05 mg / kg / day.

[0298] The dosage can also be expressed in units other than mg / kg / day. For example, the dosage for parenteral administration can be expressed as mg / m³. 2 / day. Those skilled in the art, knowing the subject's height or weight, or both, can readily determine how to convert the dose from mg / kg / day to mg / m². 2 / day. For example, for a 65 kg person, a dose of 1 mg / kg / day is approximately equal to 38 mg / m². 2 / sky.

[0299] In some embodiments, the amount of compound applied is sufficient to provide a steady-state plasma concentration of the compound, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, about 1 to about 50 µM, about 0.02 to about 25 µM, about 0.05 to about 20 µM, about 0.1 to about 20 µM, about 0.5 to about 20 µM, or about 1 to about 20 µM.

[0300] In some embodiments, the amount of compound applied is sufficient to provide a steady-state plasma concentration of the compound, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM, or about 50 to about 100 nM.

[0301] As used herein, the term "steady-state plasma concentration" refers to the concentration reached after a period of time following administration of the compound or its derivatives provided in this application. Once steady state is reached, the time-dependent curve of the compound's plasma concentration exhibits small peaks and troughs.

[0302] In some embodiments, the amount of compound applied is sufficient to provide the maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 50 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, about 1 to about 50 µM, about 0.02 to about 25 µM, about 0.05 to about 20 µM, about 0.1 to about 20 µM, about 0.5 to about 20 µM, or about 1 to about 20 µM.

[0303] In some embodiments, the amount of compound applied is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, about 1 to about 50 µM, about 0.01 to about 25 µM, about 0.01 to about 20 µM, about 0.02 to about 20 µM, about 0.02 to about 20 µM, or about 0.01 to about 20 µM.

[0304] In some embodiments, the amount of compound applied is sufficient to provide the area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr / mL, about 1,000 to about 50,000 ng*hr / mL, about 5,000 to about 25,000 ng*hr / mL, or about 5,000 to about 10,000 ng*hr / mL.

[0305] The methods provided in this application include treating patients regardless of their age, even though certain diseases or conditions are more common in specific age groups.

[0306] Depending on the disease to be treated and the condition of the subject, the compounds or derivatives thereof provided in this application may be administered via oral, non-enteric (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or local (e.g., percutaneous or local) routes of administration. The compounds or derivatives thereof provided in this application may be formulated alone or in combination into appropriate dosage units suitable for each route of administration and may be combined with pharmaceutically acceptable excipients, carriers, adjuvants, and delivery systems.

[0307] In one embodiment, the compound or its derivative provided in this application is administered orally. In another embodiment, the compound or its derivative provided in this application is administered parenterally. In yet another embodiment, the compound or its derivative provided in this application is administered intravenously.

[0308] The compounds or their derivatives provided in this application may be administered as a single dose, such as a single-dose bolus injection or oral tablets or pills; or administered over time, such as continuous infusion over time or fractionated bolus doses over time. If necessary, the compounds may be repeated, for example, until the subject experiences disease stability or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, for solid tumors, disease stability is generally defined as an increase of no more than 25% in the vertical diameter of a measurable lesion since the last measurement. (See the Responsibility Evaluation Criteria for Solid Tumors (RECIST) guidelines (J)). . Nat'l Cancer Inst. 2000, 92, 205-16). Disease stability is determined by methods known in the art, such as assessing patient symptoms, physical examination, tumor visualization using X-ray, CAT, PET or MRI scans, and other recognized assessment methods.

[0309] The compounds or derivatives thereof provided in this application may be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). Furthermore, administration may be continuous (i.e., for several consecutive days or daily) or intermittent, such as cyclical (i.e., including rest days, weeks, or months without medication). As used herein, the term "daily" means the application of a therapeutic compound (such as the compounds or derivatives thereof provided in this application) once or more daily, for example, for a period of time. The term "continuous" refers to a period of time from 10 days to 52 weeks during which a therapeutic compound (such as the compound or derivative thereof provided in this application) is administered daily without interruption. As used herein, the terms "intermittent" or "intermittently" refer to stopping and starting at regular or irregular intervals. For example, intermittent administration of the compound or derivative thereof provided in this application may be administered one to six days per week, administered cyclically (e.g., daily administration for two to eight consecutive weeks, followed by a one-week dosing rest period), or administered every other day. As used herein, the term "cycle" refers to daily or continuous administration of a therapeutic compound (such as the compound or derivative thereof provided in this application) with rest periods. In some such embodiments, administration is once daily for two to six days, followed by a five- to seven-day dosing rest period.

[0310] In some embodiments, the dosing frequency ranges from approximately once daily to approximately once monthly. In some embodiments, the dosing is once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound or its derivative provided in this application is administered once daily. In another embodiment, the compound or its derivative provided in this application is administered twice daily. In yet another embodiment, the compound or its derivative provided in this application is administered three times daily. In still another embodiment, the compound or its derivative provided in this application is administered four times daily.

[0311] In some embodiments, the compound or its derivative provided in this application is administered once daily for one to six months, one to three months, one to four weeks, one to three weeks, or one to two weeks. In some embodiments, the compound or its derivative provided in this application is administered once daily for one, two, three, or four weeks. In one embodiment, the compound or its derivative provided in this application is administered once daily for four days. In another embodiment, the compound or its derivative provided in this application is administered once daily for five days. In yet another embodiment, the compound or its derivative provided in this application is administered once daily for six days. In yet another embodiment, the compound or its derivative provided in this application is administered once daily for one week. In yet another embodiment, the compound or its derivative provided in this application is administered once daily for two weeks. In yet another embodiment, the compound or its derivative provided in this application is administered once daily for three weeks. In yet another embodiment, the compound or its derivative provided in this application is administered once daily for four weeks.

[0312] VI. Treatment methods: In one embodiment, this application provides a method for treating, preventing, or improving one or more symptoms of a disease or condition in which ARNT is overexpressed and / or in which ARNT activity is undesirable and / or in which ARNT is a pro-oncogene active factor.

[0313] In another embodiment, this application provides a method for treating, preventing, or improving one or more symptoms of an ARNT-mediated disease or condition in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound provided in this application, such as a compound of formula (A) or (I), or an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, or mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a pharmaceutically acceptable derivative thereof.

[0314] In some implementations, ARNT-mediated diseases or conditions are cancer.

[0315] In another embodiment, this application provides a method for treating, preventing, or improving one or more symptoms of cancer in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound provided in this application, such as a compound of formula (A) or (I), or an enantiomer, mixture of enantiomers, diastereomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a pharmaceutically acceptable derivative thereof.

[0316] In yet another embodiment, this application provides a method for inhibiting cell growth, comprising contacting the cells with an effective amount of a compound provided in this application, such as a compound of formula (A) or (I), or an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, or mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a pharmaceutically acceptable derivative thereof.

[0317] In some implementations, the cells are cancer cells.

[0318] In yet another embodiment, this application provides a method for inducing ARNT degradation, comprising contacting ARNT with an effective amount of a compound provided in this application, such as a compound of formula (A) or (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a pharmaceutically acceptable derivative thereof.

[0319] VII. Combination therapy with a second therapeutic agent The compounds or their derivatives provided in this application may be used in combination with a second therapeutic agent for the treatment or prevention of diseases or conditions in which ARNT is overexpressed and / or in which ARNT activity is undesirable and / or in which ARNT acts as an oncogene active factor.

[0320] In one embodiment, this application provides a method for treating, preventing, or controlling cancer, including administering to a subject a combination of the compound or its derivative provided in this application with a second therapeutic agent.

[0321] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more preventive and / or therapeutic agents). However, the use of the term "combination" does not limit the order of administration of the therapies (e.g., preventive and / or therapeutic agents). A first therapy (e.g., a preventive or therapeutic agent, such as a compound or derivative thereof provided in this application) may be administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks earlier), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later). Triple therapy is also considered herein.

[0322] The compounds or derivatives thereof provided in this application may be administered simultaneously or sequentially with a second therapeutic agent via the same or different routes of administration. The suitability of a particular route of administration for a specific therapeutic agent will depend on the active pharmaceutical ingredient itself (e.g., whether it can be orally administered into the bloodstream without degradation) and the disease or condition being treated.

[0323] The route of administration of the compound or its derivative provided in this application is independent of the route of administration of the second therapy. In one embodiment, the compound or its derivative provided in this application is administered orally. In another embodiment, the compound or its derivative provided in this application is administered intravenously. Thus, according to these embodiments, the compound or its derivative provided in this application is administered orally or intravenously, while the second therapy may be administered orally, enterically, intraperitoneally, intravenously, intra-arterially, percutaneously, sublingually, intramuscularly, rectically, buccally, nasally, liposomeically, by inhalation, vaginally, intraocularly, locally via catheter or stent, subcutaneously, intra-abdominally, intra-articularly, intrathecally, or in a sustained-release formulation. In one embodiment, the compound or its derivative provided in this application is administered in the same manner as the second therapy, orally or intravenously. In another embodiment, the compound or its derivative provided in this application is administered by one manner of administration, such as intravenously, while the second therapy is administered by another manner of administration, such as orally.

[0324] In one embodiment, the second active drug is administered intravenously or subcutaneously once or twice daily in a dose of about 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. The specific dose of the second active drug will depend on the specific drug used, the type of disease being treated or controlled, the severity and stage of the disease, and the dose of the compound or its derivatives provided in this application and any optional additional active drugs concurrently administered to the subject.

[0325] VIII. Example: The following examples are intended to illustrate certain implementations provided in this application, and are not intended to limit the scope of this disclosure.

[0326] As used herein, the symbols and conventions used in these methods, schemes and embodiments, whether or not specific abbreviations are explicitly defined, are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry.Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimolecular concentration); μM (micromolar concentration); mmol (millimole); min (minute); h (hour); ACN (acetonitrile); AcOH (acetic acid); AIBN (azobisisobutyronitrile); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc (tert-butyloxycarbonyl); tBu (tert-butyl); tBuOH (tert-butanol); Cbz (benzyloxycarbonyl); DCE (dichloroethane); DCM (dichloromethane). DIBAL-H (diisobutylaluminum hydride); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DME (dimethyl ether); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); HATU (zabenzotriazole tetramethylurea hexafluorophosphate); IPA (isopropanol); MeOH (methanol); MsNH2 (methanesulfonamide); MTBE (methyl tert-butyl ether); NaBH(OAc)3 (sodium triacetoxyborohydride); Mn(dpm)3 (tris(2,2,6,6-tetramethyl) Manganese(III) (3,5-heptadecyl-3,5-heptadecyl)manganese(III)); NaBH(OAc)3 (sodium triacetoxyborohydride); NBS (N-bromosuccinimide); NiCl2·dtbpy ((4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine)nickel(II)); Pd2(dppf)Cl2 ((1,1'-bis(diphenylphosphino)ferrocene)palladium(II)); Pd(OAc)2 (palladium acetate); PE (petroleum ether); SO3·Py (sulfur trioxide pyridine complex); TEA (triethylamine); TFA (trifluoroacetic acid); TFE (tetrafluoroethylene); THF (tetrahydrofuran); TMSCF3 (trifluoromethyltrimethylsilane); T4P (3-(2,6,8-trioxo-9-((2R,3R,4R)-2,3,4,5-tetrahydroxypentyl)-3H-purine-7-yl)propyl phosphate dihydrogen ester); Ts (toluenesulfonyl); TsCl (p-toluenesulfonyl chloride); TsOH (p-toluenesulfonic acid); TTMSS (tris(trimethylsilyl)silane); MS (mass spectrometry); NMR (nuclear magnetic resonance); prep-HPLC (preparative high-performance liquid chromatography); SFC (supercritical fluid chromatography); and prep-TLC (preparative thin-layer chromatography).

[0327] For all the following embodiments, standard post-processing and purification methods well known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methods shown herein are intended to illustrate applicable chemical methods by specific examples and are not intended to limit the scope of this disclosure.

[0328] .

[0329] Method 1: DIPEA (3 equivalents) and NaBH(OAc)3 (2 equivalents) were added to a 100 µmol (1 equivalent) HCl salt solution of compound 1a and a 0.5 mL DMF and 0.5 mL DCM solution of compound 1b (120 µmol (1.2 equivalents). After stirring at 30 °C for 16 h, the reaction mixture was concentrated and purified by prep-HPLC to obtain compound 1c.

[0330] Method 2: AcOH (300 µmol, 3 equivalents) and NaBH3CN (200 µmol, 2 equivalents) were added to a solution of compound 1a (100 µmol, 1 equivalent) and compound 1b (120 µmol, 1.2 equivalents) in MeOH (1 mL). After stirring at 50 °C for 16 hours, the reaction mixture was concentrated and purified by prep-HPLC to obtain compound 1c.

[0331] Method 3: AcOH (300 µmol, 3 equivalents) and NaBH3CN (200 µmol, 2 equivalents) were added to a solution of compound 1a (100 µmol, 1 equivalent) and compound 1b (120 µmol, 1.2 equivalents) in MeOH (1 mL). After stirring at 120 °C for 6 hours under microwave conditions, the reaction mixture was concentrated and purified by prep-HPLC to obtain compound 1c.

[0332] Example 1: (2-(1-benzyl-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6-yl) H -pyrrolo[3,4- b Synthesis of pyridin-6-yl)piperidine-2,6-dione A001: ; Compound A001 was prepared according to Scheme 1: .

[0333] Preparation of methyl 2-(bromomethyl)-6-chloronicotinate 1.2. NBS (26.3 g, 148 mmol) was added to a mixture of methyl 6-chloro-2-methylnicotinate 1.1 (25 g, 134 mmol) and AIBN (4.42 g, 26.9 mmol) in CCl4 (120 mL) under N2. After stirring at 80 °C for 12 hours under N2, the reaction mixture was filtered, concentrated, and purified by column chromatography (SiO2, EtOAc / PE) to give compound 1.2 (30 g), 50% yield. 1 H NMR (400 MHz, CDCl3) δ 8.26-8.24(m, 1H), 7.38-7.36 (m, 1H), 4.98 (s, 2H), 3.98 (s, 3H); MS (ESI) m / z 265.8 [M+H] + .

[0334] 3-(2-chloro-5-oxo-5,7-dihydro-6) H -pyrrolo[3,4- b Preparation of pyridin-6-yl)piperidin-2,6-dione 1.3. A mixture of compound 1.2 (30 g, 65.7 mmol), an HCl salt of 3-aminopiperidin-2,6-dione (10.8 g, 65.7 mmol), and DIPEA (25.5 g, 197 mmol) in DMF (300 mL) was stirred at 110 °C for 3 h under N2. The reaction mixture was then diluted with H2O (500 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, MeOH / DCM) to give compound 1.3 (11 g), yield 44%. 1 H NMR (400 MHz, CDCl3) δ 8.13-8.11 (m, 1H), 7.50-7.48 (m,1H), 5.26-5.21 (m, 1H), 4.56-4.37 (m, 2H), 3.95 (s, 1H), 2.90-2.85 (m, 1H),2.44-2.39 (m, 2H), 2.89-2.7 (m, 2H; MS (ESI) m / z 279.9 [M+H] + .

[0335] tert-butyl4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b Preparation of pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1.5. Tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1.4 (16.5 g, 53.6 mmol), K3PO4 (9.11 g, 42.9 mmol), and Pd(dppf)Cl2 (2.92 g, 3.58 mmol) were added to a mixture of compound 1.3 (10 g, 35.7 mmol) in DMF (160 mL) and protected under N2. After stirring at 90 °C for 16 hours under N2, the reaction mixture was diluted with H2O (600 mL) and extracted with EtOAc (3 × 500 mL). The organic layers were combined, washed with brine (3 × 500 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, MeOH / DCM) to give compound 1.5 (3.8 g), yield 24%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.0 (s, 1H), 8.12-8.10 (m, 1H), 7.72-7.70(m, 1H), 6.88 (s, 1H), 5.19-5.15 (m, 1H), 4.53-4.31 (m, 2H), 4.09 (s, 2H),3.57-3.54 (m, 2H), 2.97-2.88 (m, 1H), 2.62-2.60 (m, 4H), 2.04-2.01 (m, 1H),1.43 (s, 9H); MS (ESI) m / z 371.0 [M-55] + .

[0336] tert-butyl4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- bPreparation of pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate 1.6. To a solution of compound 1.5 (1 g, 2.34 mmol) in DCM (12 mL), DMF (4 mL), and IPA (12 mL) at 0 °C, phenylsilane (512 mg, 4.74 mmol) and Mn(dpm)3 (709 mg, 1.17 mmol) were added. After stirring at 0 °C under O2 for 16 hours, the reaction was quenched with a saturated aqueous solution of Na2S2O3 (30 mL), and the reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, MeOH / DCM) to give compound 1.6 (0.34 g) in 35% yield. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.0 (s, 1H), 8.16-8.14 (m, 1H), 7.86-7.84 (m, 1H), 5.19-5.14 (m, 1H), 4.52-4.30 (m, 2H), 4.10-4.07 (m, 1H), 3.90-3.87 (m, MS (ESI) m / z 389.1 [M-55] + .

[0337] Preparation of 3-(2-(4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione 1.7. A solution of compound 1.6 (340 mg, 764 µmol) in dioxane in 4 M HCl (10 mL) was stirred under N2 for 4 hours. The reaction mixture was then filtered and concentrated to give an HCl salt of compound 1.7 (280 mg), in 95% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 11.0 (s, 1H), 8.89-8.86 (m, 1H), 8.57-8.50 (m, 1H), 5.19-5.14 (m, 1H), 8.21-8.19 (m, 1H), 7.87-7.85 (m, 1H), 5.21-5.16 (m, 1H), 4.54-4.32 (m, 2H), 3.57 (s, 1H), 3.24-3.18 (m, 4H), 2.90-2.59(m, 1H), 2.45-2.36 (m, 3H), 2.11-1.98 (m, 1H), 1.79-1.75 (m, 2H); MS (ESI) m / z 345.1 [M+H] + .

[0338] 3-(2-(1-benzyl-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b Preparation of pyridin-6-yl)piperidine-2,6-dione A001. Benzaldehyde (90.5 mg, 853 μmol) and NaBH(OAc)3 (347 mg, 1.64 mmol) were added to a solution of the HCl salt of compound 1.7 (250 mg, 656 μmol) in DCM (4 mL) and DMF (4 mL) under N2. After stirring under N2 for 1 hour, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC (C18, ACN / water containing 0.5% TFA) to give compound A001 (109 mg), yield 37%. 1 H NMR (400 MHz, DMSO- d 6 ) δ11.0 (s, 1H), 9.56-9.55 (m, 1H), 8.21-8.19 (m, 1H), 7.87-7.85 (m, 1H), 7.58-7.56 (m, 2H), 7.51-7.49 (m, 3H), 5.98-5.93 (m, 1H), 5.20-5.16 (m, 1H), 4.52-4.31 (m, 4H), 3.35-3.28 (m, 4H), 2.93-2.63 (m, 1H), 2.60-2.51 (m, 1H), 2.45-2.40 (m, 3H), 2.21-1.98 (m, 1H), 1.84-1.82 (m, 2H); MS (ESI) m / z 435.0 [M+H] + .

[0339] Example 2: 3-(2-(1-((1-(3-chlorophenyl)-4-piperidinyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b Synthesis of pyridin-6-yl)piperidine-2,6-dione A063: ; Com...

Claims

1. Compounds having the structure of formula (A): ； Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, or mixtures of two or more tautomers; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; or its pharmaceutically acceptable derivatives; wherein: R 1 For C1-C 10 Alkyl, C3-C 10 cycloalkyl, C6-C 14 Aryl, C7-C 15 Aryl, heteroaryl, or heterocyclic alkyl; R 2 and R 3 Each is independently H, deuterium, C1-C 10 Alkyl or C3-C 10 cycloalkyl; or R 2 and R 3 Together with the carbon atom it is attached to, it forms C(O) or C3-C. 10 cycloalkyl; R 13 It can be H, deuterium, or hydroxyl; X is CR 4 R 5 Or C(O), where R 4 and R 5 Each is independently H, deuterium, or Cl-C 10 Alkyl; and c and d are each an independent integer, either 0, 1, or 2; Each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocycloalkyl group is optionally substituted by one, two, three, or four substituents, each substituent being independently deuterium, cyano, halogen, oxo, nitro, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted heterocyclic alkyl groups, -COR', -CO2R', -CONR'R", -OR', -OC(O)R', -OC(O)NR'R", -NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'C(O)NR"R"', -NRSO2R', -NRSO2NR'R", -SR', -S(O)R', -S(O)2R' or -S(O)2NR'R"; and Each of R', R" and R"' is independently hydrogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C1-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl groups, substituted or unsubstituted heteroaryl groups, or substituted or unsubstituted heterocyclic alkyl groups.

2. The compound according to claim 1, having the structure of formula (I): ； or pharmaceutically acceptable derivatives thereof, wherein: R 1 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R 2 and R 3 Each is independently H, alkyl or cycloalkyl, or R 2 and R 3 Together they form spirocycloalkyl groups; a and b are each independent integers from 1 to 3; and X is CR 4 R 5 Or C(O), where R 4 and R 5 Each can be independently H, alkyl, or aralkyl.

3. The compound according to claim 2, having the structure of formula (Ia): ； or pharmaceutically acceptable derivatives thereof, wherein: R 1 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R 2 It is H, alkyl, or cycloalkyl; and X is CR 4 R 5 Or C(O), where R 4 and R 5 Each can be independently H, alkyl, or aralkyl.

4. The compound according to any one of claims 1 to 3, wherein X is CR 4 R 5 .

5. The compound according to claim 1 or 4, having the structure of formula (II): ； Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, or mixtures of two or more tautomers; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; or its pharmaceutically acceptable derivatives.

6. The compound according to any one of claims 1 to 5, wherein: (i) R 1 It is either aryl or heteroaryl, each optionally converted to -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)-(CH2) m -R 10 or -S(O) p -(CH2) q -R 11 Replace; where R 6 It is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 7 and R 8 Independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 7 and R 8 Together with the atoms it is attached to, it forms a heterocyclic alkyl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl group, or a fused, bridged, or spiro-bicyclic cycloalkyl group, or a monocyclic heterocyclic alkyl group, or a fused, bridged, or spiro-bicyclic heterocyclic alkyl group; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and each m, n, p, and q is an independent integer from 0 to 2; or (ii) R 1 It is aryl or heteroaryl, each optionally fused with a cycloalkyl or heterocycloalkyl ring.

7. The compound according to any one of claims 1 to 6, wherein R 1 It is either aryl or heteroaryl, each optionally converted to -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)-(CH2) m -R 10 or -S(O) p -(CH2) q -R 11 Replace; where R 6 It is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 7 and R 8 Independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 7 and R 8 Together with the atoms it is attached to, it forms a heterocyclic alkyl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl group, or a fused, bridged, or spiro-bicyclic cycloalkyl group, or a monocyclic heterocyclic alkyl group, or a fused, bridged, or spiro-bicyclic heterocyclic alkyl group; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and each m, n, p, and q is an independent integer from 0 to 2.

8. The compound according to any one of claims 1 to 7, wherein R 1 For aryl, optionally -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)R 10 or -S(O)2R 11 Replace; where R 6 It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each R 7 and R 8 Independently H, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 7 and R 8 Together with the atoms it is attached to, it forms a heterocyclic alkyl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl group, or a fused, bridged, or spiro-bicyclic cycloalkyl group, or a monocyclic heterocyclic alkyl group, or a fused, bridged, or spiro-bicyclic heterocyclic alkyl group; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and each n and p is an independent integer from 0 to 2.

9. The compound according to any one of claims 1 to 8, wherein R 1 For aryl, optionally -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 12 -S(O) p NR 7 R 8 -NR 7 S(O) p R 12 -C(O)R 10 or -S(O)2R 11 Replace; where R 6 It is a heterocyclic alkyl or aryl group; R 7 For H; R 8 It is a heterocyclic alkyl or aryl group; R 9 R 10 and R 11 Each is independently a monocyclic cycloalkyl group, or a fused, bridged, or spirocyclic bicyclic heterocyclic alkyl group; R 12 It is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and n is an integer 0 or 1, and p is an integer between 0 and 2.

10. The compound according to any one of claims 1 to 9, wherein R 1 For aryl, optionally -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)R 10 or -S(O)2R 11 Replace; where R 6 It is a heterocyclic alkyl or aryl group; R 7 For H; R 8 It is a heterocyclic alkyl or aryl group; R 9 R 10 and R 11 Each is independently a monocyclic heterocyclic alkyl group, or a fused, bridged, or spirocyclic bicyclic heterocyclic alkyl group; and n is an integer 0 or 1.

11. The compound according to any one of claims 1 to 10, wherein R 1 The phenyl group is optionally substituted.

12. The compound according to any one of claims 1 to 9 and 11, wherein R 1 For phenyl, optionally with -OR 6 -NR 7 R 8 -(CH2) n -R 9 -C(O)NR 7 R 8 -NR 7 C(O)R 8 -C(O)R 10 or -S(O)2R 11 Replace; where R 6 It is a heterocyclic alkyl or aryl group; R 7 For H; R 8 It is a heterocyclic alkyl or aryl group; R 9 R 10 and R 11 Each is independently a monocyclic heterocyclic alkyl group, or a fused, bridged, or spirocyclic bicyclic heterocyclic alkyl group; and n is an integer 0 or 1.

13. The compound according to any one of claims 1 to 12, wherein R 1 It is an unsubstituted phenyl group.

14. The compound according to any one of claims 1 to 6, wherein R 1 It is aryl and optionally fused with cycloalkyl or heterocycloalkyl rings.

15. The compound according to any one of claims 1 to 6 and 14, wherein R 1 It is a phenyl group, optionally fused with a heterocyclic alkyl ring.

16. The compound according to any one of claims 1, 4 and 5, wherein R 1 For C1-C 10 Alkyl, C3-C 10 cycloalkyl, C6-C 14 Aryl, C7-C 15 Aryl, heteroaryl, or heterocyclic alkyl groups, each optionally substituted with one, two, three, or four substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

17. The compound according to any one of claims 1, 4, 5 and 16, wherein R 1 For C1-C 10 Alkyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

18. The compound according to any one of claims 1, 4, 5, 16 and 17, wherein R 1 It is isopropyl.

19. The compound according to any one of claims 1 to 5 and 16, wherein R 1 For C3-C 10 Cycloalkyl, optionally substituted with one, two or three substituents, each substituent being independently deuterium, cyano, halogen, oxo, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

20. The compound according to any one of claims 1 to 5, 16 and 19, wherein R 1 C3-C is a single-ring or double-ring C3-C 10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently deuterated, cyano, halogenated, oxo, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

21. The compound according to any one of claims 1 to 5, 16, 19 and 20, wherein R 1 It is cyclohexyl, 4-aminocyclohexyl or 3-fluorobicyclo[1.1.1]pentan-1-yl.

22. The compound according to any one of claims 1 to 5 and 16, wherein R 1 For C6-C 14 The aryl group is optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

23. The compound according to any one of claims 1 to 5, 16 and 22, wherein R 1 It is a phenyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

24. The compound according to any one of claims 1 to 5, 16, 22 and 23, wherein R 1 It is a phenyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C6-C 14 Aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic alkyl, or -OR'; wherein R' is a substituted or unsubstituted C1-C group. 10 Alkyl, or substituted or unsubstituted C6-C 14 Aryl.

25. The compound according to any one of claims 1 to 5, 16, 22 and 23, wherein R 1 It is phenyl, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, oxacyclohexylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methylpyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, oxacyclohexyl, morpholino, 8-azabicyclo-[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, oxacyclohexyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl.

26. The compound according to any one of claims 1 to 5, 16 and 22 to 25, wherein R 1 It is phenyl, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, morpholinylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazolyl, methylpyrazolyl, piperidinyl, morpholinyl, 8-azabicyclo[3.2.1]octyl or phenoxy.

27. The compound according to any one of claims 1 to 5, 16, 22, 23 and 25, wherein R 1 The phenyl group is optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxecyclohexane-4-ylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxecyclobutane-3-yl, oxecyclohexane Alkyl-4-yl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-aza-bicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, oxacyclohexane-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl or aminosulfonyl.

28. The compound according to any one of claims 1 to 5, 16 and 22 to 27, wherein R 1 It is phenyl, optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, morpholinylmethyl, methoxymethyl, phenoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholinyl, 8-azabicyclo[3.2.1]octane-8-yl or phenoxy.

29. The compound according to any one of claims 1 to 5, 16, 22, 23, 25 and 27, wherein R 1 The following are listed: phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 4-(oxacyclohexane-4-ylmethyl)phenyl, 4-(morpholinylmethyl)phenyl. 4-Hydroxymethylphenyl, 4-Methoxymethylphenyl, 4-Phenoxymethylphenyl, 4-((dimethylamino)methyl)phenyl, 4-Chloro-3-fluorophenyl, 4-Chloro-3-methylphenyl, 3,4-Di(trifluoromethyl)phenyl, 3-Cyclobutylphenyl, 4-Cyclobutylphenyl, 4-Cyclohexylphenyl, 4-Phenylphenyl, 4-Pyrazol-1-ylphenyl, 4-(1-methylpyrazol-3-yl)phenyl, 4-(1-methylpyrazol-4-yl)phenyl, 4-(2-methylpyrazol-3-yl)phenyl, 3-(oxetane-3-yl)phenyl, 4-(oxetane-3-yl)phenyl, 3-oxetane Alkyl-4-phenyl, 4-oxacyclohexane-4-phenyl, 3-(piperidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(4,4-difluoropiperidin-1-yl)phenyl, 4-(4-(hydroxymethyl)piperidin-1-yl)phenyl, 4-(4-hydroxypiperidin-1-yl)phenyl, 3-morpholinylphenyl, 4-morpholinylphenyl, 3-(8-azabicyclo-[3.2.1]octane-8-yl)phenyl, 4-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-Methoxyphenyl, 4-trifluoromethoxyphenyl, 4-(2-hydroxyethoxy)phenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzylmethoxyphenyl, 4-(piperidin-4-yloxy)phenyl, 4-(oxacyclohexane-4-yl)oxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 4-phenylaminophenyl, 3-aminocarbonylphenyl, 4-aminocarbonylphenyl, 3-methylaminocarbonylphenyl, 4-methylaminocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-(methanesulfonyl)phenyl or 4-aminosulfonylphenyl.

30. The compound according to any one of claims 1 to 5, 16 and 22 to 29, wherein R 1 The following are listed: phenyl, 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethylphenyl, 3-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-(oxacyclohexane-4-ylmethyl)phenyl, 4-methoxymethyl 4-Phenylene, 4-Pyrazol-1-ylphenyl, 4-(1-methylpyrazol-3-yl)phenyl, 4-(1-methylpyrazol-4-yl)phenyl, 4-(piperidin-1-yl)phenyl, 3-morpholinylphenyl, 3-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 4-(8-azabicyclo[3.2.1]octane-8-yl)phenyl, 3-phenoxyphenyl or 4-phenoxyphenyl.

31. The compound according to any one of claims 1 to 5, 16 and 22, wherein R 1 For dual-ring C8-C 14 The aryl group is optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

32. The compound according to any one of claims 1, 4, 5, 16, 22 and 31, wherein R 1 It is 2,3-dihydroinden-2-yl.

33. The compound according to any one of claims 1, 4, 5 and 16, wherein R 1 C7-C 15 Aryl group, optionally substituted with one, two or three substituents, each substituent being independently deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

34. The compound according to any one of claims 1, 4, 5, 16 and 33, wherein R 1 It is benzyl or 3-fluorobenzyl.

35. The compound according to any one of claims 1 to 5 and 16, wherein R 1 It is a heteroaryl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

36. The compound according to any one of claims 1 to 5, 16 and 35, wherein R 1 It refers to a monocyclic heteroaryl group that is either substituted or unsubstituted.

37. The compound according to any one of claims 1 to 5, 16, 35 and 36, wherein R 1 It is a 5- or 6-membered heteroaryl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterated, cyano, halogenated, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

38. The compound according to any one of claims 1 to 5, 16 and 35 to 37, wherein R 1 It is isoxazolyl, oxazolyl, pyrazolyl, thiazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, tetrazolyl or pyridyl, each optionally substituted by one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl or phenyl.

39. The compound according to any one of claims 1 to 5, 16 and 35 to 38, wherein R 1 It is isoxazol-4-yl, oxazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, thiazolyl-2-yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl.

40. The compound according to any one of claims 1, 4, 5, 16 and 35 to 39, wherein R 1 It is isoxazol-4-yl, oxazol-2-yl, pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 3-methylpyrazol-4-yl, 1-(trifluoromethyl)pyrazol-4-yl, 1-(isopropyl)pyrazol-3-yl, 1-(isopropyl)pyrazol-4-yl, 1-phenylpyrazol-4-yl, thiazole-2-yl, 5-methylthiazole-2-yl, 1,2,4-triazole-3-yl, 5-methyl-1,3,4-thiadiazole-2-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-hydroxypyridin-4-yl, or 1-methyl-2-oxo-1,2-dihydropyridin-4-yl.

41. The compound according to any one of claims 1 to 5, 16 and 35, wherein R 1 For substituted or unsubstituted bicyclic heteroaryl groups.

42. The compound according to any one of claims 1 to 5, 16, 35 and 41, wherein R 1 It is a 5,5-, 5,6-, or 6,6-fused heteroaryl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

43. The compound according to any one of claims 1 to 5, 16, 35, 41 and 42, wherein R 1 It is 5,6-dihydrocyclopentane[ d ]Thiazolyl, 6,7-dihydropyrrolo[1,2- a Imidazolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzo[ d [1,2,3]triazolyl, imidazo[1,2- a ]pyridyl, indole, indazole, pyrazolo[1,5- a ]pyridyl, pyrrolo[2,3- b ]pyridyl, pyrrolo[3,2- b ]pyridyl, [1,2,4]triazolo[1,5- a ]pyridyl, 2,3-dihydroisoindolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, benzo[ d [1,3]dioxanepentyl, 5,6,7,8-tetrahydroimidazole[1,2- a ]pyridyl, 4,5,6,7-tetrahydropyrazolo[1,5- a ]pyridyl, quinolinyl, chromanyl, 3,4-dihydropyrido[3,2- b [1,4]oxazinyl or 3,4-dihydro-1,4-benzoxazinyl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl or phenyl.

44. The compound according to any one of claims 1 to 5, 16, 35 and 41 to 43, wherein R 1 It is 5,6-dihydrocyclopentane[ d ]Thiazol-2-yl, 6,7-dihydropyrrolo[1,2- a Imidazol-2-yl, benzofuran-6-yl, benzimidazol-5-yl, benzoxazol-2-yl, benzothiazol-2-yl, benzo[ d [1,2,3]triazol-5-yl, imidazo-[1,2- a ]pyridin-2-yl, indole-5-yl, indole-6-yl, indazole-4-yl, indazole-5-yl, indazole-6-yl, pyrazolo[1,5- a ]Pyridin-6-yl, pyrrolo[2,3- b ]Pyridin-5-yl, pyrrolo[3,2- b ]Pyridin-2-yl, pyrrolo[3,2- b [Pyridin-6-yl, [1,2,4]triazolo[1,5-] a ]Pyridin-7-yl, 2,3-dihydroisoindol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 1,3-dihydroisobenzofuran-5-yl, benzo[ d [1,3]dioxanepent-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-] a ]pyridin-2-yl, 4,5,6,7-tetrahydropyrazolo[1,5- a ]pyridin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-6-yl, chroman-6-yl, chroman-7-yl, 3,4-dihydropyrido[3,2- b [1,4]-oxazin-7-yl or 3,4-dihydro-1,4-benzoxazin-6-yl, each optionally substituted with one or two substituents, each substituent being independently deuterium, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, or phenyl.

45. The compound according to any one of claims 1 to 5, 16, 35 and 41 to 44, wherein R 1 It is 5,6-dihydrocyclopentane[ d ]Thiazol-2-yl, 6,7-dihydropyrrolo[1,2- a Imidazol-2-yl, benzofuran-6-yl, 1-methylbenzimidazol-5-yl, 3-methylbenzimidazol-5-yl, benzoxazole-2-yl, benzothiazol-2-yl, 1-methylbenzo[ d [1,2,3]triazol-5-yl, imidazo[1,2-] a ]pyridin-2-yl, 1-methylindole-5-yl, 1-methylindole-6-yl, indazole-5-yl, 1-methylindazole-4-yl, 1-methylindazole-5-yl, 1-methylindazole-6-yl, pyrazolo[1,5- a ]Pyridin-6-yl, 2,2-difluorobenzo[ d [1,3]dioxacyclopentan-5-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrrolo[3,2- b ]Pyridin-2-yl, pyrrolo[3,2- b ]pyridin-6-yl, 2,2-dimethylbenzo[ d [1,3]dioxacyclopentan-5-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-6-yl, [1,2,4]triazolo[1,5- a ]Pyridin-7-yl, 1,3-dihydroisobenzofuran-5-yl, 2,3-dihydrobenzofuran-5-yl, 3-oxo-3,4-dihydro-1,4-benzoxazin-6-yl, 2,3-dihydroindene-2-yl, 2,3-dihydroisoindole-5-yl, 3-oxo-2,3-dihydroisoindole-5-yl, 2,3-dihydrobenzofuran-6-yl, 5,6,7,8-tetrahydroimidazo[1,2- a ]pyridin-2-yl, 4,5,6,7-tetrahydropyrazolo[1,5- a ]pyridin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-6-yl, chroman-6-yl, chroman-7-yl, 4-methyl-3,4-dihydropyrido[3,2- b [1,4]Oxazin-7-yl or 3-oxo-3,4-dihydro-1,4-benzoxazin-6-yl.

46. ​​The compound according to any one of claims 1 to 5 and 16, wherein R 1 It is a heterocyclic alkyl group, optionally substituted with one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

47. The compound according to any one of claims 1 to 5, 16 and 46, wherein R 1 It refers to a monocyclic heterocyclic alkyl group, whether substituted or unsubstituted.

48. The compound according to any one of claims 1 to 5, 16, 46 and 47, wherein R 1 It is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic alkyl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterium, cyano, halogen, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

49. The compound according to any one of claims 1 to 5, 16 and 46 to 48, wherein R 1 It is azacyclobutyl, oxacyclohexyl, piperidinyl, tetrahydrothiapyranyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 3-azaspiro[5.5]undecyl or 8-azabicyclo-[3.2.1]octyl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, phenyl or pyridyl.

50. The compound according to any one of claims 1 to 5, 16 and 46 to 49, wherein R 1 It is azacyclobut-3-yl, oxacyclohexane-2-yl, oxacyclohexane-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiapyran-4-yl, 2-azaspiro[3.3]heptane-6-yl, 2-azaspiro[3.5]nonane-7-yl, 3-azaspiro[5.5]undecane-9-yl or 8-aza-bicyclo[3.2.1]octane-3-yl, each optionally substituted with one or two substituents, each substituent being independently oxo, cyano, chlorine, fluorine, methyl, trifluoromethyl, isopropyl, phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

51. The compound according to any one of claims 1 to 5, 16 and 46 to 50, wherein R 1 The derivatives are 1-phenylazacyclobut-3-yl, oxacyclohexane-2-yl, oxacyclohexane-3-yl, piperidin-4-yl, 1-(isopropyl)piperidin-4-yl, 1-phenylpiperidin-3-yl, 1-phenylpiperidin-4-yl, 1-(2-chlorophenyl)piperidin-4-yl, 1-(3-chlorophenyl)piperidin-4-yl, 1-(4-chlorophenyl)piperidin-4-yl, 1-benzylpiperidin-4-yl, 1- (pyridin-3-yl)piperidin-4-yl, 1-(pyridin-2-yl)piperidin-4-yl, 1-acetylpiperidin-4-yl, 1,1-tetrahydrothiapyran-4-yl, 2-azaspiro[3.3]heptane-6-yl, 2-azaspiro[3.5]nonane-7-yl, 8-phenyl-8-azabicyclo-[3.2.1]octane-3-yl or 3-azaspiro[5.5]undecane-9-yl.

52. The compound according to any one of claims 1 to 5, 16 and 46 to 51, wherein R 1 It is 1-phenylpiperidin-3-yl, 1-phenylpiperidin-4-yl, 1-(3-chlorophenyl)piperidin-4-yl or 1-(4-chlorophenyl)piperidin-4-yl.

53. The compound according to claim 1, 4 or 5, having the structure of formula (IV): ； Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; or its pharmaceutically acceptable derivatives; wherein: R 1a R 1b R 1c R 1d and R 1e Each is independently H, deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R"; or R 1a and R 1b Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic alkyl group; or R 1b and R 1c Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterocyclic alkyl group.

54. The compound according to claim 53, having the structure of formula (V): ； Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs; or pharmaceutically acceptable derivatives thereof.

55. The compound according to claim 53 or 54, wherein R 1a R 1b R 1c R 1d and R 1e Each is independently H, deuterium, cyano, halogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

56. The compound according to any one of claims 53 to 55, wherein R 1a H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

57. The compound according to any one of claims 53 to 56, wherein R 1a The following are the radicals: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, oxacyclohexylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methylpyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, oxacyclohexyl, morpholino, 8-azabicyclo[3.2.1]-octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, oxacyclohexyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl.

58. The compound according to any one of claims 53 to 57, wherein R 1a The following are not part of the given description: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxacyclohexane-4-ylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxacyclobutane-3-yl, oxacyclohexane-4-yl, piperidin-1-yl. 4,4-Difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, oxacyclohexane-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl or aminosulfonyl.

59. The compound according to any one of claims 53 to 58, wherein R 1a It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxacyclohexane-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo-[3.2.1]octane-8-yl or phenoxy.

60. The compound according to any one of claims 53 to 59, wherein R 1a For H.

61. The compound according to any one of claims 53 to 60, wherein R 1b H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

62. The compound according to any one of claims 53 to 61, wherein R 1b The following are the radicals: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, oxacyclohexylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methylpyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, oxacyclohexyl, morpholino, 8-azabicyclo[3.2.1]-octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, oxacyclohexyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl, or aminosulfonyl.

63. The compound according to any one of claims 53 to 62, wherein R 1b The following are not part of the given description: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxacyclohexane-4-ylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxacyclobutane-3-yl, oxacyclohexane-4-yl, piperidin-1-yl. 4,4-Difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]octane-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, oxacyclohexane-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methanesulfonyl or aminosulfonyl.

64. The compound according to any one of claims 53 to 63, wherein R 1b It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxacyclohexane-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]oct-8-yl or phenoxy.

65. The compound according to any one of claims 53 to 64, wherein R 1c H, deuterium, cyano, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

66. The compound according to any one of claims 53 to 65, wherein R 1c It is H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, difluoroethyl, propyl, butyl, oxacyclohexylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazolyl, methylpyrazolyl, oxacyclobutyl, piperidinyl, difluoropiperidinyl, (hydroxymethyl)piperidinyl, hydroxypiperidinyl, oxacyclohexyl, morpholino, 8-azabicyclo[3.2.1]octyl, hydroxy, methoxy, trifluoromethoxy, hydroxyethoxy, phenoxy, benzoxy, oxacyclohexyloxy, piperidinyloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfonyl or aminosulfonyl.

67. The compound according to any one of claims 53 to 66, wherein R 1c The following are not part of the given description: H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxacyclohexane-4-ylmethyl, morpholinomethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclobutyl, cyclohexyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrazol-3-yl, oxacyclobutane-3-yl, oxacyclohexane-4-yl, piperidin-1-yl. 4,4-Difluoropiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]oct-8-yl, hydroxy, methoxy, trifluoromethoxy, 2-hydroxyethoxy, phenoxy, benzoxy, piperidin-4-yloxy, oxacyclohexane-4-yloxy, amino, dimethylamino, phenylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfonyl or aminosulfonyl.

68. The compound according to any one of claims 53 to 67, wherein R 1c It can be H, cyano, chlorine, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, isopropyl, tert-butyl, oxacyclohexane-4-ylmethyl, methoxymethyl, phenyl, pyrazol-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, piperidin-1-yl, morpholino, 8-azabicyclo[3.2.1]oct-8-yl or phenoxy.

69. The compound according to any one of claims 53 to 68, wherein R 1d For H.

70. The compound according to any one of claims 53 to 69, wherein R 1e For H.

71. The compound according to any one of claims 53 to 55 and 65 to 68, wherein R 1a and R 1b Together with the carbon atom to which it is attached, it forms a heteroaryl or heterocyclic alkyl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterated, oxo, cyano, halogenated, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

72. The compound according to any one of claims 53 to 55 and 65 to 69, wherein R 1a and R 1b Together with the carbon atom it is attached to, it forms tetrahydrofuran-2,3-diyl, 5,5-dimethyl-tetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 2-oxopyrrolidine-3,4-diyl, 2,2-difluoro-1,3-dioxacyclopentane-4,5-diyl, 2,2-dimethyl-1,3-dioxacyclopentane-4,5-diyl, oxacyclohexane-2,3-diyl, 4-methylmorpholine-2,3-diyl, or 5-oxomorpholine-2,3-diyl.

73. The compound according to any one of claims 53 to 60, 69 and 70, wherein R 1b and R 1c Together with the carbon atom to which it is attached, it forms a heteroaryl or heterocyclic alkyl group, each optionally substituted by one, two, or three substituents, each substituent being independently deuterated, oxo, cyano, halogenated, substituted, or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C7-C 15 Aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic alkyl group, -COR', -CONR'R", -OR', -NR'R", -S(O)2R' or -S(O)2NR'R".

74. The compound according to any one of claims 53 to 60 and 69 to 73, wherein R 1b and R 1c Together with the carbon atom it is attached to, it forms tetrahydrofuran-2,3-diyl, 5,5-dimethyl-tetrahydrofuran-2,3-diyl, tetrahydrofuran-3,4-diyl, pyrrolidine-3,4-diyl, 2-oxopyrrolidine-3,4-diyl, 2,2-difluoro-1,3-dioxacyclopentane-4,5-diyl, 2,2-dimethyl-1,3-dioxacyclopentane-4,5-diyl, oxacyclohexane-2,3-diyl, 4-methylmorpholine-2,3-diyl, or 5-oxomorpholine-2,3-diyl.

75. The compound according to any one of claims 1 to 74, wherein R 2 For H.

76. The compound according to any one of claims 1 to 75, wherein R 3 For H.

77. The compound according to any one of claims 1 to 74, wherein R 2 and R 3 Together with the carbon atom it is attached to, it forms C(O).

78. The compound according to any one of claims 1 to 77, wherein R 4 H, or substituted or unsubstituted C1-C 10 alkyl.

79. The compound according to any one of claims 1 to 78, wherein R 4 For H.

80. The compound according to any one of claims 1 to 78, wherein R 4 It is a methyl group.

81. The compound according to any one of claims 1 to 80, wherein R 5 H, or substituted or unsubstituted C1-C 10 alkyl.

82. The compound according to any one of claims 1 to 81, wherein R 5 For H.

83. The compound according to any one of claims 1 to 82, wherein R 5 It is a methyl group.

84. The compound according to any one of claims 1 to 83, wherein R 13 For H.

85. The compound according to any one of claims 1 to 83, wherein R 13 It is a hydroxyl group.

86. The compound according to claim 1, wherein the compound is: 3-(2-(1-benzyl-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A001; 3-(2-(4-hydroxy-1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A002; 3-(2-(4-hydroxy-1-(2-methylbenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A003; 3-(2-(4-hydroxy-1-(4-methylbenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A004; 3-(2-(4-hydroxy-1-phenylethylpiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A005; 3-(2-(4-hydroxy-1-(2-hydroxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A006; 3-(2-(4-hydroxy-1-(3-hydroxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] -b ]Pyridin-6-yl)piperidine-2,6-dione A007; 3-(2-(4-hydroxy-1-(2-cyanobenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] -b ]pyrido-6-yl)piperidin-2,6-dione; 3-(2-(4-hydroxy-1-(4-cyanobenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] -b ]Pyrido-6-yl)piperidine-2,6-dione A009; 3-(2-(4-hydroxy-1-(3-cyanobenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4] -b ]pyrido-6-yl)piperidine-2,6-dione A010; 3-(2-(4-hydroxy-1-(4-(hydroxymethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A011; 3-(2-(1-(2,4-difluorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A012; 3-(2-(1-(2,4-difluorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A013; 3-(2-(1-(4-(dimethylamino)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A014; 3-(2-(1-([1,1'-biphenyl]-4-ylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A015; 3-(2-(4-hydroxy-1-(4-(methanesulfonyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A016; 3-(2-(4-hydroxy-1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A017; 3-(2-(4-hydroxy-1-(3-phenoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A018; 3-(2-(1-(cyclohexylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A019; 3-(2-(4-hydroxy-1-(3-methylbenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A020; 3-(2-(1-(3-aminobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A021; 3-(2-(4-hydroxy-1-((2-oxo-1,2-dihydropyridin-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A022; 3-(2-(4-hydroxy-1-(2-methoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A023; 3-(2-(4-hydroxy-1-(3-methoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A024; 3-(2-(4-hydroxy-1-(4-methoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A025; 3-(2-(1-(3-chlorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A026; 3-(2-(1-(benzofuran-6-ylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A027; 3-(2-(1-((1H-indazol-5-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A028; 3-(2-(4-hydroxy-1-(pyrazolo[1,5-a]pyridin-6-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A029; 3-(2-(1-((2,3-dihydro-1H-inden-2-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A030; 3-(2-(4-hydroxy-1-(4-aminocarbonylphenylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A031; 3-(2-(4-hydroxy-1-(3-aminocarbonylphenylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A032; 3-(2-(1-(3-(dimethylamino)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A033; 3-(2-(4-hydroxy-1-(4-(methoxymethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A034; 3-(2-(4-hydroxy-1-(quinolin-6-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A035; 3-(2-(4-hydroxy-1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A036; 3-(2-(1-((1,1-dioxotetrahydro-2H-thiaran-4-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A037; 3-(2-(4-hydroxy-1-((1-phenyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A038; 3-(2-(4-hydroxy-1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A039; 4-((4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5-yl) H -pyrrolo[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)-N,N-dimethylbenzamide A040; 3-(2-(1-((2,2-difluorobenzo[ d [1,3]m-dioxacyclopentan-5-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-diA041; 3-(2-(4-hydroxy-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A042; 3-(2-(1-(4-(benzyloxy)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A043; 3-(2-(4-hydroxy-1-((1-methyl-1) H -Indazol-5-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A044; 3-(2-(4-hydroxy-1-((1-methyl-1) H -pyrazol-3-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A045; 4-((4-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5-yl) H -pyrrolo[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)-N-methylbenzamide A046; 3-(2-(4-hydroxy-1-((1-(trifluoromethyl)-1 H -pyrazol-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A047; 3-(2-(4-hydroxy-1-(4-(1-methyl-1-hydroxy ... H -pyrazol-4-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A048; 3-(2-(4-hydroxy-1-((1-phenylpiperidin-4-yl)methyl)piperidin-4-yl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A049; 3-(2-(4-hydroxy-1-(4-(phenylamino)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A050; 3-(2-(4-hydroxy-1-(4-(4-hydroxypiperidin-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A051; 3-(2-(1-((1 H -pyrrolo[3,2-b]pyrido-6-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H- Pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A052; 3-(2-(1-((2,2-dimethylbenzo[ d [1,3]m-dioxacyclopentan-5-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A053; 3-(2-(1-((2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A054; 3-(2-(4-hydroxy-1-(isoxazo-4-ylmethyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A055; 3-(2-(4-hydroxy-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A056; 3-(2-(4-hydroxy-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridino-6-yl)piperidin-2,6-dione A057; 3-(2-(1-(4-((dimethylamino)methyl)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A058; 3-(2-(4-hydroxy-1-(4-phenoxybenzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A059; 3-(2-(4-hydroxy-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A060; 3-(2-(4-hydroxy-1-(4-(4-(hydroxymethyl)piperidin-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A061; 3-(2-(4-hydroxy-1-(4-(phenoxymethyl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A062; 3-(2-(1-((1-(3-chlorophenyl)-4-piperidinyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A063; 3-(2-(1-((1-(2-chlorophenyl)-4-piperidinyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A064; 3-(2-(1-((1-(4-chlorophenyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A065; 3-(2-(4-hydroxy-1-((4-(1-methylpyrazol-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A066; 3-(2-(4-hydroxy-1-((4-(2-methylpyrazol-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A067; 3-(2-(4-hydroxy-1-((4-pyrazol-1-ylphenyl)methyl)-4-piperidinyl)-5-oxo-7H-pyrrolo[3,4-b]pyridino-6-yl)piperidin-2,6-dione A068; 3-(2-(4-hydroxy-1-((1-(2-pyridyl)-4-piperidinyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A069; 3-(2-(4-hydroxy-1-(((R)-1-phenylpiperidin-3-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A070; 3-(2-(4-hydroxy-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A071; 3-(2-(4-hydroxy-1-((8-phenyl-8-azabicyclo[3.2.1]octane-3-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A072; 3-(2-(4-hydroxy-1-((1-phenylazacyclobutane-3-yl)methyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A073; 3-(2-(1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A074; 3-(2-(1-(3,4-dimethoxybenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A075; 3-(2-(4-hydroxy-1-((1-methylindol-5-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A076; 3-(2-(4-hydroxy-1-((1-methylindazole-4-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A077; 3-(2-(4-hydroxy-1-((4-(oxecyclobutane-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A078; 3-(2-(4-hydroxy-1-((3-(1-piperidinyl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A079; 3-(2-(1-((4-(4,4-difluoro-1-piperidinyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A080; 3-(2-(4-hydroxy-1-(4-(piperidin-1-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A081; 3-(2-(4-hydroxy-1-((4-tetrahydropyran-4-ylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A082; 3-(2-(4-hydroxy-1-(3-(tetrahydro-2H-pyran-4-yl)benzyl)piperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A083; 3-(2-(1-((3-fluorophenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A084; 3-(2-(4-hydroxy-1-((4-morpholinylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A085; 3-(2-(4-hydroxy-1-((3-morpholinylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A086; 3-(2-(4-hydroxy-1-((3-(oxecyclobutane-3-yl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A087; 3-(2-(4-hydroxy-1-((4-(tetrahydropyran-4-ylmethyl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A088; 3-(2-(1-((2-fluorophenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A089; 3-(2-(4-hydroxy-1-isobutyl-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)-piperidine-2,6-dione A090; 3-(2-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A091; 3-(2-(4-hydroxy-1-((1-methylbenzimidazol-5-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A092; 3-(2-(4-hydroxy-1-((3-methylbenzimidazol-5-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A093; 3-(2-(4-hydroxy-1-((1-methylindole-6-yl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A094; 3-(2-(4-hydroxy-1-((4-(morpholinylmethyl)phenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A095; 3-(2-(1-((4-fluorophenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-Pyridin-6-yl)piperidine-2,6-dione A096; (3 S )-3-((7 S )-2-(1-Benzyl-4-hydroxy-4-piperidinyl)-7-methyl-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A097; ( S )-3-(( R )-2-(4-hydroxy-1-((1-phenylpiperidin-4-yl)methyl)piperidin-4-yl)-7-methyl-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A098; 3-(2-(1-(2-(3-fluorophenyl)ethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A099; 3-(2-(1-(chroman-7-ylmethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-Pyridin-6-yl)piperidine-2,6-dione A100; 3-(2-(1-(chroman-6-ylmethyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A101; 3-(2-(1-((2,3-dihydrobenzofuran-6-yl)methyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A102; 3-(2-(1-(2,3-dihydrobenzofuran-5-ylmethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A103; 3-(2-(1-(1,3-dihydroisobenzofuran-5-ylmethyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A104; 3-(2-((3 S 4 S )-1-Benzyl-3,4-dihydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A105; 3-(2-((3 R 4 R )-1-Benzyl-3,4-dihydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A106; 3-(2-(1-((3,4-bis(trifluoromethyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A107; 3-(2-(1-((4-tert-butylphenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A108; 3-(2-(1-((3-tert-butylphenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A109; 3-(2-(4-hydroxy-1-((4-isopropylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A110; 3-(2-(4-hydroxy-1-((3-isopropylphenyl)methyl)-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]-pyridin-6-yl)piperidine-2,6-dione A111; 3-(2-(1-((3-(1,1-difluoroethyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A112; 3-(2-(1-((4-(1,1-difluoroethyl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A113; 3-(2-(1-(4-ethylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A114; 3-(2-(1-(4-chloro-3-methylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A115; 3-(2-(1-(4-((1 R 5 S )-8-azabicyclo[3.2.1]octane-8-yl)benzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A116; 3-(2-(1-(4-cyclobutylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A117; 3-(2-(1-(3-ethylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A118; 3-(2-(1-(4-chloro-3-fluorobenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A119; 3-(2-(1-(3-cyclobutylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo[3,4- b Pyrido-6-yl)piperidin-2,6-dione A120; 3-(2-(1-((3-((1 R 5 S )-8-azabicyclo[3.2.1]octane-8-yl)phenyl)methyl)-4-hydroxy-4-piperidinyl)-5-oxo-7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A121; 3-(2-(1-(4-cyclohexylbenzyl)-4-hydroxypiperidin-4-yl)-5-oxo-5,7-dihydro-6 H -pyrrolo-[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A122; 4-((4-(6-(( S )-2,6-dioxopiperidin-3-yl)-7-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)benzylnitrile A123; 4-((4-(( R )-6-(( S )-2,6-dioxopiperidin-3-yl)-7-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo-[3,4- b ]Pyridin-2-yl)-4-hydroxypiperidin-1-yl)methyl)benzylnitrile A124; 3-(2-{4-hydroxy-1-[(1 H [-pyrazol-4-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A125; 3-(2-{4-hydroxy-1-[(1,3-oxazol-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A126; 3-(2-{4-hydroxy-1-[(1 H -1,2,4-triazol-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A127; 3-(2-{4-hydroxy-1-[(pyridin-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A128; 3-(2-{4-hydroxy-1-[(pyridin-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidin-2,6-dione A129; 3-(2-{4-hydroxy-1-[(1-methyl-1-hydroxy ... H [-pyrazol-4-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A130; 3-(2-{4-hydroxy-1-[(1,3-thiazolyl-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A131; 3-(2-{4-hydroxy-1-[(piperidin-4-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A132; 3-(2-{4-hydroxy-1-[(tetrahydro-2-)- H [-pyran-2-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A133; 3-(2-{4-hydroxy-1-[(tetrahydropyran-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A134; 3-(2-{4-hydroxy-1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A135; 3-{2-[1-({2-azaspiro[3.3]heptane-6-yl}methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A136; 3-(2-{4-hydroxy-1-[(5-methyl-1,3-thiazo-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A137; 3-[2-(4-hydroxy-1-{[(1 r 4 r [4-Aminocyclohexyl]methyl[piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A138; 3-{2-[4-hydroxy-1-({5-hydroxy-1-(4 ... H 6 H 7 H -pyrrolo[1,2- a [imidazol-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4-b]pyrido-6-yl}piperidin-2,6-dione A139; 3-(2-{4-hydroxy-1-[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidin-2,6-dione A140; 3-[2-(4-hydroxy-1-{[1-(propyl-2-yl)-1-] H -pyrazol-4-yl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A141; 3-{2-[4-hydroxy-1-({imidazo[1,2- a [pyridin-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A142; 3-{2-[4-hydroxy-1-({1 H -pyrrolo[2,3- b [pyridin-5-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A143; 3-(2-{1-[(1,3-benzoxazol-2-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A144; 3-{2-[4-hydroxy-1-({[1,2,4]triazolo[1,5- a [pyridin-7-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A145; 3-(2-{1-[(2,3-dihydro-1 ... H [-isoindol-5-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A146; 3-{2-[4-hydroxy-1-({4-hydroxy-1-( ... H 5 H 6 H 7 H -pyrazolo[1,5- a [pyridin-3-yl]methyl)-piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A147; 3-{2-[1-({4 H 5 H 6 H -Cyclopenta[ d [1,3]thiazolyl-2-yl]methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A148; 3-{2-[1-({2-azaspiro[3.5]nonane-7-yl}methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A149; 3-(2-{1-[(1-acetylpiperidin-4-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A150; 3-[2-(4-hydroxy-1-{[1-(propyl-2-yl)piperidin-4-yl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A151; 3-(2-{4-hydroxy-1-[(quinolin-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo-[3,4- b ]pyridin-6-yl)piperidine-2,6-dione A152; 3-(2-{4-hydroxy-1-[(3-oxo-2,3-dihydro-1-]) H -isoindol-5-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A153; 3-[(4-{6-[2,6-dioxopiperidin-3-yl]-5-oxo-5-yl] H 6 H 7 H -pyrrolo[3,4- b [Pyridin-2-yl]-4-hydroxypiperidin-1-yl)methyl]-N-methylbenzamide A154; 3-(2-{1-[(1,3-benzothiazol-2-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A155; 3-[2-(4-hydroxy-1-{[4-(2-hydroxyethoxy)phenyl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidin-2,6-dione A156; 3-[2-(4-hydroxy-1-{[4-(2 ... H -1,2,3,4-Tetrazol-5-yl)phenyl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A157; 3-(2-{4-hydroxy-1-[(3-oxo-3,4-dihydro-2- H -1,4-Benzoxazine-6-yl)methyl]-piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A158; 3-{2-[4-hydroxy-1-({4-methyl-2-hydroxy-1-( ...(4-hydroxy- H ,3 H 4 H -pyrido[3,2- b [1,4]oxazine-7-yl]methyl)-piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4-b]pyrido-6-yl}piperidin-2,6-dione A159; 3-{2-[1-({3-azaspiro[5.5]undecane-9-yl}methyl)-4-hydroxypiperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A160; 4-[(4-{6-[2,6-dioxopiperidin-3-yl]-5-oxo-5-yl] H 6 H 7 H -pyrrolo[3,4- b [Pyridin-2-yl]-4-hydroxypiperidin-1-yl)methyl]benzene-1-sulfonamide A161; 3-(2-{4-hydroxy-1-[(5-methyl-1-]) H [-pyrazol-4-yl]methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A162; 3-(2-{4-hydroxy-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]Pyrido-6-yl)piperidine-2,6-dione A163; 3-[2-(4-hydroxy-1-{[1-(propyl-2-yl)-1H-pyrazol-3-yl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A164; 3-{2-[4-hydroxy-1-({1 H -pyrrolo[3,2- b [pyridin-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A165; 3-{2-[4-hydroxy-1-({5-hydroxy-1-(4 ... H 6 H 7 H 8 H -imidazo[1,2- a [pyridin-2-yl]methyl)piperidin-4-yl]-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b Pyrido-6-ylpiperidine-2,6-dione A166; 3-[2-(4-hydroxy-1-{[4-(piperidin-4-yloxy)phenyl]methyl}piperidin-4-yl)-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b [Pyrido-6-yl]piperidine-2,6-dione A167; 3-(2-{1-[(1-benzylpiperidin-4-yl)methyl]-4-hydroxypiperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo[3,4- b ]pyrido-6-yl)piperidine-2,6-dione A168; or 3-(2-{4-hydroxy-1-[(quinolin-3-yl)methyl]piperidin-4-yl}-5-oxo-5 H 6 H 7 H -pyrrolo-[3,4- b ]Pyridin-6-yl)piperidine-2,6-dione A169; Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

87. A pharmaceutical composition comprising the compound of any one of claims 1 to 86, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

88. The pharmaceutical composition according to claim 87, wherein the pharmaceutical composition is in a single-dose form.

89. The pharmaceutical composition according to claim 87 or 88, wherein the pharmaceutical composition is in the form of an oral, parenteral, or intravenous dose.

90. The pharmaceutical composition according to any one of claims 87 to 89, wherein the pharmaceutical composition is formulated into an oral dosage form.

91. The pharmaceutical composition according to claim 90, wherein the oral dosage form is a tablet or a capsule.

92. A method of treating, preventing, or improving one or more symptoms of an ARNT-mediated disease or condition in a subject, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1 to 86 or any one of claims 87 to 91 of a pharmaceutical composition.

93. The method of claim 92, wherein the disease or condition is cancer, inflammation, or an autoimmune disease.

94. A method of treating, preventing, or improving one or more symptoms of a proliferative disease in a subject, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1 to 86 or any one of claims 87 to 91 of a pharmaceutical composition.

95. The method of claim 94, wherein the proliferative disease is cancer.

96. The method according to any one of claims 92 to 95, wherein the subject is a human being.

97. A method for inhibiting cell growth, comprising contacting the cells with an effective amount of the compound of any one of claims 1 to 86 or the pharmaceutical composition of any one of claims 87 to 91.

98. The method of claim 97, wherein the cell is a cancer cell.

99. A method for inducing ARNT degradation, comprising contacting ARNT with an effective amount of the compound of any one of claims 1 to 86 or the pharmaceutical composition of any one of claims 87 to 91.

100. A method for inhibiting ARNT activity, comprising contacting ARNT with an effective amount of the compound of any one of claims 1 to 86 or the pharmaceutical composition of any one of claims 87 to 91.

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