G protein-coupled receptor kinase 2 (GRK2) degrading compounds and uses thereof

Abstract

The present disclosure relates to G protein-coupled receptor kinase 2 (GRK2) degrading compounds and their uses. Specifically, the present disclosure relates to novel compounds that degrade G protein-coupled receptor kinase 2 (GRK2), or their pharmaceutically acceptable salts, isomers, isotopes, prodrugs, solvates, or polymorphs, pharmaceutical compositions comprising them, kits comprising them, and their uses in preventing or treating various diseases or conditions, such as diseases or conditions that are at least partially medicated by GRK2, or diseases or conditions that can benefit from the degradation of GRK2.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to PCT Application No. PCT / CN2023 / 075491, filed February 10, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to novel compounds that degrade G protein-coupled receptor kinase 2 (GRK2), or pharmaceutically acceptable salts, isomers, isotopes, prodrugs, solvates, or polymorphs thereof, pharmaceutical compositions comprising same, kits comprising same, and uses thereof in preventing or treating various diseases or conditions, such as diseases or conditions that are medicated at least in part by GRK2 or that could benefit from the degradation of GRK2. [Background technology]

[0003] As the most ubiquitous and well-characterized member of G protein-coupled receptor kinases, GRK2 is known to be widely expressed in various organs and tissues, where it is involved in regulating various intracellular mechanisms. Like other GRKs, GRK2 recognizes and phosphorylates agonist-activated G protein-coupled receptors (GPCRs) on specific amino acid residues, such as threonine and serine residues. Following phosphorylation, GPCRs undergo desensitization, which is thought to be an important mechanism for individuals to maintain homeostasis and prevent injury. GRK2 can also bind to and phosphorylate non-GPCR substrates, such as platelet-derived growth factor receptor-β (PDGFRβ), EGFR, cytoskeletal proteins, transcription factors, and certain mitochondrial proteins.

[0004] GRK2 has been suggested to be involved in a large number of diseases or pathological conditions. Specifically, GRK2 is known to play an important role in maintaining cardiac structure and function. As a result, dysregulation of GRK2 may contribute to the development of cardiovascular diseases or pathological conditions. In addition, the expression and / or function of GRK2 is also known to change in certain inflammations and cancers. Therefore, inhibition of GRK2 has been proposed as a promising approach for developing new therapies for various diseases or conditions.

[0005] However, despite its therapeutic importance, relatively few examples of GRK2 degraders are known to date. As a result, there is a significant unmet need for novel compounds that can effectively degrade GRK2 and / or inhibit the activity of GRK2. Summary of the Invention [Means for solving the problem]

[0006] Provided herein is a novel compound that degrades GRK2, or its pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate or polymorph, a pharmaceutical composition comprising the same, and a kit comprising the same.Also provided herein is the use of the novel compound or pharmaceutical composition in preventing or treating various diseases or conditions, for example, diseases or conditions that are at least partially medicated by GRK2, or diseases or conditions that can benefit from the degradation of GRK2.

[0007] In some aspects, the present disclosure provides a compound of formula (1): [ka] or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, During the ceremony, the GBM is a GRK2 binding moiety; Provided is a compound, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, wherein DT is a degradation tag capable of binding to an E3 ligase.

[0008] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, and one or more pharmaceutically acceptable excipients.

[0009] In some aspects, the disclosure provides a kit comprising a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, and optionally instructions for use.

[0010] In some aspects, the disclosure provides methods for preventing or treating a disease or condition for which degradation of GRK2 is beneficial in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein.

[0011] In some aspects, the present disclosure provides a method for inhibiting tumor growth or preventing recurrence in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein.

[0012] In some aspects, the disclosure provides a method of degrading GRK2 or inhibiting the activity of GRK2 in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein.

[0013] In some aspects, the present disclosure provides a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for use in therapy.

[0014] In some aspects, the disclosure provides a compound of formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for use in preventing or treating a disease or condition for which degradation of GRK2 is beneficial in a subject.

[0015] In some aspects, the present disclosure provides a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, and one or more pharmaceutically acceptable excipients, for use in inhibiting tumor growth or preventing recurrence in a subject.

[0016] In some aspects, the disclosure provides a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for use in degrading GRK2 or inhibiting the activity of GRK2 in a subject.

[0017] In some aspects, the disclosure provides for the use of a compound of formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for the preparation of a medicament for use in preventing or treating a disease or condition for which degradation of GRK2 is beneficial in a subject.

[0018] In some aspects, the disclosure provides for the use of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for the preparation of a medicament for use in inhibiting the growth or preventing the recurrence of a tumor in a subject.

[0019] In some aspects, the disclosure provides for the use of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for the preparation of a medicament for use in degrading GRK2 in a subject or inhibiting the activity of GRK2 in a subject.

[0020] (Incorporated by reference) All publications, patent applications, or patents cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent was individually and specifically indicated to be incorporated by reference. To the extent that a publication, patent application, or patent incorporated by reference conflicts or is inconsistent with the present disclosure contained herein, the present specification is intended to supersede any such conflicting material. [Brief explanation of the drawings]

[0021] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0022] [Figure 1] FIG. 1 shows images of PVDF membranes of cellular proteins extracted from human-derived PASMCs (h-PASMCs) treated under hypoxic conditions in the presence of various test substances. [Figure 2] Figure 2 shows another PVDF membrane image of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of various test substances. [Figure 3] FIG. 3 shows the ratio of the expression level of GRK2 to the expression level of β-actin (represented by the ratio "GRK2 / β-actin") in h-PASMCs treated under hypoxic conditions in the presence of various test substances. [Figure 4] Figure 4 shows images of PVDF membranes of cellular proteins extracted from PASMCs (m-PASMCs) derived from mice treated under hypoxic conditions in the presence of various test substances. [Figure 5] Figure 5 shows another PVDF membrane image of cellular proteins extracted from m-PASMCs treated under hypoxic conditions in the presence of various test substances. [Figure 6] FIG. 6 shows the ratio of the expression level of GRK2 to the expression level of β-actin (represented by the ratio "GRK2 / β-actin") in m-PASMCs treated under hypoxic conditions in the presence of various test substances. [Figure 7] FIG. 7 shows images of PVDF membranes of cellular proteins extracted from PASMCs (r-PASMCs) derived from rats treated under hypoxic conditions in the presence of various test substances. [Figure 8] FIG. 8 shows another PVDF membrane image of cellular proteins extracted from r-PASMCs treated under hypoxic conditions in the presence of various test substances. [Figure 9] FIG. 9 shows the timeline for establishing a pulmonary arterial hypertension (PAH) model in mice. [Figure 10] Figure 10A shows an echocardiogram of the right heart of a mouse from the normoxia group 2 weeks after modeling. Figure 10B shows an echocardiogram of the right heart of a mouse from the hypoxia group 2 weeks after modeling. Figure 10C shows an echocardiogram of the right heart of a mouse from the hypoxia + Compound 1 group 2 weeks after modeling. [Figure 11]Figure 11A shows the data on the body weight (g) of mice from the hypoxia group and the hypoxia + compound 1 group after 2 weeks of modeling. No statistical difference was found between the body weight data of the two experimental groups. Figure 11B shows the data on the right ventricular internal dimension (RVID) (mm) of mice from the normoxia group, hypoxia group, and hypoxia + compound 1 group after 2 weeks of modeling. Figure 11C shows the data on the right ventricular anterior wall (RVAW) thickness (mm) of mice from the normoxia group, hypoxia group, and hypoxia + compound 1 group after 2 weeks of modeling. [Figure 12] Figure 12A shows the pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) of mice from the normoxia group after 2 weeks of modeling. Figure 12B shows the pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) of mice from the hypoxia group after 2 weeks of modeling. Figure 12C shows the pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) of mice from the hypoxia + Compound 1 group after 2 weeks of modeling. [Figure 13] FIG. 13 shows the ratio of PAT / PET in mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after two weeks of modeling. [Figure 14] Figure 14A shows the blood flow velocity of the tricuspid orifice E-peak (TVE) and the blood flow velocity of the tricuspid orifice A-peak (TVA) of a mouse from the normoxia group after two weeks of modeling. Figure 14B shows the blood flow velocity of the tricuspid orifice E-peak (TVE) and the blood flow velocity of the tricuspid orifice A-peak (TVA) of a mouse from the hypoxia group after two weeks of modeling. Figure 14C shows the blood flow velocity of the tricuspid orifice E-peak (TVE) and the blood flow velocity of the tricuspid orifice A-peak (TVA) of a mouse from the hypoxia + Compound 1 group after two weeks of modeling. [Figure 15] FIG. 15 shows the ratio of TVE / TVA (ie, TV E / A) of mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 2 weeks of modeling. [Figure 16]Figure 16A shows a schematic representation of the right ventricular systolic pressure (RVSP) of mice from the normoxia group after 4 weeks of modeling. Figure 16B shows a schematic representation of the right ventricular systolic pressure (RVSP) of mice from the hypoxia group after 4 weeks of modeling. Figure 16C shows a schematic representation of the right ventricular systolic pressure (RVSP) of mice from the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 17] Figure 17A shows the data of right ventricular systolic pressure (RVSP) (mmHg) of mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 4 weeks of modeling. Figure 17B shows the data of right ventricular hypertrophy index (RVHI, calculated according to the formula RV / (LV+S)) (mmHg) of mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 18] Figure 18A shows an echocardiogram of the right heart of a mouse from the normoxia group 4 weeks after modeling. Figure 18B shows an echocardiogram of the right heart of a mouse from the hypoxia group 4 weeks after modeling. Figure 18C shows an echocardiogram of the right heart of a mouse from the hypoxia + Compound 1 group 4 weeks after modeling. [Figure 19] Figure 19A shows data on right ventricular internal dimension (RVID) (mm) of mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 4 weeks of modeling. Figure 19B shows data on right ventricular anterior wall (RVAW) thickness (mm) of mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 20] Figure 20A shows a schematic representation of the pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) of mice from the normoxia group after 4 weeks of modeling. Figure 20B shows a schematic representation of the pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) of mice from the hypoxia group after 4 weeks of modeling. Figure 20C shows a schematic representation of the pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) of mice from the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 21]FIG. 21 shows the ratio of PAT / PET in mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 22] Figure 22A shows the blood flow velocity of the tricuspid orifice E-peak (TVE) and the blood flow velocity of the tricuspid orifice A-peak (TVA) of a mouse from the normoxia group after 4 weeks of modeling. Figure 22B shows the blood flow velocity of the tricuspid orifice E-peak (TVE) and the blood flow velocity of the tricuspid orifice A-peak (TVA) of a mouse from the hypoxia group after 4 weeks of modeling. Figure 22C shows the blood flow velocity of the tricuspid orifice E-peak (TVE) and the blood flow velocity of the tricuspid orifice A-peak (TVA) of a mouse from the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 23] FIG. 23 shows the ratio of TVE / TVA (ie, TV E / A) of mice from the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group after 4 weeks of modeling. [Figure 24] Figure 24 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 2 (20 μM), MG132 (1 μM), and their combination (20 μM Compound 2 plus 1 μM MG132). [Figure 25] Figure 25 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 3 (20 μM), MG132 (1 μM), and their combination (20 μM Compound 3 plus 1 μM MG132). [Figure 26] Figure 26 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 20 (20 μM), MG132 (1 μM), and their combination (20 μM compound 20 plus 1 μM MG132). [Figure 27]Figure 27 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 21 (20 μM), MG132 (1 μM), and their combination (20 μM compound 21 plus 1 μM MG132). [Figure 28] Figure 28 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 22 (20 μM), MG132 (1 μM), and their combination (20 μM compound 22 plus 1 μM MG132). [Figure 29] Figure 29 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 23 (20 μM), MG132 (1 μM), and their combination (20 μM compound 23 plus 1 μM MG132). [Figure 30] Figure 30 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 25 (20 μM), MG132 (1 μM), and their combination (20 μM compound 25 plus 1 μM MG132). [Figure 31] Figure 31 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 26 (20 μM), MG132 (1 μM), and their combination (20 μM compound 26 plus 1 μM MG132). [Figure 32] Figure 32 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 27 (20 μM), MG132 (1 μM), and their combination (20 μM compound 27 plus 1 μM MG132). [Figure 33] Figure 33 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 28 (20 μM), MG132 (1 μM), and their combination (20 μM compound 28 plus 1 μM MG132). [Figure 34]Figure 34 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 29 (20 μM), MG132 (1 μM), and their combination (20 μM compound 29 plus 1 μM MG132). [Figure 35] Figure 35 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 30 (20 μM), MG132 (1 μM), and their combination (20 μM compound 30 plus 1 μM MG132). [Figure 36] Figure 36 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 33 (20 μM), MG132 (1 μM), and their combination (20 μM compound 33 plus 1 μM MG132). [Figure 37] Figure 37 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 34 (20 μM), MG132 (1 μM), and their combination (20 μM compound 34 plus 1 μM MG132). [Figure 38] Figure 38 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 35 (20 μM), MG132 (1 μM), and their combination (20 μM compound 35 plus 1 μM MG132). [Figure 39] Figure 39 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 37 (20 μM), MG132 (1 μM), and their combination (20 μM compound 37 plus 1 μM MG132). [Figure 40] FIG. 40 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 1-P1 (0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM). [Figure 41]FIG. 41 shows images of PVDF membranes for cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of compound 1-P2 (0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM). DETAILED DESCRIPTION OF THE INVENTION

[0023] I. Definition Unless otherwise defined, all scientific and technical terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art.

[0024] As used in this specification and claims, when referring to a noun as used in this disclosure, the singular form "a" or "an" includes both the singular and plural units of that noun (i.e., includes the expressions "at least one" or "one or more"), and vice versa, unless the context clearly dictates otherwise.

[0025] As used in this specification and claims, unless otherwise indicated, ranges are intended to explicitly disclose that each of the endpoints of the range and each integer is included within the range. Additionally, any subrange consisting of these integers is intended to be included within the scope of the present disclosure.

[0026] The terms "GRK2" and "GRK2 protein" are used interchangeably and refer to G protein-coupled receptor kinase 2, which belongs to the G protein-coupled receptor kinase subfamily of Ser / Thr protein kinases. GRK2 is known to be encoded by the ADRBK1 gene. Both wild-type GRK2 and its naturally occurring variants, such as those having at least 85% amino acid sequence identity with wild-type GRK2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or higher), are intended to be encompassed by this term.

[0027] The terms "degradation," "degrading," or degradation, when used in the context of a protein (e.g., GRK2), refer to breaking down or metabolizing said protein in vivo or in vitro. Generally, degradation of GRK2 leads to a decrease in GRK2 activity or downstream effects compared to a baseline or control level of GRK2 activity.

[0028] The term "degrading agent" refers to a small molecule compound that, when interacting with a protein (eg, GRK2) in vivo or in vitro, results in the partial or complete degradation of the protein.

[0029] The term "degradation tag" refers to a moiety whose binding with an E3 ligase leads to partial or complete degradation of a protein (e.g., GRK2).

[0030] The term "moiety" is used interchangeably with "chemical moiety" or "structural fragment" and refers to a portion or functional group of a molecule. A moiety may contain smaller moieties and functional groups.

[0031] The term "about," when used in conjunction with a number, includes not only the particular point value but also a range of numbers that would be recognized by one of ordinary skill in the art as having substantially the same effect (e.g., a range of ±10%, ±5%, ±4%, ±3%, ±2%, or ±1% of the particular point value).

[0032] "Comprise," "include," "contain," and variations thereof are intended to mean open-ended transitional phrases that do not exclude the possibility of additional substances or methods. When these terms are used to describe a particular pharmaceutical composition, kit, use, or method of the present disclosure, they also encompass the situation where the pharmaceutical composition, kit, use, or method consists of the listed substances or methods. In the context of the present disclosure, the term "consisting of" is intended to mean closed-ended transitional phrases that exclude the possibility of additional substances or methods.

[0033] "C x-y The term "alkyl," when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include chemical moieties containing x to y carbons in the chain. For example, "C 1-6 The term "alkyl" refers to alkyls containing 1 to 6 carbons, including straight and branched chain alkyl groups.

[0034] The term "alkyl" refers to a saturated monovalent straight or branched chain hydrocarbon group. As used in the context of this disclosure, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), for example, may contain 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond.

[0035] The term "alkenyl" refers to an unsaturated monovalent linear or branched hydrocarbon group containing at least one C=C double bond. As used in the context of this disclosure, alkenyl refers to an alkyl group having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), for example, may contain 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 2 to 3, or 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, penta-1,4-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl, and the like.

[0036] The term "alkynyl" refers to an unsaturated monovalent linear or branched hydrocarbon group containing at least one C≡C triple bond. As used in the context of this disclosure, alkynyl refers to an alkyl group having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), which may contain, for example, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 2 to 3, or 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0037] The term "halogen" or "halo" refers to fluoro, chloro, bromo, or iodo.

[0038] The term "CN" or "cyano" refers to --C.ident.N.

[0039] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0040] The term "heteroalkyl" refers to an alkyl group, as defined above, in which at least one of the constituent carbon atoms is replaced by one or more heteroatoms. Examples of heteroatoms include, but are not limited to, O, N, P, Si, or S, preferably O, N, or S, where the N, S, or P atom may optionally be oxidized, and the N heteroatom may optionally be quaternized. Attachment to the remainder of the molecule may be through either the heteroatom or a carbon in the heteroalkyl group.

[0041] The term "carbocyclyl" refers to a non-aromatic ring or ring system in which each member atom of the ring or ring system is carbon. A "non-aromatic ring or ring system" refers to a carbocyclic or heterocyclic ring or ring system that does not meet the requirements described below for an aromatic ring or ring system and can be either saturated or partially unsaturated. A carbocyclyl as used in the context of the present disclosure typically contains 3 to 12 carbon atoms (i.e., a 3-12-membered carbocyclyl), for example, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, or 5 to 6 carbon atoms. A carbocyclyl may be a monocyclic ring (e.g., 3-12 membered, 3-10 membered, 3-8 membered, 3-6 membered, 3-4 membered, or 5-6 membered) or a polycyclic ring such as a bicyclic ring (e.g., 6-12 membered) or tricyclic ring (e.g., 11-14 membered). Each ring of a polycyclic carbocyclyl may be selected from saturated, partially unsaturated, and aromatic rings, provided that at least one ring of the polycyclic carbocyclyl is not an aromatic ring. A polycyclic carbocyclyl may be a fused, bridged, or spiro ring system. In some embodiments, a carbocyclyl is a cycloalkyl. In some embodiments, a carbocyclyl is a cycloalkenyl. In some embodiments, a carbocyclyl is a cycloalkynyl. In some embodiments, an aromatic ring, e.g., phenyl, may be fused to a saturated or partially unsaturated ring, e.g., cyclohexyl, cyclopentyl, or cyclohexenyl. Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclopentenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexenyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl.

[0042] The term "cycloalkyl" refers to a fully saturated carbocyclyl. As used in the context of this disclosure, cycloalkyl typically contains 3 to 12 carbon atoms (i.e., a 3-12-membered cycloalkyl), e.g., 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, or 5 to 6 carbon atoms. A cycloalkyl may be a monocyclic ring (e.g., 3 to 12-membered, 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 3 to 4-membered, or 5 to 6-membered) or a polycyclic ring, such as a bicyclic ring (e.g., 6 to 12-membered) or tricyclic ring (e.g., 11 to 14-membered). A polycyclic cycloalkyl may be a fused, bridged, or spiro ring system. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.2]nonyl.

[0043] The term "aryl" refers to an aromatic ring or ring system in which each atom forming the ring or ring system is a carbon atom. An "aromatic ring or ring system" refers to a carbocyclic or heterocyclic ring or ring system containing a planar ring system with a delocalized π orbital consisting of conjugated [4n+2]p orbitals, where n is an integer from 0 to 6. As used in the context of this disclosure, aryl typically contains 6 to 12 carbon atoms. Aryl may be a monocyclic aryl, such as phenyl, a bicyclic aryl, such as naphthyl and indenyl, and a tricyclic aryl, such as fluorenyl. Examples of aryl include, but are not limited to, phenyl and naphthyl.

[0044] The term "heterocyclyl" refers to a non-aromatic ring or ring system containing one or more carbon atoms and one or more heteroatoms (e.g., 1, 2, 3, or 4, preferably 1 or 2 heteroatoms). A heterocyclyl, as used in the context of the present disclosure, typically contains 3 to 12 member atoms (i.e., a 3-12-membered heterocyclyl), such as 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, or 5 to 6 member atoms (i.e., carbon atoms or heteroatoms). Examples of heteroatoms include, but are not limited to, O, N, P, Si, or S, preferably O, N, or S, where the N, S, or P atom may be optionally oxidized, and the N heteroatom may be optionally quaternized. When the total number of S and O atoms in a heterocyclyl exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heterocyclyl is 2 or less, preferably 1 or less. A heterocyclyl may be a monocyclic ring (e.g., 3-12 membered, 3-10 membered, 3-8 membered, 3-6 membered, 3-4 membered, or 5-6 membered) or a polycyclic ring such as a bicyclic ring (e.g., 6-12 membered) or tricyclic ring (e.g., 11-14 membered). Each ring of a polycyclic heterocyclyl may be selected from saturated, partially unsaturated, and aromatic rings, provided that at least one ring of the polycyclic heterocyclyl is not an aromatic ring. A heterocyclyl may be attached to the remainder of the molecule through any atom of the heterocyclyl, valence permitting, such as a carbon or nitrogen atom of the heterocyclyl. A polycyclic heterocyclyl may be a fused, bridged, or spiro ring system. In some embodiments, a heterocyclyl is a heterocycloalkyl. In some embodiments, a heterocyclyl is a heterocycloalkenyl. In some embodiments, a heterocyclyl is a heterocycloalkynyl.Examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, dithietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxathienyl, dioxepanyl, oxathiepanyl, oxazepanyl, dithiepanyl, thiazepanyl, diazepanyl, dithianyl, azathianyl, Heterocyclyls include, but are not limited to, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolinyl, indolinyl, dioxanyl, dioxolanyl, pyrazolinyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. When referring to the number of carbon atoms in a heterocyclyl, it is understood that the number of carbon atoms in the heterocyclyl is not the same as the total number of atoms (including heteroatoms) making up the heterocyclyl (i.e., the member atoms of the heterocyclyl ring).

[0045] The term "heteroaryl" refers to an aromatic ring or ring system containing one or more carbon atoms and one or more heteroatoms (e.g., 1, 2, 3, or 4, preferably 1 or 2 heteroatoms). Heteroaryls used in the context of the present disclosure typically contain 5 to 12 member atoms (i.e., 5- to 12-membered heteroaryls), for example, 5 to 6 or 8 to 12 member atoms (i.e., carbon atoms or heteroatoms). Examples of heteroatoms include, but are not limited to, N, O, and S atoms. When the total number of S and O atoms in a heteroaryl exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl is 2 or less, preferably 1 or less. A heteroaryl may be a monocyclic ring (e.g., 5- to 6-membered) or a polycyclic ring, such as a bicyclic ring (e.g., 8- to 12-membered) or a tricyclic ring (e.g., 11- to 14-membered).Examples of heteroaryl groups include pyrazolyl, imidazolyl (such as 2,4-imidazolyl), imidazopyridinyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl (such as 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, or 1-oxa-3,4-diazolyl), thiazolyl, isothiazolyl, thiadiazolyl (such as 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, or 1-thia-3,4-diazolyl), triazolyl, pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, pyrimidinyl (such as 2,4-pyrimidinyl, or 3,5-diazolyl), and the like. pyrimidinyl, pyridazinyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, phthalazinyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrrolopyridinyl, pyrazolopyridinyl, benzoxazolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinyl.

[0046] The term "substituted" refers to a moiety having substituents replacing one or more substitutable carbon or heteroatoms, e.g., hydrogen on a nitrogen atom of a compound. When substituents are specified by their conventional chemical formula written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left. For example, -CHO- is equivalent to -OCH-. As used in this disclosure, the term "substituted" is intended to include all permissible substituents of organic compounds, including acyclic and cyclic, straight-chain and branched-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents can be one or more and can be the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen atoms, may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described in the present disclosure, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, acetyl, or formyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocyclyl, heterocyclyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc. In some embodiments, "substituted" refers to a moiety having substituents replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo group, an imino group, or a thioxo group.It will be understood by those skilled in the art that, where appropriate, substituents can themselves be substituted.

[0047] The term "optionally" means that the subsequently described circumstance event may or may not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the foregoing description includes both substituted and unsubstituted aryl groups.

[0048] The term "isomer" refers to different compounds having the same molecular formula. Certain compounds as described herein contain one or more asymmetric centers and can therefore give rise to stereoisomeric forms, including enantiomers, diastereomers, and other stereoisomers, which can be defined in terms of absolute stereochemistry as (R)- or (S)-. Compounds as described herein may, in some embodiments, exist as diastereomers, enantiomers, other stereoisomeric forms, as well as appropriate mixtures thereof. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. The present chemical entities, pharmaceutical compositions, and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including, but not limited to, chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other can be determined. Unless otherwise stated, a reference to one isomer applies to any of the possible isomers.Whenever the isomeric composition is unspecified, all possible isomers are included.

[0049] Compounds as described herein that have a carbon-carbon double bond or a carbon-nitrogen double bond may exist in the Z or E form (or cis or trans form). Moreover, some compounds as described herein may exist in various tautomeric forms (i.e., tautomers). The term "tautomer" refers to a molecule in which a proton is capable of shifting from one atom of the molecule to another atom of the same molecule. In some embodiments, compounds as described herein may exist as tautomers. Under conditions in which tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers will depend on several factors, including temperature, solvent, physical conditions, and pH. For example, a compound containing a -CHC(O)- group (keto form) may undergo tautomerization to form a -CH=C(OH)- group (enol form). Unless otherwise specified, compounds as described herein are intended to include all Z-, E-, and tautomeric forms as well.

[0050] Separation of stereoisomers may be carried out by chromatography, or by forming diastereomers and separating them by recrystallization, or chromatography, or any combination thereof. See Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981, incorporated herein by reference for this disclosure. Stereoisomers may also be obtained by stereoselective synthesis.

[0051] The term "isotope" refers to a compound as described in the present disclosure in which one or more of the atoms that constitute the compound have been artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. Compounds as described in the present disclosure optionally contain an unnatural proportion of atomic isotopes at one or more of the atoms that constitute such compounds. For example, a compound may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It may be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 Isotopic substitutions with I are all contemplated. All isotopes of the compounds as described in this disclosure, whether radioactive or not, are encompassed within the scope of this disclosure. For example, hydrogen is 1 H (protium), 2 H (deuterium), and 3H (tritium) has three naturally occurring isotopes. Protium is the most abundant isotope of hydrogen in nature. Enriching with deuterium may provide certain therapeutic benefits, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating drug elimination and metabolic pathways in vivo. In some embodiments, compounds as described in the present disclosure are deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 Radioactive isotopes such as C may be used in accordance with the present disclosure. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0052] The term "prodrug" refers to any compound that is converted under physiological conditions into a compound as described in this disclosure. In some embodiments, a compound or its salt may exist as a prodrug; for example, a hydroxyl in a parent compound is presented as an ester or carbonate, or a carboxylic acid present in a parent compound is presented as an ester. Prodrugs are useful because, under some circumstances, they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may serve to enhance the cell permeability of a compound compared to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues or increase drug retention within cells. One method for creating a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in a host animal, such as a specific target cell within the host animal. For example, esters or carbonates (eg, esters of alcohols or carboxylic acids or carbonates and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0053] The term "solvate" refers to an aggregate consisting of a solute ion or molecule with one or more solvent molecules. Compounds as described in the present disclosure can exist in unsolvated as well as solvated forms (i.e., solvates) using one or more pharmaceutically acceptable solvents, such as water (i.e., hydrates), ethanol (i.e., ethanolates), and the like. When the solvent is water, the "solvate" is specifically referred to as a hydrate.

[0054] The term "polymorph" refers to a variety of solid materials that exist in more than one form. In the context of the present disclosure, the term "polymorph" encompasses both "amorphous form" and "crystalline form." As a result, compounds as described in the present disclosure may exist not only in amorphous form but also in crystalline form.

[0055] The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and other animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0056] The phrase "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, carrier, or vehicle used for preparing a pharmaceutical composition or dosage form in accordance with the present disclosure. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition or dosage form and not injurious to the patient.

[0057] The term "pharmaceutically acceptable salt" refers to salts derived from various pharmaceutically acceptable organic or inorganic counterions known in the art. Compounds described in this disclosure that have acidic, basic, or both functional groups may react with any of a number of inorganic and organic acids and bases to form salts. Alternatively, inherently charged compounds, such as those with quaternary nitrogen, can form salts with a suitable counterion, e.g., a halide ion such as bromide, chloride, or fluoride. Pharmaceutically acceptable acid addition salts can be formed using inorganic or organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, glycolic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. Examples of suitable pharmaceutically acceptable salts can be found, for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.

[0058] The terms "subject," "individual," and "patient" are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cattle, ungulates, lagomorphs, and the like). In some embodiments, a subject can be a human (e.g., a male child, a female child, an adolescent male, an adolescent female, an adult male, an adult female) under the care of a physician or other healthcare professional in a hospital, as an outpatient, or in other clinical settings. In some embodiments, a subject may not be under the care or prescription of a physician or other healthcare professional.

[0059] The phrase "subject in need thereof" refers to a subject suffering from or at risk of a pathology to be treated prophylactically or therapeutically with a compound, composition, or dosage form as described in this disclosure.

[0060] The terms "administration," "administered," "administer," and "administering" are defined as providing a compound, composition, formulation, and / or dosage form according to the present disclosure to a subject in need thereof via a route known in the art, including, but not limited to, oral, buccal, topical, transmucosal, transdermal, rectal, and parenteral routes of administration. In some embodiments, the oral route of administration is used. In some embodiments, parenteral routes of administration are used, including intravenous, intraarterial, intramuscular, subcutaneous, intraosseous, and intraperitoneal.

[0061] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound as described in the present disclosure that is sufficient to produce the intended application, including, but not limited to, disease treatment as defined below. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease or condition being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, and the like, and can be readily determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a specific response in target cells, such as up-regulation or down-regulation of the activity of a target protein. A specific dose can vary depending on the particular compound chosen, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0062] The terms "prevention," "prevention," or "preventing" in reference to a disease or condition may refer to a compound, composition, or dosage form as described in the present disclosure that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of, or reduces the severity of, one or more symptoms of the disorder or condition compared to an untreated control sample. In some embodiments, for a prophylactic effect, a compound, composition, or dosage form as described in the present disclosure is administered to a subject at risk of developing a particular disease or condition to alleviate one or more physiological symptoms of the disease or condition, even if the disease or condition has not been diagnosed.

[0063] The terms "treatment," "therapy," or "treating" refer to an approach for obtaining a beneficial or desired result (i.e., a therapeutic benefit) with respect to a disease or condition. In some embodiments, treating, treating, or treating involves administering to a subject a compound, composition, dosage form as described in this disclosure. Treating can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease, disorder, or condition, or reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. In some embodiments, the therapeutic effect can include eradication or amelioration of the underlying disease being treated. In some embodiments, the therapeutic effect can be achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such as observing an improvement in a subject, even though the subject may still be afflicted by the underlying disease.

[0064] II. Compounds Provided herein are novel compounds that degrade GRK2, or pharmaceutically acceptable salts, isomers, isotopes, prodrugs, solvates, or polymorphs thereof. The compounds are bivalent compounds that include a GRK2-binding moiety conjugated to a degradation tag that has E3 ligase binding ability.

[0065] Without wishing to be bound by any particular theory, it is believed that, at least in some embodiments, attaching a degradation tag as described herein to a GRK2 binding moiety as described herein can recruit the corresponding ubiquitination machinery to GRK2, leading to subsequent degradation of GRK2 in or near the proteasome and / or loss of GRK2 function.

[0066] Without wishing to be bound by any particular theory, it is believed that novel compounds as described herein that potently degrade GRK2 are useful in preventing or treating a variety of diseases or conditions, such as diseases or conditions that are medicated at least in part by GRK2, or that could benefit from the degradation of GRK2, including, but not limited to, hyperproliferative diseases (e.g., tumors), cardiovascular diseases (e.g., hypertension, more particularly pulmonary (arterial) hypertension), hematological diseases, infectious diseases, endocrine diseases, metabolic diseases, gastrointestinal diseases, respiratory diseases, inflammation, opioid addiction, and urinary diseases.

[0067] Thus, in some aspects, the present disclosure provides a compound represented by formula (1): [ka] or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof; During the ceremony, GBM is a GRK2 binding moiety, DT is a degradation tag with E3 ligase binding ability.

[0068] In some embodiments, the GBM is a moiety derived from a polyanionic compound and a polycationic compound.

[0069] In some embodiments, the polyanionic and polycationic compounds are selected from heparin and dextran sulfate.

[0070] In some embodiments, the GBM is a moiety derived from balanol, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

[0071] In some embodiments, the GBM is [ka] or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

[0072] In some embodiments, the GBM is [ka] or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

[0073] In some embodiments, the GBM is a moiety derived from the indazole or dihydropyrimidine series represented by formula (2), or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof: [ka] During the ceremony, R is [ka] is selected from R' is selected from H and halogen; and R'' is [ka] is selected from.

[0074] In some embodiments, the GBM is represented by formula (3): [ka] In the formula, ★ indicates the point of attachment to DT, Formula I is a moiety covalently linked to Formula II, wherein Formula I contains a thiazole or triazole ring in its backbone and has the ability to bind to GRK2, either by itself or together with Formula II; and Formula II is a moiety covalently bonded to both Formula I and DT, and Formula II includes an acyclic or cyclic saturated or unsaturated carbon, an ethylene glycol group, an amide group, an ester group, an amino group, an oxy group, a thio group, an ether group, a urea group, a carbamate group, an aromatic group, a heteroaromatic group, a heterocyclic group, a carbonyl group, or a combination thereof.

[0075] In some embodiments, Formula I is represented by formula (4): [ka] During the ceremony, ◆ indicates the point of attachment to Formula II; Q is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , and Cy; Cy is aryl, C 3~12 selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, or more R'; L A is the bond, -(CH2) a C(R1)(R2)(CH2) b selected from -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-; R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NRd C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0076] In some embodiments, Q is optionally substituted C 1-6 Alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0077] In some embodiments, Q is C 1-6 Alkyl, -SR a , and Cy.

[0078] In some embodiments, Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

[0079] In some embodiments, Q is selected from isopropyl, isopropylthio, and Cy.

[0080] In some embodiments, Q is Cy.

[0081] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8and selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

[0082] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, azolyl, benzoyl ... and selected from clidinyl, phenothiazinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

[0083] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

[0084] In some embodiments, Cy is phenyl optionally substituted with 1, 2, 3, or more R'.

[0085] In some embodiments, Q is [ka] is selected from.

[0086] In some embodiments, Q is [ka] is selected from.

[0087] In some embodiments, L A is selected from a bond, —C(R1)(R2)—, —N(R1)—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0088] In some embodiments, L A is selected from a bond, —CH—, —CF—, —CCl—, —CBr—, —CFCl—, —CFBr—, —CClBr—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0089] In some embodiments, L A is selected from a bond, —CH—, —CF—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0090] In some embodiments, L A is -CH2-.

[0091] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -ORa , -SR a , and -NR b R c is selected from.

[0092] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0093] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0094] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0095] In some embodiments, R is selected from H and —OH.

[0096] In some embodiments, R is H.

[0097] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0098] In some embodiments, each of R and R is independently H, halogen, C-C alkyl optionally substituted with 1, 2, or 3 halogens, C-C alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0099] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0100] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0101] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0102] In some embodiments, both R1 and R2 are H.

[0103] In some embodiments, both R1 and R2 are F.

[0104] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0105] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, or C 3-6 Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0106] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0107] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0108] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0109] In some embodiments, R' is Cl.

[0110] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0111] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0112] In some embodiments, each R a are independently H or isopropyl.

[0113] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0114] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0115] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl, and R c is H.

[0116] In some embodiments, each R d are independently H and C 1-6alkyl.

[0117] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0118] In some embodiments, each R d are independently H or methyl.

[0119] In some embodiments, a is selected from 0 and 1 and b is selected from 0 and 1.

[0120] In some embodiments, a is 0 and b is 0.

[0121] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0122] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0123] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0124] In some embodiments, Formula I is represented by formula (4A): [ka] During the ceremony, ◆ indicates the point of attachment to Formula II; Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)Ra , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Cy is aryl, C 3~12 selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, or more R'; R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SRa , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R cmay be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d However, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0125] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0126] In some embodiments, each of R1 and R2 is independently H, halogen, 1、 C1-C6 alkyl optionally substituted with 2 or 3 halogens, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0127] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0128] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0129] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0130] In some embodiments, both R1 and R2 are H.

[0131] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0132] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0133] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0134] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0135] In some embodiments, R is selected from H and —OH.

[0136] In some embodiments, R is H.

[0137] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8 and selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

[0138] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, azolyl, benzoyl ... and selected from clidinyl, phenothiazinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

[0139] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

[0140] In some embodiments, Cy is phenyl optionally substituted with 1, 2, 3, or more R'.

[0141] In some embodiments, Cy is [ka] is selected from.

[0142] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0143] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, or C 3-6 Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0144] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0145] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0146] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0147] In some embodiments, R' is Cl.

[0148] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0149] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0150] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0151] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0152] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0153] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0154] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0155] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0156] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0157] In some embodiments, Formula I is represented by formula (4B): [ka] During the ceremony, m is selected from 0, 1, 2, 3, 4, and 5.

[0158] In some embodiments, m is selected from 0, 1, and 2.

[0159] In some embodiments, m is 0 or 1.

[0160] In some embodiments, Formula I is represented by formula (5): [ka] During the ceremony, ◆ indicates the point of attachment to Formula II; R 1A , R 2A , R 1B , and R 2B each independently represents H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3~6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R 1A and R 2A Or R 1B and R 2B are taken together with the atoms to which they are attached and optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R 3A , R 3B , and R 3C each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -C(=O)R a , -C(=S)R a , -C(=O)OR a , -S(=O)R a , -S(=O)2R a, -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , optionally substituted aryl, optionally substituted C 3-12 selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; D1, D2, D3, D4, and D5 each independently represent N or CR 4A and Each of E1, E2, E3, and E4 independently represents N or CR 4B and Each of F1, F2, F3, and F4 independently represents N or CR 4C and R 4A , R 4B , and R 4C each independently represents H, halogen, —CN, —N(═O), —NO, —ON(═O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NRd C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -ORa , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0161] In some embodiments, R 1A , R 2A , R 1B , and R 2B each independently represents H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0162] In some embodiments, R 1A , R 2A , R 1B , and R 2B each independently selected from H, halogen, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0163] In some embodiments, R 1A , R 2A , R 1B , and R2B are each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0164] In some embodiments, R 1A , R 2A , R 1B , and R 2B are each independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0165] In some embodiments, R 1A , R 2A , R 1B , and R 2B are each independently selected from H and F.

[0166] In some embodiments, R 1A , R 2A , R 1B , and R 2B each independently is H.

[0167] In some embodiments, R 3A , R 3B , and R 3C each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, and optionally substituted C 2-6 alkynyl.

[0168] In some embodiments, R 3A , R 3B , and R 3C each independently represents a C optionally substituted with H, 1, 2, or 3 halogens; 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl and C optionally substituted with 1, 2, or 3 halogens 2-6 alkynyl.

[0169] In some embodiments, R 3A , R 3B , and R 3C are each independently selected from H, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, and propyl optionally substituted with 1, 2, or 3 halogens.

[0170] In some embodiments, R 3A , R 3B , and R 3C are each independently selected from H, methyl, ethyl, and propyl.

[0171] In some embodiments, R 3A , R 3B , and R 3C are each independently selected from H.

[0172] In some embodiments, at least one of D1, D2, D3, D4, and D5 is N, and the others are CR A is.

[0173] In some embodiments, one of D1, D2, D3, D4, and D5 is N and the others are CR A is.

[0174] In some embodiments, D3 is N and the others are CR 4A is.

[0175] In some embodiments, each of E1, E2, E3, and E4 is independently CR 4B is.

[0176] In some embodiments, each of F1, F2, F3, and F4 is independently CR 4C is.

[0177] In some embodiments, R 4A , R 4B , and R 4C each independently represents H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0178] In some embodiments, R 4A , R 4B , and R 4C each independently represents H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0179] In some embodiments, R 4A , R 4B , and R 4Care each independently selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0180] In some embodiments, R 4A , R 4B , and R 4C are each independently selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0181] In some embodiments, R 4A , R 4B , and R 4C each independently is H.

[0182] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0183] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0184] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0185] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0186] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0187] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0188] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0189] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0190] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0191] In some embodiments, Formula I is represented by formula (5A): [ka]

[0192] In some embodiments, Formula I is represented by formula (5B): [ka]

[0193] In some embodiments, Formula I is represented by formula (5C): [ka]

[0194] In some embodiments, Formula II includes an amide group or an ester group.

[0195] In some embodiments, Formula II is represented by formula (6): [ka] During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, A, T, and B, in each occurrence, independently represent null, -C(=O)-, -C(=O)O-, or -C(=O)NR 1 -, -C(=S)NR 1 -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR 1 -, -NR 1 -, -NR 1 C(=O)-, -NR 1 C(=O)NR 2 -, -NR 1C(=S)-, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused Cycloalkyl, Optionally Substituted C-C 13 Fused heterocyclyl, optionally substituted C-C 13 Bridged Cycloalkyl, Optionally Substituted C-C 13 Bridged Heterocyclyl, Optionally Substituted C3-C 13 Spirocycloalkyl and optionally substituted C-C 13 spiroheterocyclyl, wherein R 1 and R 2 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl; p is 0 to 15.

[0196] In some embodiments, Formula II is represented by formula (6A): [ka] During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, R 1 , R 2 , R 3 , and R 4 is independently selected in each occurrence from hydrogen, halogen, —CN, —OH, —NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl. A, T, and B, in each occurrence, independently represent null, -C(=O)-, -C(=O)O-, or -C(=O)NR 5 -, -C(=S)NR 5 -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR 5 -, -NR 5 -, -NR 5 C(=O)-, -NR 5 C(=O)NR 6 -, -NR 5 C(=S)-, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused Cycloalkyl, Optionally Substituted C-C 13 Fused heterocyclyl, optionally substituted C-C 13Bridged Cycloalkyl, Optionally Substituted C-C 13 Bridged Heterocyclyl, Optionally Substituted C3-C 13 Spirocycloalkyl and optionally substituted C-C 13 spiroheterocyclyl, wherein R 5 and R 6 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl; p is 0 to 15; Each q is between 0 and 15, and o is a number between 0 and 15.

[0197] In some embodiments, Formula II is represented by formula (6B): [ka] During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, Each R 1 , and each R 2are independently selected from hydrogen, halogen, —CN, —OH, —NH2, and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, or C1-C6 alkylaminoC1-C6 alkyl; Each A and each B independently represent null, -C(=O)-, -C(=O)O-, or -C(=O)NR 3 -, -C(=S)NR 3 -, -O-, -S-, -S(=O)-, -S(=O)2NR 3 -, -NR 3 -, -NR 3 C(=O)-, -NR 3 C(=O)NR 4 -, -NR 3 C(=S)-, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused Cycloalkyl, Optionally Substituted C-C 13 Fused heterocyclyl, optionally substituted C-C 13 Bridged Cycloalkyl, Optionally Substituted C-C 13 Bridged Heterocyclyl, Optionally Substituted C3-C 13 Spirocycloalkyl, or C3-C 13 spiroheterocyclyl, wherein R 3 and R 4 are independently selected from hydrogen, and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, or C1-C6 alkylaminoC1-C6 alkyl; each p is between 0 and 15, and q is between 0 and 15.

[0198] In some embodiments, Formula II is represented by formula (6C): [ka] During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, X is -O-, -NH, and -NR 7 - selected from R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is independently selected in each occurrence from hydrogen, halogen, —CN, —OH, —NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl; A and B, in each occurrence, independently represent null, -C(=O)-, -C(=O)O-, or -C(=O)NR 7 -, -C(=S)NR 7 -, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR 7 -, -NR 7 -, -NR 7 C(=O)-, -NR 7 C(=O)NR 8 -, -NR 7 C(=S)-, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused Cycloalkyl, Optionally Substituted C-C 13 Fused heterocyclyl, optionally substituted C-C 13 Bridged Cycloalkyl, Optionally Substituted C-C 13 Bridged Heterocyclyl, Optionally Substituted C3-C 13 Spirocycloalkyl and optionally substituted C-C 13 spiroheterocyclyl, wherein R 7 and R 8is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl; Each p is 0 to 15, Each q is 0 to 15, o is 0 to 15, and r is a number between 0 and 15.

[0199] In some embodiments, Formula II is represented by formula (7A): [ka] where * indicates the point of attachment to Formula I; # indicates the connection point with DT, A is C 1-20 Alkylene, -O-, -S-, -N(R e )-, and -N(R e )-C 1-20 alkylene-, optionally selected from C 1-20 One, two, three, or more methylenes in an alkylene group may independently be —O—, —S—, —N(R e )-, -C(=O)-, and -C(=S)-; B is a bond or arylene, C 3-12 and a 5- to 12-membered heteroarylene, a 5- to 12-membered heteroarylene, and a 3- to 12-membered heterocyclylene, each of which is selected from halogen, —CN, —NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c optionally substituted by one, two, three or more substituents selected from the group consisting of Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; R e is H and optionally substituted C 1-6 alkyl; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0200] In some embodiments, A is C 1-8Alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally C 1-8 One, two, three, or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-.

[0201] In some embodiments, A is selected from —CH 2 —, —O—, —NH—, —NH—(CH 2 ) 3 —, —NH—(CH 2 ) 5 —, and —NH—C(═O)—(CH 2 ) 3 —O—(CH 2 ) 3 —.

[0202] In some embodiments, A is selected from -CH2-, -O-, and -NH-.

[0203] In some embodiments, A is —NH—.

[0204] In some embodiments, B is selected from a bond, or an arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and a 5- or 6-membered heteroarylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0205] In some embodiments, B is a bond or is selected from phenylene, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyranylene, pyrazinylene, pyrimidinylene, pyrazinylene, triazolylene, tetrazolylene, and triazinylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and propyl.

[0206] In some embodiments, B is a bond or phenylene optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, and Br.

[0207] In some embodiments, B is a bond or phenylene.

[0208] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0209] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0210] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0211] In some embodiments, R b and R care each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0212] In some embodiments, R e is H.

[0213] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0214] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0215] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0216] In some embodiments, Formula (7A) is: [ka] is a moiety selected from

[0217] In some embodiments, Formula (7A) is: [ka] is a moiety selected from

[0218] In some embodiments, Formula II is represented by Formula (7B): [ka] During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, [ka] is a single or double bond, R'' is halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NRd S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; e is 0 or 1, f is selected from 0, 1, 2, and 3; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a, -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0219] In some embodiments, [ka] is a single bond.

[0220] In some embodiments, [ka] is a double bond.

[0221] In some embodiments, R″ is a halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0222] In some embodiments, R″ is selected from the group consisting of halogen, —CN, —NO, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens ... 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0223] In some embodiments, R'' is selected from halogen, -CN, -NO2, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0224] In some embodiments, R'' is selected from F, Cl, Br, methyl, ethyl, propyl, -OH, and -NH2.

[0225] In some embodiments, e is 0.

[0226] In some embodiments, e is 1.

[0227] In some embodiments, f is 0.

[0228] In some embodiments, formula (7B) is: [ka] is a moiety selected from

[0229] In some embodiments, the DT has the ability to bind to an E3 ligase for recruitment of the corresponding ubiquitination machinery to GRK2, leading to subsequent degradation of GRK2 in or near the proteasome and / or loss of function of GRK2.

[0230] In some embodiments, the DT is selected from the group consisting of a cereblon ligand, a VHL ligand, an MDM2 ligand, a TRIM24 ligand, a TRIM21 ligand, a KEAP1 ligand, an RNF114 ligand, an IAP ligand, a DCAF16 ligand, a DCAF15 ligand, a FEM1B ligand, and a ligand of the aryl hydrocarbon receptor.

[0231] In some embodiments, DT is a moiety represented by formula (8A), (8B), (8C), or (8D): [ka] [ka] During the ceremony, [ka] indicates the point of attachment to Formula II, U is independently selected from —CH—, —NH—, and —O—; each of V and W is independently selected from —C(═O)— and —CH—; each of X, Y, and Z is independently selected from CR6 and N; R5 is selected from H, halogen, and optionally substituted C1-C6 alkyl; R6 is selected from H, halogen, and optionally substituted C1-C6 alkyl.

[0232] In some embodiments, U is —CH 2 —.

[0233] In some embodiments, U is —O—.

[0234] In some embodiments, U is —NH—.

[0235] In some embodiments, V is -C(=O)- and W is -CH2-.

[0236] In some embodiments, V is -CH2- and W is -C(=O)-.

[0237] In some embodiments, both V and W are —C(═O)—.

[0238] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0239] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0240] In some embodiments, R5 is H.

[0241] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0242] In some embodiments, R6 is H or F.

[0243] In some embodiments, DT is [ka] is a moiety selected from

[0244] In some embodiments, DT is a moiety represented by formula (9): [ka] During the ceremony, [ka] indicates the point of attachment to Formula II, R 1 and R 2 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; R 3is hydrogen, optionally substituted -C(=O)C1-C8 alkyl, optionally substituted -C(=O)C1-C8 alkoxyC1-C8 alkyl, optionally substituted -C(=O)C1-C8 haloalkyl, optionally substituted -C(=O)C1-C8 hydroxyalkyl, optionally substituted -C(=O)C1-C8 aminoalkyl, optionally substituted -C(=O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted -C(=O)C3-C7 cycloalkyl, optionally substituted -C(=O)(3 1-7 membered heterocyclyl), optionally substituted -C(=O)C2-C8 alkenyl, optionally substituted -C(=O)C2-C8 alkynyl, optionally substituted -C(=O)OC1-C8 alkoxyC1-C8 alkyl, optionally substituted -C(=O)OC1-C8 haloalkyl, optionally substituted -C(=O)OC1-C8 hydroxyalkyl, optionally substituted -C(=O)OC1-C8 aminoalkyl, optionally substituted -C(=O)OC1-C8 alkylaminoC1-C8 alkyl, optionally substituted -C(=O)OC1-C8 alkylaminoC1-C8 alkyl, optionally substituted -C(=O)OC3-C7 cycloalkyl, optionally substituted -C(=O)O(3- to 7-membered heterocyclyl), optionally substituted -C(=O)OC2-C8 alkenyl, optionally substituted -C(=O)OC2-C8 alkynyl, optionally substituted -C(=O)NC1-C8 alkoxyC1-C8 alkyl, optionally substituted -C(=O)NC1-C8 haloalkyl, optionally substituted -C(=O)NC1-C8 hydroxyalkyl, optionally substituted -C(=O)NC1-C8 aminoalkyl ... optionally substituted -C(=O)NC-C alkylaminoC-C alkyl, optionally substituted -C(=O)NC-C cycloalkyl, optionally substituted -C(=O)N(3- to 7-membered heterocyclyl), optionally substituted -C(=O)NC-C alkenyl, optionally substituted -C(=O)NC-C alkynyl, optionally substituted -P(=O)(OH), optionally substituted -P(=O)(OC-C alkyl), and optionally substituted -P(=O)(OC-C aryl).

[0245] In some embodiments, DT is a moiety represented by formula (10): [ka] During the ceremony, [ka] indicates the point of attachment to Formula II, V, W, X, and Z are independently 4 and N, R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl.

[0246] In some embodiments, DT is a moiety derived from any of the following: [ka]

[0247] In some embodiments, DT is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

[0248] In some embodiments, the compound is represented by formula (11): [ka] During the ceremony, A is C 1-20 Alkylene, -O-, -S-, -N(R e )-, and -N(R e )-C 1-20 alkylene-, optionally selected from C 1-20 One, two, three, or more methylenes in an alkylene group may independently be —O—, —S—, —N(R e )-, -C(=O)-, and -C(=S)-; B is a bond or arylene, C 3-12 and a 5- to 12-membered heteroarylene, a 5- to 12-membered heteroarylene, and a 3- to 12-membered heterocyclylene, each of which is selected from halogen, —CN, —NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c optionally substituted by one, two, three or more substituents selected from the group consisting of U is independently selected from —CH—, —NH—, and —O—; each of V and W is independently selected from —C(═O)— and —CH—; each of X, Y, and Z is independently selected from CR6 and N; Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a, -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Cy is aryl, C 3-12 selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, or more R'; R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR dC(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R5 is selected from H, halogen, and optionally substituted C1-C6 alkyl; R6 is selected from H, halogen, and optionally substituted C1-C6 alkyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R e is H and optionally substituted C 1-6 alkyl; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0249] In some embodiments, A is C 1-8 Alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally C 1-8 One, two, three, or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-.

[0250] In some embodiments, A is selected from —CH 2 —, —O—, —NH—, —NH—(CH 2 ) 3 —, —NH—(CH 2 ) 5 —, and —NH—C(═O)—(CH 2 ) 3 —O—(CH 2 ) 3 —.

[0251] In some embodiments, A is selected from -CH2-, -O-, and -NH-.

[0252] In some embodiments, A is —NH—.

[0253] In some embodiments, B is selected from a bond, or an arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and a 5- or 6-membered heteroarylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0254] In some embodiments, B is a bond or is selected from phenylene, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyranylene, pyrazinylene, pyrimidinylene, pyrazinylene, triazolylene, tetrazolylene, and triazinylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and propyl.

[0255] In some embodiments, B is a bond or phenylene optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, and Br.

[0256] In some embodiments, B is a bond or phenylene.

[0257] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0258] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0259] In some embodiments, U is —CH 2 —.

[0260] In some embodiments, U is —O—.

[0261] In some embodiments, U is —NH—.

[0262] In some embodiments, V is -C(=O)- and W is -CH2-.

[0263] In some embodiments, V is -CH2- and W is -C(=O)-.

[0264] In some embodiments, both V and W are —C(═O)—.

[0265] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0266] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0267] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0268] In some embodiments, each of R1 and R2 is independently H, halogen, 1、 C1-C6 alkyl optionally substituted with 2 or 3 halogens, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0269] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0270] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0271] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0272] In some embodiments, both R1 and R2 are H.

[0273] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0274] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0275] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0276] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0277] In some embodiments, R is selected from H and —OH.

[0278] In some embodiments, R is H.

[0279] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8 and selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

[0280] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, azolyl, benzoyl ... and selected from clidinyl, phenothiazinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

[0281] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

[0282] In some embodiments, Cy is phenyl optionally substituted with 1, 2, 3, or more R'.

[0283] In some embodiments, Cy is [ka] is selected from.

[0284] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0285] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6Alkynyl, or C 3-6 Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0286] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0287] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0288] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0289] In some embodiments, R' is Cl.

[0290] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0291] In some embodiments, R5 is H.

[0292] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0293] In some embodiments, R6 is H or F.

[0294] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0295] In some embodiments, each R ais independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0296] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0297] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0298] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0299] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0300] In some embodiments, R e is H.

[0301] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0302] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0303] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0304] In some embodiments, the compound is represented by formula (12A), (12B), (12C), (12D), (12E), or (12F): [ka] [ka] [ka] [ka] [ka] [ka] Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c, -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2Ra , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR bR c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R5 is selected from H, halogen, and optionally substituted C1-C6 alkyl; R6 is selected from H, halogen, and optionally substituted C1-C6 alkyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a, -NO2, =O, -CN, and C 3-6 cycloalkyl, optionally substituted with one, two, three or more substituents selected from the group consisting of Ph represents phenylene; and m is selected from 0, 1, 2, 3, 4, and 5.

[0305] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0306] In some embodiments, each of R and R is independently H, halogen, C-C alkyl optionally substituted with 1, 2, or 3 halogens, C-C alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0307] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0308] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0309] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0310] In some embodiments, both R1 and R2 are H.

[0311] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0312] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0313] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0314] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0315] In some embodiments, R is selected from H and —OH.

[0316] In some embodiments, R is H.

[0317] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0318] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, or C 3-6Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0319] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0320] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0321] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0322] In some embodiments, R' is Cl.

[0323] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0324] In some embodiments, R5 is H.

[0325] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0326] In some embodiments, R6 is H or F.

[0327] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0328] In some embodiments, each R ais independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0329] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0330] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0331] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0332] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0333] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0334] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0335] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0336] In some embodiments, Ph is [ka] Represents.

[0337] In some embodiments, m is selected from 0, 1, and 2.

[0338] In some embodiments, m is 0 or 1.

[0339] In some embodiments, the compound is [ka] [ka] [ka] [ka] is selected from.

[0340] In some embodiments, the compound is [ka] is selected from.

[0341] In some embodiments, Formula I is represented by formula (13): [ka] During the ceremony, ◆ indicates the point of attachment to Formula II; [ka] each is independently a single bond or a double bond; Q is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , and Cy; Cy is aryl, C 3-12 selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, or more R'; L A is the bond, -(CH2) a C(R1)(R2)(CH2) b selected from -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-; X1, X2, and X3 are each independently selected from CR, S, or N; provided that at least one of X1, X2, and X3 is N and one of X1, X2, and X3 is S; R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NRb R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0342] In some embodiments, Q is optionally substituted C 1-6 Alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0343] In some embodiments, Q is C 1-6 Alkyl, -SR a , and Cy.

[0344] In some embodiments, Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

[0345] In some embodiments, Q is selected from isopropyl, isopropylthio, and Cy.

[0346] In some embodiments, Q is Cy.

[0347] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8 and selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

[0348] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, azolyl, benzoyl ... and selected from clidinyl, phenothiazinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

[0349] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

[0350] In some embodiments, Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R'.

[0351] In some embodiments, Q is [ka] is selected from.

[0352] In some embodiments, Q is [ka] is selected from.

[0353] In some embodiments, L A is selected from a bond, —C(R1)(R2)—, —N(R1)—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0354] In some embodiments, L A is selected from a bond, —CH—, —CF—, —CCl—, —CBr—, —CFCl—, —CFBr—, —CClBr—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0355] In some embodiments, L A is selected from a bond, —CH—, —CF—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0356] In some embodiments, LA is -CH2-.

[0357] In some embodiments, X 1 is CR or N.

[0358] In some embodiments, X2 is S or N.

[0359] In some embodiments, X3 is S or N.

[0360] In some embodiments, [ka] teeth, [ka] is selected from.

[0361] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0362] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0363] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0364] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0365] In some embodiments, R is selected from H, methyl, and —OH.

[0366] In some embodiments, R is H.

[0367] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0368] In some embodiments, each of R and R is independently H, halogen, C-C alkyl optionally substituted with 1, 2, or 3 halogens, C-C alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NRb R c is selected from.

[0369] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0370] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0371] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0372] In some embodiments, both R1 and R2 are H.

[0373] In some embodiments, both R1 and R2 are F.

[0374] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0375] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, or C 3-6 Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0376] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0377] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0378] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0379] In some embodiments, R' is Cl or F.

[0380] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0381] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0382] In some embodiments, each Ra are independently H or isopropyl.

[0383] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0384] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0385] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl, and R c is H.

[0386] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0387] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0388] In some embodiments, each R d are independently H or methyl.

[0389] In some embodiments, a is selected from 0 and 1 and b is selected from 0 and 1.

[0390] In some embodiments, a is 0 and b is 0.

[0391] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0392] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0393] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0394] In some embodiments, Formula I is represented by formula (14A), (14B), or (14C): [ka] [ka] [ka] During the ceremony, ◆ indicates the point of attachment to Formula II; Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR bR c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Q is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , and Cy; Cy is aryl, C 3-12 selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, or more R'; L A is the bond, -(CH2) a C(R1)(R2)(CH2) b selected from -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-; R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0395] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0396] In some embodiments, each of R and R is independently H, halogen, C-C alkyl optionally substituted with 1, 2, or 3 halogens, C-C alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0397] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0398] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0399] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0400] In some embodiments, both R1 and R2 are H.

[0401] In some embodiments, both R1 and R2 are F.

[0402] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0403] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0404] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0405] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0406] In some embodiments, R is selected from H, methyl, and —OH.

[0407] In some embodiments, R is H.

[0408] In some embodiments, Q is optionally substituted C 1-6 Alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0409] In some embodiments, Q is C 1-6 Alkyl, -SR a , and Cy.

[0410] In some embodiments, Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

[0411] In some embodiments, Q is selected from isopropyl, isopropylthio, and Cy.

[0412] In some embodiments, Q is Cy.

[0413] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8 and selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

[0414] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, azolyl, benzoyl ... and selected from clidinyl, phenothiazinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

[0415] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

[0416] In some embodiments, Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R'.

[0417] In some embodiments, Q is [ka] is selected from.

[0418] In some embodiments, Q is [ka] is selected from.

[0419] In some embodiments, L A is selected from a bond, —C(R1)(R2)—, —N(R1)—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0420] In some embodiments, L A is selected from a bond, —CH—, —CF—, —CCl—, —CBr—, —CFCl—, —CFBr—, —CClBr—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0421] In some embodiments, L A is selected from a bond, —CH—, —CF—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0422] In some embodiments, L A is -CH2-.

[0423] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0424] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, or C 3-6 Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0425] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0426] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0427] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0428] In some embodiments, R' is Cl or F.

[0429] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0430] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0431] In some embodiments, each R a are independently H or isopropyl.

[0432] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0433] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0434] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl, and R c is H.

[0435] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0436] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0437] In some embodiments, each R d are independently H or methyl.

[0438] In some embodiments, a is selected from 0 and 1 and b is selected from 0 and 1.

[0439] In some embodiments, a is 0 and b is 0.

[0440] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0441] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0442] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0443] In some embodiments, DT is a moiety represented by formula (15A), (15B), (15C), or (15D): [ka] During the ceremony, [ka] indicates the point of attachment to Formula II, U is independently selected from a bond, —CH—, —NH—, and —O—; each of V and W is independently selected from —C(═O)— and —CH—; each of X, Y, and Z is independently selected from CR6 and N; R5 is selected from H, halogen, and optionally substituted C1-C6 alkyl; R6 is selected from H, halogen, and optionally substituted C1-C6 alkyl.

[0444] In some embodiments, U is a bond.

[0445] In some embodiments, U is —CH 2 —.

[0446] In some embodiments, V is -C(=O)- and W is -CH2-.

[0447] In some embodiments, V is -CH2- and W is -C(=O)-.

[0448] In some embodiments, both V and W are —C(═O)—.

[0449] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0450] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0451] In some embodiments, R5 is H.

[0452] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0453] In some embodiments, R6 is H or F.

[0454] In some embodiments, DT is [ka] is a moiety selected from

[0455] In some embodiments, DT is [ka] is a moiety selected from

[0456] In some embodiments, the compound is represented by formula (16A) or (16B): [ka] During the ceremony, [ka] each is independently a single bond or a double bond; Q is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , and Cy; Cy is aryl, C 3-12 selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, or more R'; L A is the bond, -(CH2) a C(R1)(R2)(CH2) bselected from -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-; X1, X2, and X3 are each independently selected from CR, S, or N; provided that at least one of X1, X2, and X3 is N and one of X1, X2, and X3 is S; A is C 1-20 Alkylene, -O-, -S-, -N(R e )-, and -N(R e )-C 1-20 alkylene-, optionally selected from C 1-20 One, two, three, or more methylenes in an alkylene group may independently be —O—, —S—, —N(R e )-, -C(=O)-, and -C(=S)-; B is a bond or arylene, C 3-12 and a 5- to 12-membered heteroarylene, a 5- to 12-membered heteroarylene, and a 3- to 12-membered heterocyclylene, each of which is selected from halogen, —CN, —NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c optionally substituted by one, two, three or more substituents selected from the group consisting of U is independently selected from a bond, —CH—, —NH—, and —O—; each of V and W is independently selected from —C(═O)— and —CH—; each of X, Y, and Z is independently selected from CR6 and N; Each of R1 and R2 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR b R c , -S(=O)R a , -S(=O)2R a , -S(=O)2NR b R c , optionally substituted C 3-6 carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or R1 and R2, taken together with the atoms to which they are attached, are selected from optionally substituted C 3-12 may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl, R is H, halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NRb R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R' is a halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a, -NR d C(=O)NR b R c , -NR d S(=O)R a , -NR d S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R'' is halogen, -CN, -N(=O), -NO2, -ON(=O), optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -C(=O)R a , -C(=S)R a , -C(=O)OR a , -OC(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -NR b R c , -C(=O)NR b R c , -S(=O)NR b R c , -S(=O)2NR b R c , -NR d C(=O)R a , -NR d C(=O)OR a , -NR d C(=O)NR b R c , -NR d S(=O)R a , -NRd S(=O)2R a , -NR d S(=O)NR b R c , -NR d S(=O)2NR b R c , -SN(=O), -NR d N(=O), optionally substituted aryl, optionally substituted C 3-12 selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R5 is selected from H, halogen, and optionally substituted C1-C6 alkyl; R6 is selected from H, halogen, and optionally substituted C1-C6 alkyl; Each R a are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R b and R c each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, or R b and R c may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; R e is H and optionally substituted C 1-6 alkyl, a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, provided that a+b≦5; and e is 0 or 1, f is selected from 0, 1, 2, and 3; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is optionally substituted with halogen, C 1-6 Alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of:

[0457] In some embodiments, Q is optionally substituted C 1-6 Alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0458] In some embodiments, Q is C 1-6 Alkyl, -SR a , and Cy.

[0459] In some embodiments, Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

[0460] In some embodiments, Q is selected from isopropyl, isopropylthio, and Cy.

[0461] In some embodiments, Q is Cy.

[0462] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8 and selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

[0463] In some embodiments, Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, azolyl, benzoyl ... and selected from clidinyl, phenothiazinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

[0464] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

[0465] In some embodiments, Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R'.

[0466] In some embodiments, Q is [ka] is selected from.

[0467] In some embodiments, Q is [ka] is selected from.

[0468] In some embodiments, L A is selected from a bond, —C(R1)(R2)—, —N(R1)—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0469] In some embodiments, L A is selected from a bond, —CH—, —CF—, —CCl—, —CBr—, —CFCl—, —CFBr—, —CClBr—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0470] In some embodiments, L A is selected from a bond, —CH—, —CF—, —NH—, —O—, —S—, —C(═O)—, and —C(═S)—.

[0471] In some embodiments, LA is -CH2-.

[0472] In some embodiments, X 1 is CR or N.

[0473] In some embodiments, X2 is S or N.

[0474] In some embodiments, X3 is S or N.

[0475] In some embodiments, [ka] is selected from.

[0476] In some embodiments, A is C 1-8 Alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally C 1-8 One, two, three, or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-.

[0477] In some embodiments, A is selected from —CH 2 —, —O—, —NH—, —NH—(CH 2 ) 3 —, —NH—(CH 2 ) 5 —, and —NH—C(═O)—(CH 2 ) 3 —O—(CH 2 ) 3 —.

[0478] In some embodiments, A is selected from -CH2-, -O-, and -NH-.

[0479] In some embodiments, A is —NH—.

[0480] In some embodiments, B is selected from a bond, or an arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and a 5- or 6-membered heteroarylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0481] In some embodiments, B is a bond or is selected from phenylene, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyranylene, pyrazinylene, pyrimidinylene, pyrazinylene, triazolylene, tetrazolylene, and triazinylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and propyl.

[0482] In some embodiments, B is a bond or phenylene optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, and Br.

[0483] In some embodiments, B is a bond or phenylene.

[0484] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0485] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0486] In some embodiments, U is a bond.

[0487] In some embodiments, U is —CH 2 —.

[0488] In some embodiments, V is -C(=O)- and W is -CH2-.

[0489] In some embodiments, V is -CH2- and W is -C(=O)-.

[0490] In some embodiments, both V and W are —C(═O)—.

[0491] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0492] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0493] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0494] In some embodiments, each of R and R is independently selected from H, halogen, optionally substituted C-C alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0495] In some embodiments, each of R and R is independently H, halogen, C-C alkyl optionally substituted with 1, 2, or 3 halogens, C-C alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c is selected from.

[0496] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0497] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0498] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0499] In some embodiments, both R1 and R2 are H.

[0500] In some embodiments, both R1 and R2 are F.

[0501] In some embodiments, R is H, halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0502] In some embodiments, R is H, halogen, —CN, —NO, C optionally substituted with 1, 2, or 3 halogens. 1-6 C optionally substituted with alkyl, 1, 2, or 3 halogens 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0503] In some embodiments, R is selected from H, halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH).

[0504] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH 3 ), and —NH 2 .

[0505] In some embodiments, R is selected from H, methyl, and —OH.

[0506] In some embodiments, R is H.

[0507] In some embodiments, R' is a halogen, -CN, -NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0508] In some embodiments, R' is a halogen, -CN, -NO2, C optionally substituted with 1, 2, or 3 halogens. 1-6 Alkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 1-6 Heteroalkyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, or C 3-6 cycloalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, or C 3-6 Cycloalkyl, -OR a , -SR a , and -NR b R c is selected from.

[0509] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

[0510] In some embodiments, R' is halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0511] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0512] In some embodiments, R' is Cl or F.

[0513] In some embodiments, [ka] in [ka] is a single bond.

[0514] In some embodiments, [ka] in [ka] is a double bond.

[0515] In some embodiments, R″ is a halogen, —CN, —NO, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0516] In some embodiments, R″ is selected from the group consisting of halogen, —CN, —NO, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens ... 1-6 Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkenyl, C optionally substituted with 1, 2, or 3 halogens 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from.

[0517] In some embodiments, R'' is selected from halogen, -CN, -NO2, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0518] In some embodiments, R'' is selected from F, Cl, Br, methyl, ethyl, propyl, -OH, and -NH2.

[0519] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0520] In some embodiments, R5 is H.

[0521] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0522] In some embodiments, R6 is H or F.

[0523] In some embodiments, each R a are independently H and C 1-6 alkyl.

[0524] In some embodiments, each R ais independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0525] In some embodiments, each R a are independently H or isopropyl.

[0526] In some embodiments, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl.

[0527] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0528] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl, and R c is H.

[0529] In some embodiments, each R d are independently H and C 1-6 alkyl.

[0530] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0531] In some embodiments, R e is H.

[0532] In some embodiments, a is selected from 0 and 1 and b is selected from 0 and 1.

[0533] In some embodiments, a is 0 and b is 0.

[0534] In some embodiments, e is 0.

[0535] In some embodiments, e is 1.

[0536] In some embodiments, f is 0.

[0537] In some embodiments, [ka] teeth, [ka] is a moiety selected from

[0538] In some embodiments, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is substituted with halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: cycloalkyl;

[0539] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0540] In some embodiments, the term "optionally substituted" in front of a chemical group, without specifying the substituents, indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0541] In some embodiments, the compound is represented by formula (17A) or (17B): [ka] [ka] During the ceremony, [ka] each is independently a single bond or a double bond; Q is an optionally substituted C 1-6 Alkyl, -OR a , -SR a , -NR b R c and Cy; Cy is phenyl, naphthyl, anthranyl, phenanthryl, C 3-8 carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'; L A is selected from a bond, —C(R1)(R2)—, —N(R1)—, —O—, —S—, —C(═O)—, and —C(═S)—; [ka] teeth [ka] is selected from A is C 1-8 Alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally C 1-8 one, two, three or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-; B is selected from a bond, or an arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and a 5- or 6-membered heteroarylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, —CN, —NO, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH), —NH, —NH(CH), and —N(CH); U is independently selected from a bond, —CH—, —NH—, and —O—; Each of R1 and R2 is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c Selected from; R is H, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from R' is a halogen, -CN, -NO2, optionally substituted C1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, -OR a , -SR a , and -NR b R c is selected from R5 is selected from H, F, Cl, and Br; R6 is selected from H, F, Cl, and Br; Each R a are independently H and C 1-6 alkyl, R b and R c each independently represents H, C 1-6 Alkyl, and C 3-6 cycloalkyl; e is 0 or 1, and In the formula, the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of halogen, C 1-6 Alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 indicates that the group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

[0542] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0543] In some embodiments, the compound is selected from those listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0544] III. Pharmaceutical Compositions and Kits In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, and one or more pharmaceutically acceptable excipients. For brevity, "a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof" is also referred to hereinafter as "a compound as described in the present disclosure."

[0545] In some embodiments, the compound of formula (1) is selected from any one of the compounds as described in any one of the embodiments disclosed in Section "II. Compounds." In some embodiments, the compound of formula (1) is selected from any one of compounds 1-15 as described herein.

[0546] In some embodiments, the pharmaceutical composition includes one or more additional active pharmaceutical agents (e.g., one or more additional active compounds other than the "compounds as described in this disclosure" described above). In some embodiments, the additional active pharmaceutical agent is necessary for a particular indication prevented or treated by a compound as described in this disclosure. The additional active pharmaceutical agent may have complementary activities that do not adversely affect the activity of a compound as described in this disclosure. Such pharmaceutical agents may be present in combination with a compound as described in this disclosure in an amount effective for the intended purpose.

[0547] Pharmaceutical compositions as described in this disclosure may be provided in any suitable form depending on the route of administration. In some embodiments, the pharmaceutical compositions are formulated for oral, buccal, topical, transdermal, rectal, nasal, pulmonary, transmucosal, inhalation, or parenteral, such as intravenous, intraarterial, intramuscular, subcutaneous, intraosseous, or intraperitoneal, administration.

[0548] In some embodiments, the pharmaceutical composition is formulated as a dosage form for oral administration. Dosage forms suitable for oral administration can be presented as discrete dosage forms such as capsules, troches, lozenges, tablets, solutions, suspensions, emulsions, or aerosol sprays, each containing a predetermined amount of the active ingredient (i.e., a compound as described in the present disclosure and optionally one or more additional active pharmaceutical agents). In some embodiments, the pharmaceutical composition is formulated as a tablet. The tablet may be provided with a coating that protects the tablet from the acidic environment of the stomach. For example, the coating may be an enteric coating that maintains its integrity in the stomach and releases the active ingredient in the intestine. In some embodiments, the pharmaceutical composition is formulated as a capsule. The capsule may contain a liquid excipient such as a fatty oil. In some embodiments, the pharmaceutical composition is formulated as various liquid oral dosage forms, such as an aqueous solution, emulsion, or suspension. In some embodiments, the liquid oral dosage form is a solution and / or suspension reconstituted from non-effervescent or effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Elixirs are clear, sweetened hydroalcoholic preparations. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and may also contain one or more preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may be oil-in-water or water-in-oil emulsions. The excipients used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions are heterogeneous mixtures in which solute particles do not dissolve but are suspended throughout the bulk of the solvent, leaving them floating freely in the medium. https: / / en.wikipedia.org / wiki / Solutehttps: / / en.wikipedia.org / wiki / Dissolution_(chemistry)https: / / en.wikipedia.org / wiki / SolventSuspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents.Acceptable materials used in effervescent granules that are reconstituted into liquid oral dosage forms include organic acids and carbon dioxide sources.Coloring agents and flavoring agents are used in all of the above dosage forms.In some embodiments, pharmaceutical compositions are formulated as oral inhalation dosage forms.Oral inhalation dosage forms include metered dose inhalers, dry powder inhalers, and liquid preparations for administration from nebulizers or metered dose liquid dispensing systems.For both metered dose inhalers and dry powder inhalers, the crystalline form of active agent is the preferred physical form for providing longer product stability.

[0549] In some embodiments, pharmaceutical compositions are formulated and administered in unit dosage forms or multiple dosage forms. As used in this disclosure, a unit dosage form refers to a physically discrete unit suitable for a subject in need thereof and is individually packaged as known in the art. Each unit dosage form contains a predetermined amount of active ingredient, associated with one or more pharmaceutically acceptable excipients, sufficient to produce the desired prophylactic or therapeutic effect. Examples of unit dosage forms include, but are not limited to, ampoules and syringes, and individually packaged tablets or capsules. A unit dosage form may be administered in fractions or multiples. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single package that are administered in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dosage form is a multiple of a unit dosage that is not separated in packaging.

[0550] Pharmaceutical compositions as described in this disclosure may be prepared using procedures well known in the art (see, e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)). Procedures typically include the step of bringing the active ingredient into association with one or more pharmaceutically acceptable excipients. In general, pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form. For example, tablets can be prepared by compressing or molding the active ingredient, optionally with one or more pharmaceutically acceptable auxiliary excipients. In cases where the active ingredient exhibits insufficient solubility, solubilization methods such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions or tertiary templating may be used.

[0551] Any pharmaceutically acceptable excipient conventionally used in the pharmaceutical industry may be employed to prepare the pharmaceutical compositions described in the present disclosure. Examples of pharmaceutically acceptable excipients useful for preparing the pharmaceutical compositions described in the present disclosure include water, ethanol, glycerin, propylene glycol, DMSO, polyethylene glycol, fatty oils such as sesame oil, corn oil, cottonseed oil, or peanut oil, liquid paraffin, and solvents such as ethyl oleate or isopropyl myristate; sulfates, sulfonates, quaternary ammonium compounds, lecithin, Span®, Tween®, Myri, polyoxyl 40 stearate, peregol emulsifiers such as gelatin, acacia, tragacanth, bentonite, or surfactants such as polyoxyethylene sorbitan monooleate; suspending agents such as sodium carboxymethylcellulose, pectin, tragacanth, Veegum, or acacia; fillers such as lactose, sucrose, trehalose, lysine, leucine, kaolin, dicalcium phosphate, mannitol, microcrystalline cellulose, or pregelatinized starch; adhesives such as cellulose, PVP, or dextrin; croscarmellose sodium, sodium starch glycolate, alginate, corn starch, potato starch, bentonite, methylcellulose disintegrating agents such as talc, polyethylene glycol, calcium stearate, magnesium stearate, lycopodium, or stearic acid; glidants such as colloidal silicon dioxide; coloring agents such as approved certified water soluble FD and C dyes or water insoluble FD and C dyes (e.g., suspended on alumina hydrate); wetting agents such as propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, or polyoxyethylene lauryl ether; enteric coating agents such as fatty acids, fats, waxes, shellac, ammoniated shellac, or cellulose acetate phthalate;Film coating agents such as hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, or cellulose acetate phthalate; modified-release agents such as polymers such as the Eudragit® series and cellulose esters; sweeteners such as fructose, glucose, sucrose, artificial sweeteners (such as sucralose, aspartame, or saccharin), agave syrup, maple syrup, or corn syrup; natural flavors extracted from plants such as fruits, peppermint, or methyl salicylate; citrates, phosphates, and other organic acids and / or their salts, etc. antioxidants such as ascorbic acid, methionine, citric acid, D,L-α-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, or propyl gallate; preservatives such as benzoic acid, sodium benzoate, parabens such as methylparaben or propylparaben, sorbic acid, or benzalkonium bromide; pH adjusters such as citric acid, sodium citrate, hydrochloric acid, NaOH, or other weak acids or bases; and chelating agents or other materials capable of binding metal ions such as ethylenediaminetetraacetic acid (EDTA) or its salts.

[0552] In some embodiments, the pharmaceutical composition is formulated as an injection. Examples of injections include, but are not limited to, sterile solutions, suspensions, or emulsions in aqueous or oily vehicles. Aqueous solutions in saline are conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, cyclodextrin derivatives, and vegetable oils may also be used. Oily vehicles that may be used for injection include, but are not limited to, lipophilic solvents such as fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may also contain substances such as wetting agents, suspending agents, and / or flocculating or disaggregating agents. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Pharmaceutical compositions may also be formulated for bolus injection or continuous infusion. Alternatively, the pharmaceutical composition may be lyophilized or in powder form for reconstitution with a suitable vehicle, such as sterile, pyrogen-free water, immediately before use.

[0553] In some embodiments, pharmaceutical compositions are formulated as topical dosage forms, such as for topical application to skin and mucous membranes, such as eyes.The topical dosage forms useful for active ingredients can be solutions, suspensions, or emulsions.Alternatively, active ingredients can be formulated as creams, gels, ointments, elixirs, lotions, tinctures, pastes, foams, aerosols, irrigation, sprays, suppositories, bandages, skin patches, or any other dosage forms suitable for topical administration.Active ingredients can also be formulated as aerosols for topical application, such as by inhalation.These dosage forms for administration to the respiratory tract can be in the form of aerosols or solutions for nebulizers, or can be ultrafine powders for pneumoperitoneum, alone or combined with inert carriers such as lactose.In such cases, the particles of the dosage form will have a mass median geometric diameter of less than 5 micrometers in some embodiments, and less than 10 micrometers in other embodiments.

[0554] In some embodiments, the pharmaceutical composition is formulated as a microcapsule. The microcapsule may be prepared in a colloidal drug delivery system (e.g., microemulsions, liposomes, microspheres (e.g., albumin microspheres), nanoparticles, and nanocapsules), or in a macroemulsion, by coacervation techniques, or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively).

[0555] In some embodiments, pharmaceutical compositions are formulated as sustained-release dosage forms.Examples of sustained-release dosage forms include, but are not limited to, shaped articles (for example, films or microcapsules) formed by semipermeable matrices of solid hydrophobic polymers, which may contain the compound described in the present disclosure and optionally one or more additional active pharmaceutical agents.Examples of sustained-release matrices include, but are not limited to, hydrogels, polylactides, polyesters, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, and poly-D-(-)-3-hydroxybutyric acid.

[0556] In some embodiments, the pharmaceutical composition is formulated as a controlled-release dosage form. Such dosage forms can be used, for example, to provide controlled release of one or more active ingredients using hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof, to provide a desired release profile at various rates. All controlled-release dosage forms share the common goal of improving drug therapy over that achieved by their non-controlled counterparts. Most controlled-release dosage forms are designed to initially release a certain amount of active ingredient that immediately produces the desired preventive or therapeutic effect, and then gradually and continuously release another amount of active ingredient to maintain this level of preventive or therapeutic effect over an extended period of time. To maintain this constant level of active ingredient in the body, the active ingredient must be released from the dosage form at a rate that replaces the amount of active ingredient metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds. The advantages of controlled-release dosage forms include extending the activity of active ingredients, reducing the frequency of administration, and increasing patient compliance.In addition, controlled-release dosage forms can be used to affect the time of onset of action or other characteristics such as blood level of active ingredients, and therefore affect the occurrence of undesirable side effects.Suitable controlled-release dosage forms can be easily selected for use with the active ingredients provided in the present disclosure.

[0557] In some embodiments, pharmaceutical compositions are formulated as dosage forms for rectal administration, such as rectal suppositories, capsules, and tablets. Rectal suppositories, as used in this disclosure, refer to solid objects inserted into the rectum that melt or soften at body temperature and release one or more active ingredients. Examples of bases used in rectal suppositories include, but are not limited to, cocoa butter, glycerin-gelatin, carbowax, and suitable mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may also be used. Agents for raising the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared by either compression or molding. Tablets and capsules for rectal administration are manufactured using the same materials and by the same methods as dosage forms for oral administration.

[0558] In some embodiments, the pharmaceutical composition is subject to sterilization.Sterilization refers to any process that removes, kills, or inactivates all forms of life (especially microorganisms) and other biological agents, such as prions, present in or on a particular surface, object, or fluid.Sterilization can be achieved by various means, including heating, chemical action, irradiation, high pressure, and filtration.For example, sterilization can be achieved by sterile filtration.

[0559] The level of active ingredient in a pharmaceutical composition as described herein is effective for delivery of an amount upon administration that treats, prevents, or ameliorates one or more symptoms of a disease or condition described herein. Specifically, the amount of a compound as described herein and any additional active pharmaceutical agent will depend on the subject being treated, the severity of the disease or condition, the rate of administration, absorption, inactivation, and excretion rate of the administered active ingredient, the judgment of the prescribing physician, as well as other factors known to those of skill in the art. In some embodiments, the pharmaceutical composition comprises 0.05%-80%, 0.1%-50%, 0.2%-40%, 0.5%-25%, 1%-20%, 5%-15%, or 7%-12% (wt / wt) of a compound as described herein. In some embodiments, the pharmaceutical composition comprises 0% to 50%, 0.05% to 25%, 0.1% to 20%, 0.2% to 15%, 0.5% to 10%, or 1% to 5% (wt / wt) of an additional active pharmaceutical agent, with the remainder of the pharmaceutical composition consisting of one or more pharmaceutically acceptable excipients.

[0560] In some aspects, the present disclosure provides a kit comprising a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, and optionally instructions for use. The compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or pharmaceutical composition may be enclosed in suitable packaging. Packaging materials for use in packaged kits are well known in the art. Examples of packaging materials include any packaging suitable for the selected dosage form and intended mode of administration and treatment, including blister packs, tubes, bottles, inhalers, pumps, bags, vials, syringes, bottles, or other containers. The kit may have instructions for use included in written materials. In addition, additional information useful to healthcare professionals, such as clinical trial results and discussion of the results, a list of side effects, drug interactions, and / or references to scientific literature, may also be included in the written materials. In some embodiments, the kit further comprises one or more additional active pharmaceutical agents. In some embodiments, the compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof and one or more additional active pharmaceutical agents are provided as separate compositions, optionally in separate containers within the kit. In some embodiments, the compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof and one or more additional active pharmaceutical agents are provided as a single composition in the same container within the kit. Additional items for use (e.g., measuring cups for liquid preparation, foil wrapping to minimize exposure to air, and the like) may also be included in the kit.

[0561] IV. Methods of Treatment and Therapeutic Uses In some aspects, the disclosure provides methods for preventing or treating a disease or condition for which degradation of GRK2 is beneficial in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein.

[0562] In some embodiments, the compound of formula (1) is selected from any one of the compounds as described in any one of the embodiments disclosed in Section "II. Compounds." In some embodiments, the compound of formula (1) is selected from any one of compounds 1-15 as described herein.

[0563] In some embodiments, the pharmaceutical composition includes one or more additional active pharmaceutical agents (e.g., one or more additional active compounds other than the "compounds as described in this disclosure" described above). In some embodiments, the additional active pharmaceutical agent is necessary for a particular indication prevented or treated by a compound as described in this disclosure. The additional active pharmaceutical agent may have complementary activities that do not adversely affect the activity of a compound as described in this disclosure. Such pharmaceutical agents may be present in combination with a compound as described in this disclosure in an amount effective for the intended purpose.

[0564] In some embodiments, the method further comprises administering to a subject in need thereof one or more additional active pharmaceutical agents, wherein the one or more additional active pharmaceutical agents are in the same pharmaceutical composition as the compound of Formula (1), or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof. In some embodiments, the method further comprises administering to a subject in need thereof one or more additional active pharmaceutical agents, wherein the one or more additional active pharmaceutical agents are in a different composition from the composition of the compound of Formula (1), or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, and wherein the one or more additional active pharmaceutical agents are administered before, simultaneously with, or after administration of the compound of Formula (1), or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

[0565] In some embodiments, the disease or condition is selected from a hyperproliferative disease, a cardiovascular disease, a hematological disease, an infectious disease, an endocrine disease, a metabolic disease, a gastrointestinal disease, a respiratory disease, inflammation, opioid addiction, and a urinary disease.

[0566] In some embodiments, the disease or condition is a hyperproliferative disease.

[0567] In some embodiments, the hyperproliferative disease is a tumor.

[0568] In some embodiments, the tumor is a carcinoma or a sarcoma.

[0569] In some embodiments, the cancer is a hematopoietic cancer or a solid tumor.

[0570] In some embodiments, the hematopoietic cancer is selected from leukemia, lymphoma, heavy chain disease, myeloproliferative disorder, multiple myeloma, plasma cell neoplasm, familial hypereosinophilia, inflammatory myofibroblastic tumor, and immunocytic amyloidosis.

[0571] In some embodiments, the solid tumor is selected from nervous system cancer, exocrine cancer, musculoskeletal cancer, gastrointestinal cancer, respiratory cancer, genitourinary cancer, gynecological cancer, skin cancer, soft tissue cancer, oral cancer, head and neck cancer, esophageal cancer, liver cancer, and pancreatic cancer.

[0572] In some embodiments, the disease or condition is a cardiovascular disease.

[0573] In some embodiments, the cardiovascular disease is selected from atherosclerosis, cardiac hypertrophy, hypertension, coronary artery disease, myocarditis, pericarditis, valvular heart disease, stenosis, restenosis, in-stent stenosis, angina pectoris, myocardial infarction, acute coronary syndrome, coronary artery bypass graft, cardiopulmonary bypass surgery, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia, renal reperfusion injury, embolism, and myocardial ischemia.

[0574] In some embodiments, the disease or condition is pulmonary hypertension.

[0575] In some embodiments, the disease or condition is pulmonary arterial hypertension.

[0576] In some embodiments, the disease or condition is selected from idiopathic pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, drug- or toxin-induced pulmonary arterial hypertension, idiopathic pulmonary veno-occlusive disease, hereditary pulmonary veno-occlusive disease, drug-, toxin-, or radiation-induced pulmonary veno-occlusive disease, idiopathic pulmonary capillary hemangiomatosis, hereditary pulmonary capillary hemangiomatosis, drug-, toxin-, or radiation-induced pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.

[0577] In some aspects, the present disclosure provides a method for inhibiting tumor growth or preventing recurrence in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein.

[0578] In some aspects, the disclosure provides a method of degrading GRK2 or inhibiting the activity of GRK2 in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein.

[0579] For use in treating or preventing diseases or conditions as described in the present disclosure, the active ingredient is administered in a therapeutically effective amount. The attending physician will determine the most appropriate administration regimen according to the age, weight, stage of the disease, and other factors specific to the subject being treated. The therapeutically effective amount of the active ingredient varies depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The frequency and dosage (or administration amount) also vary according to factors specific to each subject. The active ingredient may be administered at once or may be divided into several smaller doses administered at intervals of time. Exemplary dosages (or administration amounts) of the compounds as described in the present disclosure, one or more additional active pharmaceutical agents, or combinations thereof include, but are not limited to, about 1 mg / kg to about 100 mg / kg, about 2 mg / kg to about 75 mg / kg, about 5 mg / kg to about 50 mg / kg, or about 10 mg / kg to about 25 mg / kg. It is understood that the exact dosage and duration of treatment is a function of the disease or condition being treated, and can be determined empirically using known test protocols, or by extrapolation from in vivo or in vitro test data or subsequent clinical trials.It is understood that for any particular subject, specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person who manages or supervises the administration behavior.In some cases, as will be clear to those skilled in the art, it may be necessary to use a dose (or dosage) of active ingredient outside the range disclosed in this disclosure.In addition, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the subject's response.

[0580] In some aspects, the present disclosure provides a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for use in therapy.

[0581] In some aspects, the disclosure provides a compound of formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for use in preventing or treating a disease or condition for which degradation of GRK2 is beneficial in a subject.

[0582] In some aspects, the present disclosure provides a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, and one or more pharmaceutically acceptable excipients, for use in inhibiting tumor growth or preventing recurrence in a subject.

[0583] In some aspects, the disclosure provides a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for use in degrading GRK2 or inhibiting the activity of GRK2 in a subject.

[0584] In some aspects, the disclosure provides for the use of a compound of formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for the preparation of a medicament for use in preventing or treating a disease or condition for which degradation of GRK2 is beneficial in a subject.

[0585] In some aspects, the disclosure provides for the use of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for the preparation of a medicament for use in inhibiting the growth or preventing the recurrence of a tumor in a subject.

[0586] In some aspects, the disclosure provides for the use of a compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition as described herein, for the preparation of a medicament for use in degrading GRK2 in a subject or inhibiting the activity of GRK2 in a subject.

[0587] V. General Synthetic Scheme Compounds as described in this disclosure can be synthesized according to organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature, given suitable references that describe or provide references to articles describing the synthesis of reactants useful in synthesizing compounds as described in this disclosure (e.g., "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York). "Commercially available chemicals" may be obtained from standard commercial sources, including, but not limited to, Fisher Scientific Co. (Pittsburgh, PA). Additionally, chemicals known in catalogs but not commercially available are optionally prepared by custom chemical synthesis houses, and many standard chemical supply houses offer custom synthesis services.

[0588] The following general synthetic schemes for the compounds described in this disclosure are provided for illustrative purposes only. It is understood that those skilled in the art may be able to prepare these compounds by analogous methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art may be able to prepare compounds similar to those described below by using appropriate starting materials and modifying the synthetic route as necessary.

[0589] Scheme 1 Scheme 1 illustrates a general synthetic method for synthesizing compounds according to the present application that contain a thiazole ring in their backbone: [ka] wherein R, R1, R2, R', m, B, and DT are as defined above.

[0590] Various target compounds according to the present application can be synthesized by reacting the corresponding precursor compound P with compound Q according to Scheme 1. Briefly, in one embodiment, compound P (0.9 mmol) is dissolved in 5 ml of N,N-dimethylformamide (DMF) and triethylamine (EtN) (3.6 mmol), and compound Q (0.9 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 500 mg, 1.32 mmol) are added sequentially at room temperature. After about 1 hour of reaction, the reaction of starting material compound Q is complete (e.g., by LCMS detection). The reaction is quenched by adding 20 ml of distilled water, and ethyl acetate is added to extract and separate the liquid. The extraction is repeated three times until the extraction is complete. The organic phases are combined and washed with saturated brine, dried, and concentrated, and the concentrate is purified by column chromatography (solvent: dichloromethane:methanol=100:1 to 20:1) or reverse-phase high-performance liquid chromatography (eluent: acetonitrile-water, gradient 35 to 60%) to obtain a white or off-white solid product, i.e., Compound AF.

[0591] Scheme 2 Scheme 2 illustrates another general synthetic method for synthesizing compounds according to the present application: [ka]

[0592] In the formula, Q, L A, X1, X2, X3, B, and DT are as defined above. Various target compounds according to the present application can be synthesized by reacting the corresponding precursor compound P1 with compound Q according to Scheme 2. Briefly, in one embodiment, DIEA (0.099 mmol) and HATU (0.073 mmol) are added to a mixture of compound Q (0.066 mmol) and compound P1 (0.066 mmol) in DMF (3 mL). The solution is stirred at room temperature for 4 hours. Water (20 mL) is added to the residue, and the mixture is extracted with DCM (5 mL x 3). The combined organic layer is dried over Na2SO4, concentrated in vacuo, and the residue is purified by preparative HPLC to obtain the target compound. It will be understood by those skilled in the art that the reagents and procedures described above are for illustrative purposes only and should not be construed as limiting. For example, in another embodiment, DIEA may be replaced with a similar base, such as TEA. [Example]

[0593] The present disclosure will now be described with reference to the following examples, which are intended to illustrate but not limit the present invention. Unless otherwise specified, examples are carried out according to conventional conditions or conditions suggested by the manufacturer, unless specific conditions are indicated in the examples. Reagents or equipment used without manufacturer's instructions are commercially available conventional products. Those skilled in the art will understand that the examples described herein are not intended to limit the scope of the invention as claimed.

[0594] As used herein, if there is a discrepancy between the structure and the chemical name provided for a particular compound, the structure shall control.

[0595] Synthesis Example Example 1: Preparation of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (Compound 1) [ka]

[0596] Step 1: Synthesis of tert-butyl (5-(hydroxy(phenyl)methyl)thiazol-2-yl)carbamate N-Boc-2-aminothiazole (2 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and the reaction mixture was cooled to -70°C. n-Butyllithium solution (10 mL, 2.5 N THF solution) was slowly added dropwise under argon protection. The reaction was continued at this temperature for 30 minutes. Benzaldehyde (1.27 g, 12 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the above reaction mixture. The reaction was continued at -70°C for 30 minutes, and then the reaction mixture was slowly heated to room temperature. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution to the reaction mixture and extracted with ethyl acetate. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to remove the solvent, and the concentrate was separated and purified by column chromatography to obtain the target product compound, tert-butyl (5-(hydroxy(phenyl)methyl)thiazol-2-yl)carbamate (2.9 g, yield 95%) as an off-white solid.

[0597] Step 2: Synthesis of 5-benzyl-2-aminothiazole The compound (5-(hydroxy(phenyl)methyl)thiazol-2-yl) tert-butyl carbamate (1.84 g, 6 mmol) was dissolved in dichloromethane (36 mL) solvent, and triethylsilane (2.09 g, 18 mmol) and trifluoroacetic acid (6.83 g, 60 mmol) were added dropwise successively while stirring in an ice bath. After the addition was completed, the reaction mixture was stirred at room temperature for about 2 hours. After the reaction was completed, the solvent was removed by concentration, water was added, and the pH was adjusted to about 7 with saturated sodium bicarbonate solution. The liquid was extracted and separated with dichloromethane. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to remove the solvent, and the concentrate was separated and purified by column chromatography to obtain the target product compound 5-benzyl-2-aminothiazole (0.97 g, 85% yield) as an off-white solid.

[0598] Step 3: Synthesis of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide 5-Benzyl-2-aminothiazole (173 mg, 0.9 mmol) was dissolved in 4 ml of N,N-dimethylformamide (DMF), and triethylamine (EtN) (183 mg, 1.8 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (275 mg, 0.9 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 500 mg, 1.3 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (Compound 1) (176 mg, 40% yield) as an off-white solid.

[0599] 1 H NMR(400MHz,DMSO-d6)δ 12.15(s,1H),10.98(s,1 H),7.74-7.64(m,1H),7.54(s,2H),7.29(t,J=7.5Hz,2H),7.26-7.15(m,4H),5.10(dd,J=13.3,5.1Hz,1H),4.43(d,J=17.2Hz,1H) ),4.30(d,J=17.2Hz,1H),4.06(s,2H),3.85(s,2H),2.96-2.85(m,1H),2.62-2.57(m,1H),2.43-2.34(m,1H),2.03-1.95(m,1H). Chemical formula:C 25 H 22 N4O4S, MS calculated: 474.5; MS found: 475.3 [M+1] + .

[0600] Example 2: Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide (Compound 2) [ka]

[0601] Step 1: Synthesis of tert-butyl (5-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate N-Boc-2-aminothiazole (2 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and the reaction mixture was cooled to -70°C. n-Butyllithium solution (10 mL, 2.5 N THF solution) was slowly added dropwise under argon protection. The reaction was continued at this temperature for 30 minutes. p-Chlorobenzaldehyde (1.7 g, 12 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the above reaction mixture. The reaction was continued at -70°C for 30 minutes, and then the reaction mixture was slowly heated to room temperature. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to remove the solvent, and the concentrate was separated and purified by column chromatography to obtain the target product compound, tert-butyl (5-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate (3.1 g, 91% yield) as an off-white solid.

[0602] Step 2: Synthesis of 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine The compound, tert-butyl (5-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate (2.04 g, 6 mmol) was dissolved in dichloromethane (36 mL) solvent, and triethylsilane (2.09 g, 18 mmol) and trifluoroacetic acid (6.83 g, 60 mmol) were added dropwise successively while stirring in an ice bath. The reaction was continued to stir at room temperature for about 5 hours. After completion of the reaction, the reaction was concentrated to remove the solvent. Water was added, and the pH was adjusted to about 7 with saturated sodium bicarbonate solution. The liquid was extracted and separated with dichloromethane. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to remove the solvent, and the concentrate was separated and purified by column chromatography to obtain the target product compound 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (1.08 g, yield 80%) as an off-white solid.

[0603] Step 3: Synthesis of N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (22 mg, 0.1 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (EtN) (15 mg, 0.15 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetic acid (32 mg, 0.1 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 45 mg, 0.12 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until completion. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide (Compound 2) (18 mg, 35% yield) as an off-white solid.

[0604] 1 H NMR(400MHz,DMSO-d6)δ 12.32(s,1H),11.12(s,1H),7.88(d,J=6.8Hz,2H),7.78(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,2H),7.32-7.20(m,3H),5.14(dd ,J=12.9,5.3Hz,1H),4.07(s,2H),3.99(s,2H),2.94-2.87(m,1H),2.63-2.59(m,1H),2.58-2.55(m,1H),2.09-2.01(m,1H). Chemical formula:C 25 H 19 ClNOS, MS calculated: 523.0; MS found: 523.3 [M+1] + .

[0605] Example 3 Preparation of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-oxoisoindolin-5-yl)acetamide (Compound 3) [ka]

[0606] 5-Benzyl-2-aminothiazole (19 mg, 0.1 mmol) was dissolved in 2 ml of N,N-dimethylformamide (DMF), and triethylamine (EtN) (15 mg, 0.15 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-oxoisoindolin-5-yl)acetic acid (32 mg, 0.1 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 45 mg, 0.12 mmol) were added sequentially with stirring at room temperature. After stirring the reaction at room temperature for about 1 hour, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to the reaction, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-oxoisoindolin-5-yl)acetamide (Compound 3) (16 mg, 32% yield) as a white solid.

[0607] 1H NMR(400MHz,DMSO-d6)δ 12.25(s,1H),11.00(s,1H),7.56(s,1H),7.43(d,J=9.8Hz,1H),7.30( t,J=6.9Hz,2H),7.24(q,J=9.7,9.0Hz,4H),5.15-5.06(m,1H),4.54(d, J=17.0Hz,1H),4.37(d,J=17.3Hz,1H),4.07(s,2H),3.89(s,2H),2.97 -2.85(m,1H),2.63-2.59(m,1H),2.46-2.39(m,1H),2.03-1.95(m,1H). Chemical formula:C 25 H 21 FN4O4S, MS calculated: 492.5; MS found: 493.4 [M+1] + .

[0608] Example 4 Preparation of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide (Compound 4) [ka]

[0609] 5-Benzyl-2-aminothiazole (19 mg, 0.1 mmol) was dissolved in 2 ml of N,N-dimethylformamide (DMF), and triethylamine (EtN) (15 mg, 0.15 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetic acid (32 mg, 0.1 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 45 mg, 0.12 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection showed that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide (Compound 4) (14 mg, 29% yield) as a white solid.

[0610] 1 H NMR(400MHz,DMSO-d6)δ 12.30(s,1H),11.12(s,1H),7.88(d,J=6.8Hz,2H),7.78(d,J=7.9Hz,1H),7.38-7.34(m,3H),7.32-7.20(m,3H),5.14(dd, J=12.9,5.3Hz,1H),4.07(s,2H),3.97(s,2H),2.94-2.87(m,1H),2.62-2.58(m,1H),2.56-2.53(m,1H),2.09-2.01(m,1H). Chemical formula:C 25 H 20 N4O5S, MS calculated: 488.5; MS found: 489.3 [M+1] + .

[0611] Example 5 Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 5) [ka]

[0612] 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (11 mg, 0.05 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (EtN) (10 mg, 0.10 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetic acid (15 mg, 0.05 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 23 mg, 0.06 mmol) were added sequentially with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 8 mL of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 5) (8 mg, 32% yield) as a white solid.

[0613] 1H NMR (400 MHz, DMSO-d6) δ 12.29(s,1H),10.98(s,1H),7.68(d,J=7.8Hz,1H),7.52(s,1H),7.43(d,J=7 .9Hz,1H),7.40-7.31(m,2H),7.31-7.19(m,3H),5.10(dd,J=13.2,5.1Hz,1H ),4.44(d,J=17.3Hz,1H),4.31(d,J=17.3Hz,1H),4.07(s,2H),3.87(s,2H), 2.97-2.86(m,1H),2.62-2.57(m,1H),2.44-2.35(m,1H),2.03-1.94(m,1H). Chemical formula:C 25 H 21 ClNOS, MS calculated: 509.0; MS found: 509.3 [M+1] + .

[0614] Example 6 Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (Compound 6) [ka]

[0615] 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (11 mg, 0.05 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (EtN) (10 mg, 0.10 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (15 mg, 0.05 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 23 mg, 0.06 mmol) were added sequentially with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 8 mL of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (Compound 6) (7.6 mg, 30% yield) as a white solid.

[0616] 1 H NMR(400MHz,DMSO-d6)δ 12.27(s,1H),10.98(s,1H),7.69(s,1H),7.55(s,2H),7.35(d,J=8.3Hz,2H),7.26(d,J=7.7Hz,3H),5.10(dd,J=13.4,5.1Hz,1H),4.43(d,J =17.2Hz,1H),4.30(d,J=17.2Hz,1H),4.07(s,2H),3.85(s,2H),2.97-2.86(m,1H),2.62-2.57(m,1H),2.44-2.35(m,1H),2.03-1.97(m,1H). Chemical formula:C 25 H 21 ClNOS, MS calculated: 509.0; MS found: 509.4 [M+1]+ .

[0617] Example 7 Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzamide (Compound 7) [ka]

[0618] Step 1: Synthesis of methyl 4-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate Tert-butyl 4-hydroxybenzoate (300 mg, 1.5 mmol), potassium carbonate (427 mg, 3.1 mmol), and methyl 4-fluoro-2-methylbenzoate (260 mg, 1.5 mmol) were dissolved in 10 mL of N,N-dimethylformamide (DMF). The reaction mixture was heated to 100°C and stirred at this temperature for approximately 3 hours. LCMS analysis indicated that the starting material had completely reacted. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with 20 mL of water and extracted and separated with ethyl acetate (2 x 10 mL). The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromatography (ethyl acetate / petroleum ether=1 / 20 to 1 / 10), methyl 4-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate (317 mg, yield 60%) was obtained as a yellowish solid.

[0619] Step 2: Synthesis of methyl 2-(bromomethyl)-4-(4-(tert-butoxycarbonyl)phenoxy)benzoate The intermediate methyl 4-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate (317 mg, 0.93 mmol) and N-bromosuccinimide (NBS) (247 mg, 1.39 mmol) were dissolved in 10 ml of chloroform and heated to 65° C. Then, a catalytic amount of azobisisobutyronitrile (AIBN) (7 mg) was added to initiate the reaction, and the reaction was continued at this temperature with stirring for about 4 hours. LCMS detection showed that the starting material had reacted completely. The reaction was cooled to room temperature, and insoluble matter was removed by suction filtration. The filtrate was diluted by adding 15 ml of water, and extracted and separated by adding dichloromethane (2×10 ml). The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10), a yellowish liquid, methyl 2-(bromomethyl)-4-(4-(tert-butoxycarbonyl)phenoxy)benzoate (311 mg, yield 80%) was obtained.

[0620] Step 3: Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoate The intermediate, methyl 2-(bromomethyl)-4-(4-(tert-butoxycarbonyl)phenoxy)benzoate (311 mg, 0.74 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (146 mg, 0.89 mmol) were dissolved in 5 ml of N,N-dimethylformamide (DMF), and diisopropylethylamine (DIEA) (239 mg, 1.85 mmol) was added at room temperature. The mixture was heated to 90° C., and the reaction was stirred at this temperature for about 4 hours. LCMS detection showed that the reaction was complete. The reaction was diluted by adding 20 mL of water, and extracted and separated by adding dichloromethane (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromatography (methanol / dichloromethane=1 / 100 to 1 / 30), an off-white solid, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoate (145 mg, 45% yield) was obtained.

[0621] Step 4: Synthesis of compound 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoic acid The intermediate, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoate (145 mg, 10 mmol) was dissolved in 3 ml of dichloromethane, 1 ml of trifluoroacetic acid (TFA) was added at room temperature, and the temperature was raised to 40° C. to initiate the reaction. After about 1 hour of reaction, LCMS detection showed that the starting material had disappeared. The excess trifluoroacetic acid solution, by-products, and solvent were removed by concentration under reduced pressure to give crude 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoic acid (120 mg, 95% yield).

[0622] Step 5: Synthesis of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzamide 5-Benzyl-2-aminothiazole (5 mg, 0.026 mmol) was dissolved in 2 ml of N,N-dimethylformamide (DMF), and triethylamine (EtN) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.026 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection showed that the starting material had completely reacted. The reaction was quenched by adding 3 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product, N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzamide (Compound 7) (5 mg, 35% yield) as a white solid.

[0623] 1H NMR (400 MHz, DMSO-d6) δ 12.45(s,1H),10.99(s,1H),8.13(d,J=8.6Hz,2H),7.79(d,J=8.3Hz,1H),7 .43-7.26(m,6H),7.27-7.21(m,2H),7.18(d,J=8.6Hz,2H),5.11(dd,J=13. 3,5.1Hz,1H),4.45(d,J=17.6Hz,1H),4.32(d,J=17.5Hz,1H),4.12(s,2H), 2.92-2.86(m,1H),2.68-2.62(m,1H),2.42-2.37(m,1H),2.04-1.97(m,1H). Chemical formula:C 30 H 24 N4O5S, MS calculated: 552.6; MS found: 553.4 [M+1] + .

[0624] Example 8 Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzamide (Compound 8) [ka]

[0625] 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (T1-4) (6 mg, 0.026 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (EtN) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.026 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added sequentially with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product, N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzamide (Compound 8) (4.6 mg, 30% yield) as a white solid.

[0626] 1 H NMR (400 MHz, DMSO-d6) δ 12.47(s,1H),10.98(s,1H),8.13(d,J=8.6Hz,2H),7.80(d,J=8.3Hz,1H),7 .46-7.29(m,5H),7.29-7.25(m,2H),7.21(d,J=8.6Hz,2H),5.16(dd,J=13. 3,5.1Hz,1H),4.48(d,J=17.6Hz,1H),4.37(d,J=17.5Hz,1H),4.15(s,2H), 2.94-2.86(m,1H),2.68-2.61(m,1H),2.45-2.37(m,1H),2.06-1.99(m,1H). Chemical formula:C 30 H 23ClNOS, MS calculated: 587.0; MS found: 587.4 [M+1] + .

[0627] Example 9 Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzamide (Compound 9) [ka]

[0628] Step 1: Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoate Tert-butyl 4-hydroxybenzoate (300 mg, 1.5 mmol), potassium carbonate (427 mg, 3.1 mmol), and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (427 mg, 1.5 mmol) were dissolved in 10 mL of N,N-dimethylformamide (DMF), the mixture was heated to 130 °C, and the reaction was stirred at this temperature for approximately 3 hours. LCMS detection indicated that the starting material had disappeared. After the mixture was cooled to room temperature, it was filtered, and the filtrate was diluted by adding 15 mL of water and extracted and separated by adding ethyl acetate (2 × 10 mL). The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromatography (ethyl acetate / petroleum ether=1 / 20 to 1 / 1), tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoate (383 mg, 55% yield) was obtained as a yellowish solid.

[0629] Step 2: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoic acid The intermediate, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoate (383 mg, 0.85 mmol) was dissolved in 5 ml of dichloromethane, 2 ml of trifluoroacetic acid (TFA) was added at room temperature, and the temperature was raised to 40° C. to initiate the reaction. After about 1 hour of reaction, LCMS detection showed that the starting material had disappeared. The excess trifluoroacetic acid solution and solvent were removed by concentration under reduced pressure to give 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoic acid (322 mg, 96% yield).

[0630] Step 3: Synthesis of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzamide 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (6 mg, 0.026 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (EtN) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.025 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 5 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain a white solid product, N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzamide (Compound 9) (5.2 mg, 34% yield).

[0631] 1 H NMR(400MHz,DMSO-d6)δ 12.52(s,1H),11.13(s,1H),8.16(dd,J=8.9,2.3Hz,2H),7.98(dd,J=8.1,2.1Hz,1H),7.59-7.46(m,2H),7.46-7.36(m,2H),7.37-7 .11(m,5H),5.16(dd,J=12.9,5.4Hz,1H),4.13(s,2H),2.96-2.86(m,1H),2.67-2.62(m,1H),2.59-2.55(m,1H),2.14-2.03(m,1H). Chemical formula:C 30 H 21 ClNOS, MS calculated: 601.0; MS found: 601.4 [M+1]+ .

[0632] Example 10 Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzamide (Compound 10) [ka]

[0633] 5-Benzyl-2-aminothiazole (5.3 mg, 0.028 mmol) was dissolved in 2 ml of N,N-dimethylformamide (DMF), and triethylamine (EtN) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.025 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection showed that the starting material had completely reacted. The reaction was quenched by adding 5 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product, N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzamide (Compound 10) (4.3 mg, 30% yield) as a white solid.

[0634] 1H NMR(400MHz,DMSO-d6)δ 12.51(s,1H),11.13(s,1H),8.16(d,J=8.6Hz,2H),7.98(d,J=7.9Hz,1H),7.52(d,J=8.1Hz,2H),7.40-7.18(m,8H),5 .16(dd,J=12.8,5.3Hz,1H),4.12(s,2H),2.95-2.87(m,1H),2.63-2.58(m,1H),2.56-2.53(m,1H),2.10-2.04(m,1H). Chemical formula:C 30 H 22 N4O6S, MS calculated: 566.6; MS found: 567.4 [M+1] + .

[0635] Example 11: Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzamide (Compound 11) [ka]

[0636] Step 1: Synthesis of methyl 5-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate Tert-butyl 4-fluorobenzoate (300 mg, 1.5 mmol), potassium carbonate (427 mg, 3.1 mmol), and methyl 4-fluoro-2-methylbenzoate (260 mg, 1.5 mmol) were dissolved in 10 mL of N,N-dimethylformamide (DMF). The mixture was heated to 100° C., and the reaction was stirred at this temperature for approximately 3 hours. LCMS detection showed that the starting material had disappeared. After the mixture was cooled to room temperature, it was filtered, and the filtrate was diluted by adding 20 mL of water, and extracted and separated by adding ethyl acetate (2×10 mL). The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromatography (ethyl acetate / petroleum ether=1 / 20 to 1 / 10), a yellowish solid, methyl 5-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate (277 mg, yield 53%) was obtained.

[0637] Step 2: Synthesis of methyl 2-(bromomethyl)-5-(4-(tert-butoxycarbonyl)phenoxy)benzoate The intermediate, methyl 5-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate (277 mg, 0.81 mmol) and N-bromosuccinimide (NBS) (217 mg, 1.22 mmol) were dissolved in 10 ml of chloroform and heated to 65° C. Then, a catalytic amount of azobisisobutyronitrile (AIBN) (6 mg) was added, and the reaction was continued at this temperature with stirring for about 4 hours. LCMS detection showed that the starting material had disappeared. The reaction was cooled to room temperature, diluted by adding 15 mL of water to the reaction, and extracted and separated by adding dichloromethane (2×10 mL) to it. The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. After column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10), a yellowish liquid, methyl 2-(bromomethyl)-5-(4-(tert-butoxycarbonyl)phenoxy)benzoate (255 mg, yield 75%) was obtained.

[0638] Step 3: Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoate The intermediate, methyl 2-(bromomethyl)-5-(4-(tert-butoxycarbonyl)phenoxy)benzoate (255 mg, 0.61 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (146 mg, 0.89 mmol) were dissolved in 5 ml of N,N-dimethylformamide (DMF), and diisopropylethylamine (DIEA) (239 mg, 1.85 mmol) was added at room temperature. The mixture was heated to 90° C., and the reaction was stirred at this temperature for about 4 hours. LCMS detection showed that the reaction was complete. The reaction was diluted by adding 10 mL of water, and extracted and separated by adding dichloromethane (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After column chromatography (methanol / dichloromethane=1 / 100 to 1 / 30), an off-white solid, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoate (111 mg, 42% yield) was obtained.

[0639] Step 4: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid The intermediate, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoate (111 mg, 0.25 mmol) was dissolved in 3 ml of dichloromethane, 1 ml of trifluoroacetic acid (TFA) was added at room temperature, and the temperature was raised to 40° C. to initiate the reaction. After about 1 hour of reaction, LCMS detection showed that the starting material had disappeared. The excess trifluoroacetic acid solution and solvent were removed by concentration under reduced pressure to give 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid (106 mg, 95% yield).

[0640] Step 5: Synthesis of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzamide 5-Benzyl-2-aminothiazole (5 mg, 0.026 mmol) was dissolved in 2 ml of N,N-dimethylformamide (DMF), and triethylamine (EtN) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.026 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added successively with stirring at room temperature. After reacting at room temperature for about 1 hour, LCMS detection showed that the starting material had completely reacted. The reaction was quenched by adding 6 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product, N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzamide (Compound 11) (4.5 mg, 31% yield) as a white solid.

[0641] 1H NMR(400MHz,DMSO-d6)δ 12.11(s,1H),10.85(s,1H),8.03-7.98(m,2H),7.80(d,J=8.9Hz,2H),7. 51-7.44(m,2H),7.42-7.32(m,3H),7.23-7.04(m,4H),5.15(dd,J=13.4,5 .1Hz,1H),4.39(d,J=17.2Hz,1H),4.28(d,J=17.2Hz,1H),4.03(s,2H),2. 95-2.85(m,1H),2.61-2.55(m,1H),2.40-2.33(m,1H),2.03-1.97(m,1H). Chemical formula:C 30 H 24 N4O5S, MS calculated: 552.6; MS found: 553.4 [M+1] + .

[0642] Example 12 Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzamide (Compound 12) [ka]

[0643] 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (6 mg, 0.026 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (EtN) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.026 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added successively with stirring at room temperature. After about 1 hour of reaction, LCMS detection indicated that the starting material had completely reacted. The reaction was quenched by adding 6 ml of distilled water to the reaction mixture, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellowish crude concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product, N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzamide (Compound 12) (4.3 mg, 28% yield) as a white solid.

[0644] 1 H NMR(400MHz,DMSO-d6)δ 12.31(s,1H),10.97(s,1H),8.07(d,J=8.9Hz,2H),7.85(s,1H),7.52-7 .45(m,3H),7.43-7.33(m,2H),7.28-7.08(m,4H),5.16(dd,J=13.4,5.1H z,1H),4.40(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),4.05(s,2H),2.9 7-2.86(m,1H),2.62-2.57(m,1H),2.44-2.35(m,1H),2.03-1.97(m,1H). Chemical formula:C 30 H 23ClNOS, MS calculated: 587.0; MS found: 587.4 [M+1] + .

[0645] Example 13 Preparation of N-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzamide (Compound 13) [ka]

[0646] Step 1: Synthesis of tert-butyl (3-aminobenzyl)carbamate 3-(Aminomethyl)aniline (60.0 g, 0.49 mol, 1.0 equiv.) and MeCN (900 mL) were added to a 3 L four-neck flask, and a solution of BocO (107 g, 0.49 mol, 1.0 equiv.) in MeCN (300 mL) was added dropwise. The reaction was stirred at room temperature for 1 h and concentrated to dryness to give the crude product, which was purified by column chromatography (PE / EtOAc = 5:1) to give the product (110 g, 100% yield) as a yellow solid.

[0647] Step 2: Synthesis of (Z)-isonicotinohydrazonamide Isonicotinonitrile (50.0 g, 0.48 mol, 1.0 equiv.), EtOH (120 mL), EtO (120 mL), and 80% hydrazine hydrate (250 mL) were added sequentially to a 1 L single-neck bottle, and the reaction was stirred at 30 °C for 24 h, concentrated to remove most of the ethanol and diethyl ether, stirred in an ice-water bath for 2 h, and filtered. The filter cake was dried under vacuum to give the product (60 g, 91.8% yield) as an off-white solid.

[0648] Step 3: Synthesis of ethyl 3-(2,2,2-trifluoroacetamido)benzoate Ethyl 3-aminobenzoate (83.0 g, 0.50 mol, 1.0 equiv.), THF (1.66 L), and TEA (76.0 g, 0.75 mol, 1.5 equiv.) were added to a 3 L four-neck flask. The reaction was cooled to 0-5°C in an ice-water bath, and TFAA (110.0 g, 0.53 mol, 1.05 equiv.) was added dropwise while maintaining the temperature at <10°C. After the addition was complete, the reaction was stirred at room temperature for 1 hour. The reaction was quenched by adding 1 N HCl (1 L). Water (1 L) and EtOAc (1 L) were added, and the reaction was stirred and then allowed to separate. The organic phase was washed successively with saturated sodium bicarbonate (1 L) and saturated brine (0.5 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the product (120 g, 91.4% yield) as a yellow solid, which was used directly in the next step.

[0649] Step 4: Synthesis of ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate Ethyl 3-(2,2,2-trifluoroacetamido)benzoate (120.0 g, 0.46 mol, 1.0 equiv.), DMF (1.2 L), benzyl bromoacetate (116.0 g, 0.50 mol, 1.1 equiv.), and KCO (95.0 g, 0.69 mol, 1.5 equiv.) were added sequentially to a 3 L single-neck bottle. The reaction was stirred at 25 °C for 16 h. Water (5 L) and EtOAc (2.5 L) were added, and the reaction was stirred and then allowed to separate. The organic phase was washed with saturated brine (1.5 L*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the product (170 g, 90.4% yield) as an off-white solid, which was used directly in the next step.

[0650] Step 5: Synthesis of N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine Ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate (170.0 g, 0.42 mol, 1.0 equiv.), EtOH (2.1 L), and 10% wet Pd / C (34.0 g, 57% water content) were added sequentially into a 5 L four-neck flask. The reaction was stirred under H (15 psi) at 15 °C for 4 h. The reaction was filtered, and the filtrate was concentrated to give the product (132 g, 100% yield) as a slightly yellow, transparent solid, which was used directly in the next step.

[0651] Step 6: Synthesis of ethyl (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine (132.0 g, 0.41 mol, 1.0 equiv), (Z)-isonicotinohydrazonamide (58.0 g, 0.43 mol, 1.04 equiv), DMF (1.4 L), HOBt (59.0 g, 0.44 mol, 1.06 equiv), and EDCI (136.0 g, 0.71 mol, 1.73 equiv) were added sequentially to a 2 L single-neck bottle. The reaction was stirred at 15 °C under N protection for 4 h. The reaction was quenched by pouring into water (6 L) and extracted with EtOAc (7 L). The organic phase was washed with saturated brine (2 L*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 190 g of crude product. The crude product was slurried in EtOAc (760 mL) at 70° C. for 3 h, stirred in an ice-water bath for 2 h, filtered, and the filter cake was dried in vacuo to give the product (118 g, 65.2% yield) as a white solid.

[0652] Step 7: Synthesis of ethyl (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)amino)benzoate (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)-2,2,2-trifluoroacetamido)ethyl benzoate (110.0 g, 0.25 mol, 1.0 equiv.), KCO (104.0 g, 0.75 mol, 3.0 equiv.), and EtOH (2.2 L) were added to a 3 L single-neck bottle. The reaction was stirred at 65 °C for 2 h. The reaction was poured into stirred water (11 L), and a large amount of solid precipitated. The reaction was filtered, and the filter cake was dried under vacuum to give the product (68 g, 79.2% yield) as a white solid, which was used directly in the next step.

[0653] Step 8: Synthesis of ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate Ethyl (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)amino)benzoate (68.0 g, 0.20 mol, 1.0 equiv), EtOH (2.2 L), and AcOH (136 mL) were added sequentially into a 2 L single-neck flask. The reaction was stirred under reflux at 90° C. for 6 hours. The reaction was concentrated to dryness, EtOAc (600 mL) and 1 M sodium carbonate (600 mL) were added, the layers were separated, and the aqueous phase was extracted once more with EtOAc (400 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 60 g of crude product. The crude product was slurried in ethyl acetate (420 mL) at 60° C. for 1 hour, stirred in an ice-water bath for 0.5 hour, filtered, and the filter cake was dried under vacuum to give the product (60.3 g, 98.6% yield) as a white solid.

[0654] Step 9: Synthesis of 3-(((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid Ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (60.0 g, 0.19 mol, 1.0 equiv), EtOH (300 mL), THF (300 mL), and 4 M NaOH (450 mL, 1.8 mol, 9.7 equiv) were added sequentially to a 5 L single-neck flask. The reaction was stirred at 15° C. for 16 hours. Concentrated hydrochloric acid was added to adjust the pH to 4-5. The reaction was concentrated to remove most of the EtOH and THF, stirred in an ice-water bath for 0.5 hours, and filtered. The filter cake was dried in vacuo to give the product (47.0 g, 85.8% yield) as a white solid, which was used directly in the next step.

[0655] Step 10: Synthesis of 2,5-dioxopyrrolidin-1-yl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate 3-(((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid (46.8 g, 0.16 mol, 1.0 equiv), HOSu (20.1 g, 0.17 mol, 1.1 equiv), MeCN (500 mL), and DIC (22.0 g, 0.17 mol, 1.1 equiv) were added sequentially to a 1 L single-neck flask. The reaction was stirred at 15° C. for 4 hours. The reaction was poured into water (2 L). A large amount of solid precipitated. The solid was filtered, and the filter cake was dried under vacuum to give the product (53.7 g, 86.4% yield) as an off-white solid, which was used directly in the next step.

[0656] Step 11: Synthesis of 4-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide 4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.80 g, 6.6 mmol, 1.0 equiv.), THF (36 mL), and 4-bromohexanoyl chloride (3.67 g, 19.8 mmol, 3.0 equiv.) were added sequentially to a 100 mL single-neck flask. The reaction was stirred at 70° C. under N protection for 17 hours. The reaction was concentrated to dryness and purified by column chromatography (DCM / MeOH=60:1) to give the product (2.62 g, 83.7% yield) as a yellow solid.

[0657] Step 12: Synthesis of tert-butyl (3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)amino)benzyl)carbamate 4-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide (0.94 g, 2.22 mmol, 1.0 equiv), MeCN (20 mL), KCO (0.61 g, 4.44 mmol, 2.0 equiv), NaI (0.33 g, 2.22 mmol, 1.0 equiv), and tert-butyl (3-aminobenzyl)carbamate (0.99 g, 4.44 mol, 2.0 equiv) were added sequentially to a 100 mL four-neck flask. The reaction was stirred at 70 °C under N protection for 16 h. The reaction was concentrated to dryness, EtOAc (100 mL) and water (100 mL) were added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product, which was purified by column chromatography (PE / EtOAc=1.3 / 1) to obtain the product (200 mg, 16.0% yield) as a yellow solid.

[0658] Step 13: Synthesis of 4-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide tert-Butyl (3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)amino)benzyl)carbamate (160 mg, 0.28 mmol, 1.0 equiv) and EtOAc (3.5 mL) were added to a 100 mL four-neck flask, and to this was added 3 M HCl / EtOAc (7 mL) with stirring. The reaction was stirred at 15° C. under N protection for 2 hours. The reaction was concentrated to give the product (160 mg, 100% yield) as a brownish-yellow solid, which was used directly in the next step.

[0659] Step 14: Synthesis of N-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzamide 4-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide (160 mg, 0.28 mmol, 1.0 equiv), DMF (5.5 mL), TEA (113 mg, 1.12 mmol, 4.0 equiv), and 2,5-dioxopyrrolidin-1-yl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (110 g, 0.28 mmol, 1.0 equiv) were added sequentially to a 100 mL four-neck flask. The reaction was stirred at 30° C. under N protection for 16 hours. The reaction was poured into 50 mL of water. The mixture was filtered, and the filter cake was dried under vacuum to give the crude product. The product was purified by HPLC to give the product as a yellow solid (50 mg, 24.1% yield).

[0660] Example 14 Preparation of N-(3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzamide (Compound 14) [ka]

[0661] Step 1: Synthesis of tert-butyl (3-aminobenzyl)carbamate 3-(Aminomethyl)aniline (60.0 g, 0.49 mol, 1.0 equiv.) and MeCN (900 mL) were added to a 3 L four-neck flask, and a solution of BocO (107 g, 0.49 mol, 1.0 equiv.) in MeCN (300 mL) was added dropwise. The reaction was stirred at room temperature for 1 h and concentrated to dryness to give the crude product, which was purified by column chromatography (PE / EtOAc = 5:1) to give the product (110 g, 100% yield) as a yellow solid.

[0662] Step 2: Synthesis of (Z)-isonicotinohydrazonamide Isonicotinonitrile (50.0 g, 0.48 mol, 1.0 equiv.), EtOH (120 mL), EtO (120 mL), and 80% hydrazine hydrate (250 mL) were added sequentially to a 1 L single-neck bottle, and the reaction was stirred at 30 °C for 24 h, concentrated to remove most of the ethanol and diethyl ether, stirred in an ice-water bath for 2 h, and filtered. The filter cake was dried under vacuum to give the product (60 g, 91.8% yield) as an off-white solid.

[0663] Step 3: Synthesis of ethyl 3-(2,2,2-trifluoroacetamido)benzoate Ethyl 3-aminobenzoate (83.0 g, 0.50 mol, 1.0 equiv.), THF (1.66 L), and TEA (76.0 g, 0.75 mol, 1.5 equiv.) were added to a 3 L four-neck flask. The reaction was cooled to 0-5°C in an ice-water bath, and TFAA (110.0 g, 0.53 mol, 1.05 equiv.) was added dropwise while maintaining the temperature at <10°C. After the addition was complete, the reaction was stirred at room temperature for 1 hour. The reaction was quenched by adding 1 N HCl (1 L). Water (1 L) and EtOAc (1 L) were added, and the reaction was stirred and then allowed to separate. The organic phase was washed successively with saturated sodium bicarbonate (1 L) and saturated brine (0.5 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the product (120 g, 91.4% yield) as a yellow solid, which was used directly in the next step.

[0664] Step 4: Synthesis of ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate Ethyl 3-(2,2,2-trifluoroacetamido)benzoate (120.0 g, 0.46 mol, 1.0 equiv.), DMF (1.2 L), benzyl bromoacetate (116.0 g, 0.50 mol, 1.1 equiv.), and KCO (95.0 g, 0.69 mol, 1.5 equiv.) were added sequentially to a 3 L single-neck bottle. The reaction was stirred at 25 °C for 16 h. Water (5 L) and EtOAc (2.5 L) were added, and the reaction was stirred and then allowed to separate. The organic phase was washed with saturated brine (1.5 L*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the product (170 g, 90.4% yield) as an off-white solid, which was used directly in the next step.

[0665] Step 5: Synthesis of N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine Ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate (170.0 g, 0.42 mol, 1.0 equiv.), EtOH (2.1 L), and 10% wet Pd / C (34.0 g, 57% water content) were added sequentially into a 5 L four-neck flask. The reaction was stirred under H (15 psi) at 15 °C for 4 h. The reaction was filtered, and the filtrate was concentrated to give the product (132 g, 100% yield) as a slightly yellow, transparent solid, which was used directly in the next step.

[0666] Step 6: Synthesis of ethyl (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine (132.0 g, 0.41 mol, 1.0 equiv), (Z)-isonicotinohydrazonamide (58.0 g, 0.43 mol, 1.04 equiv), DMF (1.4 L), HOBt (59.0 g, 0.44 mol, 1.06 equiv), and EDCI (136.0 g, 0.71 mol, 1.73 equiv) were added sequentially to a 2 L single-neck bottle. The reaction was stirred at 15 °C under N protection for 4 h. The reaction was quenched by pouring into water (6 L) and extracted with EtOAc (7 L). The organic phase was washed with saturated brine (2 L*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 190 g of crude product. The crude product was slurried in EtOAc (760 mL) at 70° C. for 3 h, stirred in an ice-water bath for 2 h, filtered, and the filter cake was dried in vacuo to give the product (118 g, 65.2% yield) as a white solid.

[0667] Step 7: Synthesis of ethyl (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)amino)benzoate (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)-2,2,2-trifluoroacetamido)ethyl benzoate (110.0 g, 0.25 mol, 1.0 equiv.), KCO (104.0 g, 0.75 mol, 3.0 equiv.), and EtOH (2.2 L) were added to a 3 L single-neck bottle. The reaction was stirred at 65 °C for 2 h. The reaction was poured into stirred water (11 L), and a large amount of solid precipitated. The reaction was filtered, and the filter cake was dried under vacuum to give the product (68 g, 79.2% yield) as a white solid, which was used directly in the next step.

[0668] Step 8: Synthesis of ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate Ethyl (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)amino)benzoate (68.0 g, 0.20 mol, 1.0 equiv), EtOH (2.2 L), and AcOH (136 mL) were added sequentially into a 2 L single-neck flask. The reaction was stirred under reflux at 90° C. for 6 hours. The reaction was concentrated to dryness, EtOAc (600 mL) and 1 M sodium carbonate (600 mL) were added, the layers were separated, and the aqueous phase was extracted once more with EtOAc (400 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 60 g of crude product. The crude product was slurried in ethyl acetate (420 mL) at 60° C. for 1 hour, stirred in an ice-water bath for 0.5 hour, filtered, and the filter cake was dried under vacuum to give the product (60.3 g, 98.6% yield) as a white solid.

[0669] Step 9: Synthesis of 3-(((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid Ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (60.0 g, 0.19 mol, 1.0 equiv), EtOH (300 mL), THF (300 mL), and 4 M NaOH (450 mL, 1.8 mol, 9.7 equiv) were added sequentially to a 5 L single-neck flask. The reaction was stirred at 15° C. for 16 hours. Concentrated hydrochloric acid was added to adjust the pH to 4-5. The reaction was concentrated to remove most of the EtOH and THF, stirred in an ice-water bath for 0.5 hours, and filtered. The filter cake was dried in vacuo to give the product (47.0 g, 85.8% yield) as a white solid, which was used directly in the next step.

[0670] Step 10: Synthesis of 2,5-dioxopyrrolidin-1-yl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate 3-(((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid (46.8 g, 0.16 mol, 1.0 equiv), HOSu (20.1 g, 0.17 mol, 1.1 equiv), MeCN (500 mL), and DIC (22.0 g, 0.17 mol, 1.1 equiv) were added sequentially to a 1 L single-neck flask. The reaction was stirred at 15° C. for 4 hours. The reaction was poured into water (2 L). A large amount of solid precipitated. The solid was filtered, and the filter cake was dried under vacuum to give the product (53.7 g, 86.4% yield) as an off-white solid, which was used directly in the next step. Step 11: Synthesis of 6-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide

[0671] 4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (100.0 g, 0.37 mol, 1.0 equiv.), THF (2 L), and 6-bromohexanoyl chloride (218 g, 1.02 mol, 2.8 equiv.) were added sequentially to a 3 L single-neck flask. The reaction was stirred at 70 °C under N protection for 6 hours. The reaction was concentrated to dryness and purified by column chromatography (DCM / MeOH = 100:1) to give the product (162 g, 98.9% yield) as a yellow solid.

[0672] Step 12: Synthesis of tert-butyl (3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)amino)benzyl)carbamate 6-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide (76.0 g, 0.17 mol, 1.0 equiv.), MeCN (1.5 L), KCO (46.6 g, 0.34 mol, 2.0 equiv.), NaI (25.4 g, 0.17 mol, 2.0 equiv.), and tert-butyl (3-aminobenzyl)carbamate (75.0 g, 0.34 mol, 2.0 equiv.) were added sequentially to a 3 L four-neck flask. The reaction was stirred at 70° C. under N protection for 48 hours. The reaction was concentrated to dryness, and EtOAc (3 L) and water (3 L) were added. The liquid was separated, and the organic phase was concentrated to dryness to give 280 g of crude product, which was purified by column (DCM / EtOAc=1 / 0.3) to give the product as a yellow solid (65 g, yield 65.1%).

[0673] Step 13: Synthesis of 6-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide tert-Butyl (3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)amino)benzyl)carbamate (60.0 g, 0.10 mol, 1.0 equiv.) and EtOAc (600 mL) were added to a 2 L four-neck flask, and 3 M HCl / EtOAc (600 mL) was added under stirring. The reaction was stirred at 15° C. under N protection for 2 hours. The reaction was filtered, and the filter cake was dried under vacuum to give the product (51.7 g, 90.3% yield) as a gray-black solid.

[0674] Step 14: Synthesis of N-(3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzamide 6-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide (51.7 g, 91.6 mmol, 1.0 equiv.), DMF (520 mL), TEA (37.1 g, 0.37 mol, 4.0 equiv.), and 2,5-dioxopyrrolidin-1-yl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (36.0 g, 91.6 mmol, 1.0 equiv.) were added sequentially to a 2 L four-neck flask. The reaction was stirred under N protection at 30° C. for 16 hours. The reaction mixture was poured into 2.5 L of water, filtered, and the filter cake was dried under vacuum to obtain 70 g of crude product. The product was purified by column chromatography (DCM / MeOH=20 / 1) to obtain the product (43.0 g, yield 61.1%) as a yellowish solid.

[0675] Example 15 Preparation of N-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanamido)benzyl)-3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzamide (Compound 15) [ka]

[0676] Step 1: Synthesis of tert-butyl (3-aminobenzyl)carbamate 3-(Aminomethyl)aniline (60.0 g, 0.49 mol, 1.0 equiv.) and MeCN (900 mL) were added to a 3 L four-neck flask, and a solution of BocO (107 g, 0.49 mol, 1.0 equiv.) in MeCN (300 mL) was added dropwise. The reaction was stirred at room temperature for 1 h and concentrated to dryness to give the crude product, which was purified by column chromatography (PE / EtOAc = 5:1) to give the product (110 g, 100% yield) as a yellow solid.

[0677] Step 2: Synthesis of (Z)-isonicotinohydrazonamide Isonicotinonitrile (50.0 g, 0.48 mol, 1.0 equiv.), EtOH (120 mL), EtO (120 mL), and 80% hydrazine hydrate (250 mL) were added sequentially to a 1 L single-neck bottle, and the reaction was stirred at 30 °C for 24 h, concentrated to remove most of the ethanol and diethyl ether, stirred in an ice-water bath for 2 h, and filtered. The filter cake was dried under vacuum to give the product (60 g, 91.8% yield) as an off-white solid.

[0678] Step 3: Synthesis of ethyl 3-(2,2,2-trifluoroacetamido)benzoate Ethyl 3-aminobenzoate (83.0 g, 0.50 mol, 1.0 equiv.), THF (1.66 L), and TEA (76.0 g, 0.75 mol, 1.5 equiv.) were added to a 3 L four-neck flask. The reaction was cooled to 0-5°C in an ice-water bath, and TFAA (110.0 g, 0.53 mol, 1.05 equiv.) was added dropwise while maintaining the temperature at <10°C. After the addition was complete, the reaction was stirred at room temperature for 1 hour. The reaction was quenched by adding 1 N HCl (1 L). Water (1 L) and EtOAc (1 L) were added, and the reaction was stirred and then allowed to separate. The organic phase was washed successively with saturated sodium bicarbonate (1 L) and saturated brine (0.5 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the product (120 g, 91.4% yield) as a yellow solid, which was used directly in the next step.

[0679] Step 4: Synthesis of ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate Ethyl 3-(2,2,2-trifluoroacetamido)benzoate (120.0 g, 0.46 mol, 1.0 equiv.), DMF (1.2 L), benzyl bromoacetate (116.0 g, 0.50 mol, 1.1 equiv.), and KCO (95.0 g, 0.69 mol, 1.5 equiv.) were added sequentially to a 3 L single-neck bottle. The reaction was stirred at 25 °C for 16 h. Water (5 L) and EtOAc (2.5 L) were added, and the reaction was stirred and then allowed to separate. The organic phase was washed with saturated brine (1.5 L*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the product (170 g, 90.4% yield) as an off-white solid, which was used directly in the next step.

[0680] Step 5: Synthesis of N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine Ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate (170.0 g, 0.42 mol, 1.0 equiv.), EtOH (2.1 L), and 10% wet Pd / C (34.0 g, 57% water content) were added sequentially into a 5 L four-neck flask. The reaction was stirred under H (15 psi) at 15 °C for 4 h. The reaction was filtered, and the filtrate was concentrated to give the product (132 g, 100% yield) as a slightly yellow, transparent solid, which was used directly in the next step.

[0681] Step 6: Synthesis of ethyl (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine (132.0 g, 0.41 mol, 1.0 equiv), (Z)-isonicotinohydrazonamide (58.0 g, 0.43 mol, 1.04 equiv), DMF (1.4 L), HOBt (59.0 g, 0.44 mol, 1.06 equiv), and EDCI (136.0 g, 0.71 mol, 1.73 equiv) were added sequentially to a 2 L single-neck bottle. The reaction was stirred at 15 °C under N protection for 4 h. The reaction was quenched by pouring into water (6 L) and extracted with EtOAc (7 L). The organic phase was washed with saturated brine (2 L*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 190 g of crude product. The crude product was slurried in EtOAc (760 mL) at 70° C. for 3 h, stirred in an ice-water bath for 2 h, filtered, and the filter cake was dried in vacuo to give the product (118 g, 65.2% yield) as a white solid.

[0682] Step 7: Synthesis of ethyl (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)amino)benzoate (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)-2,2,2-trifluoroacetamido)ethyl benzoate (110.0 g, 0.25 mol, 1.0 equiv.), KCO (104.0 g, 0.75 mol, 3.0 equiv.), and EtOH (2.2 L) were added to a 3 L single-neck bottle. The reaction was stirred at 65 °C for 2 h. The reaction was poured into stirred water (11 L), and a large amount of solid precipitated. The reaction was filtered, and the filter cake was dried under vacuum to give the product (68 g, 79.2% yield) as a white solid, which was used directly in the next step.

[0683] Step 8: Synthesis of ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate Ethyl (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazinyl)-2-oxoethyl)amino)benzoate (68.0 g, 0.20 mol, 1.0 equiv), EtOH (2.2 L), and AcOH (136 mL) were added sequentially into a 2 L single-neck flask. The reaction was stirred under reflux at 90° C. for 6 hours. The reaction was concentrated to dryness, EtOAc (600 mL) and 1 M sodium carbonate (600 mL) were added, the layers were separated, and the aqueous phase was extracted once more with EtOAc (400 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 60 g of crude product. The crude product was slurried in ethyl acetate (420 mL) at 60° C. for 1 hour, stirred in an ice-water bath for 0.5 hour, filtered, and the filter cake was dried under vacuum to give the product (60.3 g, 98.6% yield) as a white solid.

[0684] Step 9: Synthesis of 3-(((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid Ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (60.0 g, 0.19 mol, 1.0 equiv), EtOH (300 mL), THF (300 mL), and 4 M NaOH (450 mL, 1.8 mol, 9.7 equiv) were added sequentially to a 5 L single-neck flask. The reaction was stirred at 15° C. for 16 hours. Concentrated hydrochloric acid was added to adjust the pH to 4-5. The reaction was concentrated to remove most of the EtOH and THF, stirred in an ice-water bath for 0.5 hours, and filtered. The filter cake was dried in vacuo to give the product (47.0 g, 85.8% yield) as a white solid, which was used directly in the next step.

[0685] Step 10: Synthesis of 2,5-dioxopyrrolidin-1-yl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate 3-(((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid (46.8 g, 0.16 mol, 1.0 equiv), HOSu (20.1 g, 0.17 mol, 1.1 equiv), MeCN (500 mL), and DIC (22.0 g, 0.17 mol, 1.1 equiv) were added sequentially to a 1 L single-neck flask. The reaction was stirred at 15° C. for 4 hours. The reaction was poured into water (2 L). A large amount of solid precipitated. The solid was filtered, and the filter cake was dried under vacuum to give the product (53.7 g, 86.4% yield) as an off-white solid, which was used directly in the next step.

[0686] Step 11: Synthesis of 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanoic acid 4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (855 mg, 3.13 mmol, 1.0 equiv.), THF (8.5 mL), and 5-oxyazelaic anhydride (1.62 g, 9.39 mmol, 3.0 equiv.) were added sequentially to a 50 mL single-neck flask. The reaction was stirred at 70° C. under N protection for 17 hours. The reaction was concentrated to dryness and purified by column chromatography (DCM / MeOH=120:1) to give the product (75 mg, 5.4% yield) as a yellow solid.

[0687] Step 12: Synthesis of tert-butyl (3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanamido)benzyl)carbamate 4-(4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanoic acid (75 mg, 0.17 mmol, 1.0 equiv), MeCN (3 mL), tert-butyl (3-aminobenzyl)carbamate (38 mg, 0.17 mmol, 1.0 equiv), DIEA (44 mg, 0.34 mmol, 2.0 equiv), and HATU (96 mg, 0.25 mmol, 1.5 equiv) were added sequentially to a 10 mL thumb flask. The reaction was stirred under N protection at 15° C. for 2 hours. The reaction was concentrated to dryness, EtOAc (50 mL) and water (50 mL) were added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product. The crude product was purified by column (DCM / MeOH=20 / 1) to give the product (95 mg, yield 87.0%) as a yellow solid.

[0688] Step 13: N-(3-((λ 2 Synthesis of (4-azaneil)methyl)phenyl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanamide tert-Butyl (3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanamido)benzyl)carbamate (95 mg, 0.15 mmol, 1.0 equiv) and EtOAc (4 mL) were added to a 10 mL thumb flask, and 3 M HCl / EtOAc (4 mL) was added with stirring. The reaction was stirred at 15° C. under N protection for 2 hours. The reaction was concentrated to give the product (85 mg, 93.2% yield) as a brownish-yellow solid, which was used directly in the next step.

[0689] Step 14: Synthesis of N-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutoxy)butanamido)benzyl)-3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzamide N-(3-((λ 2 To a 10 mL Sam's flask were added sequentially 2,5-dioxopyrrolidin-1-yl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate (54 g, 0.14 mmol, 1.0 equiv.). The reaction was stirred at 30° C. for 16 hours under N2 protection. The reaction was poured into 50 mL of water, filtered, and the filter cake was dried under vacuum to give the crude product. The product was purified by HPLC to give the product as a yellow solid (14 mg, 12.4% yield).

[0690] Example 16: Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzamide (Compound 16) [ka]

[0691] To a solution of 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzoic acid (15 mg, 0.04 mmol, commercially available from Chengdu Fendi Pharmaceutical Co. Ltd.) and 5-benzyl-2-aminothiazole (7.5 mg, 0.04 mmol) in DMF (3 mL) was added TEA (6 mg, 0.06 mmol) and HATU (18 mg, 0.048 mmol). The solution was stirred at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with DCM (5 mL × 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzamide (4.4 mg, 20%) as a white solid.

[0692] 1 H NMR(400MHz,DMSO-d6)δ 12.09(s,1H),10.83(s,1H),8.03-7.98(m,2H),7.81-7.79(m,2H),7.43-7.4 1(m,2H),7.42-7.39(m,1H),7.36-7.32(m,2H),7.23-7.04(m,4H),5.15(dd,J =13.4,5.1Hz,1H),4.39(d,J=17.2Hz,1H),4.28(d,J=17.2Hz,1H),4.03(s,2H),3.96 (s,2H),2.95-2.85(m,1H),2.61-2.55(m,1H),2.40-2.33(m,1H),2.03-1.97(m,1H). Chemical formula:C 31 H 26N4O4S, MS calculated: 550.6; MS found: 551.4 [M+1] + .

[0693] Example 17 Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzamide (Compound 17) [ka]

[0694] To 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzoic acid (20 mg, 0.053 mmol, commercially available from Chengdu Fendi Pharmaceutical Co. Ltd.) and 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (11.9 mg, 0.053 mmol) in DMF (3 mL) was added TEA (8 mg, 0.079 mmol) and HATU (18 mg, 0.048 mmol). The solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the residue, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzamide (4.9 mg, 16%) as a white solid.

[0695] 1H NMR(400MHz,DMSO-d6)δ 12.23(s,1H),10.95(s,1H),8.03-7.98(m,1H),7.85-7.83(m,2H),7.51-7.49(m,2H),7.42-7.39(m,1H),7.36-7.32(m,2H),7.29-7.25(m,2) H),7.15-7.12(m,2H),5.15(dd,J =13.4,5.1Hz,1H),4.39(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),4.05(s,2H),3.96 (s,2H),2.92-2.89(m,1H),2.61-2.55(m,1H),2.40-2.36(m,1H),2.03-1.97(m,1H). Chemical formula:C 31 H 25 ClN4O4S, MS calculated: 585.1; MS found: 585.3 [M+1] + .

[0696] Example 18: Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)benzamide (Compound 18) [ka]

[0697] To a mixture of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)benzoic acid (20 mg, 0.051 mmol, commercially available from Chengdu Fendi Pharmaceutical Co. Ltd.) and 5-benzyl-2-aminothiazole (9.7 mg, 0.051 mmol) in DMF (3 mL) was added TEA (7.7 mg, 0.077 mmol) and HATU (21.4 mg, 0.056 mmol). The solution was stirred at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)benzamide (4.9 mg, 17%) as a white solid.

[0698] 1 H NMR(400MHz,DMSO-d6)δ 12.42(s,1H),11.12(s,1H),8.02-7.95(m,2H),7.90-7.83(m,2H),7.79(dd,J=7.6,1.5 Hz,1H),7.47(d,J=1.7Hz,1H),7.45(d,J=1.8Hz,1H),7.35-7.31(m,2H),7.31-7.29(m, 2H),7.29-7.26(m,1H),7.25-7.19(m,1H),5.13(dd,J=12.8,5.4Hz,1H),4.25(s,2H),4 .11(s,2H),2.93-2.83(m,1H),2.62-2.55(m,1H),2.47-2.41(m,1H),2.07-2.00(m,1H). Chemical formula:C 31 H 24 N4O5S, MS calculated: 564.6; MS found: 565.5 [M+1] + .

[0699] Example 19: Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)benzamide (Compound 19) [ka]

[0700] To a mixture of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)benzoic acid (20 mg, 0.051 mmol, commercially available from Chengdu Fendi Pharmaceutical Co. Ltd.) and 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine (11.4 mg, 0.051 mmol) in DMF (3 mL) was added TEA (7.7 mg, 0.077 mmol) and HATU (21.4 mg, 0.056 mmol). The solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the residue, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)benzamide (4.6 mg, 16%) as a white solid.

[0701] 1H NMR(400MHz,DMSO-d6)δ 12.28(s,1H),11.00(s,1H),8.04-7.98(m,2H),7.94-7.90(m,1H),7.87-7.83( m,1H),7.73-7.71(m,1H),7.54(d,J=1.4Hz,2H),7.30-7.27(m,1H),7.27-7.22( m,2H),7.16-7.07(m,2H),5.11(dd,J=13.3,5.0Hz,1H),4.06(s,2H),3.85(s,2 H),2.95-2.86(m,1H),2.63-2.55(m,1H),2.47-2.32(m,1H),2.03-1.94(m,1H). Chemical formula:C 31 H 23 ClNOS, MS calculated: 599.1; MS found: 599.4 [M+1] + .

[0702] Example 20 Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(phenylcarbonothioyl)thiazol-2-yl)acetamide (Compound 20) [ka]

[0703] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (15 mg, 0.05 mmol) and (2-aminothiazol-5-yl)(phenyl)methanethione (10.9 mg, 0.05 mmol, commercially available from Chengdu Fendi Pharmaceutical Co., Ltd.) in DMF (3 mL) solution, TEA (8 mg, 0.08 mmol) and HATU (21 mg, 0.055 mmol) were added. The solution was stirred at room temperature for 5 hours. Water (20 mL) was added, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over NaSO, concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH / DCM=1 / 100 to 1 / 30) to give the product, 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(phenylcarbonothioyl)thiazol-2-yl)acetamide (5 mg, 20%) as a green solid.

[0704] 1 H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),11.00(s,1H),7.85(s,1H),7.74(d,J=1.3Hz,1H),7.68(d,J=1.2Hz,1H) ,7.66(d,J=1.5Hz,1H),7.61(d,J=7.4Hz,1H),7.59(d,J=1.3Hz,2H),7.48(t,J=7.7Hz ,2H),5.12(dd,J=13.3,5.0Hz,1H),4.46(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),4. 00(s,2H),2.92-2.87(m,1H),2.64-2.57(m,1H),2.43-2.34(m,1H),2.04-1.97(m,1H). Chemical formula:C 25 H 20 N4O4S2, MS calculated: 504.6; MS found: 505.5 [M+1] + .

[0705] Example 21: Preparation of N-(5-benzoylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (Compound 21) [ka]

[0706] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (20 mg, 0.066 mmol) and (2-aminothiazol-5-yl)(phenyl)methanone (13.5 mg, 0.066 mmol, commercially available from Chengdu Fendi Pharmaceutical Co., Ltd.) in DMF (3 mL) was added TEA (10 mg, 0.099 mmol) and HATU (27.7 mg, 0.073 mmol). The solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the residue, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, N-(5-benzoylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (4.8 mg, 15%) as a white solid.

[0707] 1 H NMR(400MHz,DMSO-d6)δ 12.98(s,1H),11.01(s,1H),8.11(s,1H),7.85(t,J=1.3Hz,1H),7.86-7.84(m,1H), 7.74(d,J=1.2Hz,1H),7.72-7.64(m,1H),7.59(t,J=2.0Hz,2H),7.59-7.53(m,2H), 5.12(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.99( s,2H),2.98-2.84(m,1H),2.64-2.56(m,1H),2.45-2.34(m,1H),2.04-1.97(m,1H). Chemical formula:C 25 H20 N4O5S, MS calculated: 488.5; MS found: 489.2 [M+1] + .

[0708] Example 22: Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(phenylamino)thiazol-2-yl)acetamide (Compound 22) [ka]

[0709] 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (30.2 mg, 0.1 mmol) and N 5 N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (33.6 mg, 0.12 mmol) was added to 1-methylimidazole (24.6 mg, 0.3 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (33.6 mg, 0.12 mmol). The solution was stirred at 80°C for 3 hours. Water (20 mL) was then added, and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over NaSO and concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH / DCM=1 / 100 to 1 / 30) and preparative HPLC to give the product, 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(phenylamino)thiazol-2-yl)acetamide (4.9 mg, 10%) as a white solid.

[0710] 1H NMR (400 MHz, DMSO-d6) δ 12.22(s,1H),11.00(s,1H),8.12(s,1H),7.72(d,J=1.3Hz,1H),7.57(d,J=1. 2Hz,2H),7.21-7.10(m,3H),6.86-6.76(m,2H),6.75-6.68(m,1H),5.11(dd,J =13.3,5.1Hz,1H),4.44(d,J=17.3Hz,1H),4.31(d,J=17.2Hz,1H),3.87(s,2H) ),2.96-2.86(m,1H),2.63-2.56(m,1H),2.44-2.34(m,1H),2.04-1.95(m,1H). Chemical formula:C 24 H 21 N5O4S, MS calculated: 475.5; MS found: 476.3 [M+1] + .

[0711] Example 23 Preparation of N-(5-(1H-indol-3-yl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (Compound 23) [ka]

[0712] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (20 mg, 0.066 mmol) and 5-(1H-indol-3-yl)thiazol-2-amine (10.7 mg, 0.05 mmol, commercially available from Chengdu Fendi Pharmaceutical Co., Ltd.) in DMF (3 mL) was added 1-methylimidazole (16.3 mg, 0.198 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (22.3 mg, 0.079 mmol). The solution was stirred at 80°C for 3 hours. Water (20 mL) was added to the residue, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, N-(5-(1H-indol-3-yl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetamide (5.9 mg, 18%) as a white solid.

[0713] 1 H NMR(400MHz,DMSO-d6)δ 12.36(s,1H),11.43(s,1H),11.00(s,1H),7.79(d,J=7.9Hz,1H),7.75(s,1H),7.71- 7.64(m,2H),7.64-7.55(m,2H),7.46-7.40(m,1H),7.19-7.14(m,1H),7.12-7.08(m,1 H),5.12(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.2Hz,1H),3.9 2(s,2H),2.96-2.86(m,1H),2.63-2.56(m,1H),2.44-2.35(m,1H),2.05-1.96(m,1H). Chemical formula:C 26 H 21 N5O4S, MS calculated: 499.5; MS found: 500.3 [M+1] + .

[0714] Example 24 Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(naphthalen-1-yl)thiazol-2-yl)acetamide (Compound 24) [ka]

[0715] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (20 mg, 0.066 mmol) and 5-(naphthalen-1-yl)thiazol-2-amine (15 mg, 0.066 mmol, commercially available from Chengdu Fendi Pharmaceutical Co., Ltd.) in DMF (3 mL) was added 1-methylimidazole (16.3 mg, 0.198 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (22.3 mg, 0.079 mmol). The solution was stirred at 80°C for 3 hours. Water (20 mL) was added to the residue, and the mixture was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give the product, 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(naphthalen-1-yl)thiazol-2-yl)acetamide (5.7 mg, 17%) as a white solid.

[0716] 1H NMR (400 MHz, DMSO-d6) δ 12.58(s,1H),11.00(s,1H),8.15-8.08(m,1H),8.02-7.95(m,2H),7.76(s ,1H),7.67(s,1H),7.63-7.59(m,2H),7.59-7.53(m,4H),5.12(dd,J=13.3, 5.1Hz,1H),4.45(d,J=17.3Hz,1H),4.32(d,J=17.3Hz,1H),3.96(s,2H),2 .96-2.86(m,1H),2.64-2.55(m,1H),2.45-2.35(m,1H),2.04-1.97(m,1H...

Claims

1. Formula (1): 【Transformation 136】 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, During the ceremony, GBM is a GRK2 binding moiety; A compound, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, wherein DT is a degradation tag with E3 ligase binding ability.

2. The compound of claim 1 , wherein the GBM is a moiety derived from a polyanionic compound and a polycationic compound.

3. 3. The compound of claim 2, wherein the polyanionic and polycationic compounds are selected from heparin and dextran sulfate.

4. 2. The compound of claim 1, wherein the GBM is a moiety derived from balanol, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

5. The GBM is 【Chemistry 137】 10. The compound of claim 1, which is a moiety derived from a Takeda inhibitor selected from:

6. The GBM is 【Chemistry 138】 10. The compound of claim 1, which is a moiety from the paroxetine series selected from:

7. the GBM is a moiety derived from the indazole or dihydropyrimidine series represented by formula (2), or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof; 【Chemistry 139】 During the ceremony, R is, [Chemical 140] is selected from R' is selected from H and halogen; and R'' is 【Chemistry 141】 2. The compound of claim 1 selected from: 【Chemistry 142】 ．

8. The GBM is represented by formula (3), 【Chemistry 143】 wherein * indicates the point of attachment to the DT; wherein said Formula I is a moiety covalently linked to said Formula II, said Formula I containing a thiazole or triazole ring in its backbone and having the ability to bind to GRK2 by itself or together with said Formula II; and 2. The compound of claim 1, wherein said Formula II is a moiety covalently bonded to both said Formula I and said DT, said Formula II comprising an acyclic or cyclic saturated or unsaturated carbon, an ethylene glycol group, an amide group, an ester group, an amino group, an oxy group, a thio group, an ether group, a urea group, a carbamate group, an aromatic group, a heteroaromatic group, a heterocyclic group, a carbonyl group, or a combination thereof.

9. wherein the formula I is represented by formula (4): 【Chemistry 144】 During the ceremony, ◆ indicates the point of attachment to formula II; Q is optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ and Cy; Cy is aryl, C ３－１２ selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R'; L Ａ is a bond, -(CH ２ ) ａ C (R １ ) (R ２ ) (CH ２ ) ｂ -, -N(R １ )-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O) ２ - selected from; R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, represent optionally substituted C ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

10. Q is optionally substituted C １－６ Alkyl, -OR ａ , -SR ａ , -NR ｂ R ｃ and Cy.

11. Q is C １－６ Alkyl, -SR ａ 10. The compound of claim 9, wherein the compound is selected from:

12. 10. The compound of claim 9, wherein Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

13. 10. The compound of claim 9, wherein Q is selected from isopropyl, isopropylthio, and Cy.

14. 10. The compound of claim 9, wherein Q is Cy.

15. Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ 10. The compound of claim 9, wherein the heteroaryl is selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

16. Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazolyl, 10. The compound of claim 9, wherein R is selected from cinnolinyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with one, two, three, or more R'.

17. 10. The compound of claim 9, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

18. 10. The compound of claim 9, wherein Cy is phenyl optionally substituted with 1, 2, 3, or more R'.

19. Q is, 【Chemistry 145】 10. The compound of claim 9 selected from:

20. Q is, 【Chemistry 146】 10. The compound of claim 9 selected from:

21. L Ａ is a bond, -C(R １ ) (R ２ ) -, -N(R １ 10. The compound of claim 9, wherein the group is selected from —O—, —S—, —C(═O)—, and —C(═S)—.

22. L Ａ is a bond, -CH ２ -, -CF2-, -CCl ２ --, --CBr ２ 10. The compound of claim 9, wherein the compound is selected from -, -CFCl-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

23. L Ａ is a bond, -CH ２ -, -CF ２ 10. The compound of claim 9, wherein the group is selected from -, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

24. L Ａ But -CH ２ The compound according to claim 9, wherein

25. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 10. The compound of claim 9 selected from:

26. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 10. The compound of claim 9 selected from:

27. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 10. The compound of claim 9 selected from:

28. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 10. The compound of claim 9 selected from:

29. 10. The compound of claim 9, wherein R is selected from H and —OH.

30. 10. The compound of claim 9, wherein R is H.

31. R １ and R ２ each independently selected from H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 10. The compound of claim 9 selected from:

32. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 10. The compound of claim 9 selected from:

33. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 10. The compound of claim 9 selected from:

34. R １ and R ２ 10. The compound of claim 9, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

35. R １ and R ２ 10. The compound of claim 9, wherein each of is independently selected from H and F.

36. R １ and R ２ and R are H.

37. R １ and R ２ and R are F.

38. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 10. The compound of claim 9 selected from:

39. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ 10. The compound of claim 9 selected from:

40. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 10. The compound of claim 9, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

41. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 10. The compound of claim 9, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

42. 10. The compound of claim 9, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

43. 10. The compound of claim 9, wherein R' is Cl.

44. Each R ａ are independently H and C １－６ 10. The compound of claim 9, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

45. Each R ａ 10. The compound of claim 9, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

46. Each R ａ 10. The compound of claim 9, wherein is independently H or isopropyl.

47. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 10. The compound of claim 9, wherein the aryl group is selected from cycloalkyl.

48. R ｂ and R ｃ 10. The compound of claim 9, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

49. R ｂ is H and R ｃ is cyclopropyl, or R ｂ is cyclopropyl, and R ｃ The compound of claim 9 , wherein is H.

50. Each R ｄ are independently H and C １－６ 10. The compound of claim 9, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

51. Each R ｄ 10. The compound of claim 9, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

52. Each R ｄ 10. The compound of claim 9, wherein is independently H or methyl.

53. 10. The compound of claim 9, wherein a is selected from 0 and 1, and b is selected from 0 and 1.

54. 10. The compound of claim 9, wherein a is 0 and b is 0.

55. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 10. The compound of claim 9, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

56. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 10. The compound of claim 9, wherein the compound is optionally substituted with one, two, or three substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

57. 10. The compound of claim 9, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

58. wherein the formula I is represented by formula (4A): 【Chemistry 147】 During the ceremony, ◆ indicates the point of attachment to formula II; R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, represent optionally substituted C ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Cy is aryl, C ３－１２ selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R'; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

59. R １ and R ２ each independently selected from H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 59. The compound of claim 58, selected from:

60. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 59. The compound of claim 58, selected from:

61. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 59. The compound of claim 58, selected from:

62. R １ and R ２ 59. The compound of claim 58, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

63. R １ and R ２ 59. The compound of claim 58, wherein each of is independently selected from H and F.

64. R １ and R ２ and R are H.

65. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 59. The compound of claim 58, selected from:

66. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 59. The compound of claim 58, selected from:

67. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 59. The compound of claim 58, selected from:

68. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 59. The compound of claim 58, selected from:

69. 59. The compound of claim 58, wherein R is selected from H and —OH.

70. 59. The compound of claim 58, wherein R is H.

71. Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ 59. The compound of claim 58, wherein the heteroaryl is selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

72. Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazolyl, 59. The compound of claim 58, wherein R is selected from nyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with one, two, three, or more R'.

73. 59. The compound of claim 58, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

74. 59. The compound of claim 58, wherein Cy is phenyl optionally substituted with 1, 2, 3, or more R'.

75. Cy is, 【Chemistry 148】 59. The compound of claim 58, selected from:

76. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 59. The compound of claim 58, selected from:

77. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ 59. The compound of claim 58, selected from:

78. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 59. The compound of claim 58, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

79. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 59. The compound of claim 58, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

80. 59. The compound of claim 58, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

81. 59. The compound of claim 58, wherein R' is Cl.

82. Each R ａ are independently H and C １－６ 59. The compound of claim 58, wherein the alkyl is selected from alkyl.

83. Each R ａ 59. The compound of claim 58, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

84. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 59. The compound of claim 58, wherein the aryl group is selected from cycloalkyl.

85. R ｂ and R ｃ 59. The compound of claim 58, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

86. Each R ｄ are independently H and C １－６ 59. The compound of claim 58, wherein the alkyl is selected from alkyl.

87. Each R ｄ 59. The compound of claim 58, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

88. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 59. The compound of claim 58, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

89. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 59. The compound of claim 58, wherein the compound is optionally substituted with one, two, or three substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

90. 59. The compound of claim 58, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

91. wherein the formula I is represented by formula (4B): 【Chemistry 149】 During the ceremony, 59. The compound of claim 58, wherein m is selected from 0, 1, 2, 3, 4, and 5.

92. 92. The compound of claim 91, wherein m is selected from 0, 1, and 2.

93. 92. The compound of claim 91, wherein m is 0 or 1.

94. wherein the formula I is represented by formula (5): [Chemical 150] During the ceremony, ◆ indicates the point of attachment to formula II; R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １Ａ and R ２Ａ Or R １Ｂ and R ２Ｂ taken together with the atoms to which they are attached, ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R ３Ａ , R ３Ｂ , and R ３Ｃ each independently being H, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —C(═O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , optionally substituted aryl, optionally substituted C ３－１２ selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; D １ , D ２ , D ３ , D ４ , and D ５ each independently represents N or CR ４Ａ and E １ , E ２ , E ３ , and E ４ each independently represents N or CR ４Ｂ and F １ , F ２ , F ３ , and F ４ each independently represents N or CR ４Ｃ and R ４Ａ , R ４Ｂ , and R ４Ｃ each independently represents H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

95. R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 95. The compound of claim 94, selected from:

96. R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ each independently represents H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 95. The compound of claim 94, selected from:

97. R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 95. The compound of claim 94, selected from:

98. R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ 95. The compound of claim 94, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

99. R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ 95. The compound of claim 94, wherein each of is independently selected from H and F.

100. R １Ａ , R ２Ａ , R １Ｂ , and R ２Ｂ 95. The compound of claim 94, wherein each of is independently H.

101. R ３Ａ , R ３Ｂ , and R ３Ｃ each independently being H, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ alkenyl, and optionally substituted C ２－６ 95. The compound of claim 94, selected from alkynyl.

102. R ３Ａ , R ３Ｂ , and R ３Ｃ each independently represents a C optionally substituted with H, 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, and C optionally substituted with 1, 2, or 3 halogens ２－６ 95. The compound of claim 94, selected from alkynyl.

103. R ３Ａ , R ３Ｂ , and R ３Ｃ 95. The compound of claim 94, wherein each of is independently selected from H, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, and propyl optionally substituted with 1, 2, or 3 halogens.

104. R ３Ａ , R ３Ｂ , and R ３Ｃ 95. The compound of claim 94, wherein each of is independently selected from H, methyl, ethyl, and propyl.

105. R ３Ａ , R ３Ｂ , and R ３Ｃ 95. The compound of claim 94, wherein each of: is independently selected from H.

106. D １ , D ２ , D ３ , D ４ , and D ５ At least one of them is N and the others are CR Ａ 95. The compound of claim 94, wherein:

107. D １ , D ２ , D ３ , D ４ , and D ５ One of them is N and the others are CR Ａ 95. The compound of claim 94, wherein:

108. D ３ is N and the others are CR ４Ａ 95. The compound of claim 94, wherein:

109. E １ , E ２ , E ３ , and E ４ Each of the above may independently be a CR ４Ｂ 95. The compound of claim 94, wherein:

110. F １ , F ２ , F ３ , and F ４ Each of the above may independently be a CR ４Ｃ 95. The compound of claim 94, wherein:

111. R ４Ａ , R ４Ｂ , and R ４Ｃ each independently represents H, a halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 95. The compound of claim 94, selected from:

112. R ４Ａ , R ４Ｂ , and R ４Ｃ each independently represents H, a halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 95. The compound of claim 94, selected from:

113. R ４Ａ , R ４Ｂ , and R ４Ｃ each independently represents H, a halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 95. The compound of claim 94, selected from:

114. R ４Ａ , R ４Ｂ and R ４Ｃ each independently represents H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 95. The compound of claim 94, selected from:

115. R ４Ａ , R ４Ｂ , and R ４Ｃ 95. The compound of claim 94, wherein each of is independently H.

116. Each R ａ are independently H and C １－６ 95. The compound of claim 94, wherein the alkyl is selected from:

117. Each R ａ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

118. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 95. The compound of claim 94, wherein the aryl group is selected from cycloalkyl.

119. R ｂ and R ｃ 95. The compound of claim 94, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

120. Each R ｄ are independently H and C １－６ 95. The compound of claim 94, wherein the alkyl is selected from:

121. Each R ｄ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

122. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 95. The compound of claim 94, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

123. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 95. The compound of claim 94, wherein the group is optionally substituted with one, two, or three substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

124. 95. The compound of claim 94, wherein the term "optionally substituted" before a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

125. The formula I is represented by formula (5A): 【Chemistry 151】 95. The compound of claim 94, represented by (5A).

126. The formula I is formula (5B): 【Chemistry 152】 95. The compound of claim 94, represented by (5B):

127. The formula I is formula (5C): 【Chemistry 153】 95. The compound of claim 94, represented by (5C):

128. 9. The compound of claim 8, wherein said Formula II comprises an amide or ester group.

129. wherein the formula II is represented by formula (6): 【Chemistry 154】 During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, A, T, and B, in each occurrence, are independently selected from null, —C(═O)—, —C(═O)O—, and —C(═O)NR １ -, -C(=S)NR １ -, -O-, -S-, -S(=O)-, -S(=O) ２ -, -S(=O) ２ NR １ -, -NR １ -, -NR １ C(=O)-, -NR １ C(=O)NR ２ -, -NR １ C(=S)-, optionally substituted C １ -C ８ Alkyl, optionally substituted C １ -C ８ Alkoxy, optionally substituted C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted C １ -C ８ Haloalkyl, optionally substituted C １ -C ８ Hydroxyalkyl, optionally substituted C ２ -C ８ Alkenyl, optionally substituted C ２ -C ８ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ３ -C ８ Cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ３ -C １３ fused cycloalkyl, optionally substituted C ３ -C １３ fused heterocyclyl, optionally substituted C ３ -C １３ Bridged cycloalkyl, optionally substituted C ３ -C １３ Bridged heterocyclyl, optionally substituted C ３ -C １３ Spirocycloalkyl, and optionally substituted C ３ -C １３ spiroheterocyclyl, wherein R １ and R ２ are independently hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, and optionally substituted C １ -C ６ Alkylamino C １ -C ６ alkyl, The compound of claim 8, wherein p is 0 to 15.

130. wherein the formula II is represented by formula (6A): 【Chemistry 155】 During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, R １ , R ２ , R ３ , and R ４ is independently in each occurrence hydrogen, halogen, —CN, —OH, —NH ２ , optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, and optionally substituted C １ -C ６ Alkylamino C １ -C ６ alkyl, A, T, and B, in each occurrence, are independently selected from null, —C(═O)—, —C(═O)O—, and —C(═O)NR ５ -, -C(=S)NR ５ -, -O-, -S-, -S(=O)-, -S(=O) ２ -, -S(=O) ２ NR ５ -, -NR ５ -, -NR ５ C(=O)-, -NR ５ C(=O)NR ６ -, -NR ５ C(=S)-, optionally substituted C １ -C ８ Alkyl, optionally substituted C １ -C ８ Alkoxy, optionally substituted C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted C １ -C ８ Haloalkyl, optionally substituted C １ -C ８ Hydroxyalkyl, optionally substituted C ２ -C ８ Alkenyl, optionally substituted C ２ -C ８ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ３ -C ８ Cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ３ -C １３ fused cycloalkyl, optionally substituted C ３ -C １３ fused heterocyclyl, optionally substituted C ３ -C １３ Bridged cycloalkyl, optionally substituted C ３ -C １３ Bridged heterocyclyl, optionally substituted C ３ -C １３ Spirocycloalkyl, and optionally substituted C ３ -C １３ spiroheterocyclyl, wherein R ５ and R ６ are independently hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, and optionally substituted C １ -C ６ Alkylamino C １ -C ６ alkyl, p is 0 to 15; each q is 0 to 15, and The compound of claim 8, wherein o is 0 to 15.

131. wherein the formula II is represented by formula (6B): 【Chemistry 156】 During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, Each R １ , and each R ２ are independently hydrogen, halogen, —CN, —OH, —NH ２ and optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, or C １ -C ６ Alkylamino C １ -C ６ alkyl, Each A and each B independently represent null, —C(═O)—, —C(═O)O—, or —C(═O)NR ３ -, -C(=S)NR ３ -, -O-, -S-, -S(=O)-, -S(=O) ２ NR ３ -, -NR ３ -, -NR ３ C(=O)-, -NR ３ C(=O)NR ４ -, -NR ３ C(=S)- and optionally substituted C １ -C ８ Alkyl, optionally substituted C １ -C ８ Alkoxy, optionally substituted C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted C １ -C ８ Haloalkyl, optionally substituted C １ -C ８ Hydroxyalkyl, optionally substituted C ２ -C ８ Alkenyl, optionally substituted C ２ -C ８ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ３ -C ８ Cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ３ -C １３ fused cycloalkyl, optionally substituted C ３ -C １３ fused heterocyclyl, optionally substituted C ３ -C １３ Bridged cycloalkyl, optionally substituted C ３ -C １３ Bridged heterocyclyl, optionally substituted C ３ -C １３ spirocycloalkyl, or C ３ -C １３ spiroheterocyclyl, wherein R ３ and R ４ are independently hydrogen and optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, or C １ -C ６ Alkylamino C １ -C ６ alkyl, each p is 0 to 15, and The compound of claim 8, wherein q is 0 to 15.

132. wherein the formula II is represented by formula (6C): 【Chemistry 157】 During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, X is —O—, —NH, and —NR ７ - is selected from, R １ , R ２ , R ３ , R ４ , R ５ , and R ６ is independently in each occurrence hydrogen, halogen, —CN, —OH, —NH ２ , optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, and optionally substituted C １ -C ６ Alkylamino C １ -C ６ alkyl, A and B, in each occurrence, are independently null, —C(═O)—, —C(═O)O—, or —C(═O)NR ７ -, -C(=S)NR ７ -, -O-, -S-, -S(=O)-, -S(=O) ２ -, -S(=O) ２ NR ７ -, -NR ７ -, -NR ７ C(=O)-, -NR ７ C(=O)NR ８ -, -NR ７ C(=S)-, optionally substituted C １ -C ８ Alkyl, optionally substituted C １ -C ８ Alkoxy, optionally substituted C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted C １ -C ８ Haloalkyl, optionally substituted C １ -C ８ Hydroxyalkyl, optionally substituted C ２ -C ８ Alkenyl, optionally substituted C ２ -C ８ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ３ -C ８ Cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ３ -C １３ fused cycloalkyl, optionally substituted C ３ -C １３ fused heterocyclyl, optionally substituted C ３ -C １３ Bridged cycloalkyl, optionally substituted C ３ -C １３ Bridged heterocyclyl, optionally substituted C ３ -C １３ Spirocycloalkyl, and optionally substituted C ３ -C １３ spiroheterocyclyl, wherein R ７ and R ８ are independently hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ３ -C ６ Cycloalkoxy, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C １ -C ６ Alkoxyalkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C １ -C ６ alkylamino, and optionally substituted C １ -C ６ Alkylamino C １ -C ６ alkyl, each p is 0 to 15; each q is 0 to 15; o is 0 to 15, and The compound of claim 8, wherein r is 0 to 15.

133. wherein the formula II is represented by formula (7A): 【Chemistry 158】 wherein * indicates the point of attachment to formula I; # indicates the connection point with DT, A is C １－２０ Alkylene, —O—, —S—, —N(R ｅ )-, and -N(R ｅ )-C １－２０ alkylene-, optionally selected from C １－２０ One, two, three, or more methylenes in the alkylene group may independently be —O—, —S—, —N(R ｅ )—, —C(═O)—, and —C(═S)—; B is a bond or arylene, C ３－１２ and 3- to 12-membered heterocyclylene, each of which is selected from halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ optionally substituted with one, two, three or more substituents selected from the group consisting of Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; R ｅ is H and optionally substituted C １－６ alkyl; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

134. A is C １－８ Alkylene, —O—, —NH—, —N(CH ３ ) -, -N(C ２ H ５ )-, -NH-C １－８ alkylene, and optionally C １－８ 134. The compound of claim 133, wherein one, two, three, or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-.

135. A is -CH ２ -, -O-, -NH-, -NH-(CH ２ ) ３ -, -NH-(CH ２ ) ５ -, and -NH-C(=O)-(CH ２ ) ３ -O-(CH ２ ) ３ - The compound of claim 133, wherein the compound is selected from the group consisting of:

136. A is -CH ２ 134. The compound of claim 133, wherein the group is selected from -, -O-, and -NH-.

137. 134. The compound of claim 133, wherein A is -NH-.

138. B is selected from a bond, or arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- or 6-membered heteroarylene, each of which is selected from halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 134. The compound of claim 133, optionally substituted with one, two, three, or more substituents selected from the group consisting of:

139. 134. The compound of claim 133, wherein B is a bond or is selected from phenylene, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyranylene, pyrazinylene, pyrimidinylene, pyrazinylene, triazolylene, tetrazolylene, and triazinylene, each of which is optionally substituted with one, two, three, or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and propyl.

140. 134. The compound of claim 133, wherein B is a bond or phenylene optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, and Br.

141. 134. The compound of claim 133, wherein B is a bond or phenylene.

142. Each R ａ are independently H and C １－６ 134. The compound of claim 133, wherein the alkyl is selected from alkyl.

143. Each R ａ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

144. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 134. The compound of claim 133, wherein said alkyl is selected from cycloalkyl.

145. R ｂ and R ｃ 134. The compound of claim 133, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

146. R ｅ is H.

147. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 134. The compound of claim 133, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

148. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 134. The compound of claim 133, wherein the group is optionally substituted with one, two, or three substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

149. 134. The compound of claim 133, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

150. Formula (7A) is 【Chemistry 159】 134. The compound of claim 133, wherein the moiety is selected from:

151. Formula (7A) is [Chemical 160] 134. The compound of claim 133, wherein the moiety is selected from:

152. wherein the formula II is represented by formula (7B): 【Chemistry 161】 During the ceremony, * indicates the point of attachment to Formula I; # indicates the connection point with DT, 【Chemistry 162】 is a single bond or a double bond, R'' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; e is 0 or 1; f is selected from 0, 1, 2, and 3; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

153. 【Chemical 163】 is a single bond.

154. 【Chemistry 164】 is a double bond.

155. R'' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 153. The compound of claim 152, selected from:

156. R'' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 153. The compound of claim 152, selected from:

157. R'' is halogen, -CN, -NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 153. The compound of claim 152, selected from:

158. R″ is F, Cl, Br, methyl, ethyl, propyl, —OH, and —NH ２ 153. The compound of claim 152, selected from:

159. 153. The compound of claim 152, wherein e is 0.

160. 153. The compound of claim 152, wherein e is 1.

161. 153. The compound of claim 152, wherein f is 0.

162. Formula (7B) is 【Chemistry 165】 153. The compound of claim 152, wherein the moiety is selected from:

163. The compound of claim 1, wherein the DT has the ability to bind to an E3 ligase for recruitment of the corresponding ubiquitination machinery to GRK2, leading to subsequent degradation of GRK2 in or near the proteasome and / or loss of function of GRK2.

164. 2. The compound of claim 1, wherein the DT is selected from the group consisting of a cereblon ligand, a VHL ligand, an MDM2 ligand, a TRIM24 ligand, a TRIM21 ligand, a KEAP1 ligand, an RNF114 ligand, an IAP ligand, a DCAF16 ligand, a DCAF15 ligand, a FEM1B ligand, and a ligand of the aryl hydrocarbon receptor.

165. DT is a moiety represented by formula (8A), (8B), (8C), or (8D), 【Chemistry 166】 During the ceremony, 【Chemical 235】 indicates the point of attachment to Formula II, U is independently —CH ２ -, -NH-, and -O-; V and W are each independently —C(═O)— and —CH ２ - is selected from, Each of X, Y, and Z is independently CR ６ and N; R ５ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, R ６ is selected from H, halogen, and optionally substituted C １ -C ６ 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

166. U is -CH ２ The compound of claim 165, wherein

167. 166. The compound of claim 165, wherein U is -O-.

168. 166. The compound of claim 165, wherein U is -NH-.

169. V is —C(═O)— and W is —CH ２ The compound of claim 165, wherein

170. V is -CH ２ - and W is -C(=O)-.

171. 166. The compound of claim 165, wherein both V and W are -C(=O)-.

172. Each of X, Y, and Z is independently CR ６ 166. The compound of claim 165, selected from:

173. R ５ 166. The compound of claim 165, wherein is selected from H, F, Cl, and Br.

174. R ５ The compound of claim 165, wherein is H.

175. R ６ 166. The compound of claim 165, wherein is selected from H, F, Cl, and Br.

176. R ６ is H or F.

177. The DT is 【Chemistry 167】 166. The compound of claim 165, wherein the moiety is selected from:

178. DT is a moiety represented by formula (9), 【Chemical 168】 During the ceremony, 【Chemistry 236】 indicates the point of attachment to Formula II, R １ and R ２ are independently hydrogen, optionally substituted C １ -C ８ Alkyl, optionally substituted C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted C １ -C ８ Haloalkyl, optionally substituted C １ -C ８ Hydroxyalkyl, optionally substituted C １ -C ８ Aminoalkyl, optionally substituted C １ -C ８ Alkylamino C １ -C ８ Alkyl, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C ２ -C ８ alkenyl, and optionally substituted C ２ -C ８ alkynyl, R ３ is hydrogen, optionally substituted —C(═O)C １ -C ８ Alkyl, optionally substituted —C(═O)C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted —C(═O)C １ -C ８ Haloalkyl, optionally substituted —C(═O)C １ -C ８ Hydroxyalkyl, optionally substituted —C(═O)C １ -C ８ aminoalkyl, optionally substituted —C(═O)C １ -C ８ Alkylamino C １ -C ８ Alkyl, optionally substituted —C(═O)C ３ -C ７ Cycloalkyl, optionally substituted —C(═O)(3- to 7-membered heterocyclyl), optionally substituted —C(═O)C ２ -C ８ Alkenyl, optionally substituted —C(═O)C ２ -C ８ Alkynyl, optionally substituted —C(═O)OC １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted -C(=O)OC １ -C ８ Haloalkyl, optionally substituted —C(═O)OC １ -C ８ Hydroxyalkyl, optionally substituted —C(═O)OC １ -C ８ aminoalkyl, optionally substituted —C(═O)OC １ -C ８ Alkylamino C １ -C ８ Alkyl, optionally substituted -C(=O)OC ３ -C ７ Cycloalkyl, optionally substituted —C(═O)O(3- to 7-membered heterocyclyl), optionally substituted —C(═O)OC ２ -C ８ Alkenyl, optionally substituted -C(=O)OC ２ -C ８ Alkynyl, optionally substituted —C(═O)NC １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted —C(═O)NC １ -C ８ Haloalkyl, optionally substituted —C(═O)NC １ -C ８ Hydroxyalkyl, optionally substituted —C(═O)NC １ -C ８ Aminoalkyl, optionally substituted —C(═O)NC １ -C ８ Alkylamino C １ -C ８ Alkyl, optionally substituted —C(═O)NC ３ -C ７ Cycloalkyl, optionally substituted —C(═O)N(3- to 7-membered heterocyclyl), optionally substituted —C(═O)NC ２ -C ８ Alkenyl, optionally substituted —C(═O)NC ２ -C ８ Alkynyl, optionally substituted -P(=O)(OH) ２ , optionally substituted -P(=O)(OC １ -C ８ alkyl) ２ and optionally substituted —P(═O)(OC １ -C ８ aryl) ２ 2. The compound of claim 1, wherein:

179. DT is a moiety represented by formula (10), 【Chemistry 169】 During the ceremony, 【Chemistry 237】 indicates the point of attachment to Formula II, V, W, X, and Z are independently CR ４ and N; R １ , R ２ , R ３ , and R ４ are independently hydrogen, optionally substituted C １ -C ８ Alkyl, optionally substituted C １ -C ８ Alkoxy C １ -C ８ Alkyl, optionally substituted C １ -C ８ Haloalkyl, optionally substituted C １ -C ８ Hydroxyalkyl, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C ２ -C ８ alkenyl, and optionally substituted C ２ -C ８ The compound of claim 1 selected from alkynyl.

180. The DT is: 【Chemistry 170】 2. The compound of claim 1, which is a moiety derived from any of thalidomide.

181. 2. The compound of claim 1, wherein the DT is selected from the group consisting of: 【Chemistry 171】 【Chemistry 172】 【Chemistry 173-1】 【Chemistry 173-2】 【Chemistry 173-3】

182. The compound is represented by formula (11): 【Chemistry 174】 During the ceremony, A is C １－２０ Alkylene, —O—, —S—, —N(R ｅ )-, and -N(R ｅ )-C １－２０ alkylene-, optionally selected from C １－２０ One, two, three, or more methylenes in the alkylene group may independently be —O—, —S—, —N(R ｅ )—, —C(═O)—, and —C(═S)—; B is a bond or arylene, C ３－１２ and 3- to 12-membered heterocyclylene, each of which is selected from halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ optionally substituted with one, two, three or more substituents selected from the group consisting of U is independently —CH ２ -, -NH-, and -O-; V and W are each independently —C(═O)— and —CH ２ - is selected from, Each of X, Y, and Z is independently CR ６ and N; R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Cy is aryl, C ３－１２ selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R'; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R ５ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, R ６ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｅ is H and optionally substituted C １－６ alkyl; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 10. The compound of claim 1, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

183. A is C １－８ Alkylene, —O—, —NH—, —N(CH ３ ) -, -N(C ２ H ５ )-, -NH-C １－８ alkylene, and optionally C １－８ 183. The compound of claim 182, wherein one, two, three, or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-.

184. A is -CH ２ -, -O-, -NH-, -NH-(CH ２ ) ３ -, -NH-(CH ２ ) ５ -, and -NH-C(=O)-(CH ２ ) ３ -O-(CH ２ ) ３ - The compound of claim 182, wherein the compound is selected from the group consisting of:

185. A is -CH ２ 183. The compound of claim 182, wherein the group is selected from -, -O-, and -NH-.

186. 183. The compound of claim 182, wherein A is -NH-.

187. B is selected from a bond, or arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- or 6-membered heteroarylene, each of which is selected from halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 183. The compound of claim 182, optionally substituted with one, two, three, or more substituents selected from the group consisting of:

188. 183. The compound of claim 182, wherein B is a bond or is selected from phenylene, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyranylene, pyrazinylene, pyrimidinylene, pyrazinylene, triazolylene, tetrazolylene, and triazinylene, each of which is optionally substituted with one, two, three, or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and propyl.

189. 183. The compound of claim 182, wherein B is a bond or phenylene optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, and Br.

190. 183. The compound of claim 182, wherein B is a bond or phenylene. 【Request 191】 【Chemistry 175】 but, 【Chemistry 176】 183. The compound of claim 182, wherein the moiety is selected from: 【Request 192】 【Chemistry 177】 but, 【Chemistry 178】 183. The compound of claim 182, wherein the moiety is selected from:

193. U is -CH ２ - The compound of claim 182.

194. 183. The compound of claim 182, wherein U is -O-.

195. 183. The compound of claim 182, wherein U is -NH-.

196. V is —C(═O)— and W is —CH ２ - The compound of claim 182.

197. V is -CH ２ - and W is -C(=O)-.

198. 183. The compound of claim 182, wherein both V and W are -C(=O)-.

199. Each of X, Y, and Z is independently CR ６ 183. The compound of claim 182, selected from: [Request Item 200] [Chemistry 179] but, 【Transformation 180】 183. The compound of claim 182, wherein the moiety is selected from:

201. R １ and R ２ each independently selected from H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 183. The compound of claim 182, selected from:

202. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 183. The compound of claim 182, selected from:

203. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 183. The compound of claim 182, selected from:

204. R １ and R ２ 183. The compound of claim 182, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

205. R １ and R ２ 183. The compound of claim 182, wherein each of is independently selected from H and F.

206. R １ and R ２ and R are H.

207. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 183. The compound of claim 182, selected from:

208. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 183. The compound of claim 182, selected from:

209. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 183. The compound of claim 182, selected from:

210. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 183. The compound of claim 182, selected from:

211. 183. The compound of claim 182, wherein R is selected from H and -OH.

212. 183. The compound of claim 182, wherein R is H.

213. Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ 183. The compound of claim 182, wherein the heteroaryl is selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

214. Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazolyl, 183. The compound of claim 182, wherein R is selected from nyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted by one, two, three, or more R'.

215. 183. The compound of claim 182, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

216. 183. The compound of claim 182, wherein Cy is phenyl optionally substituted with 1, 2, 3, or more R'.

217. Cy is, 【Chemistry 181】 183. The compound of claim 182, selected from:

218. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 183. The compound of claim 182, selected from:

219. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ 183. The compound of claim 182, selected from:

220. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 183. The compound of claim 182, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

221. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 183. The compound of claim 182, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

222. 183. The compound of claim 182, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

223. 183. The compound of claim 182, wherein R' is Cl.

224. R ５ 183. The compound of claim 182, wherein is selected from H, F, Cl, and Br.

225. R ５ The compound of claim 182, wherein is H.

226. R ６ 183. The compound of claim 182, wherein is selected from H, F, Cl, and Br.

227. R ６ is H or F.

228. Each R ａ are independently H and C １－６ 183. The compound of claim 182, wherein the alkyl is selected from alkyl.

229. Each R ａ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

230. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 183. The compound of claim 182, wherein said aryl is selected from cycloalkyl.

231. R ｂ and R ｃ 183. The compound of claim 182, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

232. Each R ｄ are independently H and C １－６ 183. The compound of claim 182, wherein the alkyl is selected from alkyl.

233. Each R ｄ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

234. R ｅ The compound of claim 182, wherein is H.

235. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 183. The compound of claim 182, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

236. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 183. The compound of claim 182, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

237. 183. The compound of claim 182, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

238. the compound is represented by formula (12A), (12B), (12C), (12D), (12E), or (12F); 【Chemistry 182】 【Chemistry 183】 【Chemistry 184】 【Chemistry 185】 【Chemical 186】 【Chemistry 187】 R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R ５ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, R ６ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is not substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ cycloalkyl; Ph represents phenylene; and 2. The compound of claim 1, wherein m is selected from 0, 1, 2, 3, 4, and 5.

239. R １ and R ２ each independently selected from H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 239. The compound of claim 238, selected from:

240. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 239. The compound of claim 238, selected from:

241. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 239. The compound of claim 238, selected from:

242. R １ and R ２ 239. The compound of claim 238, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

243. R １ and R ２ 239. The compound of claim 238, wherein each of is independently selected from H and F.

244. R １ and R ２ and R are H.

245. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 239. The compound of claim 238, selected from:

246. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 239. The compound of claim 238, selected from:

247. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 239. The compound of claim 238, selected from:

248. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 239. The compound of claim 238, selected from:

249. 239. The compound of claim 238, wherein R is selected from H and -OH.

250. 239. The compound of claim 238, wherein R is H.

251. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 239. The compound of claim 238, selected from:

252. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ 239. The compound of claim 238, selected from:

253. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 239. The compound of claim 238, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

254. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 239. The compound of claim 238, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

255. 239. The compound of claim 238, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

256. 239. The compound of claim 238, wherein R' is Cl.

257. R ５ 239. The compound of claim 238, wherein is selected from H, F, Cl, and Br.

258. R ５ The compound of claim 238, wherein is H.

259. R ６ 239. The compound of claim 238, wherein is selected from H, F, Cl, and Br.

260. R ６ is H or F.

261. Each R ａ are independently H and C １－６ The compound of claim 238, wherein the alkyl is selected from alkyl.

262. Each R ａ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

263. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 239. The compound of claim 238, wherein said alkyl is selected from cycloalkyl.

264. R ｂ and R ｃ 239. The compound of claim 238, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

265. Each R ｄ are independently H and C １－６ The compound of claim 238, wherein the alkyl is selected from alkyl.

266. Each R ｄ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

267. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 239. The compound of claim 238, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

268. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 239. The compound of claim 238, wherein the group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

269. 239. The compound of claim 238, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

270. Ph is, 【Chemical 188】 The compound of claim 238, wherein

271. 239. The compound of claim 238, wherein m is selected from 0, 1, and 2.

272. 239. The compound of claim 238, wherein m is 0 or 1.

273. The compound is 【Chemistry 189-1】 【Chemistry 189-2】 【Chemistry 189-3】 and 【Chemistry 189-4】 2. The compound of claim 1 selected from the group consisting of:

274. The compound is 【Chemistry 190】 2. The compound of claim 1 selected from the group consisting of:

275. wherein the formula I is represented by formula (13): 【Chemistry 191】 During the ceremony, ◆ indicates the point of attachment to formula II; 【Chemistry 192】 each is independently a single bond or a double bond; Q is optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ and Cy; Cy is aryl, C ３－１２ selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R'; L Ａ is a bond, -(CH ２ ) ａ C (R １ ) (R ２ ) (CH ２ ) ｂ -, -N(R １ )-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O) ２ - selected from; X １ , X ２ , and X ３ are each independently selected from CR, S, or N; However, X １ , X ２ , and X ３ At least one of X is N, １ , X ２ , and X ３ is S, R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

276. Q is optionally substituted C １－６ Alkyl, -OR ａ , -SR ａ , -NR ｂ R ｃ and Cy.

277. Q is C １－６ Alkyl, -SR ａ 276. The compound of claim 275, wherein said compound is selected from:

278. 276. The compound of claim 275, wherein Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

279. 276. The compound of claim 275, wherein Q is selected from isopropyl, isopropylthio, and Cy.

280. 276. The compound of claim 275, wherein Q is Cy.

281. Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ 276. The compound of claim 275, wherein the heteroaryl is selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

282. Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazolyl, 276. The compound of claim 275, wherein R is selected from nyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with one, two, three, or more R'.

283. 276. The compound of claim 275, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

284. 276. The compound of claim 275, wherein Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R'.

285. Q is, 【Chemistry 193】 276. The compound of claim 275, selected from:

286. Q is, 【Chemistry 194】 276. The compound of claim 275, selected from:

287. L Ａ is a bond, -C(R １ ) (R ２ ) -, -N(R １ 276. The compound of claim 275, wherein the group is selected from -O-, -S-, -C(=O)-, and -C(=S)-.

288. L Ａ is a bond, -CH ２ -, -CF2-, -CCl ２ --, --CBr ２ 276. The compound of claim 275, wherein the compound is selected from -, -CFCl-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

289. L Ａ is a bond, -CH ２ -, -CF ２ 276. The compound of claim 275, wherein the group is selected from -, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

290. L Ａ But -CH ２ The compound of claim 275, wherein

291. X １ is CR or N.

292. X ２ is S or N.

293. X ３ is S or N.

294. 【Chemistry 195】 but, 【Chemistry 196】 276. The compound of claim 275, selected from:

295. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 276. The compound of claim 275, selected from:

296. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 276. The compound of claim 275, selected from:

297. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 276. The compound of claim 275, selected from:

298. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 276. The compound of claim 275, selected from:

299. 276. The compound of claim 275, wherein R is selected from H, methyl, and -OH.

300. 276. The compound of claim 275, wherein R is H.

301. R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 276. The compound of claim 275, selected from:

302. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 276. The compound of claim 275, selected from:

303. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 276. The compound of claim 275, selected from:

304. R １ and R ２ 276. The compound of claim 275, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

305. R １ and R ２ 276. The compound of claim 275, wherein each of is independently selected from H and F.

306. R １ and R ２ and R are H.

307. R １ and R ２ and R are F.

308. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 276. The compound of claim 275, selected from:

309. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ 276. The compound of claim 275, selected from:

310. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 276. The compound of claim 275, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

311. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 276. The compound of claim 275, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

312. 276. The compound of claim 275, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

313. 276. The compound of claim 275, wherein R' is Cl or F.

314. Each R ａ are independently H and C １－６ 276. The compound of claim 275, wherein said alkyl is selected from:

315. Each R ａ 276. The compound of claim 275, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

316. Each R ａ is independently H or isopropyl.

317. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 276. The compound of claim 275, wherein said compound is selected from cycloalkyl.

318. R ｂ and R ｃ 276. The compound of claim 275, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

319. R ｂ is H and R ｃ is cyclopropyl, or R ｂ is cyclopropyl, and R ｃ The compound of claim 275, wherein is H.

320. Each R ｄ are independently H and C １－６ 276. The compound of claim 275, wherein said alkyl is selected from:

321. Each R ｄ 276. The compound of claim 275, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

322. Each R ｄ is independently H or methyl.

323. 276. The compound of claim 275, wherein a is selected from 0 and 1, and b is selected from 0 and 1.

324. The compound of claim 275, wherein a is 0 and b is 0.

325. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 276. The compound of claim 275, wherein said compound is optionally substituted with one, two, or three substituents selected from the group consisting of cycloalkyl.

326. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 276. The compound of claim 275, wherein the compound is optionally substituted with one, two, or three substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

327. 276. The compound of claim 275, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

328. wherein said formula I is represented by formula (14A), (14B), or (14C): 【Chemistry 197】 【Chemistry 198】 【Chemistry 199】 During the ceremony, ◆ indicates the point of attachment to formula II; R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Q is optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ and Cy; Cy is aryl, C ３～１２ selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R'; L Ａ is a bond, -(CH ２ ) ａ C (R １ ) (R ２ ) (CH ２ ) ｂ -, -N(R １ )-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O) ２ - selected from; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 9. The compound of claim 8, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

329. R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ The compound of claim 328, selected from:

330. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ The compound of claim 328, selected from:

331. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ The compound of claim 328, selected from:

332. R １ and R ２ 329. The compound of claim 328, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

333. R １ and R ２ 329. The compound of claim 328, wherein each of is independently selected from H and F.

334. R １ and R ２ and R are H.

335. R １ and R ２ and R are F.

336. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ The compound of claim 328, selected from:

337. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ The compound of claim 328, selected from:

338. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ The compound of claim 328, selected from:

339. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ The compound of claim 328, selected from:

340. 329. The compound of claim 328, wherein R is selected from H, methyl, and -OH.

341. 329. The compound of claim 328, wherein R is H.

342. Q is optionally substituted C １－６ Alkyl, -OR ａ , -SR ａ , -NR ｂ R ｃ and Cy.

343. Q is C １－６ Alkyl, -SR ａ 329. The compound of claim 328, wherein said compound is selected from:

344. 329. The compound of claim 328, wherein Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

345. 329. The compound of claim 328, wherein Q is selected from isopropyl, isopropylthio, and Cy.

346. 329. The compound of claim 328, wherein Q is Cy.

347. Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ 329. The compound of claim 328, wherein the heteroaryl is selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

348. Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazolyl, 329. The compound of claim 328, wherein R is selected from nyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with one, two, three, or more R'.

349. 329. The compound of claim 328, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

350. 329. The compound of claim 328, wherein Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R'.

351. Q is, 【Chemistry 200】 The compound of claim 328, selected from:

352. Q is, 【Chemical Engineering 201】 The compound of claim 328, selected from:

353. L Ａ is a bond, -C(R １ ) (R ２ ) -, -N(R １ 329. The compound of claim 328, wherein the group is selected from —O—, —S—, —C(═O)—, and —C(═S)—.

354. L Ａ is a bond, -CH ２ -, -CF2-, -CCl ２ --, --CBr ２ 329. The compound of claim 328, wherein the compound is selected from -, -CFCl-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

355. L Ａ is a bond, -CH ２ -, -CF ２ 329. The compound of claim 328, wherein the group is selected from -, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

356. L Ａ But -CH ２ The compound of claim 328, wherein:

357. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ The compound of claim 328, selected from:

358. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ The compound of claim 328, selected from:

359. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 329. The compound of claim 328, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

360. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 329. The compound of claim 328, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

361. 329. The compound of claim 328, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

362. 329. The compound of claim 328, wherein R' is Cl or F.

363. Each R ａ are independently H and C １－６ The compound of claim 328, wherein the alkyl is selected from alkyl.

364. Each R ａ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

365. Each R ａ is independently H or isopropyl.

366. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 329. The compound of claim 328, wherein said compound is selected from cycloalkyl.

367. R ｂ and R ｃ 329. The compound of claim 328, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

368. R ｂ is H and R ｃ is cyclopropyl, or R ｂ is cyclopropyl, and R ｃ The compound of claim 328, wherein is H.

369. Each R ｄ are independently H and C １－６ The compound of claim 328, wherein the alkyl is selected from alkyl.

370. Each R ｄ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

371. Each R ｄ is independently H or methyl.

372. 329. The compound of claim 328, wherein a is selected from 0 and 1, and b is selected from 0 and 1.

373. The compound of claim 328, wherein a is 0 and b is 0.

374. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 329. The compound of claim 328, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

375. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ , cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

376. 329. The compound of claim 328, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

377. DT is a moiety represented by formula (15A), (15B), (15C), or (15D), 【Chemical Engineering 202】 During the ceremony, 【Chemical 238】 indicates the point of attachment to Formula II, U is independently a bond, —CH ２ -, -NH-, and -O-; V and W are each independently —C(═O)— and —CH ２ - is selected from, Each of X, Y, and Z is independently CR ６ and N; R ５ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, R ６ is selected from H, halogen, and optionally substituted C １ -C ６ 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

378. 378. The compound of claim 377, wherein U is a bond.

379. U is -CH ２ The compound of claim 377, wherein:

380. V is —C(═O)— and W is —CH ２ The compound of claim 377, wherein:

381. V is -CH ２ - and W is -C(=O)-.

382. 378. The compound of claim 377, wherein both V and W are -C(=O)-.

383. Each of X, Y, and Z is independently CR ６ The compound of claim 377, selected from:

384. R ５ 378. The compound of claim 377, wherein is selected from H, F, Cl, and Br.

385. R ５ The compound of claim 377, wherein is H.

386. R ６ 378. The compound of claim 377, wherein is selected from H, F, Cl, and Br.

387. R ６ is H or F.

388. The DT is 【Chemical 203】 The compound of claim 377, wherein the moiety is selected from:

389. The DT is 【Chemical 204】 The compound of claim 377, wherein the moiety is selected from:

390. The compound is represented by formula (16A) or (16B): 【Chemical 205】 During the ceremony, 【Chemical 206】 each is independently a single bond or a double bond; Q is optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ and Cy; Cy is aryl, C ３－１２ selected from carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R'; L Ａ is a bond, -(CH ２ ) ａ C (R １ ) (R ２ ) (CH ２ ) ｂ -, -N(R １ )-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O) ２ - selected from; X １ , X ２ , and X ３ are each independently selected from CR, S, or N; However, X １ , X ２ , and X ３ At least one of X is N, １ , X ２ , and X ３ is S, A is C １－２０ Alkylene, —O—, —S—, —N(R ｅ )-, and -N(R ｅ )-C １－２０ alkylene-, optionally selected from C １－２０ One, two, three, or more methylenes in the alkylene group may independently be —O—, —S—, —N(R ｅ )—, —C(═O)—, and —C(═S)—; B is a bond or arylene, C ３－１２ and 3- to 12-membered heterocyclylene, each of which is selected from halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ optionally substituted with one, two, three or more substituents selected from the group consisting of U is independently a bond, —CH ２ -, -NH-, and -O-; V and W are each independently —C(═O)— and —CH ２ - is selected from, Each of X, Y, and Z is independently CR ６ and N; R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , —C(═O)NR ｂ R ｃ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｂ R ｃ , optionally substituted C ３－６ carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or R １ and R ２ taken together with the atoms to which they are attached, ３－１２ may form a carbocyclyl or an optionally substituted 3- to 12-membered heterocyclyl; R is H, halogen, —CN, —N(═O), —NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R'' is halogen, -CN, -N(=O), -NO ２ , -ON(=O), optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -C(=O)R ａ , -C(=S)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -NR ｂ R ｃ , —C(═O)NR ｂ R ｃ , -S(=O)NR ｂ R ｃ , -S(=O) ２ NR ｂ R ｃ , -NR ｄ C(=O)R ａ , -NR ｄ C(=O)OR ａ , -NR ｄ C(=O)NR ｂ R ｃ , -NR ｄ S(=O)R ａ , -NR ｄ S (= O) ２ R ａ , -NR ｄ S(=O)NR ｂ R ｃ , -NR ｄ S (= O) ２ NR ｂ R ｃ , -SN(=O), -NR ｄ N(=O), optionally substituted aryl, optionally substituted C ３－１２ selected from carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R ５ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, R ６ is selected from H, halogen, and optionally substituted C １ -C ６ alkyl, Each R ａ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｂ and R ｃ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, or R ｂ and R ｃ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R ｄ However, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; R ｅ is H and optionally substituted C １－６ alkyl, a is selected from 0, 1, 2, 3, 4, and 5, and b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b≦5; e is 0 or 1; f is selected from 0, 1, 2, and 3; and The term "optionally substituted" before a chemical group that does not have a substituent specified means that said chemical group is substituted with halogen, C １－６ Alkyl, -OR ａ , -NR ｂ R ｃ , -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -NO ２ , ═O, —CN, and C ３－６ 10. The compound of claim 1, wherein the compound is optionally substituted with one, two, three or more substituents selected from the group consisting of cycloalkyl.

391. Q is optionally substituted C １－６ Alkyl, -OR ａ , -SR ａ , -NR ｂ R ｃ and Cy.

392. Q is C １－６ Alkyl, -SR ａ 391. The compound of claim 390, wherein said compound is selected from:

393. 391. The compound of claim 390, wherein Q is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and Cy.

394. 391. The compound of claim 390, wherein Q is selected from isopropyl, isopropylthio, and Cy.

395. 391. The compound of claim 390, wherein Q is Cy.

396. Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ 391. The compound of claim 390, wherein the heteroaryl is selected from carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'.

397. Cy is phenyl, naphthyl, anthranyl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazolyl, 391. The compound of claim 390, wherein R is selected from nyl, phenazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, tetrahydrobenzofuryl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with one, two, three, or more R'.

398. 391. The compound of claim 390, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuryl, and tetrahydrobenzofuryl, each of which is optionally substituted with one, two, three, or more R'.

399. 391. The compound of claim 390, wherein Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R'.

400. Q is, 【Chemical 207】 391. The compound of claim 390, selected from:

401. Q is, 【Chemical 208】 391. The compound of claim 390, selected from:

402. L Ａ is a bond, -C(R １ ) (R ２ ) -, -N(R １ 391. The compound of claim 390, wherein the group is selected from -O-, -S-, -C(=O)-, and -C(=S)-.

403. L Ａ is a bond, -CH ２ -, -CF2-, -CCl ２ --, --CBr ２ 391. The compound of claim 390, wherein the compound is selected from -, -CFCl-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

404. L Ａ is a bond, -CH ２ -, -CF ２ 391. The compound of claim 390, wherein the group is selected from -, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

405. L Ａ But -CH ２ - The compound according to claim 390.

406. X １ is CR or N.

407. X ２ is S or N.

408. X ３ is S or N. 【Request Item 409】 【Chemistry 209】 but, 【Chemical 210】 391. The compound of claim 390, selected from:

410. A is C １－８ Alkylene, —O—, —NH—, —N(CH ３ ) -, -N(C ２ H ５ )-, -NH-C １－８ alkylene, and optionally C １－８ 391. The compound of claim 390, wherein one, two, three, or more methylenes in the alkylene group are independently replaced with a group selected from -O- and -C(=O)-.

411. A is -CH ２ -, -O-, -NH-, -NH-(CH ２ ) ３ -, -NH-(CH ２ ) ５ -, and -NH-C(=O)-(CH ２ ) ３ -O-(CH ２ ) ３ - The compound of claim 390, wherein

412. A is -CH ２ 391. The compound of claim 390, wherein the group is selected from -, -O-, and -NH-.

413. The compound of claim 390, wherein A is -NH-.

414. B is selected from a bond, or arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- or 6-membered heteroarylene, each of which is selected from halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 391. The compound of claim 390, optionally substituted with one, two, three, or more substituents selected from the group consisting of:

415. 391. The compound of claim 390, wherein B is a bond or is selected from phenylene, pyrrolylene, furylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyranylene, pyrazinylene, pyrimidinylene, pyrazinylene, triazolylene, tetrazolylene, and triazinylene, each of which is optionally substituted by one, two, three, or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and propyl.

416. 391. The compound of claim 390, wherein B is a bond or phenylene optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of F, Cl, and Br.

417. 391. The compound of claim 390, wherein B is a bond or phenylene. 【Request Item 418】 【Chemistry 211】 but, 【Chemical Engineering 212】 391. The compound of claim 390, wherein the moiety is selected from: 【Request Item 419】 【Chemistry 213】 but, 【Chemical 214】 391. The compound of claim 390, wherein the moiety is selected from:

420. 391. The compound of claim 390, wherein U is a bond.

421. U is -CH ２ - The compound according to claim 390.

422. V is —C(═O)— and W is —CH ２ - The compound according to claim 390.

423. V is -CH ２ - and W is -C(=O)-.

424. 391. The compound of claim 390, wherein both V and W are -C(=O)-.

425. Each of X, Y, and Z is independently CR ６ 391. The compound of claim 390, selected from: 【Request Item 426】 【Chemistry 215】 but, 【Chemical 216】 391. The compound of claim 390, wherein the moiety is selected from: 【Request Item 427】 【Chemistry 217】 but, 【Chemical 218】 391. The compound of claim 390, wherein the moiety is selected from:

428. R １ and R ２ each independently being H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

429. R １ and R ２ each independently being H, halogen, C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

430. R １ and R ２ each independently selected from H, halogen, methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —CN, —NO ２ , -OH, -O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 391. The compound of claim 390, selected from:

431. R １ and R ２ 391. The compound of claim 390, wherein each of is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

432. R １ and R ２ 391. The compound of claim 390, wherein each of is independently selected from H and F.

433. R １ and R ２ and R are H.

434. R １ and R ２ and R are each independently 0 or 1. The compound of claim 390, wherein both of

435. R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

436. R is H, halogen, —CN, —NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

437. R is H, halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 391. The compound of claim 390, selected from:

438. R is H, F, Cl, Br, methyl, ethyl, propyl, —OH, —O(CH ３ ), and —NH ２ 391. The compound of claim 390, selected from:

439. 391. The compound of claim 390, wherein R is selected from H, methyl, and -OH.

440. 391. The compound of claim 390, wherein R is H.

441. R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

442. R' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １－６ Alkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens １－６ heteroalkyl, or C ３－６ cycloalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, or C ３－６ cycloalkyl, 1, 2, or ３ C optionally substituted with halogens ２－６ Alkynyl, or C ３－６ cycloalkyl, —OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

443. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, —O(CH ３ ), -O(C ３－６ cycloalkyl), -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , and —NH(C ３－６ 391. The compound of claim 390, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

444. R' is halogen, -CH ２ (C ３－６ cycloalkyl), —OH, and —NH(C ３－６ 391. The compound of claim 390, wherein the aryl group is selected from the group consisting of aryl, aryl cycloalkyl ...

445. 391. The compound of claim 390, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

446. 391. The compound of claim 390, wherein R' is Cl or F.

447. 【Chemical 219】 in 【Chemical 220】 is a single bond. 【Request Item 448】 【Chemistry 221】 in 【Chemistry 222】 is a double bond.

449. R'' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

450. R'' is halogen, -CN, -NO ２ , C optionally substituted with 1, 2, or 3 halogens １ -C ６ C optionally substituted with alkyl, 1, 2, or 3 halogens １－６ Heteroalkyl, C optionally substituted with 1, 2, or 3 halogens ２－６ alkenyl, C optionally substituted with 1, 2, or 3 halogens ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ 391. The compound of claim 390, selected from:

451. R'' is halogen, -CN, -NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ 391. The compound of claim 390, selected from:

452. R″ is F, Cl, Br, methyl, ethyl, propyl, —OH, and —NH ２ 391. The compound of claim 390, selected from:

453. R ５ 391. The compound of claim 390, wherein is selected from H, F, Cl, and Br.

454. R ５ The compound of claim 390, wherein is H.

455. R ６ 391. The compound of claim 390, wherein is selected from H, F, Cl, and Br.

456. R ６ is H or F.

457. Each R ａ are independently H and C １－６ 391. The compound of claim 390, wherein said alkyl is selected from:

458. Each R ａ 391. The compound of claim 390, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

459. Each R ａ is independently H or isopropyl.

460. R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ 391. The compound of claim 390, selected from cycloalkyl.

461. R ｂ and R ｃ 391. The compound of claim 390, wherein each of is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

462. R ｂ is H and R ｃ is cyclopropyl, or R ｂ is cyclopropyl, and R ｃ The compound of claim 390, wherein is H.

463. Each R ｄ are independently H and C １－６ 391. The compound of claim 390, wherein said alkyl is selected from:

464. Each R ｄ 391. The compound of claim 390, wherein is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

465. R ｅ The compound of claim 390, wherein is H.

466. 391. The compound of claim 390, wherein a is selected from 0 and 1, and b is selected from 0 and 1.

467. The compound of claim 390, wherein a is 0 and b is 0.

468. The compound of claim 390, wherein e is 0.

469. The compound of claim 390, wherein e is 1.

470. The compound of claim 390, wherein f is 0. 【Request Item 471】 【Chemistry 223】 but, 【Chemistry 224】 391. The compound of claim 390, wherein the moiety is selected from:

472. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is not substituted with halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 391. The compound of claim 390, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

473. The term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH ２ 391. The compound of claim 390, wherein the compound is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

474. The compound of claim 390, wherein the term "optionally substituted" in front of a chemical group without specifying the substituents indicates that the chemical group is optionally substituted with one, two, or three substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

475. The compound is represented by formula (17A) or (17B): 【Chemical 225】 【Chemistry 226】 During the ceremony, 【Chemistry 227】 each is independently a single bond or a double bond; Q is optionally substituted C １－６ Alkyl, -OR ａ , -SR ａ , -NR ｂ R ｃ and Cy; Cy is phenyl, naphthyl, anthranyl, phenanthryl, C ３－８ carbocyclyl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted by 1, 2, 3, or more R'; L Ａ is a bond, -C(R １ ) (R ２ ) -, -N(R １ )—, —O—, —S—, —C(═O)—, and —C(═S)—; 【Chemistry 228】 but 【Chemistry 229】 is selected from A is C １－８ Alkylene, —O—, —NH—, —N(CH ３ ) -, -N(C ２ H ５ )-, -NH-C １－８ alkylene, and optionally C １－８ one, two, three or more methylenes in the alkylene group are independently replaced with a group selected from —O— and —C(═O)—; B is selected from a bond, or arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- or 6-membered heteroarylene, each of which is selected from halogen, —CN, —NO ２ , methyl optionally substituted with 1, 2, or 3 halogens, ethyl optionally substituted with 1, 2, or 3 halogens, propyl optionally substituted with 1, 2, or 3 halogens, —OH, —O(CH ３ ), -NH ２ , -NH(CH ３ ), and -N(CH ３ ) ２ optionally substituted with one, two, three or more substituents selected from the group consisting of U is independently a bond, —CH ２ -, -NH-, and -O-; R １ and R ２ each independently selected from H, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, —CN, —NO ２ , -OR ａ , -SR ａ , and -NR ｂ R ｃ Selected from: R is H, halogen, —CN, —NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ is selected from R' is halogen, -CN, -NO ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, -OR ａ , -SR ａ , and -NR ｂ R ｃ is selected from R ５ is selected from H, F, Cl, and Br; R ６ is selected from H, F, Cl, and Br; Each R ａ independently H and C １－６ alkyl, R ｂ and R ｃ each independently represents H, C １－６ Alkyl, and C ３－６ cycloalkyl; e is 0 or 1, and wherein the term "optionally substituted" in front of a chemical group without specifying the substituents means that said chemical group is selected from the group consisting of halogen, C １－６ Alkyl, —OH, —NH ２ , -NO ２ , -CN, and C ３－６ 10. The compound of claim 1, wherein the compound is optionally substituted with one, two, or three substituents selected from the group consisting of cycloalkyl.

476. The compound is 【Chemistry 230-1】 【Chemistry 230-2】 【Chemistry 230-3】 【Chemistry 230-4】 【Chemistry 230-5】 2. The compound of claim 1 selected from the group consisting of:

477. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, and one or more pharmaceutically acceptable excipients.

478. 477. A kit comprising a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, and optionally instructions for use.

479. 477. A method for preventing or treating a disease or condition in which degradation of GRK2 is beneficial in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477.

480. The method of claim 479, wherein the disease or condition is selected from a hyperproliferative disease, a cardiovascular disease, a hematological disease, an infectious disease, an endocrine disease, a metabolic disease, a gastrointestinal disease, a respiratory disease, inflammation, opioid addiction, and a urinary disease.

481. 479. The method of claim 479, wherein the disease or condition is a hyperproliferative disease.

482. The method of claim 481, wherein the hyperproliferative disease is a tumor.

483. The method of claim 482, wherein the tumor is a cancer or sarcoma.

484. The method of claim 483, wherein the cancer is a hematopoietic cancer or a solid tumor.

485. The method of claim 484, wherein the hematopoietic cancer is selected from leukemia, lymphoma, heavy chain disease, myeloproliferative disorder, multiple myeloma, plasma cell neoplasm, familial hypereosinophilia, inflammatory myofibroblastic tumor, and immunocytic amyloidosis.

486. The method of claim 484, wherein the solid tumor is selected from nervous system cancer, exocrine cancer, musculoskeletal cancer, gastrointestinal cancer, respiratory cancer, genitourinary cancer, gynecological cancer, skin cancer, soft tissue cancer, oral cancer, head and neck cancer, esophageal cancer, liver cancer, and pancreatic cancer.

487. 479. The method of claim 479, wherein the disease or condition is a cardiovascular disease.

488. The method of claim 487, wherein the cardiovascular disease is selected from atherosclerosis, cardiac hypertrophy, hypertension, coronary artery disease, myocarditis, pericarditis, valvular heart disease, stenosis, restenosis, in-stent stenosis, angina pectoris, myocardial infarction, acute coronary syndrome, coronary artery bypass grafting, cardiopulmonary bypass surgery, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia, renal reperfusion injury, embolism, and myocardial ischemia.

489. 479. The method of claim 479, wherein the disease or condition is pulmonary hypertension.

490. 489. The method of claim 489, wherein the disease or condition is pulmonary arterial hypertension.

491. The method of claim 490, wherein the disease or condition is selected from idiopathic pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, drug- or toxin-induced pulmonary arterial hypertension, idiopathic pulmonary veno-occlusive disease, hereditary pulmonary veno-occlusive disease, drug-, toxin-, or radiation-induced pulmonary veno-occlusive disease, idiopathic pulmonary capillary hemangiomatosis, hereditary pulmonary capillary hemangiomatosis, drug-, toxin-, or radiation-induced pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.

492. 477. A method for inhibiting tumor growth or preventing recurrence in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477.

493. 477. A method for degrading GRK2 or inhibiting the activity of GRK2 in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477.

494. 477. A compound according to any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition according to claim 477, for use in therapy.

495. 478. A compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, for use in the prevention or treatment of a disease or condition in a subject in which degradation of GRK2 is beneficial.

496. 477. A compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, and one or more pharmaceutically acceptable excipients, for use in inhibiting tumor growth or preventing recurrence in a subject.

497. 478. A compound according to any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition according to claim 477, for use in inhibiting the degradation of GRK2 or the activity of GRK2 in a subject.

498. 477. Use of a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, for the preparation of a medicament for use in the prevention or treatment of a disease or condition in a subject in which degradation of GRK2 is beneficial.

499. 477. Use of a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, for the preparation of a medicament for use in inhibiting the growth or preventing the recurrence of a tumor in a subject.

500. 478. Use of a compound of any one of claims 1 to 476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, for the preparation of a medicament for use in inhibiting the degradation of GRK2 or the activity of GRK2 in a subject.

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