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 uses thereof. In particular, 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 the novel compounds; kits comprising the novel compounds; and the use of said novel compounds in the prevention or treatment of various diseases or conditions (e.g., diseases or conditions at least partially treated by a GRK2 drug or diseases or conditions that may benefit from degradation of GRK2).

Description

[0001] Related Applications

[0002] This application claims priority to PCT Application No. PCT / CN2023 / 075491, filed February 10, 2023, the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure relates to novel compounds or pharmaceutically acceptable salts, isomers, isotopes, prodrugs, solvates, or polymorphs thereof that degrade G protein-coupled receptor kinase 2 (GRK2); pharmaceutical compositions comprising the novel compounds; kits comprising the novel compounds; and uses of the novel compounds in preventing or treating various diseases or conditions, e.g., diseases or conditions that are at least partially treated by a GRK2 drug or diseases or conditions that can benefit from degradation of GRK2. BACKGROUND

[0004] GRK2, as the most prevalent and well-characterized member of the G protein-coupled receptor kinases, is known to be widely expressed in various organs and tissues where it is involved in the regulation of various intracellular mechanisms. Like other GRKs, GRK2 recognizes agonist-activated G protein-coupled receptors (GPCRs) on certain amino acid residues such as threonine residues and serine residues and phosphorylates the GPCRs. Upon phosphorylation, the GPCRs undergo desensitization, which is believed to be an important mechanism for individuals to maintain homeostasis and prevent disorders. GRK2 can also bind to and phosphorylate non-GPCR substrates such as platelet-derived growth factor receptor-beta (PDGFRbeta), EGFR, cytoskeletal proteins, transcription factors, and certain mitochondrial proteins.

[0005] GRK2 has been implicated in many diseases or conditions. In particular, GRK2 is known to play a key role in maintaining cardiac structure and function. Thus, dysregulation of GRK2 can contribute to the development of cardiovascular diseases or conditions. In addition, it is also known that the expression and / or function of GRK2 is altered in certain inflammation and cancer. Therefore, inhibition of GRK2 has been proposed as a promising approach to developing novel therapies for various diseases or conditions.

[0006] However, despite the therapeutic importance of GRK2 degraders, relatively few examples thereof have been known to date. Thus, there is a great unmet need for novel compounds that can effectively degrade GRK2 and / or inhibit the activity of GRK2. SUMMARY

[0007] Provided herein are novel compounds or pharmaceutically acceptable salts, isomers, isotopes, prodrugs, solvates, or polymorphs thereof that degrade GRK2; pharmaceutical compositions comprising the novel compounds; and kits comprising the novel compounds. Also provided herein are uses of the novel compounds or the pharmaceutical compositions in preventing or treating various diseases or conditions (e.g., diseases or conditions that are at least partially mediated by pharmacological treatment of GRK2 or diseases or conditions that can benefit from degradation of GRK2).

[0008] In some aspects, the present disclosure provides a compound represented by Formula (1):

[0009] GBM-DT (1)

[0011] or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof;

[0012] wherein:

[0013] GBM is a GRK2 binding moiety; and

[0014] DT is a degradation tag having E3 ligase binding capability.

[0015] 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.

[0016] 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.

[0017] In some aspects, the present disclosure provides a method for preventing or treating a disease or condition in 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.

[0018] In some aspects, the present disclosure provides a method for inhibiting tumor growth or preventing tumor 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.

[0019] In some aspects, the disclosure provides a method for degrading GRK2 in a subject or inhibiting the activity of GRK2 in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition.

[0020] In some aspects, the disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for use in therapy.

[0021] In some aspects, the disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for use in preventing or treating a disease or condition in a subject for which degradation of GRK2 is beneficial.

[0022] In some aspects, the disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for use in inhibiting tumor growth or preventing tumor recurrence in a subject.

[0023] In some aspects, the disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for use in degrading GRK2 in a subject or inhibiting the activity of GRK2 in a subject.

[0024] In some aspects, the disclosure provides use of a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for the manufacture of a medicament for preventing or treating a disease or condition in a subject for which degradation of GRK2 is beneficial.

[0025] In some aspects, the disclosure provides use of a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for the manufacture of a medicament for inhibiting tumor growth or preventing tumor recurrence in a subject.

[0026] In some aspects, the disclosure provides use of a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for the manufacture of a medicament for degrading GRK2 in a subject or inhibiting the activity of GRK2 in a subject.

[0027] INCORPORATED BY REFERENCE

[0028] All publications, patent applications, or patents cited in this specification are incorporated by reference herein to the same extent as if each individual publication, patent application, or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict between the disclosure of this specification and the publications, patent applications, or patents incorporated by reference, the disclosure of this specification shall control. BRIEF DESCRIPTION OF DRAWINGS

[0029] 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 present disclosure are utilized, and the accompanying drawings of which:

[0030] Figure 1 Images of a PVDF membrane of cellular proteins extracted from human-derived PASMCs (h-PASMCs) treated under hypoxic conditions in the presence of various test substances are shown.

[0031] Figure 2 Images of another PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of various test substances are shown.

[0032] Figure 3 The ratio of the expression level of GRK2 to the expression level of β-actin (represented by the ratio of “GRK2 / β-actin”) in m-PASMCs treated under hypoxic conditions in the presence of various test substances is shown.

[0033] Figure 4 Images of a PVDF membrane of cellular proteins extracted from mouse-derived PASMCs (m-PASMCs) treated under hypoxic conditions in the presence of various test substances are shown.

[0034] Figure 5 Images of another PVDF membrane of cellular proteins extracted from m-PASMCs treated under hypoxic conditions in the presence of various test substances are shown.

[0035] Figure 6 The ratio of the expression level of GRK2 to the expression level of β-actin (represented by the ratio of “GRK2 / β-actin”) in m-PASMCs treated under hypoxic conditions in the presence of various test substances is shown.

[0036] Figure 7Images of a PVDF membrane of cellular proteins extracted from r-PASMCs treated in the presence of various test substances under hypoxic conditions are shown.

[0037] Figure 8 Images of another PVDF membrane of cellular proteins extracted from r-PASMCs treated in the presence of various test substances under hypoxic conditions are shown.

[0038] Figure 9 A timeline of establishing a model of pulmonary arterial hypertension (PAH) in mice is shown.

[0039] Figure 10 A shows echocardiograms of the right heart from mice in the normoxic group two weeks after modeling. Figure 10 B shows echocardiograms of the right heart from mice in the hypoxic group two weeks after modeling. Figure 10 C shows echocardiograms of the right heart from mice in the hypoxic + Compound 1 group two weeks after modeling.

[0040] Figure 11 A shows data of body weight (g) from mice in the hypoxic group and the hypoxic + Compound 1 group two weeks after modeling. No statistical difference was found between the body weight data of the two experimental groups. Figure 11 B shows data of right ventricular internal dimension (RVID) (mm) from mice in the normoxic group, the hypoxic group, and the hypoxic + Compound 1 group two weeks after modeling. Figure 11 C shows data of right ventricular anterior wall (RVAW) thickness (mm) from mice in the normoxic group, the hypoxic group, and the hypoxic + Compound 1 group two weeks after modeling.

[0041] Figure 12 A schematically shows pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) from mice in the normoxic group two weeks after modeling. Figure 12 B schematically shows pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) from mice in the hypoxic group two weeks after modeling. Figure 12 C schematically shows pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) from mice in the hypoxic + Compound 1 group two weeks after modeling.

[0042] Figure 13 A ratio of PAT / PET from mice in the normoxic group, the hypoxic group, and the hypoxic + Compound 1 group two weeks after modeling is shown.

[0043] Figure 14 A schematically shows blood flow velocity of tricuspid valve orifice E peak (TVE) and blood flow velocity of tricuspid valve orifice A peak (TVA) from mice in the normoxic group two weeks after modeling.Figure 14 B schematically illustrates blood flow velocity at tricuspid valve orifice E peak (TVE) and blood flow velocity at tricuspid valve orifice A peak (TVA) from mice in the hypoxia group two weeks post-modeling. Figure 14 C schematically illustrates blood flow velocity at tricuspid valve orifice E peak (TVE) and blood flow velocity at tricuspid valve orifice A peak (TVA) from mice in the hypoxia + Compound 1 group two weeks post-modeling.

[0044] Figure 15 A ratio of TVE / TVA (i.e., TV E / A) from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group two weeks post-modeling is shown.

[0045] Figure 16 A schematically illustrates right ventricular systolic pressure (RVSP) from mice in the normoxia group four weeks post-modeling. Figure 16 B schematically illustrates right ventricular systolic pressure (RVSP) from mice in the hypoxia group four weeks post-modeling. Figure 16 C schematically illustrates right ventricular systolic pressure (RVSP) from mice in the hypoxia + Compound 1 group four weeks post-modeling.

[0046] Figure 17 A shows data for right ventricular systolic pressure (RVSP) (mmHg) from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group four weeks post-modeling. Figure 17 B shows data for right ventricular hypertrophy index (RVHI, calculated according to the formula RV / (LV+S)) from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group four weeks post-modeling.

[0047] Figure 18 A shows echocardiogram of the right heart from mice in the normoxia group four weeks post-modeling. Figure 18 B shows echocardiogram of the right heart from mice in the hypoxia group four weeks post-modeling. Figure 18 C shows echocardiogram of the right heart from mice in the hypoxia + Compound 1 group four weeks post-modeling.

[0048] Figure 19 A shows data for right ventricular internal dimension (RVID) (mm) from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group four weeks post-modeling. Figure 19 B shows data for right ventricular anterior wall (RVAW) thickness (mm) from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group four weeks post-modeling.

[0049] Figure 20 A schematically illustrates pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) from mice in the normoxia group four weeks post-modeling. Figure 20B schematically illustrates pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) from mice in the hypoxia group four weeks post modeling. Figure 20 C schematically illustrates pulmonary artery acceleration time (PAT) and pulmonary artery ejection time (PET) from mice in the hypoxia + Compound 1 group four weeks post modeling.

[0050] Figure 21 The ratio of PAT / PET from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group four weeks post modeling is shown.

[0051] Figure 22 A schematically illustrates blood flow velocity of tricuspid valve orifice E-peak (TVE) and blood flow velocity of tricuspid valve orifice A-peak (TVA) from mice in the normoxia group four weeks post modeling. Figure 22 B schematically illustrates blood flow velocity of tricuspid valve orifice E-peak (TVE) and blood flow velocity of tricuspid valve orifice A-peak (TVA) from mice in the hypoxia group four weeks post modeling. Figure 22 C schematically illustrates blood flow velocity of tricuspid valve orifice E-peak (TVE) and blood flow velocity of tricuspid valve orifice A-peak (TVA) from mice in the hypoxia + Compound 1 group four weeks post modeling.

[0052] Figure 23 The ratio of TVE / TVA (i.e., TV E / A) from mice in the normoxia group, the hypoxia group, and the hypoxia + Compound 1 group four weeks post modeling is shown.

[0053] Figure 24 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 2 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 2 plus 1 μΜ of MG132) is shown.

[0054] Figure 25 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 3 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 3 plus 1 μΜ of MG132) is shown.

[0055] Figure 26 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 20 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 20 plus 1 μΜ of MG132) is shown.

[0056] Figure 27 ​Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 21 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 21 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0057] Figure 28 Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 22 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 22 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0058] Figure 29 Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 23 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 23 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0059] Figure 30 Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 25 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 25 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0060] Figure 31 Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 26 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 26 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0061] Figure 32 Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 27 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 27 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0062] Figure 33 Images of PVDF membranes of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 28 (20 μΜ), MG132 (1 μΜ), and a combination thereof (Compound 28 at 20 μΜ plus MG132 at 1 μΜ) are shown.

[0063] Figure 34An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 29 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 29 plus 1 μΜ of MG132) is shown.

[0064] Figure 35 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 30 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 30 plus 1 μΜ of MG132) is shown.

[0065] Figure 36 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 33 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 33 plus 1 μΜ of MG132) is shown.

[0066] Figure 37 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 34 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 34 plus 1 μΜ of MG132) is shown.

[0067] Figure 38 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 35 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 35 plus 1 μΜ of MG132) is shown.

[0068] Figure 39 An image of a PVDF membrane of cellular proteins extracted from h-PASMCs treated under hypoxic conditions in the presence of Compound 37 (20 μΜ), MG132 (1 μΜ), and a combination thereof (20 μΜ of Compound 37 plus 1 μΜ of MG132) is shown.

[0069] Figure 40 An image of a PVDF membrane of 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 μΜ, and 10 μΜ) is shown.

[0070] Figure 41 An image of a PVDF membrane of 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 μΜ, and 10 μΜ) is shown. Detailed Implementation

[0071] I. Definition

[0072] 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.

[0073] As used in the specification and claims, when referring to a term as used in this disclosure, unless the context clearly indicates otherwise, the singular form “a” or “an” covers both the singular and plural units of the term (i.e., covers expressions of “at least one” or “one or more”), and vice versa.

[0074] As used in the specification and claims, unless otherwise stated, the scope is intended to explicitly disclose each endpoint of the scope and each integer included within the scope. Furthermore, any subscopes consisting of these integers are intended to be included within the scope of this disclosure.

[0075] 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 natural variants, such as those having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% or greater) of the amino acid sequence of wild-type GRK2, are expected to be covered by the terminology.

[0076] When used in the context of proteins (e.g., GRK2), the terms "degrade," "degrading," or "degradation" refer to the breakdown or metabolism of the protein in vivo or in vitro. Typically, GRK2 degradation results in a decrease in GRK2 activity or downstream effects relative to baseline or control levels of GRK2 activity.

[0077] The term "degrader" refers to a small molecule compound that causes partial or complete degradation of a protein (e.g., GRK2) when it interacts with the protein in vivo or in vitro.

[0078] The term "degradation tag" refers to the portion of a protein (e.g., GRK2) that, when bound to an E3 ligase, results in partial or complete degradation.

[0079] The terms “moiety” and “chemical moiety” or “structural fragment” are used interchangeably and refer to a portion or functional group of a molecule. Moieties can contain smaller moieties and functional groups.

[0080] The term “about,” when used in connection with a number, includes the specific point value as well as a range of numbers that are considered to have essentially the same effect by a person of ordinary skill in the art (e.g., a range of ±10%, ±5%, ±4%, ±3%, ±2%, or ±1% relative to the specific point value).

[0081] The terms “comprising,” “including,” “containing,” and variations thereof, are intended to mean an open transition phrase that does not exclude the possibility of additional substances or methods. When such terms are used in describing certain pharmaceutical compositions, kits, uses, or methods of the present disclosure, they also encompass the situation where the pharmaceutical compositions, kits, uses, or methods consist of the recited substances or methods. In the context of the present disclosure, the term “consisting of’ is intended to mean a closed transition phrase that excludes the possibility of additional substances or methods.

[0082] The term “C x-y ” when used in connection with a chemical moiety, such as an alkyl, alkenyl, or alkynyl group, is intended to include chemical moieties that contain from x to y carbons in their chain. For example, the term “C 1-6 alkyl” refers to an alkyl group containing from 1 to 6 carbons, including straight chain alkyl and branched alkyl groups.

[0083] The term “alkyl” refers to saturated monovalent straight or branched chain hydrocarbon groups. Alkyl groups used in the context of the present disclosure can contain from 1-20 carbon atoms (i.e., C 1-20 alkyl), for example, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, i-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. Alkyl groups are attached to the rest of the molecule by a single bond.

[0084] The term “alkenyl” refers to unsaturated monovalent straight or branched chain hydrocarbon groups containing at least one C=C double bond. Alkenyl groups used in the context of the present disclosure can contain from 2-20 carbon atoms (i.e., C 2-20ethenyl / vinyl), prop-1 -enyl, prop-2-enyl, but-1 -enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, pent-1 -enyl, pent-1,4-dienyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl, and the like.

[0085] The term "alkynyl" refers to an unsaturated monovalent straight-chain or branched hydrocarbon group containing at least one CºC triple bond. Alkynyl groups used in the context of the present disclosure can contain 2 to 20 carbon atoms (i.e., C2-20alkynyl), 2 to 18 carbon atoms (i.e., C2-18alkynyl), 2 to 16 carbon atoms (i.e., C2-16alkynyl), 2 to 14 carbon atoms (i.e., C2-14alkynyl), 2 to 12 carbon atoms (i.e., C2-12alkynyl), 2 to 10 carbon atoms (i.e., C2-10alkynyl), 2 to 8 carbon atoms (i.e., C2-8alkynyl), 2 to 6 carbon atoms (i.e., C2-6alkynyl), 2 to 4 carbon atoms (i.e., C2-4alkynyl), 2 to 3 carbon atoms (i.e., C2-3alkynyl), or 2 carbon atoms (i.e., C2alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. 2-20 ethenyl / vinyl), prop-1 -enyl, prop-2-enyl, but-1 -enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, pent-1 -enyl, pent-1,4-dienyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl, and the like.

[0086] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0087] The term "CN" or "cyano" refers to -CºN.

[0088] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups 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.

[0089] The term "heteroalkyl" refers to an alkyl group as defined above in which at least one constituent carbon atom has been replaced with one or more heteroatoms. Examples of heteroatoms include, but are not limited to, O, N, P, Si, or S, preferably O, N, or S, wherein the N, S, or P atoms can optionally be oxidized, and the N heteroatom can optionally be quaternized. Attachment to the remainder of the molecule can be through a heteroatom or carbon in the heteroalkyl group.

[0090] 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” means a carbocyclic ring or ring system or heterocyclic ring or ring system that does not meet the requirements set forth below for an aromatic ring or ring system and can be saturated or partially unsaturated. Carbocyclyl groups used in the context of the present disclosure generally contain 3-12 carbon atoms (i.e., 3- to 12-membered carbocyclyl), for example, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-6, 4-5, or 5-6 carbon atoms. Carbocyclyl groups can be monocyclic (e.g., 3- to 12-, 3- to 10-, 3- to 8-, 3- to 6-, 3- to 4-, or 5- to 6-membered) or polycyclic, such as bicyclic (e.g., 6- to 12-membered) or tricyclic (e.g., 11- to 14-membered). Each ring of a polycyclic carbocyclyl group can be selected from saturated, partially unsaturated, aromatic rings, provided that at least one ring of the polycyclic carbocyclyl group is not an aromatic ring. Polycyclic carbocyclyl groups can be fused ring systems, bridged ring systems, or spirocyclic ring systems. In some embodiments, the carbocyclyl group is a cycloalkyl group. In some embodiments, the carbocyclyl group is a cycloalkenyl group. In some embodiments, the carbocyclyl group is a cycloalkynyl group. In some embodiments, an aromatic ring (e.g., phenyl) can be fused to a saturated or partially unsaturated ring (e.g., cyclohexyl, cyclopentyl, or cyclohexenyl). Examples of carbocyclyl groups 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-dihydronaphthenyl, 1,4-dihydronaphthenyl, tetrazinyl, decahydronaphthalenyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl.

[0091] The term “cycloalkyl” refers to a carbocyclyl group that is fully saturated. Cycloalkyl groups used in the context of the present disclosure generally contain 3-12 carbon atoms (i.e., 3- to 12-membered cycloalkyl), for example, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-6, 4-5, or 5-6 carbon atoms. Cycloalkyl groups can be monocyclic (e.g., 3- to 12-, 3- to 10-, 3- to 8-, 3- to 6-, 3- to 4-, or 5- to 6-membered) or polycyclic, such as bicyclic (e.g., 6- to 12-membered) or tricyclic (e.g., 11- to 14-membered). Polycyclic cycloalkyl groups can be fused ring systems, bridged ring systems, or spirocyclic ring systems. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and bicyclo[3.2.2]nonyl.

[0092] 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 carbocyclic ring system or a heterocyclic or heterocyclic ring system containing a planar ring system in which a delocalized pi electron orbital contains [4n+2] p orbital electrons, where n is an integer from 0 to 6. Aryl groups used in the context of the present disclosure generally contain 6-12 carbon atoms. Aryl groups can be monocyclic aryl groups, such as phenyl; bicyclic aryl groups, such as naphthyl and indenyl; and tricyclic aryl groups, such as fluorenyl. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0093] The term "heterocyclyl" refers to a non-aromatic ring or ring system comprising one or more carbon atoms and one or more heteroatoms (e.g., 1, 2, 3, or 4, preferably 1 or 2 heteroatoms). Heterocyclyl groups used in the context of the present disclosure typically contain 3-12 member atoms (i.e., 3- to 12-membered heterocyclyl), e.g., 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-6, 4-5, or 5-6 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, wherein N, S, or P atoms can optionally be oxidized, and N heteroatoms can optionally be quaternized. When the total number of S and O atoms in a heterocyclyl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heterocyclyl group is not more than 2, preferably not more than 1. A heterocyclyl group can be monocyclic (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 polycyclic, such as bicyclic (e.g., 6- to 12-membered) or tricyclic (e.g., 11- to 14-membered). Each ring in a polycyclic heterocyclyl group can be selected from saturated, partially unsaturated, aromatic rings, provided that at least one ring in a polycyclic heterocyclyl group is not aromatic. A heterocyclyl group can be attached to the rest of the molecule through any atom that the valence of the heterocyclyl group permits, such as a carbon atom or a nitrogen atom of the heterocyclyl group. A polycyclic heterocyclyl group can be a fused ring system, a bridged ring system, or a spirocyclic ring system. In some embodiments, a heterocyclyl group is a heterocycloalkyl group. In some embodiments, a heterocyclyl group is a heterocycloalkenyl group. In some embodiments, a heterocyclyl group is a heterocycloalkynyl group. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, dithietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxetanyl, homopiperazinyl, homopiperidinyl, azepinyl, oxepinyl, thiepinyl, oxasulfuranyl, dioxepinyl, oxathiepinyl, oxazepinyl, diazepinyl, dithiane, azathiane, oxazepinyl, diazepinyl, dithiepinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolinyl, indolinyl, dioxanyl, dioxolanyl, pyrazolinyl, dithiolyl, 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.It should be understood that when referring to the number of carbon atoms in a heterocyclyl group, the number of carbon atoms in the heterocyclyl group is different from the total number of atoms (i.e., member atoms of the heterocyclyl ring) comprising the heterocyclyl group, including the heteroatoms.

[0094] The term "heteroaryl" refers to an aromatic ring or ring system comprising one or more carbon atoms and one or more heteroatoms (e.g., 1, 2, 3, or 4, preferably 1 or 2 heteroatoms). Heteroaryl groups used in the context of the present disclosure typically contain 5-12 member atoms (i.e., 5- to 12-membered heteroaryl groups), e.g., 5-6 or 8-12 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 group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not more than 2, preferably not more than 1. A heteroaryl group can be monocyclic (e.g., 5- to 6-membered) or polycyclic, such as bicyclic (e.g., 8- to 12-membered) or tricyclic (e.g., 11- to 14-membered). Examples of heteroaryl groups include, but are not limited to, 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-pyrimidinyl), pyridazinyl, tetrazolyl, thiophenyl, triazinyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolyl, indolyl, isoindolyl, pteridinyl, 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.

[0095] The term“substituted” refers to moieties having substituents replacing one or more of the hydrogen atoms on a suitable atom, e.g., a nitrogen atom of a compound. Where the substituents are designated by their conventional chemical formulas, it is contemplated that the chemical equivalent of substituents written from right to left is also a chemical equivalent of the substituents. For example, -CH2O- is equivalent to -OCH2-. As used in the present disclosure, it is contemplated that the term“substituted” includes all permissible substituents of organic compounds, including noncyclic and cyclic, straight-chain and branched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. In appropriate instances, permissible substituents can be one or more and can be the same or different for appropriate positions of the

[0096] The term“optional” means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example,“optionally substituted aryl” means that the aryl group can or can not be substituted and that the foregoing description includes both substituted aryl groups and unsubstituted aryl groups.

[0097] The term "isomers" refers to different compounds that have the same molecular formula. Certain compounds as described in the present disclosure contain one or more asymmetric centers and can thus give rise to stereoisomers, including enantiomers, diastereomers, and other stereoisomers that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, compounds as described in the present disclosure can exist as diastereomers, enantiomers, other stereoisomeric forms, and appropriate mixtures thereof. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated by R or S. "Stereoisomers" are isomers that differ only in the way that atoms are arranged in space. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of one another. A 1 : 1 mixture of enantiomers is a "racemic" mixture. The term "(±)" is used to denote a racemic mixture where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric carbons whose molecules are not mirror images of each other. Absolute stereochemistry is assigned using the Cahn-Ingold-Prelog R-S system. Resolved compounds whose absolute configuration is unknown can be designated (plus) or (minus), depending on the direction in which plane-polarized light is rotated by the compound. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, 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 by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of preponderance of one stereoisomer over another can be determined. Reference to one isomer is intended to apply to any possible isomer unless otherwise indicated. Whenever a compound is depicted without a specified isomeric composition, all possible isomers are included.

[0098] Compounds as described in the present disclosure having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in Z or E form (or cis or trans form). Further, some compounds as described in the present disclosure can exist in various tautomeric forms (i.e., tautomers). The term “tautomer” refers to molecules in which the migration of a proton from one atom of a molecule to another atom of the same molecule can occur. In some embodiments, compounds as described in the present disclosure can exist as tautomers. Where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of tautomers will depend on several factors, including temperature, solvent, physical state, and pH. For example, a compound comprising a -CH2C(O)- group (keto form) can undergo tautomerization to form a -CH=C(OH)- group (enol form). Unless otherwise specified, compounds as described in the present disclosure are also intended to include all Z forms, E forms, and tautomeric forms.

[0099] Separation of stereoisomers can be achieved by chromatography or by separation of diastereomers and 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, which is hereby incorporated by reference into the present disclosure. Stereisomers can also be obtained by stereoselective synthesis.

[0100] The term “isotopically enriched” refers to a compound as described in the present disclosure in which one or more atoms constituting the compound is artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly present in nature. Compounds as described in the present disclosure optionally contain an unnatural proportion of an atomic isotope at one or more of the atoms constituting such compounds. For example, compounds can be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Envisioning the use of all 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17O、 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 I areotope substituted. All isotopes of the compounds described in the present disclosure, whether or not radioactive, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment in deuterium can provide certain therapeutic advantages, such as increased half-life and / or exposure in vivo, or can provide compounds for use in studying in vivo pathways of drug elimination and metabolism. In some embodiments, the compounds as described in the present disclosure are deuterated in 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. Radioactive isotopes such as tritium 3 H), iodine-125 125 I), or carbon-14 14 C) can be used in accordance with the present disclosure. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0101] The term "prodrug" refers to any compound that becomes a compound as described in the disclosure under physiological conditions. In some embodiments, a compound or salt thereof can exist as a prodrug, for example, where a hydroxyl group in the parent compound is present as an ester or carbonate, or a carboxylic acid present in the parent compound is present as an ester. Prodrugs are useful because they can be easier to administer than the parent drug in some cases. For example, a prodrug can be bioavailable by oral administration whereas the parent drug is not. Prodrugs can help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drug. One method for making a prodrug involves including one or more selected moieties that are hydrolyzed under physiological conditions to release the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal, such as a specific target cell of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the disclosure.

[0102] The term "solvate" refers to an aggregate that comprises one or more solvent molecules and ionic or molecular species. Compounds as described in the disclosure can exist in unsolvated as well as solvated forms (i.e., forms comprising one or more solvent molecules), such as, for example, with water (i.e., hydrates), ethanol (i.e., ethanolates), or the like. When the solvent is water, the solvate is specifically referred to as a "hydrate."

[0103] The term "polymorph" refers to the various forms in which a solid material can exist. In the context of the disclosure, the term "polymorph" encompasses both "amorphous forms" and "crystalline forms." Thus, a compound as described in the disclosure can exist in amorphous forms as well as crystalline forms.

[0104] The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable 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.

[0105] The phrase "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, carrier, or vehicle, such as is used in the preparation of a pharmaceutical composition or dosage form according to the 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.

[0106] The term“pharmaceutically acceptable salt” refers to salts derived from a variety of pharmaceutically acceptable organic or inorganic counter-ions well known in the art. Compounds, as described in the present disclosure, having an acidic functional group, a basic functional group, or both, can react with any of a number of inorganic or organic acids and bases to form a salt. Alternatively, compounds that are inherently charged (such as compounds having a quaternary nitrogen) can form salts with appropriate counter-ions (e.g., halides such as bromide, chloride, or fluoride). Pharmaceutically acceptable acid addition salts can be formed with inorganic acids 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 with inorganic or 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 such as isopropylamine, trimethylamine, diethylamine, triethylamine, propylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of an ammonium salt, a potassium salt, a sodium salt, a calcium salt, and a magnesium salt. Examples of suitable pharmaceutically acceptable salts can be found in, for example, S. M. Berge et al., J. Pharmaceutical Sciences 1977, 66, pp. 1-19.

[0107] The terms“subject,”“individual,” and“patient” are used interchangeably and refer to a human as well as a non-human mammal (e.g., a non-human primate, a canine animal, an equine animal, a feline animal, a porcine animal, a bovine animal, an ungulate animal, a lagomorph animal, and the like). In some embodiments, a subject can be a human (e.g., a male child, a female child, a male adolescent, a female adolescent, an adult male, an adult female) under the care of a physician or other health worker of a hospital, an outpatient or other clinical setting. In some embodiments, a subject can not be under the care or prescription of a physician or other health worker.

[0108] The phrase“a subject in need thereof’ refers to a subject having a pathology to be prophylactically or therapeutically treated with a compound, composition, or dosage form as described in the present disclosure or at risk of developing such a pathology.

[0109] The terms“administer,”“administered,”“administers,” and“administering” are defined as providing to a subject in need a compound, composition, formulation, and / or dosage form according to the present disclosure by routes known in the art, including but not limited to oral, buccal, topical, transmucosal, transdermal, rectal, and parenteral routes of administration. In some embodiments, an oral route of administration is used. In some embodiments, a parenteral route of administration is used, including intravenous, intra-arterial, intramuscular, subcutaneous, intraosseous, and intraperitoneal.

[0110] The term“effective amount” or“therapeutically effective amount” refers to the amount of a compound as described in the present disclosure that is sufficient to effect a desired application, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount can vary depending upon the intended application, or the subject and disease or condition to be treated, e.g., the subject’s body weight, age, the severity of the disease condition, the manner of administration, and the like, as can readily be determined by one of skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., up- or down-regulation of the activity of a target protein. The specific dose can vary depending on the particular compound chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0111] The terms“prevent,”“prevention,” or“preventing” in relation to a disease or condition can refer to a compound, composition, or dosage form as described in the present disclosure that reduces the occurrence of a disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of or lessens the severity of one or more symptoms of a disorder or condition relative to an untreated control sample, in a statistical sample. In some embodiments, to obtain a preventive benefit, 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, carrying one or more of the physiological symptoms of the disease or condition, even if such disease or condition can not have yet been diagnosed.

[0112] The terms “treat,” “treatment,” or “treatment” refer to a method for obtaining a beneficial or desired outcome (i.e., treatment benefit) with respect to a disease or condition. In some embodiments, treatment involves administering to a subject a compound, composition, or dosage form as described in this disclosure. Treatment may include, for example, reducing the severity of one or more symptoms of a disease, condition, or symptom, delaying or alleviating said one or more symptoms, or treatment may include reducing the frequency with which a patient experiences symptoms, defects, conditions, or adverse symptoms of a disease. In some embodiments, treatment benefit may include eradicating or improving the underlying condition being treated. In some embodiments, treatment benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition (e.g., observing improvement in the subject), although the subject may still have the underlying condition.

[0113] II.Compounds

[0114] This article provides novel compounds for the degradation of GRK2, or their pharmaceutically acceptable salts, isomers, isotopes, prodrugs, solvates, or polymorphs. The compounds are divalent compounds comprising a GRK2-binding moiety conjugated to a degradation tag capable of binding to an E3 ligase.

[0115] Without wishing to be bound by any particular theory, it is believed that, at least in some embodiments, linking the degradation tag as described herein to the GRK2 binding moiety as described herein can recruit the corresponding ubiquitination mechanism to GRK2, thereby causing subsequent degradation of GRK2 in or near the proteasome and / or loss of GRK2 function.

[0116] Without wishing to be bound by any particular theory, it is believed that novel compounds as described herein that potently degrade GRK2 can be used to prevent or treat a variety of diseases or conditions, such as those at least partially treated by GRK2 drugs or those that may benefit from the degradation of GRK2, including but not limited to hyperproliferative diseases (e.g., tumors), cardiovascular diseases (e.g., hypertension, more specifically, pulmonary (arterial) hypertension), hematologic disorders, infectious diseases, endocrine disorders, metabolic disorders, gastrointestinal disorders, respiratory diseases, inflammation, opioid addiction, and urinary disorders.

[0117] Therefore, in some aspects, this disclosure provides a compound represented by formula (1):

[0118] GBM-DT (1)

[0120] or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof;

[0121] wherein:

[0122] GBM is a GRK2 binding moiety; and

[0123] DT is a degradation tag having E3 ligase binding ability.

[0124] In some embodiments, the GBM is a moiety derived from a polyanionic and a polycationic compound.

[0125] In some embodiments, the polyanionic and polycationic compound is selected from heparin and dextran sulfate.

[0126] In some embodiments, the GBM is a moiety derived from balanol or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

[0127] In some embodiments, the GBM is a moiety derived from a Takeda inhibitor selected from

[0128] In some embodiments, the GBM is a moiety derived from a paroxetine series selected from

[0129] In some embodiments, the GBM is a moiety derived from an indazole or dihydropyrimidine series represented by formula (2) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof

[0130]

[0131] wherein

[0132] R is selected from

[0133] R' is selected from H and halogen; and

[0134] R" is selected from

[0135] In some embodiments, the GBM is represented by formula (3):

[0136]

[0137] wherein ★ indicates a point of attachment to the DT;

[0138] Formula I is a moiety covalently linked to Formula II, wherein the Formula I comprises a thiazole ring or a triazole ring on its backbone, and is capable of binding to GRK2, alone or together with the Formula II; and

[0139] the Formula II is a moiety covalently linked to the Formula I and the DT, wherein the Formula II comprises an acyclic or cyclic saturated or unsaturated carbon, glycol, amide, ester, amino, oxy, thio, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic, carbonyl, or a combination thereof.

[0140] In some embodiments, the Formula I is represented by Formula (4):

[0141]

[0142] wherein:

[0143] ♦ indicates a point of attachment to the Formula II;

[0144] Q is selected from the group consisting of 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;

[0145] Cy is selected from the group consisting of aryl, C 3-12 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';

[0146] L A is selected from the group consisting of a bond, -(CH2) a C(R1)(R2)(CH2) b-S(=O)2-, -NR1-, -N=O, -NO2, -ON=O, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C6cycloalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted aryl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl;

[0147] R is selected from 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;

[0148] each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 R1and R2together with the atom to which they are attached can form an optionally substituted C 3-12 carbocyclyl or optionally substituted 3- to 12-membered heterocyclyl;

[0149] R' is selected from 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 dS(=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;

[0150] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0151] each R b and R c is independently selected from 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;

[0152] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0153] a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5; and

[0154] The term “optionally substituted” preceding a chemical group for which substitution is not specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, C 1-6 alkyl, -OR a , -NR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a, -NO2, =0, -CN, and C 3-6 Cycloalkyl.

[0155] In some embodiments, Q is selected from optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0156] In some embodiments, Q is selected from C 1-6 alkyl, -SR a , and Cy.

[0157] In some embodiments, Q is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, and Cy.

[0158] In some embodiments, Q is selected from i-propyl, i-propylthio, and Cy.

[0159] In some embodiments, Q is Cy.

[0160] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

[0161] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R'.

[0162] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H- cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0163] In some embodiments, Cy is phenyl optionally substituted with 1, 2, 3, or more R’.

[0164] In some embodiments, Q is selected from:

[0165]

[0166] In some embodiments, Q is selected from:

[0167] In some embodiments, L A is selected from a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0168] In some embodiments, L A is selected from a bond, -CH2-, -CF2-, -CCl2-, -CBr2-, -CFCI-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0169] In some embodiments, L A is selected from a bond, -CH2-, -CF2-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0170] In some embodiments, L A is -CH2-.

[0171] In some embodiments, R is selected from 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 .

[0172] In some embodiments, R is selected from H, halogen, -CN, -NO2, optionally substituted C 1-6 alkyl, optionally substituted C1-6 heteroalkyl, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen 2-6 alkenyl, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

[0173] In some embodiments, R is selected from H, halogen, -CN, -NO2, methyl optionally substituted with 1, 2, or 3 halogen, ethyl optionally substituted with 1, 2, or 3 halogen, propyl optionally substituted with 1, 2, or 3 halogen, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0174] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

[0175] In some embodiments, R is selected from H and -OH.

[0176] In some embodiments, R is H.

[0177] In some embodiments, each of R1and R2is 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 .

[0178] In some embodiments, each of R1and R2is independently selected from H, halogen, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen, C 1-6 heteroalkyl, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen 2-6 alkenyl, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen 2-6 alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c .

[0179] In some embodiments, each of R1and R2is 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.

[0180] In some embodiments, each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0181] In some embodiments, each of R1and R2is independently selected from H and F.

[0182] In some embodiments, each of R1and R2is independently selected from H and F.

[0183] In some embodiments, each of R1and R2is independently selected from H and F.

[0184] In some embodiments, each of R1and R2is independently selected from H and F.

[0185] In some embodiments, R' is selected from 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 .

[0186] In some embodiments, R' is selected from halogen, -CN, -NO2, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0186] In some embodiments, R' is selected from halogen, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C3-6 cycloalkyl).

[0187] In some embodiments, R' is selected from halogens, -CH2(C 3-6 cycloalkyl), -OH and -NH (C 3-6 cycloalkyl).

[0188] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH and cyclopropylamino.

[0189] In some embodiments, R' is Cl.

[0190] In some embodiments, each R a Independently selected from H and C 1-6 alkyl.

[0191] In some embodiments, each R a It is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0192] In some embodiments, each R a It is either H or isopropyl.

[0193] In some embodiments, R b and R c Each of them is independently selected from H and C. 1-6 Alkyl and C 3-6 Cycloalkyl.

[0194] In some embodiments, R b and R c Each of them is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0195] In some embodiments, R b It is H and R c It is cyclopropyl, or R b It is cyclopropyl and R c It is H.

[0196] In some embodiments, each R d Independently selected from H and C 1-6 alkyl.

[0197] In some embodiments, each R d It is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0198] In some embodiments, each R d It is either H or methyl on its own.

[0199] In some embodiments, a is selected from 0 and 1, and b is selected from 0 and 1.

[0200] In some embodiments, a is 0 and b is 0.

[0201] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0202] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0203] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means 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.

[0204] In some embodiments, said Formula I is represented by Formula (4A):

[0205]

[0206] wherein:

[0207] ♦ represents a point of attachment to said Formula II;

[0208] each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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)2NRb R c , optionally substituted C 3-6 carbocyclyl and optionally substituted 3- to 6-membered heterocyclyl, or R1and R2together with the atom to which they are attached can form an optionally substituted C 3-12 carbocyclyl or optionally substituted 3- to 12-membered heterocyclyl;

[0209] R is selected from H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl and optionally substituted 3- to 12-membered heterocyclyl;

[0210] Cy is selected from aryl, C3-12 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';

[0211] R' is selected from halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), optionally substituted aryl, optionally substituted C 3-12 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';

[0212] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0213] R b and R c each is independently selected from 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;

[0214] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; and

[0215] The term “optionally substituted” preceding a chemical group for which no substituents are specified indicates that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0216] In some embodiments, each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

[0217] In some embodiments, each of R1and R2is independently selected from H, halogen, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

[0218] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with one, two or three halogens, ethyl optionally substituted with one, two or three halogens, propyl optionally substituted with one, two or three halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3) and -N(CH3)2.

[0219] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0220] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0221] In some embodiments, both R1 and R2 are H.

[0222] In some embodiments, R is selected from H, halogens, -CN, -NO2, and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -OR a -SR a and -NR b R c .

[0223] In some embodiments, R is selected from H, halogens, -CN, -NO2, and C optionally substituted with one, two, or three halogens. 1-6 Alkyl groups, C substituted with one, two or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne group, -OR a -SR a and -NR bRc .

[0224] In some embodiments, R is selected from H, halogen, -CN, -N02, 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, -0(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0225] In some embodiments, R is selected from H, F, CI, Br, methyl, ethyl, propyl, -OH, -0(CH3), and -NH2.

[0226] In some embodiments, R is selected from H and -OH.

[0227] In some embodiments, R is H.

[0228] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R’.

[0229] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0230] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolizinyl, indolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0231] In some embodiments, Cy is phenyl optionally substituted with 1, 2, 3, or more R’.

[0232] In some embodiments, Cy is selected from:

[0233] In some embodiments, R' is selected from 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 .

[0234] In some embodiments, R' is selected from halogen, -CN, -NO2, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0235] In some embodiments, R' is selected from 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).

[0236] In some embodiments, R' is selected from halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0237] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0238] In some embodiments, R' is Cl.

[0239] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0240] In some embodiments, each R a It is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0241] In some embodiments, R b and R c Each of them is independently selected from H and C. 1-6 Alkyl and C 3-6 Cycloalkyl.

[0242] In some embodiments, R b and R c Each of them is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0243] In some embodiments, each R d Independently selected from H and C 1-6 alkyl.

[0244] In some embodiments, each R d It is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0245] In some embodiments, the term "optionally substituted" preceding a chemical group whose substituents are not specified indicates that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: halogens, C 1-6 Alkyl groups, -OH, -NH2, -NO2, -CN, and C 3-6 Cycloalkyl.

[0246] In some embodiments, the term “optionally substituted” preceding a chemical group whose substituents are not specified means that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0247] In some embodiments, the term “optionally substituted” preceding a chemical group whose substituents are not specified means that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0248] In some embodiments, equation I is represented by equation (4B):

[0249]

[0250] in

[0251] m is selected from 0, 1, 2, 3, 4, and 5.

[0252] In some embodiments, m is selected from 0, 1, and 2.

[0253] In some embodiments, m is 0 or 1.

[0254] In some embodiments, the formula I is represented by formula (5):

[0255]

[0256] wherein:

[0257] ♦ represents a point of attachment to the formula II;

[0258] R 1A , R 2A , R 1B , and R 2B each is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 may be taken together with the atom to which they are attached to form an optionally substituted C 3-12 carbocyclyl or optionally substituted 3- to 12-membered heterocyclyl;

[0259] R 3A , R 3B , and R 3C each is independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6alkenyl, 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 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl;

[0260] each of D1, D2, D3, D4, and D5is independently N or CR 4A ;

[0261] each of E1, E2, E3, and E4is independently N or CR 4B ;

[0262] each of F1, F2, F3, and F4is independently N or CR 4C ;

[0263] each of R 4A , R 4B , and R 4C is independently selected from 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 , -NRd 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;

[0264] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0265] each of R b and R c is independently selected from 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 can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl;

[0266] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; and

[0267] The term “optionally substituted” preceding a chemical group for which substitution is not specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0268] In some embodiments, each of R 1A , R 2A , R 1B , and R 2B 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 .

[0269] In some embodiments, each of R 1A , R 2A , R 1B , and R 2B is independently selected from H, halogen, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OR a , -SR a , and -NR b R c .

[0270] In some embodiments, each of R 1A , R 2A , R 1B , and R 2B 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.

[0271] In some embodiments, each of R 1A , R 2A , R 1Band each of R 2B is independently selected from H, F, CI, Br, methyl, ethyl, and propyl.

[0272] In some embodiments, each of R 1A , R 2A , R 1B , and R 2B is independently selected from H and F.

[0273] In some embodiments, each of R 1A , R 2A , R 1B , and R 2B is independently H.

[0274] In some embodiments, each of R 3A , R 3B , and R 3C is independently selected from 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.

[0275] In some embodiments, each of R 3A , R 3B , and R 3C is independently selected from H, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, and C 2-6 alkynyl optionally substituted with 1, 2, or 3 halogens.

[0276] In some embodiments, each of R 3A , R 3B , and R 3C 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.

[0277] In some embodiments, each of R 3A , R 3B , and R 3C is independently selected from H, methyl, ethyl, and propyl.

[0278] In some embodiments, each of R 3A , R 3B , and R 3C is independently selected from H.

[0279] In some embodiments, at least one of D1, D2, D3, D4, and D5 is N, and the rest are CR A .

[0280] In some embodiments, one of D1, D2, D3, D4, and D5 is N, and the rest are CR A .

[0281] In some embodiments, D3 is N, and the rest are CR 4A .

[0282] In some embodiments, each of E1, E2, E3, and E4 is independently CR 4B .

[0283] In some embodiments, each of F1, F2, F3, and F4 is independently CR 4C .

[0284] In some embodiments, each of R 4A , R 4B , and R 4C is independently selected from 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 .

[0285] In some embodiments, each of R 4A , R 4B , and R 4C is independently selected from 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 .

[0286] In some embodiments, each of R 4A , R 4B , and R 4C is independently selected from H, halogen, -CN, -NO2, optionally substituted Ceach of R, R, and R is independently selected from the group consisting of H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

[0287] In some embodiments, R 4A , R 4B , and R 4C are each independently selected from the group consisting of H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

[0288] In some embodiments, R 4A , R 4B , and R 4C are each independently H.

[0289] In some embodiments, each R a is independently selected from the group consisting of H and C 1-6 alkyl.

[0290] In some embodiments, each R a is independently selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0291] In some embodiments, each of R b and R c is independently selected from the group consisting of H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0292] In some embodiments, each of R b and R c is independently selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0293] In some embodiments, each R d is independently selected from the group consisting of H and C 1-6 alkyl.

[0294] In some embodiments, each R d is independently selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0295] In some embodiments, the term “optionally substituted” preceding a chemical group for which no substituents are specified indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0296] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0297] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means 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.

[0298] In some embodiments, said Formula I is represented by Formula (5A):

[0299]

[0300] In some embodiments, said Formula I is represented by Formula (5B):

[0301]

[0302] In some embodiments, said Formula I is represented by Formula (5C):

[0303]

[0304] In some embodiments, said Formula II comprises an amide group or an ester group.

[0305] In some embodiments, said Formula II is represented by Formula (6):

[0306]

[0307] wherein

[0308] * denotes the point of attachment to said Formula I;

[0309] # denotes the point of attachment to said DT;

[0310] A, T, and B are independently selected at each occurrence from the group consisting of null, -C(=O)-, -C(=O)O-, -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)-, -NR1 C(=O)NR 2 -、-NR 1 C(=S)-, optionally substituted C1-C8alkyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl and optionally substituted C3-C 13 spiroheterocyclyl, wherein

[0311] R 1 and R 2 are independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl; and

[0312] p is 0 to 15.

[0313] In some embodiments, the formula II is represented by formula (6A):

[0314]

[0315] wherein

[0316] * denotes the point of attachment to the formula I;

[0317] # denotes the point of attachment to the DT;

[0318] R 1 , R 2 , R 3 and R 4independently at each occurrence selected from hydrogen, halogen, -CN, -OH, -NH2, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl;

[0319] A, T and B are independently at each occurrence selected from null, -C(=O)-, -C(=O)O-, -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-C8alkyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl, wherein

[0320] R 5 and R 6 are independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl;

[0321] p is 0 to 15;

[0322] each q is 0 to 15; and

[0323] o is 0 to 15.

[0324] In some embodiments, the formula II is represented by formula (6B):

[0325]

[0326] wherein

[0327] * represents a point of attachment to the formula I;

[0328] # represents a point of attachment to the DT;

[0329] each R 1 and each R 2 is independently selected from hydrogen, halogen, -CN, -OH, -NH2, and optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, or C1-C6alkylaminoC1-C6alkyl;

[0330] each A and each B is independently selected from null, -C(=O)-, -C(=O)O-, -C(=O)NR 3 -, 3 -, 3 -, 3 -, 3 -, 3 -, 4 -, 3 -, 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl or C3-C 13 spiroheterocyclyl, wherein

[0331] 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 3-6 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 alkylamino C1-C6 alkyl;

[0332] each p is 0 to 15; and

[0333] q is 0 to 15.

[0334] In some embodiments, the formula II is represented by formula (6C):

[0335]

[0336] wherein

[0337] * indicates the point of attachment to the formula I;

[0338] # indicates the point of attachment to the DT;

[0339] X is selected from -O-, -NH, and -NR 7 -;

[0340] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 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 alkylamino C1-C6 alkyl;

[0341] A and B are independently selected from null, -C(=O)-, -C(=O)O-, -C(=O)NR 7 -, -C(=S)NR7 -, -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-C8alkyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl and optionally substituted C3-C 13 spiroheterocyclyl, wherein

[0342] R 7 and R 8 are independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl;

[0343] each p is 0 to 15;

[0344] each q is 0 to 15;

[0345] o is 0 to 15; and

[0346] r is 0 to 15.

[0347] In some embodiments, the formula II is represented by formula (7A):

[0348]

[0349] wherein * indicates the point of attachment to the formula I;

[0350] # represents a point of attachment to the DT;

[0351] A is selected from C 1-20 alkylene, -0-, -S-, -N(R e )-, -C(=0)-, and -C(=S)-; e )-C 1-20 alkylene-, and optionally wherein 1, 2, 3, or more methylenes in said C 1-20 alkylene are independently replaced with a group selected from -0-, -S-, -N(R e )-, -C(=0)-, and -C(=S)-;

[0352] B is a bond or is selected from arylene, C 3-12 carbocyclylene, 5- to 12-membered heteroarylene, and 3- to 12-membered heterocyclylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, -CN, -N02, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c ;

[0353] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0354] each of R b and R c is independently selected from 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 together with the nitrogen atom to which they are attached can form an optionally substituted 3- to 12-membered heterocyclyl;

[0355] R e is selected from H and optionally substituted C 1-6 alkyl; and

[0356] The term "optionally substituted" preceding a chemical group for which no substituents are specified indicates that the chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0357] In some embodiments, A is selected from C 1-8 alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein 1, 2, 3, or more methylenes in said C 1-8 alkylene are independently replaced with a group selected from -O- and -C(=O).

[0358] In some embodiments, A is selected from -CH2-, -O-, -NH-, -NH-(CH2)3-, -NH-(CH2)5-, and -NH-C(=O)-(CH2)3-O-(CH2)3-.

[0359] In some embodiments, A is selected from -CH2-, -O-, and -NH-.

[0360] In some embodiments, A is -NH-.

[0361] In some embodiments, B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0362] In some embodiments, B is a bond or is selected from phenylene, pyrrolylene, furanylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyrylylene, 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.

[0363] 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.

[0364] In some embodiments, B is a bond or phenylene.

[0365] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0366] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

[0367] In some embodiments, R b and R c are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0368] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0369] In some embodiments, R e is H.

[0370] In some embodiments, the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0371] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, CI, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0372] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, CI, Br, methyl, ethyl, and cyclopropyl.

[0373] In some embodiments, formula (7A) is a moiety selected from:

[0374]

[0375] In some embodiments, formula (7A) is a moiety selected from:

[0376]

[0377] In some embodiments, said formula II is represented by formula (7B):

[0378]

[0379] wherein

[0380] * denotes the point of attachment to said formula I;

[0381] # denotes the point of attachment to said DT;

[0382] is a single or double bond;

[0383] R" is selected from halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR bR 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 Carbocyclic, optionally substituted 5- to 12-membered heteroaryl and optionally substituted 3- to 12-membered heterocyclic groups;

[0384] Each R a Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl;

[0385] R b and R c Each of them is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; or R b and R c It can form optionally substituted 3- to 12-membered heterocyclic groups together with the nitrogen atom to which it is attached;

[0386] Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl;

[0387] e is 0 or 1;

[0388] f is selected from 0, 1, 2, and 3; and

[0389] The term "optionally substituted" preceding a chemical group whose substituents are not specified indicates that the chemical group is optionally substituted by one, two, three or more substituents selected from the group consisting of: halogens, 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.

[0390] In some embodiments, It is a single key.

[0391] In some embodiments, It is a double bond.

[0392] In some embodiments, R” is selected from halogen, -CN, -NO2, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

[0393] In some embodiments, R” is selected from halogens, -CN, -NO2, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, and C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 alkynyl group, -OR a -SR a and -NR b R c .

[0394] In some embodiments, R” is selected from halogen, -CN, -NO2, methyl optionally substituted with one, two or three halogens, ethyl optionally substituted with one, two or three halogens, propyl optionally substituted with one, two or three halogens, -OH, -O(CH3), -NH2, -NH(CH3) and -N(CH3)2.

[0395] In some embodiments, R" is selected from F, Cl, Br, methyl, ethyl, propyl, -OH, and -NH2.

[0396] In some embodiments, e is 0.

[0397] In some embodiments, e is 1.

[0398] In some embodiments, f is 0.

[0399] In some embodiments, Formula (7B) is a moiety selected from:

[0400]

[0401] In some embodiments, the DT is capable of binding to an E3 ligase to recruit a corresponding ubiquitination machinery to GRK2, thereby causing subsequent degradation of GRK2 in or near the proteasome and / or loss of function of GRK2.

[0402] In some embodiments, the DT is selected from the group consisting of a cereblon ligand, a VHL ligand, a MDM2 ligand, a TRIM24 ligand, a TRIM21 ligand, a KEAP1 ligand, a RNF114 ligand, a IAP ligand, a DCAF16 ligand, a DCAF15 ligand, a FEM1B ligand, and a ligand for an Aryl Hydrocarbon Receptor.

[0403] In some embodiments, the DT is a moiety represented by Formula (8A), (8B), (8C), or (8D):

[0404]

[0405] wherein

[0406] represents a point of attachment to the Formula II;

[0407] U is independently selected from -CH2-, -NH-, and -O-;

[0408] Each of V and W is independently selected from -C(=0)- and -CH2-;

[0409] Each of X, Y, and Z is independently selected from CR6and N;

[0410] R5is selected from H, halogen, and optionally substituted C1-C6alkyl; and

[0411] R6is selected from H, halogen, and optionally substituted C1-C6alkyl.

[0412] In some embodiments, U is -CH2-.

[0413] In some embodiments, U is -O-.

[0414] In some embodiments, U is -NH-.

[0415] In some embodiments, V is -C(=O)- and w is -CH2-.

[0416] In some embodiments, V is -CH2- and w is -C(=O)-.

[0417] In some embodiments, both V and W are -C(=O)-.

[0418] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0419] In some embodiments, R5is selected from H, F, Cl, and Br.

[0420] In some embodiments, R5is H.

[0421] In some embodiments, R6is selected from H, F, Cl, and Br.

[0422] In some embodiments, R6is H or F.

[0423] In some embodiments, the DT is a moiety selected from:

[0424]

[0425] In some embodiments, the DT is a moiety represented by formula (9):

[0426]

[0427] wherein

[0428] represents a point of attachment to the formula II;

[0429] R 1 and R 2 are independently selected from hydrogen, optionally substituted C1-C8alkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C1-C8aminoalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8alkenyl, and optionally substituted C2-C8alkynyl;

[0430] R 3is hydrogen, optionally substituted C(=O)C1-C8alkyl, optionally substituted -C(=O)C1-C8alkoxyC1-C8alkyl, optionally substituted -C(=O)C1-C8haloalkyl, optionally substituted -C(=O)C1-C8hydroxyalkyl, optionally substituted -C(=O)C1-C8aminoalkyl, optionally substituted -C(=O)C1-C8alkylaminoC1-C8alkyl, optionally substituted -C(=O)C3-C7cycloalkyl, optionally substituted -C(=O)(3-7 membered heterocyclyl), optionally substituted -C(=O)C2-C8alkenyl, optionally substituted -C(=O)C2-C8alkynyl, optionally substituted -C(=O)OC1-C8alkoxyC1-C8alkyl, optionally substituted -C(=O)OC1-C8haloalkyl, optionally substituted -C(=O)OC1-C8hydroxyalkyl, optionally substituted -C(=O)OC1-C8aminoalkyl, optionally substituted -C(=O)OC1-C8alkylaminoC1-C8alkyl, optionally substituted -C(=O)OC3-C7cycloalkyl, optionally substituted -C(=O)O(3-7 membered heterocyclyl), optionally substituted -C(=O)OC2-C8alkenyl, optionally substituted -C(=O)OC2-C8alkynyl, optionally substituted -C(=O)NC1-C8alkoxyC1-C8alkyl, optionally substituted -C(=O)NC1-C8haloalkyl, optionally substituted -C(=O)NC1-C8hydroxyalkyl, optionally substituted -C(=O)NC1-C8aminoalkyl, optionally substituted -C(=O)NC1-C8alkylaminoC1-C8alkyl, optionally substituted -C(=O)NC3-C7cycloalkyl, optionally substituted -C(=O)N(3-7 membered heterocyclyl), optionally substituted -C(=O)NC2-C8alkenyl, optionally substituted -C(=O)NC2-C8alkynyl, optionally substituted -P(=O)(OH)2, optionally substituted -P(=O)(OC1-C8alkyl)2, and optionally substituted -P(=O)(OC1-C8aryl)2.

[0431] In some embodiments, the DT is a moiety represented by formula (10):

[0432]

[0433] wherein

[0434] represents the point of attachment to the formula II;

[0435] V, W, X, and Z are independently selected from CR 4 and N;

[0436] R 1 , R 2 , R 3 , and R 4independently selected from hydrogen, optionally substituted C1-C8alkyl, optionally substituted C1-C8alkoxy C1-C8alkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8alkenyl, and optionally substituted C2-C8alkynyl.

[0437] In some embodiments, the DT is a moiety derived from any of:

[0438]

[0439] In some embodiments, the DT is selected from the group consisting of:

[0440]

[0441]

[0442]

[0443] In some embodiments, the compound is represented by Formula (11)

[0444]

[0445] wherein:

[0446] A is selected from C 1-20 alkylene, -O-, -S-, -N(R e )-, -C(=O)-, and -C(=S)-; e )-C 1-20 alkylene-, and optionally wherein 1, 2, 3, or more methylenes in the C 1-20 alkylene are independently replaced with a group selected from -O-, -S-, -N(R e )-, -C(=O)-, and -C(=S)-;

[0447] B is a bond or is selected from arylene, C 3-12 carbocyclylene, 5- to 12-membered heteroarylene, and 3- to 12-membered heterocyclylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, -CN, -NO2, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR aand -NR b R c ;

[0448] U is independently selected from -CH2-, -NH-, and -O-;

[0449] each of V and W is independently selected from -C(=O)- and -CH2-;

[0450] each of X, Y, and Z is independently selected from CR6and N;

[0451] each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 R1and R2together with the atoms to which they are attached can form an optionally substituted C 3-12 carbocyclyl or optionally substituted 3- to 12-membered heterocyclyl;

[0452] R is selected from 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 Carbocyclic, optionally substituted 5- to 12-membered heteroaryl and optionally substituted 3- to 12-membered heterocyclic groups;

[0453] Cy is selected from aryl, C 3-12 Carbocyclic, 5- to 12-membered heteroaryl and 3- to 12-membered heterocyclic, each of which is optionally substituted by one, two, three or more R';

[0454] R' is selected from halogens, -CN, -N (=O), -NO2, -ON (=O), and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -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 Rc -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;

[0455] R5is selected from H, halogen, and optionally substituted C1-C6alkyl;

[0456] R6is selected from H, halogen, and optionally substituted C1-C6alkyl;

[0457] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0458] R b and R c are each independently selected from 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 form, together with the nitrogen atom to which they are attached, an optionally substituted 3- to 12-membered heterocyclyl;

[0459] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6haloalkyl and C 3-6 cycloalkyl;

[0460] R e selected from H and optionally substituted C 1-6 alkyl; and

[0461] The term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0462] In some embodiments, A is selected from C 1-8 alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein 1, 2, 3, or more methylenes in said C 1-8 alkylene are independently replaced with a group selected from -O- and -C(=O).

[0463] In some embodiments, A is selected from -CH2-, -O-, -NH-, -NH-(CH2)3-, -NH-(CH2)5-, and -NH-C(=O)-(CH2)3-O-(CH2)3-.

[0464] In some embodiments, A is selected from -CH2-, -O-, and -NH-.

[0465] In some embodiments, A is -NH-.

[0466] In some embodiments, B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0467] In some embodiments, B is a bond or is selected from phenylene, pyrrolylene, furanylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyrylylene, 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.

[0468] 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.

[0469] In some embodiments, B is a bond or phenylene.

[0470] In some embodiments, is a moiety selected from:

[0471]

[0472] In some embodiments, is a moiety selected from:

[0473]

[0474] In some embodiments, U is -CH2-.

[0475] In some embodiments, U is -O-.

[0476] In some embodiments, U is -NH-.

[0477] In some embodiments, V is -C(=O)- and w is -CH2-.

[0478] In some embodiments, V is -CH2- and w is -C(=O)-.

[0479] In some embodiments, both V and W are -C(=O)-.

[0480] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0481] In some embodiments, is a moiety selected from:

[0482]

[0483] In some embodiments, each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and -ORa. 1-6Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

[0484] In some embodiments, each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, and C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

[0485] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with one, two or three halogens, ethyl optionally substituted with one, two or three halogens, propyl optionally substituted with one, two or three halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3) and -N(CH3)2.

[0486] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0487] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0488] In some embodiments, both R1 and R2 are H.

[0489] In some embodiments, R is selected from H, halogens, -CN, -NO2, and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

[0490] In some embodiments, R is selected from H, halogens, -CN, -NO2, and C optionally substituted with one, two, or three halogens. 1-6alkyl, C optionally substituted with 1, 2, or 3 halogen 1-6 heteroalkyl, C optionally substituted with 1, 2, or 3 halogen 2-6 alkenyl, C optionally substituted with 1, 2, or 3 halogen 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

[0491] In some embodiments, R is selected from H, halogen, -CN, -NO2, methyl optionally substituted with 1, 2, or 3 halogen, ethyl optionally substituted with 1, 2, or 3 halogen, propyl optionally substituted with 1, 2, or 3 halogen, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0492] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

[0493] In some embodiments, R is selected from H and -OH.

[0494] In some embodiments, R is H.

[0495] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R’.

[0496] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothiophenyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0497] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H- cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0498] In some embodiments, Cy is phenyl optionally substituted with 1, 2, 3, or more R’.

[0499] In some embodiments, Cy is selected from:

[0500] In some embodiments, R’ is selected from 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 .

[0501] In some embodiments, R’ is selected from halogen, -CN, -NO2, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0502] In some embodiments, R’ is selected from 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).

[0503] In some embodiments, R’ is selected from halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6cycloalkyl).

[0504] In some embodiments, R' is selected from F, CI, cyclopropylmethyl, -OH, and cyclopropylamino.

[0505] In some embodiments, R' is CI.

[0506] In some embodiments, R5is selected from H, F, CI, and Br.

[0507] In some embodiments, R5is H.

[0508] In some embodiments, R6is selected from H, F, CI, and Br.

[0509] In some embodiments, R6is H or F.

[0510] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0511] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0512] In some embodiments, R b and R c are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0513] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0514] In some embodiments, each R d is independently selected from H and C 1-6 alkyl.

[0515] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0516] In some embodiments, R e is H.

[0517] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified indicates that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6Alkyl groups, -OH, -NH2, -NO2, -CN, and C 3-6 Cycloalkyl.

[0518] In some embodiments, the term “optionally substituted” preceding a chemical group whose substituents are not specified means that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0519] In some embodiments, the term “optionally substituted” preceding a chemical group whose substituents are not specified means that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0520] In some embodiments, the compound is represented by formula (12A), (12B), (12C), (12D), (12E), or (12F):

[0521]

[0522]

[0523] 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups;

[0524] R is selected from H, halogens, -CN, -N (=O), -NO2, -ON (=O), and 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;

[0525] R' is selected from the group consisting of 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 -OS(=O)R a -OS(=O)2R a -OS(=O)2OR a -OS(=O)2NR b R c -OC(=O)NR b R c -OS(=O)NR b R c -OS(=O)2NR b R c -ONR d C(=O)R a -ONR d C(=O)OR a -ONR d C(=O)NR b R c -ONR d S(=O)R a -ONR d S(=O)2R a -ONR d S(=O)NR b R c -ONR 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;

[0526] R5is selected from H, halogen, and optionally substituted C1-C6alkyl;

[0527] R6is selected from H, halogen, and optionally substituted C1-C6alkyl;

[0528] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0529] R b and R c are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6cycloalkyl; or R b and R c may form, together with the nitrogen atom to which they are attached, an optionally substituted 3- to 12-membered heterocyclyl;

[0530] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0531] The term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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;

[0532] Ph represents a phenylene group; and

[0533] m is selected from 0, 1, 2, 3, 4, and 5.

[0534] In some embodiments, each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

[0535] In some embodiments, each of R1and R2is independently selected from H, halogen, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c .

[0536] In some embodiments, each of R1and R2is 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.

[0537] In some embodiments, each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0538] In some embodiments, each of R1and R2is independently selected from H and F.

[0539] In some embodiments, both R1and R2are H.

[0540] In some embodiments, R is selected from 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 .

[0541] In some embodiments, R is selected from H, halogen, -CN, -NO2, optionally substituted C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

[0542] In some embodiments, R is selected from H, 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.

[0543] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

[0544] In some embodiments, R is selected from H and -OH.

[0545] In some embodiments, R is H.

[0546] In some embodiments, R' is selected from 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 .

[0547] In some embodiments, R' is selected from halogen, -CN, -NO2, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0548] In some embodiments, R' is selected from 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).

[0549] In some embodiments, R' is selected from halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0550] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0551] In some embodiments, R' is Cl.

[0552] In some embodiments, R5 is selected from H, F, Cl, and Br. In some embodiments, R5 is selected from H, F, Cl, and Br.

[0553] In some embodiments, R5is H.

[0554] In some embodiments, R6is selected from H, F, Cl, and Br.

[0555] In some embodiments, R6is H or F.

[0556] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0557] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

[0558] In some embodiments, R b and R c are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0559] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0560] In some embodiments, each R d is independently selected from H and C 1-6 alkyl.

[0561] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

[0562] In some embodiments, the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0563] In some embodiments, the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0564] In some embodiments, the term “optionally substituted” preceding a chemical group whose substituents are not specified means that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0565] In some embodiments, Ph represents

[0566] In some embodiments, m is selected from 0, 1, and 2.

[0567] In some embodiments, m is 0 or 1.

[0568] In some embodiments, the compound is selected from the group consisting of:

[0569]

[0570]

[0571]

[0572]

[0573] In some embodiments, the compound is selected from the group consisting of:

[0574]

[0575] In some embodiments, equation I is represented by equation (13):

[0576]

[0577] in:

[0578] ◆ Indicates the connection point with Formula II;

[0579] Each of them is independently a single bond or a double bond;

[0580] Q is selected from C, which can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -OR a -SR a -NR b R c -C(=O)R a -C(=O)OR a -OC(=O)R a -C(=O)NR b Rc -S(=O)R a -S(=O)2R a -S(=O)2NR b R c and Cy;

[0581] Cy is selected from aryl, C 3-12 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';

[0582] L A is selected from a bond, -(CH2) a C(R1)(R2)(CH2) b -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-;

[0583] X1, X2, and X3are each independently selected from CR, S, or N;

[0584] provided that at least one of X1, X2, and X3is N, and one of X1, X2, and X3is S;

[0585] R is selected from 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)NRb 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 Carbocyclic, optionally substituted 5- to 12-membered heteroaryl and optionally substituted 3- to 12-membered heterocyclic groups;

[0586] 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups;

[0587] R' is selected from halogens, -CN, -N (=O), -NO2, -ON (=O), and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -OR a -C(=O)R a -C(=S)R a -C(=O)OR a-OC(=O)R a -OS(=O)R a -OS(=O)2R a -OS(=O)2NR a -OC(=O)NR b R c -OC(=O)OR b R c -OS(=O)NR b R c -OS(=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;

[0588] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0589] each of R b and R c is independently selected from 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;

[0590] each Rd independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0591] a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5; and

[0592] The term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0593] In some embodiments, Q is selected from optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0594] In some embodiments, Q is selected from C 1-6 alkyl, -SR a , and Cy.

[0595] In some embodiments, Q is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, and Cy.

[0596] In some embodiments, Q is selected from i-propyl, i-propylthio, and Cy.

[0597] In some embodiments, Q is Cy.

[0598] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R’.

[0599] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenoxazinyl, phenoxazinyl, phenothiazinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0600] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolizinyl, indolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0601] In some embodiments, Cy is phenyl or pyridyl, optionally substituted with 1, 2, 3, or more R’.

[0602] In some embodiments, Q is selected from:

[0603]

[0604] In some embodiments, Q is selected from:

[0605] In some embodiments, L A is selected from a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0606] In some embodiments, L A is selected from a bond, -CH2-, -CF2-, -CCl2-, -CBr2-, -CFCI-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0607] In some embodiments, L Ais selected from the group consisting of a bond, -CH2-, -CF2-, -NH-, -0-, -S-, -C(=0)-, and -C(=S)-.

[0608] In some embodiments, L A is -CH2-.

[0609] In some embodiments, X1is CR or N.

[0610] In some embodiments, X2is S or N.

[0611] In some embodiments, X3is S or N.

[0612] In some embodiments, is selected from the group consisting of

[0613] In some embodiments, R is selected from the group consisting of H, halogen, -CN, -N02, 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 .

[0614] In some embodiments, R is selected from the group consisting of H, halogen, -CN, -N02, 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 .

[0615] In some embodiments, R is selected from the group consisting of H, halogen, -CN, -N02, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, -OH, -0(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0616] In some embodiments, R is selected from the group consisting of H, F, CI, Br, methyl, ethyl, propyl, -OH, -0(CH3), and -NH2.

[0617] In some embodiments, R is selected from H, methyl, and -OH.

[0618] In some embodiments, R is H.

[0619] In some embodiments, each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

[0620] In some embodiments, each of R1and R2is independently selected from H, halogen, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -CN, -NO2, -OR a , -SR a , and -NR b R c .

[0621] In some embodiments, each of R1and R2is 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.

[0622] In some embodiments, each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0623] In some embodiments, each of R1and R2is independently selected from H and F.

[0624] In some embodiments, both R1and R2are H.

[0625] In some embodiments, both R1and R2are F.

[0626] In some embodiments, R' is selected from halogen, -CN, -NO2, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 2-6alkenyl, optionally substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0627] In some embodiments, R' is selected from halogen, -CN, -NO2, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0628] In some embodiments, R' is selected from 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).

[0629] In some embodiments, R' is selected from halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0630] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0631] In some embodiments, R' is Cl or F.

[0632] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0633] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

[0634] In some embodiments, each R a is independently H or i-propyl.

[0635] In some embodiments, each of R b and R c is independently selected from the group consisting of H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0636] In some embodiments, each of R b and R c is independently selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0637] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl and R c is H.

[0638] In some embodiments, each R d is independently selected from the group consisting of H and C 1-6 alkyl.

[0639] In some embodiments, each R d is independently selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0640] In some embodiments, each R d is independently H or methyl.

[0641] In some embodiments, a is selected from 0 and 1, and b is selected from 0 and 1.

[0642] In some embodiments, a is 0 and b is 0.

[0643] In some embodiments, the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0644] In some embodiments, the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0645] In some embodiments, the term “optionally substituted” preceding a chemical group whose substituents are not specified means that the chemical group is optionally substituted by one, two, or three substituents selected from the group consisting of: F, Cl, Br, methyl, ethyl, and cyclopropyl.

[0646] In some embodiments, formula I is represented by formula (14A), (14B), or (14C):

[0647]

[0648] in:

[0649] ◆ Indicates the connection point with Formula II;

[0650] 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups;

[0651] R is selected from H, halogens, -CN, -N (=O), -NO2, -ON (=O), and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -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 Carbocyclic, optionally substituted 5- to 12-membered heteroaryl and optionally substituted 3- to 12-membered heterocyclic groups;

[0652] Q is selected from C, which can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -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;

[0653] Cy is selected from aryl, C 3-12carbocyclyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with 1, 2, 3, or more R';

[0654] L A selected from a bond, -(CH2) a C(R1)(R2)(CH2) b -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-;

[0655] R' is selected from 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 3-12carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl;

[0656] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0657] R b and R c are each independently selected from 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;

[0658] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0659] a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5; and

[0660] The term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0661] In some embodiments, each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

[0662] In some embodiments, each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, and C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

[0663] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with one, two or three halogens, ethyl optionally substituted with one, two or three halogens, propyl optionally substituted with one, two or three halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3) and -N(CH3)2.

[0664] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0665] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0666] In some embodiments, both R1 and R2 are H.

[0667] In some embodiments, both R1 and R2 are F.

[0668] In some embodiments, R is selected from H, halogens, -CN, -NO2, and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

[0669] In some embodiments, R is selected from H, halogens, -CN, -NO2, and C optionally substituted with one, two, or three halogens. 1-6 Alkyl groups, C substituted with one, two or three halogens. 1-6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0670] In some embodiments, R is selected from H, halogen, -CN, -N02, 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, -0(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0671] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -0(CH3), and -NH2.

[0672] In some embodiments, R is selected from H, methyl, and -OH.

[0673] In some embodiments, R is H.

[0674] In some embodiments, Q is selected from optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0675] In some embodiments, Q is selected from C 1-6 alkyl, -SR a , and Cy.

[0676] In some embodiments, Q is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, and Cy.

[0677] In some embodiments, Q is selected from i-propyl, i-propylthio, and Cy.

[0678] In some embodiments, Q is Cy.

[0679] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R’.

[0680] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenoxazinyl, phenoxazinyl, phenothiazinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0681] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolizinyl, indolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0682] In some embodiments, Cy is phenyl or pyridyl, optionally substituted with 1, 2, 3, or more R’.

[0683] In some embodiments, Q is selected from:

[0684]

[0685]

[0686] In some embodiments, Q is selected from:

[0687] In some embodiments, L A is selected from a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0688] In some embodiments, L ASelected from the following: -CH2-, -CF2-, -CCl2-, -CBr2-, -CFCl-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)- and -C(=S)-.

[0689] In some embodiments, L A Selected from the following: -CH2-, -CF2-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0690] In some embodiments, L A It is -CH2-.

[0691] In some embodiments, R' is selected from halogens, -CN, -NO2, and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

[0692] In some embodiments, R' is selected from halogens, -CN, -NO2, optionally by one, two, or three halogens or C. 3-6 Cycloalkyl-substituted C 1-6 Alkyl group, optionally with one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 1-6 Heteroalkyl groups, optionally with one, two, or three halogens or C atoms. 3-6 Cycloalkyl-substituted C 2-6 Alkenyl group, optionally surrounded by one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

[0693] In some embodiments, R' is selected from halogens, -CH2(C 3-6 cycloalkyl), -OH, -O(CH3), -O(C 3-6 cycloalkyl groups, -NH2, -NH(CH3), -N(CH3)2 and -NH(C 3-6 (cycloalkyl).

[0694] In some embodiments, R' is selected from halogens, -CH2(C 3-6 cycloalkyl), -OH and -NH (C 3-6 (cycloalkyl).

[0695] In some embodiments, R' is selected from F, CI, cyclopropylmethyl, -OH, and cyclopropylamino.

[0696] In some embodiments, R' is CI or F.

[0697] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0698] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0699] In some embodiments, each R a is independently H or i-propyl.

[0700] In some embodiments, R b and R c are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0701] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0702] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl and R c is H.

[0703] In some embodiments, each R d is independently selected from H and C 1-6 alkyl.

[0704] In some embodiments, each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0705] In some embodiments, each R d is independently H or methyl.

[0706] In some embodiments, a is selected from 0 and 1, and b is selected from 0 and 1.

[0707] In some embodiments, a is 0 and b is 0.

[0708] In some embodiments, the term "optionally substituted" preceding a chemical group for which substituents are not specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0709] In some embodiments, the term "optionally substituted" preceding a chemical group for which substituents are not specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0710] In some embodiments, the term "optionally substituted" preceding a chemical group for which substituents are not specified means 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.

[0711] In some embodiments, the DT is a moiety represented by formula (15A), (15B), (15C), or (15D):

[0712]

[0713] wherein

[0714] represents a point of attachment to the formula II;

[0715] U is independently selected from the group consisting of a bond, -CH2-, -NH-, and -O-;

[0716] each of V and W is independently selected from the group consisting of -C(=O)- and -CH2-;

[0717] each of X, Y, and Z is independently selected from CR6and N;

[0718] R5is selected from the group consisting of H, halogen, and optionally substituted C1-C6alkyl; and

[0719] R6is selected from the group consisting of H, halogen, and optionally substituted C1-C6alkyl.

[0720] In some embodiments, U is a bond.

[0721] In some embodiments, U is -CH2-.

[0722] In some embodiments, V is -C(=O)- and w is -CH2-.

[0723] In some embodiments, V is -CH2- and w is -C(=O)-.

[0724] In some embodiments, both V and W are -C(=O)-.

[0725] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0726] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0727] In some embodiments, R5 is H.

[0728] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0729] In some embodiments, R6 is H or F.

[0730] In some embodiments, the DT is selected from the following:

[0731]

[0732]

[0733] In some embodiments, the DT is selected from the following:

[0734]

[0735]

[0736] In some embodiments, the compound is represented by formula (16A) or (16B).

[0737]

[0738] in:

[0739] Each of them is independently a single bond or a double bond;

[0740] Q is selected from C, which can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -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;

[0741] Cy is selected from aryl, C 3-12 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';

[0742] L A is selected from a bond, -(CH2) a C(R1)(R2)(CH2) b -, -N(R1)-, -O-, -S-, -C(=O)-, -C(=S)-, -S(=O)-, and -S(=O)2-;

[0743] X1, X2, and X3are each independently selected from CR, S, or N;

[0744] provided that at least one of X1, X2, and X3is N, and one of X1, X2, and X3is S;

[0745] A is selected from C 1-20 alkylene, -O-, -S-, -N(R e )-, and -N(R e )-C 1-20 alkylene-, and optionally wherein 1, 2, 3, or more methylenes in said C 1-20 alkylene are independently replaced with a group selected from -O-, -S-, -N(R e )-, -C(=O)-, and -C(=S)-;

[0746] B is a bond or is selected from arylene, C 3-12 carbocyclylene, 5- to 12-membered heteroarylene, and 3- to 12-membered heterocyclylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, -CN, -NO2, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c ;

[0747] U is independently selected from the bond, -CH2-, -NH-, and -O-;

[0748] Each of V and W is independently selected from -C(=O)- and -CH2-;

[0749] Each of X, Y, and Z is independently selected from CR6 and N;

[0750] 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups;

[0751] R is selected from H, halogens, -CN, -N (=O), -NO2, -ON (=O), and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -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 Rc -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;

[0752] R' is selected from the group consisting of 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 Rc , -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;

[0753] R" is selected from the group consisting of 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)2NRb 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;

[0754] R5is selected from H, halogen, and optionally substituted C1-C6alkyl;

[0755] R6is selected from H, halogen, and optionally substituted C1-C6alkyl;

[0756] each R a is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0757] R b and R c are each independently selected from 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 together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclyl;

[0758] each R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0759] R e is selected from H and optionally substituted C 1-6 alkyl;

[0760] a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5;

[0761] e is 0 or 1;

[0762] f is selected from 0, 1, 2, and 3; and

[0763] The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, C1-6 alkyl, -OR a , -SR b R c , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -NO2, =O, -CN, and C 3-6 cycloalkyl.

[0764] In some embodiments, Q is selected from the group consisting of optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c , and Cy.

[0765] In some embodiments, Q is selected from the group consisting of C 1-6 , -SR a , and Cy.

[0766] In some embodiments, Q is selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, and Cy.

[0767] In some embodiments, Q is selected from the group consisting of isopropyl, isopropylthio, and Cy.

[0768] In some embodiments, Q is Cy.

[0769] In some embodiments, Cy is selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

[0770] In some embodiments, Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenoxazinyl, phenoxazinyl, phenothiazinyl, phenazinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0771] In some embodiments, Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolinyl, isoindolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

[0772] In some embodiments, Cy is phenyl or pyridyl, optionally substituted with 1, 2, 3, or more R’.

[0773] In some embodiments, Q is selected from:

[0774]

[0775]

[0776] In some embodiments, Q is selected from:

[0777] In some embodiments, L A is selected from a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0778] In some embodiments, L A is selected from a bond, -CH2-, -CF2-, -CCl2-, -CBr2-, -CFCI-, -CFBr-, -CClBr-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0779] In some embodiments, L Ais selected from the group consisting of a bond, -CH2-, -CF2-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

[0780] In some embodiments, L A is -CH2-.

[0781] In some embodiments, X1is CR or N.

[0782] In some embodiments, X2is S or N.

[0783] In some embodiments, X3is S or N.

[0784] In some embodiments, is selected from

[0785] In some embodiments, A is selected from C 1-8 alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein 1, 2, 3, or more methylenes in said C 1-8 alkylene are independently replaced with a group selected from -O- and -C(=O).

[0786] In some embodiments, A is selected from -CH2-, -O-, -NH-, -NH-(CH2)3-, -NH-(CH2)5-, and -NH-C(=O)-(CH2)3-O-(CH2)3-.

[0787] In some embodiments, A is selected from -CH2-, -O-, and -NH-.

[0788] In some embodiments, A is -NH-.

[0789] In some embodiments, B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

[0790] In some embodiments, B is a bond or is selected from phenylene, pyrrolylene, furanylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyrylylene, 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.

[0791] 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.

[0792] In some embodiments, B is a bond or phenylene.

[0793] In some embodiments, is a moiety selected from:

[0794]

[0795] In some embodiments, is a moiety selected from:

[0796]

[0797] In some embodiments, U is a bond.

[0798] In some embodiments, U is -CH2-.

[0799] In some embodiments, V is -C(=O)- and w is -CH2-.

[0800] In some embodiments, V is -CH2- and w is -C(=O)-.

[0801] In some embodiments, both V and W are -C(=O)-.

[0802] In some embodiments, each of X, Y, and Z is independently selected from CR6.

[0803] In some embodiments, is a moiety selected from:

[0804]

[0805]

[0806] In some embodiments, is a moiety selected from:

[0807]

[0808] In some embodiments, each of R1 and R2 is independently selected from H, halogens, optionally substituted C1-C6 alkyl groups, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

[0809] In some embodiments, each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, and C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

[0810] In some embodiments, each of R1 and R2 is independently selected from H, halogen, methyl optionally substituted with one, two or three halogens, ethyl optionally substituted with one, two or three halogens, propyl optionally substituted with one, two or three halogens, -CN, -NO2, -OH, -O(CH3), -NH2, -NH(CH3) and -N(CH3)2.

[0811] In some embodiments, each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

[0812] In some embodiments, each of R1 and R2 is independently selected from H and F.

[0813] In some embodiments, both R1 and R2 are H.

[0814] In some embodiments, both R1 and R2 are F.

[0815] In some embodiments, R is selected from H, halogens, -CN, -NO2, and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -OR a -SR aand -NR b R c .

[0816] In some embodiments, R is selected from H, halogen, -CN, -N02, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0817] In some embodiments, R is selected from H, halogen, -CN, -N02, 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.

[0818] In some embodiments, R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

[0819] In some embodiments, R is selected from H, methyl, and -OH.

[0820] In some embodiments, R is H.

[0821] In some embodiments, R' is selected from halogen, -CN, -N02, 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 .

[0822] In some embodiments, R' is selected from halogen, -CN, -N02, C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 halogens or C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens or C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 halogens or C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens or C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 halogens or C 2-6alkenyl, -OR 3-6 cycloalkyl-substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

[0823] In some embodiments, R' is selected from 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).

[0824] In some embodiments, R' is selected from halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

[0825] In some embodiments, R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

[0826] In some embodiments, R' is Cl or F.

[0827] In some embodiments, is a single bond. In some embodiments,

[0828] is a double bond. In some embodiments, is a double bond.

[0829] In some embodiments, R" is selected from 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 .

[0830] In some embodiments, R" is selected from halogen, -CN, -NO2, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SRa and -NR b R c .

[0831] 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.

[0832] In some embodiments, R" is selected from F, Cl, Br, methyl, ethyl, propyl, -OH, and -NH2.

[0833] In some embodiments, R5 is selected from H, F, Cl, and Br.

[0834] In some embodiments, R5 is H.

[0835] In some embodiments, R6 is selected from H, F, Cl, and Br.

[0836] In some embodiments, R6 is H or F.

[0837] In some embodiments, each R a is independently selected from H and C 1-6 alkyl.

[0838] In some embodiments, each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

[0839] In some embodiments, each R a is independently H or i-propyl.

[0840] In some embodiments, R b and R c are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0841] In some embodiments, R b and R c are each independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0842] In some embodiments, R b is H and R c is cyclopropyl, or R b is cyclopropyl and R c is H.

[0843] In some embodiments, each R d is independently selected from the group consisting of H and C 1-6 alkyl.

[0844] In some embodiments, each R d is independently selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

[0845] In some embodiments, R e is H.

[0846] In some embodiments, a is selected from 0 and 1, and b is selected from 0 and 1.

[0847] In some embodiments, a is 0 and b is 0.

[0848] In some embodiments, e is 0.

[0849] In some embodiments, e is 1.

[0850] In some embodiments, f is 0.

[0851] In some embodiments, is a moiety selected from the group consisting of:

[0852]

[0853] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0854] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0855] In some embodiments, the term "optionally substituted" preceding a chemical group for which no substituents are specified means 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.

[0856] In some embodiments, the compound is represented by formula (17A) or (17B)

[0857]

[0858] in:

[0859] Each of them is independently a single bond or a double bond;

[0860] Q is selected from C, which can be arbitrarily substituted. 1-6 Alkyl, -OR a -SR a -NR b R c and Cy;

[0861] Cy is selected from phenyl, naphthyl, anthracene, phenanthryl, C 3-8 Carbocyclic groups, 5- to 10-membered heteroaryl groups comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, and 5- to 10-membered heterocyclic groups comprising 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'.

[0862] L A Selected from the following: -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-;

[0863] Selected from:

[0864] A is selected from C 1-8 Alkylene, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 Alkylene, and optionally wherein the C 1-8 One, two, three or more methylene groups in the alkylene group are independently replaced by groups selected from -O- and -C (=O);

[0865] B is a bond or a 5- or 6-membered heteroaryl group selected from arylene and 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 substituents selected from the group consisting of: halogen, -CN, -NO2, methyl optionally substituted by 1, 2 or 3 halogens, ethyl optionally substituted by 1, 2 or 3 halogens, propyl optionally substituted by 1, 2 or 3 halogens, -OH, -O(CH3), -NH2, -NH(CH3) and -N(CH3)2;

[0866] U is independently selected from the bond, -CH2-, -NH-, and -O-;

[0867] Each of R1 and R2 is independently selected from 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 , and -NR b R c ;

[0868] R is selected from 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 ;

[0869] R' is selected from 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 ;

[0870] R5is selected from H, F, Cl, and Br;

[0871] R6is selected from H, F, Cl, and Br;

[0872] each R a is independently selected from H and C 1-6 alkyl;

[0873] R b and R c are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl;

[0874] e is 0 or 1 ; and

[0875] The term "optionally substituted" preceding a chemical group for which substitution is not specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

[0876] In some embodiments, the compound is selected from the group consisting of:

[0877]

[0878]

[0879]

[0880]

[0881]

[0882] In some embodiments, the compound is selected from the compounds listed in Table 1:

[0883] Table 1

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894] III. Pharmaceutical Compositions and Kits

[0895] In some aspects, this 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 “the compound as described in this disclosure”.

[0896] In some embodiments, the compound of formula (1) is selected from any of the embodiments disclosed in section "II. Compounds". In some embodiments, the compound of formula (1) is selected from any of compounds 1-15 as described herein.

[0897] In some embodiments, the pharmaceutical composition comprises one or more additional active agents (e.g., one or more additional active compounds in addition to the “compound as described in the disclosure” mentioned above). In some embodiments, the additional active agent is necessary for the particular indication being prevented or treated by the compound as described in the disclosure. The additional active agent can have complementary activity to the compound as described in the disclosure such that when combined, the in vivo, in vitro, or in situ multi- component activities of the individual components are enhanced. Such combination can be achieved by mixing or formulating the individual components in a single composition, by formulating each component in separate compositions and combining them in a unit dose, or by formulating each component in separate compositions and administering them concurrently or sequentially.

[0898] The pharmaceutical composition as described in the disclosure can be provided in any suitable form depending on the route of administration. In some embodiments, the pharmaceutical composition is formulated for oral, buccal, topical, transdermal, rectal, intranasal, intrapulmonary, transmucosal, inhalation, or parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous, intraosseous, or intraperitoneal) administration.

[0899] In some embodiments, the pharmaceutical composition is formulated in a dosage form for oral administration. Dosage forms suitable for oral administration can be presented in discrete dosage forms (such as capsules, dragees, tablets, sachets, 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. Tablets can contain coatings to protect the tablet from the acidic environment of the stomach. For example, a coating can maintain the integrity of the tablet in the stomach and release the active ingredient in the intestine. In some embodiments, the pharmaceutical composition is formulated as a capsule. Capsules can 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 aqueous solutions, emulsions, suspensions. In some embodiments, the liquid oral dosage forms are solutions and / or suspensions reconstituted from non-effervescent or effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Elixirs are clear, sweetened, water-alcohol preparations. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and can contain one or more preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the other in the form of small globules. Emulsions can be oil-in-water or water-in-oil. Emulsions use non-aqueous liquids, emulsifying agents, and preservatives. Suspensions are heterogeneous mixtures in which the solute particles are not dissolved but remain suspended as a free-floating heterogeneous mixture throughout the solvent bulk. Suspensions 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 substances used in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and sources of carbon dioxide. Coloring agents and flavoring agents are used in all of the above dosage forms. In some embodiments, the pharmaceutical composition is formulated as an oral inhalation dosage form. Oral inhalation dosage forms include metered dose inhalers, dry powder inhalers, and liquid formulations for administration from a nebulizer or metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, the crystal form of the active agent is a preferred physical form to impart longer product stability.

[0900] In some embodiments, the pharmaceutical compositions are formulated and administered in unit dosage or multiple dosage form. Unit dosage form, as used in the present disclosure, refers to physically discrete units suited as unitary dosages for the subject in need and as are known in the art. Each unit dosage contains a predetermined quantity of active ingredient in association 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. Unit dosage forms can be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single package to be administered in segregated unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or pint or gallon bottles. Thus, a multiple dosage form is a multiple of unit dosages in a package that are not segregated.

[0901] The pharmaceutical compositions as described in the present disclosure can be prepared using procedures well-known in the art (see, e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)). The procedures generally include the step of bringing into association active ingredients with one or more pharmaceutically acceptable excipients. In general, pharmaceutical compositions are prepared by uniformly and intimately mixing the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired form. For example, a tablet can be prepared by compressing or molding active ingredients, optionally mixed with one or more pharmaceutically acceptable auxiliary excipients. In the case of active ingredients that exhibit insufficient solubility, solubilization methods can be used, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions, or tertiary templating.

[0902] Any pharmaceutically acceptable excipient conventionally used in the pharmaceutical industry can be employed to prepare the pharmaceutical composition as described in the present disclosure. Examples of the pharmaceutically acceptable excipient that can be used to prepare the pharmaceutical composition as described in the present disclosure can include, but are not limited to: a solvent such as water, ethanol, glycerol, propylene glycol, DMSO, polyethylene glycol; a fatty oil such as sesame oil, corn oil, cottonseed oil, or peanut oil; liquid paraffin, ethyl oleate, or isopropyl myristate; a surfactant such as a sulfate, a sulfonate, a quaternary ammonium compound, lecithin, Span, Tween, Myri, polyoxyl(40)stearate, peregol O, or poloxamer; an emulsifier such as gelatin, acacia, tragacanth, bentonite, or a surfactant such as polyoxyethylene sorbitan monooleate; a suspending agent such as sodium carboxymethylcellulose, pectin, tragacanth, Veegum, or acacia; a filler such as lactose, sucrose, trehalose, lysine, leucine, kaolin, dicalcium phosphate, mannitol, microcrystalline cellulose, or pregelatinized starch; a binder such as cellulose, PVP, or dextrin; a disintegrant such as croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, or hydroxypropyl starch; a lubricant such as talc, polyethylene glycol, calcium stearate, magnesium stearate, lycopodium, or stearic acid; a glidant such as colloidal silicon dioxide; a coloring agent such as any approved certified water-soluble FD and C dyes or water-insoluble FD and C dyes (e.g., dyes suspended on hydrated aluminum oxide); a wetting agent such as propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, or lauryl alcohol polyoxyethylene ether; an enteric coating agent such as a fatty acid, a fat, a wax, a shellac, an ammoniated shellac, or cellulose acetate phthalate; a film coating agent such as hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, or cellulose acetate phthalate; a release-modifying agent such as a polymer such as a series and cellulose esters; a sweetener such as sugar, glucose, sucrose, an artificial sweetener such as sucralose, aspartame, or saccharin, agave syrup, apple syrup, or corn syrup; a flavoring agent such as a natural flavor extracted from a plant such as a fruit, a mint, or a salicylic acid methyl ester; a buffer such as citric acid, phosphoric acid, and other organic acids and / or salts thereof; an antioxidant such as ascorbic acid, methionine, citric acid, D,L-a-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, or propyl gallate; a preservative such as benzoic acid, sodium benzoate, a p-hydroxy benzoic acid such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, sorbic acid, or benzalkonium bromide; a pH adjuster such as citric acid, sodium citrate, hydrochloric acid, NaOH, or other mild acids or bases; and a chelating agent or other material capable of binding to metal ions such as ethylenediaminetetraacetic acid (EDTA) or a salt thereof.

[0903] 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 injections. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, cyclodextrin derivatives, and vegetable oils can also be used. Oily vehicles that can be used in injections include, but are not limited to, lipophilic solvents such as fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can also contain substances such as wetting agents, suspending agents, and / or dispersing agents or flocculating agents. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. The pharmaceutical composition can also be formulated for bolus injection or continuous infusion. Alternatively, the pharmaceutical composition can be lyophilized or can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before immediate use.

[0904] In some embodiments, the pharmaceutical composition is formulated as a topical dosage form, such as for topical application to the skin and mucosa, such as in the eye. Topical dosage forms that can be used for the active ingredient can be solutions, suspensions, or emulsions. Alternatively, the active ingredient can be formulated as a cream, gel, ointment, elixir, lotion, tincture, paste, foam, aerosol, irrigant, spray, suppository, bandage, dermal patch, or any other dosage form suitable for topical application. The active ingredient can also be formulated as an aerosol for topical application, e.g., by inhalation. These dosage forms for application to the respiratory tract can be in the form of aerosols or solutions for a nebulizer, or in the form of fine powders for insufflation, alone or in combination with an inert carrier such as lactose. In this case, the mass median geometric diameter of the particles of the dosage form will be less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0905] In some embodiments, the pharmaceutical composition is formulated as a microcapsule. Microcapsules can be prepared by coacervation techniques or by interfacial polymerization, e.g., in colloidal drug delivery systems (e.g., microemulsions, liposomes, microspheres (e.g., albumin microspheres), nanoparticles, and nanocapsules) or macroemulsions.

[0906] In some embodiments, the pharmaceutical composition is formulated as a sustained release dosage form. Examples of sustained release dosage forms include, but are not limited to, shaped articles (e.g., films or microcapsules) formed from a semi-permeable matrix of a solid hydrophobic polymer which can contain a compound as described in the present disclosure, and optionally one or more additional active agents. Examples of sustained release matrices include, but are not limited to, hydrogels, polylactide, 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.

[0907] In some embodiments, the pharmaceutical composition is formulated as a controlled release dosage form. Such dosage forms can be used to provide controlled release of one or more active ingredients using, for example, different proportions of hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, layered coatings, microspheres, liposomes, nanospheres or combinations thereof to provide the desired release profile. The common goal of all controlled release dosage forms is to improve drug therapy compared to uncontrolled counterparts by which they are intended to replace. Most controlled release dosage forms are designed to initially release an amount of active ingredient that promptly produces the desired therapeutic or prophylactic effect, and then gradually and continually releases further amounts of active ingredient to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of active ingredient in the body, the dosage form must release the active ingredient(s) into the body at a rate that would replace the amount of active ingredient metabolized and excreted from the body. 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. Advantages of controlled release dosage forms include extended activity of the active ingredient, reduced frequency of administration, and increased patient compliance. Additionally, controlled release dosage forms can be used to affect the time of onset of action or other characteristics, such as blood levels of the active ingredient, and thereby can affect the incidence of undesirable side effects. Suitable controlled release dosage forms can be readily selected and used with the active ingredients provided in the present disclosure.

[0908] In some embodiments, the pharmaceutical composition is formulated as a dosage form for rectal administration, such as rectal suppositories, capsules, and tablets. Rectal suppositories as used in the present disclosure refer to solid bodies which are inserted into the rectum and which melt or soften at body temperature to 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 monoglycerides, diglycerides, and triglycerides of fatty acids. Combinations of various bases can be used. Agents for raising the melting point of the suppository include sperm oil and waxes. Rectal suppositories can be prepared by compression methods or by molding. Tablets and capsules for rectal administration are manufactured using the same substances and by the same methods as are used for oral administration.

[0909] In some embodiments, the pharmaceutical composition is subjected to sterilization. Sterilization refers to any process to remove, kill, or de-activate all forms of life, particularly microorganisms, and other biological agents (such as prions) present in or on a particular surface, object, or fluid. Sterilization can be achieved in various ways, including heat, chemical action, irradiation, high pressure, and filtration. For example, sterilization can be accomplished by sterile filtration.

[0910] The level of active ingredients in the pharmaceutical compositions as described in the present disclosure is effective to deliver an amount that, at the time of administration, treats one or more symptoms of a disease or condition described in the present disclosure, causes prevention or amelioration of the one or more symptoms. Specifically, the amount of the compounds as described in the present disclosure and optional additional active pharmaceutical agents will depend on the subject being treated, the severity of the disease or condition, the rate of administration, the absorption, inactivation, and excretion rates of the active ingredients being administered, the judgment of the prescribing physician, and other factors known to those of skill in the art. In some embodiments, the pharmaceutical composition comprises 0.05% to 80%, 0.1% to 50%, 0.2% to 40%, 0.5% to 25%, 1% to 20%, 5% to 15%, or 7% to 12% (wt / wt) of a compound as described in the present disclosure. 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. The remainder of the pharmaceutical composition is comprised of one or more pharmaceutically acceptable excipients.

[0911] 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. The compound of Formula (1) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition can be surrounded by suitable packaging material. Packaging materials for use in packaging the kits are well known in the art. Examples of packaging materials include any packaging material suitable for the selected dosage form and intended mode of administration and treatment, including blister packs, tubes, bottles, inhalers, pumps, pouches, vials, syringes, bottles, or other containers. The kits can have instructions for use included in written material. In addition, clinical trial results and discussion of results, lists of side effects, drug interactions, and / or additional information useful to health care providers, such as scientific literature references, can also be included in the written material. 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 within the same container in the kit. Additional articles of manufacture for use (e.g., graduated cylinders for liquid formulations, foil packaging to minimize exposure to air, etc.) can be included in the kit.

[0912] IV. Therapeutic methods and therapeutic uses

[0913] In some aspects, the disclosure provides a method for preventing or treating a disease or condition in 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.

[0914] In some embodiments, the compound of Formula (1) is selected from any one described in any 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.

[0915] In some embodiments, the pharmaceutical composition comprises one or more additional active agents (e.g., one or more additional active compounds in addition to the “compound as described in the disclosure” mentioned above). In some embodiments, the additional active agent is necessary for the particular indication being prevented or treated by the compound as described in the disclosure. The additional active agent can have complementary activity to the compound as described in the disclosure such that they do not adversely affect each other when concurrently administered. Such agents can be administered in conjunction with the compound as described in the disclosure in a quantity that is effective for the purpose intended.

[0916] In some embodiments, the method further comprises administering to the subject in need thereof one or more additional active agents, wherein the one or more additional active 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 the subject in need thereof one or more additional active agents, wherein the one or more additional active 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 the one or more additional active agents are administered prior to, concurrently with, or subsequent to the administration of the compound of Formula (1), or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof.

[0917] In some embodiments, the disease or condition is selected from the group consisting of a hyperproliferative disease, a cardiovascular disease, a hematologic disease, an infectious disease, an endocrine disease, a metabolic disease, a gastrointestinal disease, a respiratory disease, inflammation, opioid addiction, and a urologic disease.

[0918] In some embodiments, the disease or condition is a hyperproliferative disease.

[0919] In some embodiments, the hyperproliferative disease is a tumor.

[0920] In some embodiments, the tumor is a cancer or a sarcoma.

[0921] In some embodiments, the cancer is a hematopoietic cancer or a solid tumor.

[0922] In some embodiments, the hematopoietic cancer is selected from the group consisting of a leukemia, a lymphoma, a heavy chain disease, a myeloproliferative disorder, a multiple myeloma, a plasmacytoma, common hypereosinophilic syndrome, inflammatory myofibroblastic tumor, and an immunocyte amyloidosis.

[0923] In some embodiments, the solid tumor is selected from nervous system cancer, exocrine cancer, musculoskeletal cancer, gastrointestinal cancer, respiratory system cancer, genitourinary system cancer, gynecological cancer, skin cancer, soft tissue cancer, oral cavity cancer, head and neck cancer, esophageal cancer, liver cancer, and pancreatic cancer.

[0924] In some embodiments, the disease or condition is a cardiovascular disease.

[0925] In some embodiments, the cardiovascular disease is selected from atherosclerosis, cardiac hypertrophy, hypertension, coronary artery disease, myocarditis, pericarditis, heart valve disease, stenosis, restenosis, in-stent stenosis, angina, 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.

[0926] In some embodiments, the disease or condition is pulmonary hypertension.

[0927] In some embodiments, the disease or condition is pulmonary arterial hypertension.

[0928] In some embodiments, the disease or condition is selected from idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, drug- or toxin-induced pulmonary arterial hypertension, idiopathic pulmonary veno-occlusive disease, heritable pulmonary veno-occlusive disease, drug-, toxin-, or radiation-induced pulmonary veno-occlusive disease, idiopathic pulmonary capillary hemangiomatosis, heritable pulmonary capillary hemangiomatosis, drug-, toxin-, or radiation-induced pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.

[0929] In some aspects, the disclosure provides a method for inhibiting tumor growth or preventing tumor 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.

[0930] In some aspects, the disclosure provides a method for degrading 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.

[0931] For use in treating or preventing a disease or condition as described in the present disclosure, the active ingredients are administered in a therapeutically effective amount. The attending physician will determine the dosage regimen, taking into account the age, weight, disease stage, and other factors specific to the subject to be treated. The therapeutically effective amount of the active ingredients will vary with the nature and severity of the disease or condition and the route of administration of the active ingredients. Frequency and dosage (or dosing) will also vary according to factors specific for each subject. The active ingredients can be administered at one time, or can be divided into a number of smaller doses, to be administered at intervals of time. Exemplary dosages (or dosing) 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 will be appreciated that the precise dosing and treatment duration are 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 testing. It will be appreciated that for any particular subject, specific dosing schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the therapies. In some instances, it can be desirable to use dosages (or dosing) of active ingredients outside the range disclosed in the present disclosure, as will be apparent to those skilled in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt or terminate therapy based on the subject’s response.

[0932] In some aspects, the present disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for use in therapy.

[0933] In some aspects, the present disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition for use in preventing or treating a disease or condition in which degradation of GRK2 is beneficial in a subject.

[0934] In some aspects, the present disclosure provides a compound of Formula (1) as described herein, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition and one or more pharmaceutically acceptable excipients for use in inhibiting tumor growth or preventing tumor recurrence in a subject.

[0935] 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 in a subject or inhibiting the activity of GRK2 in a subject.

[0936] In some aspects, the disclosure provides 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 manufacture of a medicament for preventing or treating a disease or condition in which degradation of GRK2 is beneficial in a subject.

[0937] In some aspects, the disclosure provides 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 manufacture of a medicament for inhibiting tumor growth or preventing tumor recurrence in a subject.

[0938] In some aspects, the disclosure provides 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 manufacture of a medicament for degrading GRK2 in a subject or inhibiting the activity of GRK2 in a subject.

[0939] V. General Synthetic Schemes

[0940] Compounds as described in the disclosure can be synthesized according to techniques known to those of skill in the art of organic synthesis starting from compounds described in the chemical literature and / or from commercially available chemicals in view of the descriptions of the synthesis of the reactants useful in the synthesis of compounds as described in the disclosure or providing references to the descriptions of the synthesis of the products (e.g., “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., New York). “Commercially available chemicals” can be obtained from standard commercial sources, including but not limited to Fisher Scientific Co. (Pittsburgh, PA). Additionally, chemicals known in the catalogs but not commercially available are optionally prepared by custom chemical synthesis companies, many of which standard chemical supply companies provide custom synthesis services.

[0941] The following general synthetic schemes for compounds as described in the present disclosure are provided for illustrative purposes only. It will be appreciated by those skilled in the art that the compounds can be prepared by analogous methods or by incorporating other methods known to those skilled in the art. It will also be appreciated that those skilled in the art will be able to prepare in analogous fashion as described below by using appropriate starting materials and altering the synthetic route as necessary.

[0942] Scheme 1

[0943] Scheme 1 illustrates a general synthetic method for synthesizing compounds according to the present application, which include a thiazole ring in their backbone:

[0944]

[0945] wherein R, R1, R2, R', m, B and DT are as defined above.

[0946] Various target compounds according to the present application can be synthesized according to Scheme 1 by reacting a corresponding precursor compound P with a compound Q. Briefly, in one embodiment, compound P (0.9 mmol) is dissolved in 5 ml of N,N-dimethylformamide (DMF) and triethylamine (Et3N) (3.6 mmol), 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 is complete (e.g., as detected by LCMS) of the starting material compound Q. 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 phase is 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 by reverse phase high performance liquid chromatography (eluent: acetonitrile-water, gradient 35% to 60%) to obtain the white or off-white solid product, i.e., compound AF.

[0947] Scheme 2

[0948] Scheme 2 illustrates a general synthetic method for synthesizing compounds according to the present application:

[0949]

[0950] wherein Q, L AX1, X2, X3, B, and DT are as defined above. Various target compounds according to the present application can be synthesized according to Scheme 2 by reacting the corresponding precursor compound P1 with compound Q. Briefly, in one example, to a mixture of compound Q (0.066 mmol) and compound P1 (0.066 mmol) in DMF (3 mL) is added DIEA (0.099 mmol) and HATU (0.073 mmol). 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 layers are dried over Na2S04, concentrated in vacuo, and the residue is purified by preparative HPLC to obtain the target compound. It will be appreciated by those skilled in the art that the reagents and procedures as mentioned above are for illustration purposes only and should not be construed to be limiting. For example, in another example, DIEA can be interchanged with similar bases (e.g., TEA).

[0951] Examples

[0952] The present disclosure will now be described with reference to the following examples which are intended to be illustrative, but not limiting, of the present application. Unless otherwise indicated, if specific conditions are not indicated in the examples, the examples were performed according to routine conditions or manufacturer’s recommended conditions. Reagents or instruments used in the absence of manufacturer’s indication are routine products commercially available. Those skilled in the art will appreciate that the examples described herein are not intended to limit the scope of the claimed application.

[0953] As used herein, in the event of a discrepancy between a structure and a chemical name provided for a particular compound, the structure controls.

[0954] Synthetic Examples

[0955] Example 1: Preparation of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)acetamide (Compound 1)

[0956]

[0957] Step 1 : Synthesis of tert-butyl (5-(hydroxy(phenyl)methyl)thiazol-2-yl)carbamate

[0958] N-Boc-2-aminothiazole (2 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and the reaction was cooled to -70 °C and n-butyllithium solution (10 mL, 2.5 N in THF) was added slowly dropwise under argon protection. The reaction was allowed to continue 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 and the reaction was allowed to continue at -70 °C for 30 minutes and then the reaction was slowly warmed to room temperature. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride solution to it 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) as off-white solid (2.9 g, yield 95%).

[0959] Step 2: Synthesis of 5-benzyl-2-aminothiazole

[0960] Compound tert-butyl (5-(hydroxy(phenyl)methyl)thiazol-2-yl)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 one after the other while stirring in an ice bath. After completion of the dropwise addition, the reaction was continued to stir at room temperature for about 2 hours. After completion of the reaction, 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 with dichloromethane and separated. 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, yield 85%) as off-white solid.

[0961] Step 3: Synthesis of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)acetamide Step 1 : Synthesis of tert-butyl (5-((4-chlorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate

[0962] DMSO and 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 sequentially while stirring at room temperature. After about 1 hour of reaction, LCMS check showed that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to it and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a light yellow colored concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 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) as off-white solid (176 mg, yield 40%).

[0963] 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.98 (s, 1H), 7.74-7.64 (m, 1H), 7.54 (s, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.26-7.15 (m, 4H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 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). Formula: C 25 H 22 N4O4S, MS calc: 474.5; MS found: 475.3 [M+1] + .

[0964] 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)

[0965]

[0966] Step 2: Synthesis of 5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-amine

[0967] N-Boc-2-aminothiazole (2 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and the reaction was cooled to -70 °C and n-butyllithium solution (10 mL, 2.5 N in THF) was added slowly dropwise under argon protection. The reaction was allowed to continue 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 and the reaction was allowed to continue at -70 °C for 30 minutes and then the reaction was slowly warmed to room temperature. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride solution to it 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) as off-white solid (3.1 g, yield 91 %).

[0968] Step 3: Synthesis of N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)acetamide

[0969] 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 one after the other 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 with dichloromethane and separated. 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 off-white solid.

[0970] Step 1 : Synthesis of methyl 4-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate Step 2: Synthesis of methyl 2-(bromomethyl)-4-(4-(tert-butoxycarbonyl)phenoxy)benzoate

[0971] 5-[(4-chlorophenyl)methyl]-1,3-thiazolyl-2-amine (22 mg, 0.1 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (Et3N) (15 mg, 0.15 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)acetic acid (32 mg, 0.1 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea cationic hexafluorophosphate (HATU, 45 mg, 0.12 mmol) were added sequentially with stirring at room temperature. After approximately 1 hour of reaction, LCMS analysis showed that the starting materials had reacted completely. The reaction mixture was quenched with 10 mL of distilled water, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude, pale yellow concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazolyl-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)acetamide (compound 2) (18 mg, yield 35%), which was a grayish-white solid.

[0972] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.32 (s, 1H), 11.12 (s, 1H), 7.88 (d, J = 6.8 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.32–7.20 (m, 3H), 5.14 (dd, J = 12.9, 5.3 Hz, 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 ClN4O5S, MS calculated value: 523.0; MS experimental value: 523.3 [M+1] + .

[0973] Example 3: Preparation of N-(5-benzylthiazo-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-oxoisoindoline-5-yl)acetamide (Compound 3)

[0974]

[0975] DMSO and 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 while stirring at room temperature. After the reaction was stirred at room temperature for about 1 hour, LCMS detection showed that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water thereto, and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellow concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 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) as a white solid (16 mg, yield 32%).

[0976] 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 11.00 (s, 1H), 7.56 (s, 1H), 7.43 (d, J = 9.8 Hz, 1H), 7.30 (t, J = 6.9 Hz, 2H), 7.24 (q, J = 9.7, 9.0 Hz, 4H), 5.15-5.06 (m, 1H), 4.54 (d, J = 17.0 Hz, 1H), 4.37 (d, J = 17.3 Hz, 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). Formula: C 25 H 21 FN4O4S, MS calc: 492.5; MS found: 493.4 [M+1] + .

[0977] Example 4: Preparation of N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide (Compound 4)

[0978]

[0979] DMSO and 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)acetic acid (32 mg, 0.1 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 45 mg, 0.12 mmol) were added sequentially while stirring at room temperature. After about 1 hour of reaction, LCMS check showed that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to it and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a light yellow colored concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 1 / 100 to 1 / 30) to obtain the product N-(5-benzylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)acetamide (Compound 4) as a white solid (14 mg, yield 29%).

[0980] 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 11.12 (s, 1H), 7.88 (d, J = 6.8 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.38 - 7.34 (m, 3H), 7.32 - 7.20 (m, 3H), 5.14 (dd, J = 12.9, 5.3 Hz, 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). Formula: C 25 H 20 N4O5S, MS calc: 488.5; MS exp: 489.3 [M+l] + .

[0981] Example 5: Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)acetamide (Compound 5)

[0982]

[0983] DMSO and 2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)acetic acid (15 mg, 0.05 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 23 mg, 0.06 mmol) were added sequentially while stirring at room temperature. After about 1 hour of reaction, LCMS check showed that the starting material had completely reacted. The reaction was quenched by adding 8 ml of distilled water to it and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a light yellow colored concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)acetamide (Compound 5) as a white solid (8 mg, yield 32%).

[0984] 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.98 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.31 - 7.19 (m, 3H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 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). Formula: C 25 H 21 ClN4O4S, MS calc: 509.0; MS found: 509.3 [M+l] + .

[0985] 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)

[0986]

[0987] 5-[(4-chlorophenyl)methyl]-1,3-thiazolyl-2-amine (11 mg, 0.05 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (Et3N) (10 mg, 0.10 mmol), 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)acetic acid (15 mg, 0.05 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea cationic hexafluorophosphate (HATU, 23 mg, 0.06 mmol) were added sequentially with stirring at room temperature. After approximately 1 hour of reaction, LCMS analysis showed that the starting materials had reacted completely. The reaction mixture was quenched with 8 mL of distilled water, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude, pale yellow concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain N-(5-(4-chlorobenzyl)thiazolyl-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)acetamide (compound 6) (7.6 mg, 30% yield) as a white solid.

[0988] 1 ¹H 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 ClN4O4S, MS calculated value: 509.0; MS experimental value: 509.4 [M+1] + .

[0989] Example 7: Preparation of N-(5-benzylthiazolyl-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxy)benzamide (Compound 7)

[0990]

[0991] Step 3: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-5-yl)oxy)benzoic acid tert-butyl ester

[0992] 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 was heated to 100 °C and stirred at this temperature for about 3 hours. LCMS detection showed that the starting material had completely reacted. After the temperature of the reaction was reduced to room temperature, the reaction was filtered and the filtrate was diluted by adding 20 ml of water to it and extracted and separated by adding ethyl acetate (2 x 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 obtain the crude product. After column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10), methyl 4-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate was obtained as a light yellow solid (317 mg, yield 60%).

[0993] Step 4: Synthesis of compound 4-((2-(2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-5-yl)oxy)benzoic acid

[0994] 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 allowed to continue at this temperature with stirring for about 4 hours. LCMS detection showed that the starting material had completely reacted. The reaction was allowed to cool to room temperature and the insoluble material was removed by suction filtration. The filtrate was diluted by adding 15 ml of water to it and extracted and separated by adding dichloromethane (2 x 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 obtain the crude product. After column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10), methyl 2-(bromomethyl)-4-(4-(tert-butoxycarbonyl)phenoxy)benzoate was obtained as a light yellow liquid (311 mg, yield 80%).

[0995] Step 5: Synthesis of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-5- yl)oxy)benzamide Step 1 : Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoate

[0996] 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 mixed system was heated to 90 °C and the reaction was allowed to stir 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 to it and extracted and separated by adding dichloromethane (3 x 10 mL) to it. 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), tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoate was obtained as an off-white solid (145 mg, yield 45%).

[0997] Step 2: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)benzoic acid 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

[0998] 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 solvents were removed by concentration under reduced pressure to obtain crude 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)benzoic acid (120 mg, yield 95%).

[0999] Step 1 : Synthesis of methyl 5-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate Step 2: Synthesis of methyl 2-(bromomethyl)-5-(4-(tert-butoxycarbonyl)phenoxy)benzoate

[1000] DMSO and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindoline (Compound 2) (10 mg, 0.026 mmol) were added sequentially while 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 it, and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellowish concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 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) as a white solid (5 mg, yield 35%).

[1001] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.99 (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.43 - 7.26 (m, 6H), 7.27 - 7.21 (m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.32 (d, J = 17.5 Hz, 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). Formula: C 30 H 24 N4O5S, MS calc: 552.6; MS exp: 553.4 [M+1] + .

[1002] 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)

[1003]

[1004] DMSO (2 mL) and triethylamine (Et3N) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)benzoic acid (10 mg, 0.026 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added sequentially while stirring at room temperature. After about 1 hour of reaction, LCMS check showed that the starting material had completely reacted. The reaction was quenched by adding 10 ml of distilled water to it and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until the extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a light yellow colored concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)benzamide (Compound 8) as a white solid (4.6 mg, yield 30%).

[1005] 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.98 (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.3 Hz, 1H), 7.46 - 7.29 (m, 5H), 7.29 - 7.25 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 17.5 Hz, 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). Formula: C 30 H 23 ClN4O5S, MS calc 587.0; MS found 587.4 [M+l] + .

[1006] Example 9: Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)benzamide (Compound 9)

[1007]

[1008] Step 3: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid tert-butyl ester Step 4: Synthesis of 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid

[1009] 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 mixed system was heated to 130 °C and the reaction was allowed to stir at this temperature for about 3 hours. LCMS detection showed that the starting material had disappeared. After allowing the mixed system to cool to room temperature, the mixed system was filtered and the filtrate was diluted by adding 15 ml of water to it and extracted and separated by adding ethyl acetate (2 x 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 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 was obtained as a light yellow solid (383 mg, yield 55%).

[1010] ​ ​

[1011] 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 mixed system was heated to 130 °C and the reaction was allowed to stir at this temperature for about 3 hours. LCMS detection showed that the starting material had disappeared. After allowing the mixed system to cool to room temperature, the mixed system was filtered and the filtrate was diluted by adding 15 ml of water to it and extracted and separated by adding ethyl acetate (2 x 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 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 was obtained as a light yellow solid (383 mg, yield 55%).

[1012] ​ ​

[1013] DMSO and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added sequentially while stirring at room temperature. After about 1 hour of reaction, LCMS check showed that the starting material had completely reacted. The reaction was quenched by adding 5 ml of distilled water to it and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until the extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a light yellow colored concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)oxy)benzamide (Compound 9) as a white solid (5.2 mg, yield 34%).

[1014] 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 11.13 (s, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 2H), 7.98 (dd, J = 8.1, 2.1 Hz, 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, 5.4 Hz, 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). Formula: C 30 H 21 ClN4O6S, MS calc: 601.0; MS found: 601.4 [M+l] + .

[1015] Example 10: Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)benzamide (Compound 10)

[1016]

[1017] 5-Benzyl-2-aminothiazole (5.3 mg, 0.028 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (Et3N) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)benzoic acid (10 mg, 0.025 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea cationic hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added sequentially with stirring at room temperature. After approximately 1 hour of reaction, LCMS analysis showed that the starting materials had reacted completely. The reaction mixture was quenched with 5 mL of distilled water, and ethyl acetate was added to extract and separate the liquid. The extraction was repeated three times until complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude, pale yellow concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-benzylthiazolin-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)benzamide (compound 10) (4.3 mg, yield 30%), which was a white solid.

[1018] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.51 (s, ¹H), 11.13 (s, ¹H), 8.16 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.40–7.18 (m, 8H), 5.16 (dd, J = 12.8, 5.3 Hz, 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 value: 566.6; MS experimental value: 567.4 [M+1] + .

[1019] Example 11: Preparation of N-(5-benzylthiazolyl-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)oxy)benzamide (Compound 11)

[1020]

[1021] ​

[1022] 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 mixed system was heated to 100 °C and the reaction was allowed to stir at this temperature for about 3 hours. LCMS detection showed that the starting material had disappeared. After allowing the mixed system to cool to room temperature, the mixed system was filtered and the filtrate was diluted by adding 20 ml of water to it and extracted and separated by adding ethyl acetate (2 x 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 obtain the crude product. After column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10), methyl 5-(4-(tert-butoxycarbonyl)phenoxy)-2-methylbenzoate (277 mg, yield 53%) was obtained as a light yellow solid.

[1023] ​

[1024] 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 and then a catalytic amount of azobisisobutyronitrile (AIBN) (6 mg) was added and the reaction was allowed to continue at this temperature with stirring for about 4 hours. LCMS detection showed that the starting material had disappeared. The reaction was allowed to cool to room temperature, diluted by adding 15 mL of water to it and extracted and separated by adding dichloromethane (2 x 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 obtain the crude product. After column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10), methyl 2-(bromomethyl)-5-(4-(tert-butoxycarbonyl)phenoxy)benzoate (255 mg, yield 75%) was obtained as a light yellow liquid.

[1025] ​ ​

[1026] 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 mixed system was heated to 90 °C and the reaction was allowed to stir 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 to it and extracted and separated by adding dichloromethane (3 x 10 mL) to it. 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), tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoate was obtained as an off-white solid (111 mg, yield 42%).

[1027] ​

[1028] 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 obtain 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)benzoic acid (106 mg, yield 95%).

[1029] Step 5: Synthesis of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-1 -yl)methyl)benzamide Step 5: Synthesis of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-1 -yl)methyl)benzamide

[1030] DMSO and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added sequentially while stirring at room temperature. After about 1 hour of reaction at room temperature, LCMS detection showed that the starting material had completely reacted. The reaction was quenched by adding 6 ml of distilled water to it and ethyl acetate was added to extract and separate the liquid. Extraction was repeated three times until extraction was complete. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a light yellow colored concentrate. The concentrate was then subjected to column chromatography (methanol / methylene chloride = 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) as a white solid (4.5 mg, yield 31%).

[1031] 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.85 (s, 1H), 8.03-7.98 (m, 2H), 7.80 (d, J = 8.9 Hz, 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, 5.1 Hz, 1H), 4.39 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.2 Hz, 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). Formula: C 30 H 24 N4O5S, MS calc: 552.6; MS found: 553.4 [M+l] + .

[1032] 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)

[1033]

[1034] 5-[(4-chlorophenyl)methyl]-1,3-thiazolyl-2-amine (6 mg, 0.026 mmol) was dissolved in 2 mL of N,N-dimethylformamide (DMF), and triethylamine (Et3N) (7 mg, 0.066 mmol), 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)oxy)benzoic acid (10 mg, 0.026 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea cationic hexafluorophosphate (HATU, 12 mg, 0.03 mmol) were added sequentially with stirring at room temperature. After approximately 1 hour of reaction, LCMS analysis showed that the starting materials had reacted completely. The reaction mixture was quenched with 6 mL of distilled water, and ethyl acetate was added for extraction and separation. The extraction was repeated three times until complete. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude, pale yellow concentrate. The concentrate was then subjected to column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) to obtain the product N-(5-(4-chlorobenzyl)thiazolyl-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)oxy)benzamide (compound 12) (4.3 mg, yield 28%), which was a white solid.

[1035] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.31 (s, 1H), 10.97 (s, 1H), 8.07 (d, J = 8.9 Hz, 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, 5.1 Hz, 1H), 4.40 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 4.05 (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 30 H 23 ClN4O5S, MS calculated value: 587.0; MS experimental value: 587.4 [M+1] + .

[1036] Example 13: Preparation of N-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-4-oxobutyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino) benzamide (Compound 13)

[1037]

[1038]

[1039] Step 1 : tert-Butyl (3-aminobenzyl)carbamate

[1040] To a 3 L four-necked flask was added 3-(aminomethyl)aniline (60.0 g, 0.49 mol, 1.0 eq) and MeCN (900 mL), and a solution of Boc20 (107 g, 0.49 mol, 1.0 eq) in MeCN (300 mL) was added dropwise rapidly. The reaction was allowed to stir at room temperature for 1 h, concentrated to dryness to obtain the crude product, which was purified by column (PE / EtOAc = 5: 1) to obtain the product as a yellow solid (110 g, 100% yield).

[1041] Step 2: Synthesis of (Z)-isonicotinic hydrazide

[1042] To a 1 L single-necked flask was added isonicotinonitrile (50.0 g, 0.48 mol, 1.0 eq), EtOH (120 mL), Et20 (120 mL), and 80% hydrazine hydrate (250 mL) sequentially, and the reaction was allowed to stir 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 obtain the product as an off-white solid (60 g, 91.8% yield).

[1043] Step 3: Synthesis of ethyl 3-(2,2,2-trifluoroacetamido)benzoate

[1044] Ethyl 3-amino benzoate (83.0 g, 0.50 mol, 1.0 eq), THF (1.66 L) and TEA (76.0 g, 0.75 mol, 1.5 eq) were added to a 3 L four necked flask. The reaction was cooled to 0-5 °C in an ice water bath and TFAA (110.0 g, 0.53 mol, 1.05 eq) was added drop wise while maintaining the temperature <10 °C. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The reaction was quenched by adding 1 N HC1 (1 L) to it. Water (1 L) and EtOAc (1 L) were added and the reaction was stirred and then allowed to separate. The organic phase was successively washed 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 obtain the product as a yellow solid (120 g, 91.4% yield) which was used directly in the next step.

[1045] Step 4: Synthesis of ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2- trifluoroacetamido)benzoate

[1046] Ethyl 3-(2,2,2-trifluoroacetamido)benzoate (120.0 g, 0.46 mol, 1.0 eq), DMF (1.2 L), benzyl bromoacetate (116.0 g, 0.50 mol, 1.1 eq) and K2CO3 (95.0 g, 0.69 mol, 1.5 eq) were added successively to a 3 L single necked flask. The reaction was allowed to stir 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 obtain the product as an off-white solid (170 g, 90.4% yield) which was used directly in the next step.

[1047] Step 5: Synthesis of N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2- trifluoroacetyl)glycine

[1048] Ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoate (170.0 g, 0.42 mol, 1.0 eq), EtOH (2.1 L) and 10% wet Pd / C (34.0 g, 57% water content) were added successively to a 5 L four necked flask. The reaction was allowed to stir at 15 °C under H2 (15 psi) for 4 h. The reaction was filtered and the filtrate was concentrated to obtain the product as a light yellow transparent solid (132 g, 100% yield) which was used directly in the next step.

[1049] Step 6: Synthesis of (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylidene)hydrazino)-2- oxoethyl)-2,2,2-trifluoroacetamido)benzoic acid ethyl ester Step 7: Synthesis of (Z)-3-((2-(2-(amino(pyridin-4-yl)methylidene)hydrazino)-2- oxoethyl)amino)benzoic acid ethyl ester

[1050] N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine (132.0 g, 0.41 mol, 1.0 eq), (Z)-isonicotinohydrazide (58.0 g, 0.43 mol, 1.04 eq), DMF (1.4 L), HOBt (59.0 g, 0.44 mol, 1.06 eq) and EDCI (136.0 g, 0.71 mol, 1.73 eq) were added to a 2 L single neck flask sequentially. The reaction was allowed to stir at 15 °C for 4 h under N2protection. 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 obtain 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 vacuum dried to obtain the product as a white solid (118 g, 65.2% yield).

[1051] Step 8: Synthesis of ethyl 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate Step 9: Synthesis of 3-(((3-(pyridin-4-yl)-1 H-1,2,4-triazol-5-yl)methyl)amino)benzoic acid

[1052] (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylene)hydrazino)-2-oxoethyl)-2,2,2- trifluoroacetamido)benzoic acid ethyl ester (110.0 g, 0.25 mol, 1.0 eq), K2CO3(104.0 g, 0.75 mol, 3.0 eq) and EtOH (2.2 L) were added to a 3 L single neck flask. The reaction was allowed to stir 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 vacuum dried to obtain the product as a white solid (68 g, 79.2% yield) which was used directly in the next step.

[1053] Step 10: Synthesis of 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoic acid 2,5- dioxopyrrolidin-1 -yl ester

[1054] (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazino)-2- oxoethyl)amino)benzoic acid ethyl ester (68.0 g, 0.20 mol, 1.0 equiv), EtOH (2.2 L), and AcOH (136 mL) were added sequentially to a 2 L single neck flask. The reaction was allowed to stir at 90 °C under reflux for 6 h. 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 re-extracted 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 obtain 60 g of crude product. The crude product was slurried in ethyl acetate (420 mL) at 60 °C for 1 h, stirred in an ice water bath for 0.5 h, filtered, and the filter cake was vacuum dried to obtain the product as a white solid (60.3 g, 98.6% yield).

[1055] Step 11 : Synthesis of 4-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)butanamide

[1056] Ethyl 3-(((5-(pyridin-4-yl)-4H-l,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 allowed to stir at 15 °C for 16 h. 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 h, and filtered. The filter cake was vacuum dried to obtain the product as a white solid (47.0 g, 85.8% yield) which was used directly in the next step.

[1057] 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 Step 13: Synthesis of 4-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)butanamide

[1058] 3-(((3-(pyridin-4-yl)-lH-l,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 allowed to stir at 15 °C for 4 h. The reaction was poured into water (2 L). A large amount of solid precipitated. The solid was filtered, and the filter cake was vacuum dried to yield the product as an off-white solid (53.7 g, 86.4% yield) which was used directly in the next step.

[1059] 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 Step 1 : tert-Butyl (3-aminobenzyl)carbamate

[1060] Into a 100 mL single neck flask, 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. The reaction was allowed to stir at 70 °C for 17 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 60:1) to obtain the product as a yellow solid (2.62 g, 83.7% yield).

[1061] Step 2: Synthesis of (Z)-isonicotinic hydrazide Step 3: Synthesis of ethyl 3-(2,2,2-trifluoroacetamido)benzoate

[1062] Into a 100 mL single neck flask, 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. The reaction was allowed to stir at 70 °C for 17 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 60:1) to obtain the product as a yellow solid (2.62 g, 83.7% yield).

[1063] Step 4: Synthesis of ethyl 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2- trifluoroacetamido)benzoate Step 5: Synthesis of N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2- trifluoroacetyl)glycine

[1064] Into a 100 mL single neck flask, 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. The reaction was allowed to stir at 70 °C for 17 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 60:1) to obtain the product as a yellow solid (2.62 g, 83.7% yield).

[1065] Step 6: Synthesis of (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylidene)hydrazino)-2- oxoethyl)-2,2,2-trifluoroacetamido)benzoic acid ethyl ester ​​

[1066] To a 100 mL four-necked flask, 4-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)butanamide (160 mg, 0.28 mmol, 1.0 eq), DMF (5.5 mL), TEA (113 mg, 1.12 mmol, 4.0 eq) and 3-(((5-(pyridin-4-yl)-4H- 1,2,4-triazol-3-yl)methyl)amino)benzoic acid 2,5-dioxopyrrolidin-l-yl ester (110 g, 0.28 mmol, 1.0 eq) were added sequentially. The reaction was allowed to stir at 30 °C for 16 h under N2protection. The reaction was poured into 50 mL of water. The mixture was filtered and the filter cake was vacuum dried to obtain the crude product. The product was prepared and purified by HPLC to obtain the product as a yellow solid (50 mg, 24.1% yield).

[1067] Example 14: Preparation of N-(3-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-6-oxohexyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3- yl)methyl)amino)benzamide (Compound 14)

[1068]

[1069] ​

[1070] To a 3 L four-necked flask, 3-(aminomethyl)aniline (60.0 g, 0.49 mol, 1.0 eq) and MeCN (900 mL) were added and a solution of Boc20 (107 g, 0.49 mol, 1.0 eq) in MeCN (300 mL) was added dropwise quickly. The reaction was allowed to stir at room temperature for 1 h, concentrated to dryness to obtain the crude product which was purified by column (PE / EtOAc = 5: 1) to obtain the product as a yellow solid (110 g, 100% yield).

[1071] ​

[1072] Isonicotinonitrile (50.0 g, 0.48 mol, 1.0 eq), EtOH (120 mL), Et20 (120 mL) and 80% hydrazine hydrate (250 mL) were added sequentially into a 1 L single neck flask and the reaction was allowed to stir 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 obtain the product as off-white solid (60 g, 91.8% yield).

[1073] ​

[1074] Ethyl 3-aminobenzoate (83.0 g, 0.50 mol, 1.0 eq), THF (1.66 L) and TEA (76.0 g, 0.75 mol, 1.5 eq) were added into a 3 L four necked flask. The reaction was cooled to 0-5 °C in an ice water bath and TFAA (110.0 g, 0.53 mol, 1.05 eq) was added drop wise while maintaining the temperature <10 °C. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The reaction was quenched by adding 1 N HC1 (1 L) to it. 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 obtain the product as yellow solid (120 g, 91.4% yield) which was used directly in the next step.

[1075] ​

[1076] Ethyl 3-(2,2,2-trifluoroacetamido)benzoate (120.0 g, 0.46 mol, 1.0 eq), DMF (1.2 L), benzyl bromoacetate (116.0 g, 0.50 mol, 1.1 eq) and K2C03(95.0 g, 0.69 mol, 1.5 eq) were added sequentially into a 3 L single neck flask. The reaction was allowed to stir 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 obtain the product as off-white solid (170 g, 90.4% yield) which was used directly in the next step.

[1077] ​

[1078] 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 to a 5 L four-necked flask. The reaction was allowed to stir at 15 °C under H2(15 psi) for 4 h. The reaction was filtered, and the filtrate was concentrated to obtain the product as a light yellow transparent solid (132 g, 100% yield), which was used directly in the next step.

[1079] ​ 2,2-trifluoroacetamido)benzoic acid ethyl ester

[1080] (Z)-3-(N-(2-(2-(Amino(pyridin-4-yl)methylene)hydrazino)-2-oxoethyl)-2,2,2- trifluoroacetamido)benzoic acid ethyl ester (110.0 g, 0.25 mol, 1.0 equiv), K2CO3(104.0 g, 0.75 mol, 3.0 equiv), and EtOH (2.2 L) were added to a 3 L single-necked flask. The reaction was allowed to stir 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 vacuum dried to obtain the product as a white solid (68 g, 79.2% yield), which was used directly in the next step.

[1081] Step 7: Synthesis of (Z)-3-((2-(2-(amino(pyridin-4-yl)methylidene)hydrazino)-2- oxoethyl)amino)benzoic acid ethyl ester benzoic acid ethyl ester

[1082] (Z)-3-(N-(2-(2-(Amino(pyridin-4-yl)methylene)hydrazino)-2-oxoethyl)-2,2,2- trifluoroacetamido)benzoic acid ethyl ester (110.0 g, 0.25 mol, 1.0 equiv), K2CO3(104.0 g, 0.75 mol, 3.0 equiv), and EtOH (2.2 L) were added to a 3 L single-necked flask. The reaction was allowed to stir 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 vacuum dried to obtain the product as a white solid (68 g, 79.2% yield), which was used directly in the next step.

[1083] Step 8: Synthesis of 3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino)benzoic acid ethyl ester

[1084] (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazino)-2- oxoethyl)amino)benzoic acid ethyl ester (68.0 g, 0.20 mol, 1.0 equiv), EtOH (2.2 L), and AcOH (136 mL) were added sequentially to a 2 L single neck flask. The reaction was allowed to stir at 90 °C under reflux for 6 h. 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 re-extracted 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 obtain 60 g of crude product. The crude product was slurried in ethyl acetate (420 mL) at 60 °C for 1 h, stirred in an ice water bath for 0.5 h, filtered, and the filter cake was vacuum dried to obtain the product as a white solid (60.3 g, 98.6% yield).

[1085] Step 9: Synthesis of 3-(((3-(pyridin-4-yl)-lH-l,2,4-triazol-5-yl)methyl)amino)benzoic acid

[1086] Ethyl 3-(((5-(pyridin-4-yl)-4H-l,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 allowed to stir at 15 °C for 16 h. 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 h, and filtered. The filter cake was vacuum dried to obtain the product as a white solid (47.0 g, 85.8% yield) which was used directly in the next step.

[1087] Step 10: Synthesis of 3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino)benzoic acid 2,5- dioxopyrrolidin-l-yl ester Step 11: Synthesis of 6-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hexanamide

[1088] 3-(((3-(pyridin-4-yl)-lH-l,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 allowed to stir at 15 °C for 4 h. The reaction was poured into water (2 L). A large amount of solid precipitated. The solid was filtered, and the filter cake was vacuum dried to yield the product as an off-white solid (53.7 g, 86.4% yield) which was used directly in the next step.

[1089] Step 12: Synthesis of tert-butyl (3-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-6-oxohexyl)amino)benzyl)carbamate Step 13: Synthesis of 6-((3-(aminomethyl)phenyl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)hexanamide

[1090] Into a 3 L single neck flask, 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (100.0 g, 0.37 mol, 1.0 eq), THF (2 L) and 6-bromohexanoyl chloride (218 g, 1.02 mol, 2.8 eq) were added sequentially. The reaction was allowed to stir at 70 °C for 6 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 100:1) to obtain the product as a yellow solid (162 g, 98.9% yield).

[1091] Step 14: Synthesis of N-(3-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-6- oxohexyl)amino)benzyl)-3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino)benzamide Step 1: tert-butyl (3-aminobenzyl)carbamate

[1092] Into a 3 L single neck flask, 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (100.0 g, 0.37 mol, 1.0 eq), THF (2 L) and 6-bromohexanoyl chloride (218 g, 1.02 mol, 2.8 eq) were added sequentially. The reaction was allowed to stir at 70 °C for 6 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 100:1) to obtain the product as a yellow solid (162 g, 98.9% yield).

[1093] Step 2: Synthesis of (Z)-isonicotinic hydrazide Step 3: Synthesis of 3-(2,2,2-trifluoroacetamido)benzoic acid ethyl ester

[1094] Into a 3 L single neck flask, 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (100.0 g, 0.37 mol, 1.0 eq), THF (2 L) and 6-bromohexanoyl chloride (218 g, 1.02 mol, 2.8 eq) were added sequentially. The reaction was allowed to stir at 70 °C for 6 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 100:1) to obtain the product as a yellow solid (162 g, 98.9% yield).

[1095] Step 4: Synthesis of 3-(N-(2-(benzyloxy)-2-oxoethyl)-2,2,2-trifluoroacetamido)benzoic acid ethyl ester Step 5: Synthesis of N-(3-(ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine Step 6: Synthesis of (Z)-3-(N-(2-(2-(amino(pyridin-4-yl)methylidene)hydrazino)-2-oxoethyl)-2, 2,2- trifluoroacetamido)benzoic acid ethyl ester

[1096] To a 2 L four-necked flask, 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 eq), DMF (520 mL), TEA (37.1 g, 0.37 mol, 4.0 eq) and 3-(((5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)benzoic acid 2,5-dioxopyrrolidin-1-yl ester (36.0 g, 91.6 mmol, 1.0 eq) were added sequentially. The reaction solution was allowed to stir at 30 °C for 16 hours under N2protection. The reaction solution was poured into 2.5 L of water, filtered, and the filter cake was vacuum dried to obtain 70 g of crude product. The product was purified by column (DCM / MeOH = 20 / 1) to obtain the product as a light yellow solid (43.0 g, 61.1% yield).

[1097] 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)

[1098]

[1099]

[1100] Step 7: Synthesis of (Z)-3-((2-(2-(amino(pyridin-4-yl)methylidene)hydrazino)-2-oxoethyl)amino)benzoic acid ethyl ester

[1101] To a 3 L four-necked flask, 3-(aminomethyl)aniline (60.0 g, 0.49 mol, 1.0 eq) and MeCN (900 mL) were added, and a solution of Boc2O (107 g, 0.49 mol, 1.0 eq) in MeCN (300 mL) was added dropwise quickly. The reaction solution was allowed to stir at room temperature for 1 hour, concentrated to dryness to obtain the crude product, which was purified by column (PE / EtOAc = 5:1) to obtain the product as a yellow solid (110 g, 100% yield).

[1102] benzoic acid ethyl ester

[1103] Isonicotinonitrile (50.0 g, 0.48 mol, 1.0 eq), EtOH (120 mL), Et20 (120 mL) and 80% hydrazine hydrate (250 mL) were added sequentially into a 1 L single neck flask and the reaction was allowed to stir 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 obtain the product as off-white solid (60 g, 91.8% yield).

[1104] Step 8: Synthesis of 3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino)benzoic acid ethyl ester

[1105] Ethyl 3-aminobenzoate (83.0 g, 0.50 mol, 1.0 eq), THF (1.66 L) and TEA (76.0 g, 0.75 mol, 1.5 eq) were added into a 3 L four necked flask. The reaction was cooled to 0-5 °C in an ice water bath and TFAA (110.0 g, 0.53 mol, 1.05 eq) was added drop wise while maintaining the temperature <10 °C. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The reaction was quenched by adding 1 N HC1 (1 L) to it. 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 obtain the product as yellow solid (120 g, 91.4% yield) which was used directly in the next step.

[1106] Step 9: Synthesis of 3-(((3-(pyridin-4-yl)-lH-l,2,4-triazol-5-yl)methyl)amino)benzoic acid

[1107] Ethyl 3-(2,2,2-trifluoroacetamido)benzoate (120.0 g, 0.46 mol, 1.0 eq), DMF (1.2 L), benzyl bromoacetate (116.0 g, 0.50 mol, 1.1 eq) and K2C03(95.0 g, 0.69 mol, 1.5 eq) were added sequentially into a 3 L single neck flask. The reaction was allowed to stir 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 obtain the product as off-white solid (170 g, 90.4% yield) which was used directly in the next step.

[1108] Step 10: Synthesis of 3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino)benzoic acid 2,5- dioxopyrrolidin-l-yl ester

[1109] 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 to a 5 L four-necked flask. The reaction was allowed to stir at 15 °C under H2(15 psi) for 4 h. The reaction was filtered, and the filtrate was concentrated to obtain the product as a light yellow transparent solid (132 g, 100% yield), which was used directly in the next step.

[1110] ​ ​

[1111] N-(3-(Ethoxycarbonyl)phenyl)-N-(2,2,2-trifluoroacetyl)glycine (132.0 g, 0.41 mol, 1.0 equiv), (Z)-isonicotinic hydrazide (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-necked flask. The reaction was allowed to stir at 15 °C under N2protection 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 obtain 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 vacuum dried to obtain the product as a white solid (118 g, 65.2% yield).

[1112] ​ ​

[1113] (Z)-3-(N-(2-(2-(Amino(pyridin-4-yl)methylene)hydrazino)-2-oxoethyl)-2,2,2- trifluoroacetamido)benzoic acid ethyl ester (110.0 g, 0.25 mol, 1.0 equiv), K2CO3(104.0 g, 0.75 mol, 3.0 equiv), and EtOH (2.2 L) were added to a 3 L single-necked flask. The reaction was allowed to stir 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 vacuum dried to obtain the product as a white solid (68 g, 79.2% yield), which was used directly in the next step.

[1114] ​

[1115] (Z)-3-((2-(2-(amino(pyridin-4-yl)methylene)hydrazino)-2- oxoethyl)amino)benzoic acid ethyl ester (68.0 g, 0.20 mol, 1.0 equiv), EtOH (2.2 L), and AcOH (136 mL) were added sequentially to a 2 L single neck flask. The reaction was allowed to stir at 90 °C under reflux for 6 h. 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 re-extracted 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 obtain 60 g of crude product. The crude product was slurried in ethyl acetate (420 mL) at 60 °C for 1 h, stirred in an ice water bath for 0.5 h, filtered, and the filter cake was vacuum dried to obtain the product as a white solid (60.3 g, 98.6% yield).

[1116] ​

[1117] 3-(((5-(pyridin-4-yl)-4H-l,2,4-triazol-3-yl)methyl)amino)benzoic acid ethyl ester (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 allowed to stir at 15 °C for 16 h. 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 h, and filtered. The filter cake was vacuum dried to obtain the product as a white solid (47.0 g, 85.8% yield) which was used directly in the next step.

[1118] ​ ​

[1119] 3-(((3-(pyridin-4-yl)-lH-l,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 allowed to stir at 15 °C for 4 h. The reaction was poured into water (2 L). A large amount of solid precipitated. The solid was filtered, and the filter cake was vacuum dried to yield the product as an off-white solid (53.7 g, 86.4% yield) which was used directly in the next step.

[1120] Step 11 : Synthesis of 4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 4-oxobutoxy)butanoic acid Step 12: Synthesis of tert-butyl (3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-4-oxobutoxy)butanamido)benzyl)carbamate

[1121] To a 50 mL single neck flask was added 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-oxononanoic anhydride (1.62 g, 9.39 mmol, 3.0 equiv) sequentially. The reaction was allowed to stir at 70 °C for 17 h under N2protection. The reaction was concentrated to dryness and purified by column (DCM / MeOH = 120:1) to obtain the product as a yellow solid (75 mg, 5.4% yield).

[1122] Step 11 : Synthesis of 4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 4-oxobutoxy)butanoic acid Step 12: Synthesis of tert-butyl (3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-4-oxobutoxy)butanamido)benzyl)carbamate

[1123] To a 10 mL thumb flask was added 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) sequentially. The reaction was allowed to stir at 15 °C for 2 h under N2protection. The reaction was concentrated to dryness and 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 obtain the crude product. The crude product was purified by column (DCM / MeOH = 20 / 1) to obtain the product as a yellow solid (95 mg, 87.0% yield).

[1124] Step 13: Synthesis of N-(3-((λ 2 -azanyl)methyl)phenyl)-4-(4-((2-(2,6-dioxopiperidin-3- Step 11 : Synthesis of 4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- 4-oxobutoxy)butanoic acid

[1125] To a 10 mL thumb flask was added tert-butyl (3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)-4-oxobutoxy)benzamido)benzyl)carbamate (95 mg, 0.15 mmol, 1.0 equiv) and EtOAc (4 mL) and 3M HCl / EtOAc (4 mL) was added while stirring. The reaction was allowed to stir at 15 °C for 2 h under N2protection. The reaction was concentrated to obtain the product as a brownish yellow solid (85 mg, 93.2% yield) which was used directly in the next step.

[1126] Pharmacological Example1. Hypoxia treatment of PASMCs and stimulation of the PASMCs with Compound 1 2. Extraction of cellular proteins from PASMCs

[1127] N-(3-((λ 2 To a solution of N-(3-((λ

[1128] Example 16: Preparation of N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)methyl)benzamide (Compound 16)

[1129]

[1130] 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 h. 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)-3-oxoisoindolin-5- yl)methyl)benzamide (4.4 mg, 20%) as a white solid.

[1131] 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 10.83 (s, 1H), 8.03-7.98 (m, 2H), 7.81-7.79 (m, 2H), 7.43-7.41 (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, 5.1 Hz, 1H), 4.39 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.2 Hz, 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 26 N4O4S, MS calc: 550.6; MS found: 551.4 [M+1] + .

[1132] 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)

[1133]

[1134] To a mixture of 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)benzoic acid (20 mg, 0.053 mmol; commercially available from Chengdu Found Di 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 vacuum, and the residue was purified by prep-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.

[1135] 1H NMR (400 MHz, 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, 2H), 7.15-7.12 (m, 2H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.39 (d, J = 17.2 Hz, 1H), 4.32 (d, J = 17.2 Hz, 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 calc: 585.1 ; MS found: 585.3 [M+1] + .

[1136] 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)

[1137]

[1138] To a mixture of 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl)benzoic acid (20 mg, 0.051 mmol; commercially available from Chengdu Found Di 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 Na2S04, concentrated in vacuum, and the residue was purified by preparative HPLC to give the product N-(5-benzylthiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)methyl)benzamide (4.9 mg, 17%) as a white solid.

[1139] 1H NMR (400 MHz, 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 = 1.7 Hz, 1H), 7.45 (d, J = 1.8 Hz, 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, 5.4 Hz, 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 calc: 564.6; MS found: 565.5 [M+1] + .

[1140] Example 19: Preparation of N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl)benzamide (Compound 19)

[1141]

[1142] To a mixture of 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl)benzoic acid (20 mg, 0.051 mmol; commercially available from Chengdu Found Di Pharmaceutical Co., Ltd.) and 5-[(4-chlorophenyl)methyl]-l,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 Na2S04, concentrated in vacuum, and the residue was purified by prep-HPLC to give the product N-(5-(4-chlorobenzyl)thiazol-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl)benzamide (4.6 mg, 16%) as a white solid.

[1143] 1H NMR (400 MHz, 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 = 1.4 Hz, 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, 5.0 Hz, 1H), 4.06 (s, 2H), 3.85 (s, 2H), 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 ClN4O5S, MS calc: 599.1; MS found: 599.4 [M+1] + .

[1144] Example 20: Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- (phenylcarbothioyl)thiazol-2-yl)acetamide (Compound 20)

[1145]

[1146] 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 Alfa Chemistry Co., Ltd.) in DMF (3 mL) was added TEA (8 mg, 0.08 mmol) and HATU (21 mg, 0.055 mmol). 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 Na2SO4, concentrated in vacuum, and the residue was purified by silica gel column chromatography (MeOH / DCM = 1 / 100-1 / 30) to obtain the product 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5-(phenylcarbothioyl)thiazol-2-yl)acetamide (5 mg, 20%) as a green solid.

[1147] 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 11.00 (s, 1H), 7.85 (s, 1H), 7.74 (d, J = 1.3 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 1.3 Hz, 2H), 7.48 (t, J = 7.7 Hz, 2H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H), 4.32 (d, J = 17.2 Hz, 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 calc: 504.6; MS found: 505.5 [M+1] + .

[1148] Example 21: Preparation of N-(5-benzoylthiazol-2-yl)-2-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)acetamide (Compound 21)

[1149]

[1150] 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 Alfa Chemistry 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 vacuum, and the residue was purified by prep-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.

[1151] 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 11.01 (s, 1H), 8.11 (s, 1H), 7.85 (t, J = 1.3 Hz, 1H), 7.86-7.84 (m, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.72-7.64 (m, 1H), 7.59 (t, J = 2.0 Hz, 2H), 7.59-7.53 (m, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 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 H 20 N4O5S, MS calc: 488.5; MS found: 489.2 [M+1] + .

[1152] Example 22: Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- (phenylamino)thiazol-2-yl)acetamide (Compound 22)

[1153]

[1154] 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (30.2 mg, 0.1 mmol) and N 5 phenylthiazole-2,5-diamine (19.1 mg, 0.1 mmol; commercially available from Chengdu Division Pharmaceutical Co., Ltd.) were mixed with DMF (3 mL), 1-methylimidazole (24.6 mg, 0.3 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (33.6 mg, 0.12 mmol) were added. The solution was stirred at 80 °C for 3 hours. Then water (20 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH / DCM = 1 / 100-1 / 30) and preparative HPLC to obtain 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.

[1155] 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 11.00 (s, 1H), 8.12 (s, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 1.2 Hz, 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, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 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 calc: 475.5; MS found: 476.3 [M+1] + .

[1156] 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)

[1157]

[1158] 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 Alfa Chemistry Co., Ltd.) in DMF (3 mL) was added 1-methylimidazole (16.3 mg, 0.198 mmol) and N,N,N',N'-tetramethyluronium hexafluorophosphate (22.3 mg, 0.079 mmol). The solution was stirred at 80 °C for 3 h. 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 prep-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.

[1159] 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 11.43 (s, 1H), 11.00 (s, 1H), 7.79 (d, J = 7.9 Hz, 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, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 3.92 (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 calc: 499.5; MS found: 500.3 [M+1] + .

[1160] 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)

[1161]

[1162] 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 Alfa Chemistry Co., Ltd.) in DMF (3 mL) was added 1-methylimidazole (16.3 mg, 0.198 mmol) and N,N,N',N'-tetramethyluronium hexafluorophosphate (22.3 mg, 0.079 mmol). The solution was stirred at 80 °C for 3 h. 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 prep-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.

[1163] 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, 5.1 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 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). Chemical Formula: C 28 H 22 N4O4S, MS calc: 510.1; MS found: 511.3 [M+1] + .

[1164] Example 25: Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- phenoxythiazol-2-yl)acetamide (Compound 25)

[1165]

[1166] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (20 mg, 0.066 mmol) and 5-phenoxythiazol-2-amine (12.7 mg, 0.066 mmol; commercially available from Chengdu Alfa Chemistry Co., Ltd.) in DMF (3 mL) was added 1- methylimidazole (16.3 mg, 0.198 mmol) and N,N,N',N'-tetramethyluronium hexafluorophosphate (22.3 mg, 0.079 mmol). The solution was stirred at 50 °C for 3 h. 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 prep-HPLC to give the product 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- phenoxythiazol-2-yl)acetamide (4.7 mg, 15%) as a white solid.

[1167] 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 11.00 (s, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.57 (d, J = 1.2 Hz, 2H), 7.42 - 7.32 (m, 2H), 7.25 (s, 1H), 7.16 - 7.13 (m, 1H), 7.12 - 7.11 (m, 1H), 7.10 - 7.08 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 3.87 (s, 2H), 2.98 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 - 2.33 (m, 1H), 2.03 - 1.95 (m, 1H). Chemical Formula: C 24 H 20 N4O5S, MS calc: 476.5; MS found: 477.2 [M+1] + .

[1168] Example 26: Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- picolinthiazol-2-yl)acetamide (Compound 26)

[1169]

[1170] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (20 mg, 0.066 mmol) and 5-(pyridin-2-ylmethyl)thiazol-2-amine (12.6 mg, 0.066 mmol; commercially available from Chengdu Alfa Chemistry Technology Co., Ltd.) in DMF (3 mL) was added TEA (10 mg, 0.099 mmol) and HATU (30.2 mg, 0.079 mmol). The solution was stirred at room temperature for 4 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 vacuum, and the residue was purified by prep-HPLC to obtain the product 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- picolinthiazol-2-yl)acetamide (5.3 mg, 17%) as a white solid.

[1171] 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.99 (s, 1H), 8.50-8.48 (m, 1H), 7.76-7.70 (m, 1H), 7.69 (t, J = 1.3 Hz, 1H), 7.55 (d, J = 1.3 Hz, 2H), 7.31 (dt, J = 7.8, 1.1 Hz, 1H), 7.27 (d, J = 1.1 Hz, 1H), 7.25-7.19 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.1 Hz, 1H), 4.20 (s, 2H), 3.85 (s, 2H), 2.95-2.85 (m, 1H), 2.63-2.55 (m, 1H), 2.44-2.34 (m, 1H), 2.02-1.94 (m, 1H). Chemical Formula: C 24 H 21 N5O4S, MS calc: 475.5; MS found: 476.2 [M+1] + .

[1172] Example 27: Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-(5- isobutylthiazol-2-yl)acetamide (Compound 27)

[1173]

[1174] To a mixture of 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)acetic acid (20 mg, 0.066 mmol) and 5-isobutylthiazol-2-amine (10.3 mg, 0.066 mmol; commercially available from Chengdu Alfa Chemistry Co., Ltd.) in DMF (3 mL) was added DIEA (12.8 mg, 0.099 mmol) and HATU (27.7 mg, 0.073 mmol). The solution was stirred at room temperature for 4 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 prep-HPLC to give the product 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-N-...

Claims

1. A compound represented by Formula (1): GBM-DT or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof; GBM-DT (1) wherein: GBM is a GRK2 binding moiety; and DT is a degradation tag having E3 ligase binding ability.

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

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

4. 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.

7. The compound of claim 1, wherein the GBM is a moiety derived from an indazole or dihydropyrimidine series represented by Formula (2) or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof 5. The compound of claim 1, wherein the GBM is a fraction derived from a Takeda inhibitor or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, wherein the Takeda inhibitor is selected from...

6. The compound of claim 1, wherein the GBM is a moiety derived from a paroxetine series or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, the paroxetine series selected from wherein R’ is selected from H and halogen; and R is selected from 8. The compound of claim 1, wherein the GBM is represented by Formula (3): R" is selected from wherein ★ indicates a point of attachment to the DT; Formula I is a moiety covalently linked to Formula II, wherein the Formula I comprises a thiazole ring or a triazole ring on its backbone and is capable of binding to GRK2 alone or together with the Formula II; and the Formula II is a moiety covalently linked to the Formula I and the DT, wherein the Formula II comprises an acyclic or cyclic saturated or unsaturated carbon, glycol group, amide group, ester group, amino group, oxyl group, thio group, ether group, urea group, carbamate group, aromatic group, heteroaromatic group, heterocyclic group, carbonyl group, or a combination thereof.

9. The compound of claim 8, wherein the Formula I is represented by Formula (4): wherein: ♦ indicates a point of attachment to the Formula II; a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a+b < 5; and Q is selected from the group consisting of 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 selected from aryl, C 3-12 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 selected from a bond, -(CH2) a C(R1)(R2)(CH2) b -, -N(R1)-, -0-, -S-, -C(=0)-, -C(=S)-, -S(=0)-, and -S(=0)2-; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R' is selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b each of R c is independently selected from 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 can 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; 12. The compound of claim 9, wherein Q is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, and Cy. The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

10. The compound of claim 9, wherein Q is selected from the group consisting of optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c and Cy.

11. The compound of claim 9, wherein Q is selected from C 1-6 alkyl, -SR a and Cy.

13. The compound of claim 9, wherein Q is selected from i-propyl, i-propylthio, and Cy.

14. The compound of claim 9, wherein Q is Cy. ​ 15. The compound of claim 9, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

16. The compound of claim 9, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthrydinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

17. The compound of claim 9, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolinyl, isoindolyl, 6,7-dihydro-5H- cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

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

19. The compound of claim 9, wherein Q is selected from:

20. The compound of claim 9, wherein Q is selected from:

21. The compound of claim 9, wherein L A is selected from the group consisting of a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

22. The compound of claim 9, wherein L A is selected from a bond, -CH2-, -CF2-, -CC12-, -CBr2-, -CFCl-, -CFBr-, -CClBr-, -NH-, -0-, -S-, -C(=0)-, and -C(=S)-.

23. The compound of claim 9, wherein L A is selected from the group consisting of a bond, -CH2-, -CF2-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

24. The compound of claim 9, wherein L A is -CH2-.

25. The compound of claim 9, wherein R is selected from 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 .

26. The compound of claim 9, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

27. The compound of claim 9, wherein R is selected from H, 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.

28. The compound of claim 9, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

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

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

31. The compound of claim 9, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

32. The compound according to claim 9, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

33. The compound of claim 9, wherein each of R1and R2is 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.

34. The compound of claim 9, wherein each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

35. The compound of claim 9, wherein each of R1and R2is independently selected from H and F.

36. The compound of claim 9, wherein both R1and R2are H.

37. The compound of claim 9, wherein both R1and R2are F.

38. The compound of claim 9, wherein R' is selected from 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 .

39. The compound of claim 9, wherein R' is selected from halogen, -CN, -N02, optionally substituted C 3-6 cycloalkyl-substituted C 1-6 alkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 1-6 heteroalkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkenyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

40. The compound of claim 9, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

41. The compound of claim 9, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

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

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

44. The compound of claim 9, wherein each R a is independently selected from H and C 1-6 alkyl.

45. The compound of claim 9, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

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

47. The compound of claim 9, wherein R b and each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

48. The compound of claim 9, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

50. The compound of claim 9, wherein each R d is independently selected from H and C 1-6 alkyl.

51. The compound of claim 9, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

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

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

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

55. The compound of claim 9, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

56. The compound of claim 9, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

57. The compound of claim 9, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

58. The compound of claim 8, wherein the Formula I is represented by Formula (4A): wherein: ♦ represents the point of attachment to the Formula II; 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 selected from aryl, C 3-12 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 selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b each of R c is independently selected from 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 can form, together with the nitrogen atom to which they are attached, an optionally substituted 3- to 12-membered heterocyclyl; Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

59. The compound of claim 58, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

60. The compound according to claim 58, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

61. The compound of claim 58, wherein each of R1and R2is 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.

62. The compound of claim 58, wherein each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

63. The compound of claim 58, wherein each of R1and R2is independently selected from H and F.

64. The compound of claim 58, wherein both R1and R2are H.

65. The compound of claim 58, wherein R is selected from 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 .

66. The compound of claim 58, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

67. The compound of claim 58, wherein R is selected from H, 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.

68. The compound of claim 58, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

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

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

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

72. The compound of claim 58, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthrydinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

73. The compound of claim 58, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolinyl, isoindolyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

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

75. The compound of claim 58, wherein Cy is selected from:

76. The compound of claim 58, wherein R' is selected from 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 .

77. The compound of claim 58, wherein R' is selected from halogen, -CN, -N02, optionally substituted C 3-6 cycloalkyl-substituted C 1-6 alkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 1-6 heteroalkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkenyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

78. The compound of claim 58, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

79. The compound of claim 58, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

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

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

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

83. The compound of claim 58, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

84. The compound of claim 58, wherein R b and each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

85. The compound of claim 58, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

87. The compound of claim 58, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

88. The compound of Claim 58, wherein the term "optionally substituted" preceding a chemical group for which substitution is not specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

89. The compound of claim 58, wherein the term “optionally substituted” preceding a chemical group for which no substituents are designated means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

90. The compound of claim 58, wherein the term “optionally substituted” preceding a chemical group for which no substituents are designated means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

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

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

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

94. The compound of claim 8, wherein the formula I is represented by formula (5): wherein: ♦ represents a point of attachment to the formula II; ♦ represents a point of attachment to the formula II; R 1A R 2A R 1B and R 2B Each of them 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R 1A and R 2A Or R 1B and R 2B Able to form optionally substituted C atoms together with the atoms they are attached to 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R 3A R 3B and R 3C Each of them is independently selected from H, and optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, -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 group, Optionally substituted C 3-12 Carbocyclic, optionally substituted 5- to 12-membered heteroaryl and optionally substituted 3- to 12-membered heterocyclic groups; each of D1, D2, D3, D4, and D5is independently N or CR 4A ; each of E1, E2, E3, and E4is independently N or CR 4B ; each of F1, F2, F3, and F4is independently N or CR 4C ; R 4A , R 4B , and R 4C are each independently selected from H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b each of R c is independently selected from 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 can 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; and The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

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

96. The compound of claim 94, wherein each of R 1A , R 2A , R 1B , and R 2B is independently selected from H, halogen, C1-C6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl optionally substituted with 1, 2, or 3 halogens, -CN, -NO2, -OR a , -SR a , and -NR b R c .

97. The compound of claim 94, wherein each of R 1A , R 2A , R 1B , and R 2B 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.

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

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

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

101. The compound of claim 94, wherein R 3A each of R 3B and R 3C is independently selected from 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.

102. The compound of claim 94, wherein R 3A each of R 3B and R 3C is independently selected from H, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogen, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogen, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogen, and C 2-6 alkynyl optionally substituted with 1, 2, or 3 halogen.

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

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

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

106. The compound of claim 94, wherein at least one of D1, D2, D3, D4, and D5 is N, and the rest are CR A .

107. The compound of claim 94, wherein one of D1, D2, D3, D4, and D5 is N, and the rest are CR A .

108. The compound of claim 94, wherein D3 is N, and the rest are CR 4A .

109. The compound of claim 94, wherein each of E1, E2, E3, and E4 is independently CR 4B .

110. The compound of claim 94, wherein each of F1, F2, F3, and F4 is independently CR 4C .

111. The compound of claim 94, wherein R 4A each of R 4B and R 4C is independently selected from 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 .

112. The compound of claim 94, wherein R 4A each of R 4B and R 4C is independently selected from H, halogen, -CN, -NO2, C 1-6 alkyl optionally substituted with 1, 2, or 3 halogens, C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkenyl optionally substituted with 1, 2, or 3 halogens, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

113. The compound of claim 94, wherein R 4A , R 4B , and R 4C are each independently selected from H, 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.

114. The compound of claim 94, wherein R 4A , R 4B , and R 4C are each independently selected from H, F, CI, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

115. The compound of claim 94, wherein R 4A , each of R 4B and R 4C is independently H.

116. The compound of claim 94, wherein each R a is independently selected from H and C 1-6 alkyl.

117. The compound of claim 94, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

118. The compound of claim 94, wherein R b each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

119. The compound of claim 94, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

120. The compound of claim 94, wherein each R d is independently selected from H and C 1-6 alkyl.

121. The compound of claim 94, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

122. The compound of claim 94, wherein the term "optionally substituted" preceding a chemical group for which substitution is not specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

123. The compound of claim 94, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

124. The compound of claim 94, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

125. The compound of claim 94, wherein the Formula I is represented by Formula (5A):

126. The compound of claim 94, wherein the Formula I is represented by Formula (5B):

127. The compound of claim 94, wherein the Formula I is represented by Formula (5C):

128. The compound of claim 8, wherein the Formula II comprises an amide group or an ester group.

129. The compound of claim 8, wherein the Formula II is represented by Formula (6): wherein * denotes the point of attachment to the Formula I; # denotes the point of attachment to the DT; A, T and B are independently at each occurrence selected from the group consisting of null, -C(=0)-, -C(=0)0-, -C(=0)NR 1 -, -C(=S)NR 1 -, -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2NR 1 -, -NR 1 -, -NR 1 C(=0)-, -NR 1 C(=0)NR 2 -, -NR 1 C(=S)-, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8haloalkyl, optionally substituted Ci-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl and optionally substituted C3-C 13 spiroheterocyclyl, wherein R 1 and R 2 are independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl; and p is 0 to 15.

130. The compound of claim 8, wherein the Formula II is represented by Formula (6A): wherein * denotes the point of attachment to the Formula I; # denotes the point of attachment to the DT; R 1 , R 2 , R 3 , and R 4 are independently selected for each occurrence from hydrogen, halogen, -CN, -OH, -NH2, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl; A, T and B are independently at each occurrence selected from the group consisting of null, -C(=0)-, -C(=0)0-, -C(=0)NR 5 -, -C(=S)NR 5 -, -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2NR 5 -, -NR 5 -, -NR 5 C(=0)-, -NR 5 C(=0)NR 6 -, -NR 5 C(=S)-, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8haloalkyl, optionally substituted Ci-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl and optionally substituted C3-C 13 spiroheterocyclyl, wherein R 5 and R 6 are independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl; p is 0 to 15; each q is 0 to 15; and o is 0 to 15.

131. The compound of claim 8, wherein the Formula II is represented by Formula (6B): wherein * denotes the point of attachment to the Formula I; # denotes the point of attachment to the DT; Each R 1 and each R 2 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 3-6 membered heterocyclic, 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 is independently selected from the group consisting of null, -C(=O)-, -C(=O)O-, -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-C8alkyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-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-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, or C1-C6alkylaminoC1-C6alkyl; each p is 0 to 15; and q is 0 to 15.

132. The compound of claim 8, wherein the Formula II is represented by Formula (6C): wherein * denotes the point of attachment to the Formula I; # denotes the point of attachment to the DT; X is selected from -0-, -NH and -NR 7 -; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected for each occurrence from hydrogen, halogen, -CN, -OH, -NH2, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl; A and B are independently at each occurrence selected from the group consisting of null, -C(=0)-, -C(=0)0-, -C(=0)NR 7 -, -C(=S)NR 7 -, -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2NR 7 -, -NR 7 -, -NR 7 C(=0)-, -NR 7 C(=0)NR 8 -, -NR 7 C(=S)-, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8haloalkyl, optionally substituted Ci-C8hydroxyalkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C3-C8cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl, wherein R 7 and R 8 are independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6alkoxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6alkylamino, and optionally substituted C1-C6alkylaminoC1-C6alkyl; each p is 0 to 15; each q is 0 to 15; o is 0 to 15; and r is 0 to 15.

133. The compound of claim 8, wherein the Formula II is represented by Formula (7A): wherein * denotes the point of attachment to the Formula I; # denotes the point of attachment to the DT; A is selected from C 1-20 alkylene, -0-, -S-, -N(R e )- and -N(R e )-C 1-20 alkylene-, and optionally wherein 1, 2, 3 or more methylenes in said C 1-20 alkylene are independently replaced with a group selected from -0-, -S-, -N(R e )-, -C(=0)- and -C(=S)-; B is a bond or is selected from arylene, C 3-12 carbocyclylene, 5- to 12-membered heteroarylene, and 3- to 12-membered heterocyclylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, -CN, -NO2, C1-C6alkyl, 1-6 alkyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 heteroalkyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 2-6 alkenyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 2-6 alkynyl, -OR a , -SR a , and -NR b R c ; Each R a Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; R b each of R c is independently selected from 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 can form, together with the nitrogen atom to which they are attached, an optionally substituted 3- to 12-membered heterocyclyl; R e selected from H and optionally substituted C 1-6 alkyl; and The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

134. The compound of claim 133, wherein A is selected from C 1-8 alkylene, -0-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein 1, 2, 3 or more methylenes in said C 1-8 alkylene are independently replaced with a group selected from -0- and -C(=0).

135. The compound of claim 133, wherein A is selected from -CH2-, -O-, -NH-, -NH-(CH2)3-, -NH-(CH2)5-, and -NH-C(=O)-(CH2)3-O-(CH2)3-.

136. The compound of claim 133, wherein A is selected from -CH2-, -O-, and -NH-.

137. The compound of claim 133, wherein A is -NH-.

138. The compound of claim 133, wherein B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halo, -CN, -NO2, methyl optionally substituted with 1, 2, or 3 halo, ethyl optionally substituted with 1, 2, or 3 halo, propyl optionally substituted with 1, 2, or 3 halo, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

139. The compound of claim 133, wherein B is a bond or is selected from phenylene, pyrrolylene, furanylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyrylylene, 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.

140. 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. The compound of claim 133, wherein B is a bond or phenylene.

142. The compound of claim 133, wherein each R a is independently selected from H and C 1-6 alkyl.

143. The compound of claim 133, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

144. The compound of claim 133, wherein R b each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

145. The compound of claim 133, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

146. The compound of claim 133, wherein R e is H.

147. The compound of Claim 133, wherein the term "optionally substituted" preceding a chemical group for which substitution is not specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

148. The compound of claim 133, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

149. The compound of claim 133, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

150. The compound of claim 133, wherein formula (7A) is a moiety selected from:

151. The compound of claim 133, wherein formula (7A) is a moiety selected from:

152. The compound of claim 8, wherein the formula II is represented by formula (7B): wherein * indicates the point of attachment to the formula I; # indicates the point of attachment to the DT; e is 0 or 1; f is selected from 0, 1, 2, and 3; and g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. ​ ​ ​ is a single or double bond; R" is selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; R b each of R c is independently selected from 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 can 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; ​ ​ The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

153. The compound of claim 152, wherein is a single bond.

154. The compound of claim 152, wherein is a double bond.

155. The compound of claim 152, wherein R" is selected from 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 .

156. The compound according to claim 152, wherein R” is selected from halogens, -CN, -NO2, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne group, -OR a -SR a and -NR b R c .

157. The compound of claim 152, wherein 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.

158. The compound of claim 152, wherein R” is selected from F, Cl, Br, methyl, ethyl, propyl, -OH, and -NH2.

159. The compound of claim 152, wherein e is 0.

160. The compound of claim 152, wherein e is 1.

161. The compound of claim 152, wherein f is 0.

162. The compound of claim 152, wherein formula (7B) is a moiety selected from:

163. The compound of claim 1, wherein the DT is capable of binding to an E3 ligase to recruit a corresponding ubiquitination machinery to GRK2, thereby causing subsequent degradation of GRK2 in or near the proteasome and / or loss of function of GRK2.

164. The compound of claim 1, wherein the DT is selected from the group consisting of a cereblon ligand, a VHL ligand, a MDM2 ligand, a TRIM24 ligand, a TRIM21 ligand, a KEAP1 ligand, a RNF114 ligand, a IAP ligand, a DCAF16 ligand, a DCAF15 ligand, a FEM1B ligand, and a ligand for an Aryl Hydrocarbon Receptor.

165. The compound of claim 1, wherein the DT is a moiety represented by formula (8A), (8B), (8C), or (8D): wherein U is independently selected from -CH2-, -NH-, and -O-; represents the point of attachment to said formula II; each of V and W is independently selected from -C(=O)- and -CH2-; each of X, Y, and Z is independently selected from CR6and N; R5is selected from H, halogen, and optionally substituted C1-C6alkyl; and R6is selected from H, halogen, and optionally substituted C1-C6alkyl.

166. The compound of claim 165, wherein U is -CH2-.

167. The compound of claim 165, wherein U is -O-.

168. The compound of claim 165, wherein U is -NH-.

169. The compound of claim 165, wherein V is -C(=O)- and W is -CH2-.

170. The compound of claim 165, wherein V is -CH2- and W is -C(=O)-.

171. The compound of claim 165, wherein both V and W are -C(=O)-.

172. The compound of claim 165, wherein each of X, Y, and Z is independently selected from CR6.

173. The compound of claim 165, wherein R5is selected from H, F, Cl, and Br. ​ 174. The compound of claim 165, wherein R5 is H.

175. The compound of claim 165, wherein R6 is selected from H, F, Cl, and Br.

176. The compound of claim 165, wherein R6 is H or F.

177. The compound of claim 165, wherein the DT is a moiety selected from:

178. The compound of claim 1, wherein the DT is a moiety represented by formula (9): wherein represents the point of attachment to said formula II; R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8haloalkyl, optionally substituted Ci-C8hydroxyalkyl, optionally substituted Ci-C8aminoalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8alkenyl, and optionally substituted C2-C8alkynyl; R 3 is hydrogen, optionally substituted C(=O)C1-C8alkyl, optionally substituted -C(=O)C1-C8alkoxyC1-C8alkyl, optionally substituted -C(=O)C1-C8haloalkyl, optionally substituted -C(=O)C1-C8hydroxyalkyl, optionally substituted -C(=O)C1-C8aminoalkyl, optionally substituted -C(=O)C1-C8alkylaminoC1-C8alkyl, optionally substituted -C(=O)C3-C7cycloalkyl, optionally substituted -C(=O)(3-7 membered heterocyclyl), optionally substituted -C(=O)C2-C8alkenyl, optionally substituted -C(=O)C2-C8alkynyl, optionally substituted -C(=O)OC1-C8alkoxyC1-C8alkyl, optionally substituted -C(=O)OC1-C8haloalkyl, optionally substituted -C(=O)OC1-C8hydroxyalkyl, optionally substituted -C(=O)OC1-C8aminoalkyl, optionally substituted -C(=O)OC1-C8alkylaminoC1-C8alkyl, optionally substituted -C(=O)OC3-C7cycloalkyl, optionally substituted -C(=O)O(3-7 membered heterocyclyl), optionally substituted -C(=O)OC2-C8alkenyl, optionally substituted -C(=O)OC2-C8alkynyl, optionally substituted -C(=O)NC1-C8alkoxyC1-C8alkyl, optionally substituted -C(=O)NC1-C8haloalkyl, optionally substituted -C(=O)NC1-C8hydroxyalkyl, optionally substituted -C(=O)NC1-C8aminoalkyl, optionally substituted -C(=O)NC1-C8alkylaminoC1-C8alkyl, optionally substituted -C(=O)NC3-C7cycloalkyl, optionally substituted -C(=O)N(3-7 membered heterocyclyl), optionally substituted -C(=O)NC2-C8alkenyl, optionally substituted -C(=O)NC2-C8alkynyl, optionally substituted -P(=O)(OH)2, optionally substituted -P(=O)(OC1-C8alkyl)2, and optionally substituted -P(=O)(OC1-C8aryl)2.

179. The compound of claim 1, wherein the DT is a moiety represented by formula (10): wherein represents the point of attachment to said formula II; V, W, X and Z are independently selected from CR 4 and N; R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8haloalkyl, optionally substituted Ci-C8hydroxyalkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8alkenyl, and optionally substituted C2-C8alkynyl.

180. The compound of claim 1, wherein the DT is a moiety derived from any one of:

181. The compound of claim 1, wherein the DT is selected from the group consisting of:

182. The compound of claim 1, wherein the compound is represented by formula (11): wherein: A is selected from C 1-20 alkylene, -0-, -S-, -N(R e )- and -N(R e )-C 1-20 alkylene-, and optionally wherein 1, 2, 3 or more methylenes in said C 1-20 alkylene are independently replaced with a group selected from -0-, -S-, -N(R e )-, -C(=0)- and -C(=S)-; B is a bond or is selected from arylene, C 3-12 carbocyclylene, 5- to 12-membered heteroarylene, and 3- to 12-membered heterocyclylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, -CN, -NO2, C1-C6alkyl, 1-6 alkyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 heteroalkyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 2-6 alkenyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 2-6 alkynyl, -OR a , -SR a , and -NR b R c ; U is independently selected from -CH2-, -NH-, and -O-; each of V and W is independently selected from -C(=O)- and -CH2-; each of X, Y, and Z is independently selected from CR6 and N; 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 selected from aryl, C 3-12 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 selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b and each of R c is independently selected from 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 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R e selected from H and optionally substituted C 1-6 alkyl; and The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

183. The compound of claim 182, wherein A is selected from C 1-8 alkylene, -0-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein said C 1-8 1, 2, 3 or more methylenes in said alkylene are independently replaced with a group selected from -0- and -C(=0).

184. The compound of claim 182, wherein A is selected from -CH2-, -O-, -NH-, -NH- (CH2)3-, -NH-(CH2)5-, and -NH-C(=O)-(CH2)3-O-(CH2)3-.

185. The compound of claim 182, wherein A is selected from -CH2-, -O-, and -NH-.

186. The compound of claim 182, wherein A is -NH-.

187. The compound of claim 182, wherein B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

188. The compound of claim 182, wherein B is a bond or is selected from phenylene, pyrrolylene, furanylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyrylylene, 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.

189. 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. The compound of claim 182, wherein B is a bond or phenylene.

191. The compound of Claim 182, wherein is a moiety selected from the group consisting of:

192. The compound of claim 182, wherein is a moiety selected from the group consisting of:

193. The compound of claim 182, wherein U is -CH2-.

194. The compound of claim 182, wherein U is -0-.

195. The compound of claim 182, wherein U is -NH-.

196. The compound of claim 182, wherein V is -C(=0)- and W is -CH2-.

197. The compound of claim 182, wherein V is -CH2- and W is -C(=0)-.

198. The compound of claim 182, wherein V and W are both -C(=0)-.

199. The compound of claim 182, wherein each of X, Y, and Z is independently selected from CR6.

200. The compound of claim 182, wherein is a moiety selected from:

201. The compound of claim 182, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

202. The compound according to claim 182, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

203. The compound of claim 182, wherein each of R1and R2is 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.

204. The compound of claim 182, wherein each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

205. The compound of claim 182, wherein each of R1and R2is independently selected from H and F.

206. The compound of claim 182, wherein both R1and R2are H.

207. The compound of claim 182, wherein R is selected from 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 .

208. The compound of claim 182, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

209. The compound of claim 182, wherein R is selected from H, 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.

210. The compound of claim 182, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

211. The compound of claim 182, wherein R is selected from H and -OH.

212. The compound of claim 182, wherein R is H.

213. The compound of claim 182, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

214. The compound of claim 182, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthrydinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

215. The compound of claim 182, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolinyl, indolyl, 6,7-dihydro-5H- cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

216. The compound of claim 182, wherein Cy is phenyl optionally substituted with 1, 2, 3, or more R’.

217. The compound according to claim 182, wherein Cy is selected from:

218. The compound of claim 182, wherein R' is selected from 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 .

219. The compound according to claim 182, wherein R' is selected from halogens, -CN, -NO2, optionally surrounded by one, two, or three halogens or C. 3-6 Cycloalkyl-substituted C 1-6 Alkyl group, optionally with one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 1-6 Heteroalkyl groups, optionally with one, two, or three halogens or C atoms. 3-6 Cycloalkyl-substituted C 2-6 Alkenyl group, optionally surrounded by one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

220. The compound of claim 182, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

221. The compound of claim 182, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

222. The compound of claim 182, wherein R’ is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

223. The compound of claim 182, wherein R’ is Cl.

224. The compound of claim 182, wherein R5 is selected from H, F, Cl, and Br.

225. The compound of claim 182, wherein R5 is H.

226. The compound of claim 182, wherein R6 is selected from H, F, Cl, and Br.

227. The compound of claim 182, wherein R6 is H or F.

228. The compound of claim 182, wherein each R a is independently selected from H and C 1-6 alkyl.

229. The compound of claim 182, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

230. The compound of Claim 182, wherein R b each of R c is independently selected from H, C 1-6 alkyl and C 3-6 cycloalkyl.

231. The compound of claim 182, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

232. The compound of claim 182, wherein each R d is independently selected from H and C 1-6 alkyl.

233. The compound of claim 182, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

234. The compound of claim 182, wherein R e is H.

235. The compound of claim 182, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

236. The compound of claim 182, wherein the term “optionally substituted” preceding a chemical group for which no substituents are designated means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

237. The compound of claim 182, wherein the term “optionally substituted” preceding a chemical group for which no substituents are designated means 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.

238. The compound of claim 1, wherein the compound is represented by formula (12A), (12B), (12C), (12D), (12E), or (12F): 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R5is selected from H, halogen, and optionally substituted C1-C6alkyl; R6is selected from H, halogen, and optionally substituted C1-C6alkyl; Each R a Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b and each of R c is independently selected from 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 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 12-membered heterocyclyl; Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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; Ph represents phenylene; and m is selected from 0, 1, 2, 3, 4, and 5.

239. The compound of claim 238, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

240. The compound according to claim 238, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

241. The compound of claim 238, wherein each of R1and R2is 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.

242. The compound of claim 238, wherein each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

243. The compound of claim 238, wherein each of R1and R2is independently selected from H and F.

244. The compound of claim 238, wherein both R1and R2are H.

245. The compound of claim 238, wherein R is selected from 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 .

246. The compound of claim 238, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

247. The compound of claim 238, wherein R is selected from H, 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.

248. The compound of claim 238, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

249. The compound of claim 238, wherein R is selected from H and -OH.

250. The compound of claim 238, wherein R is H.

251. The compound of claim 238, wherein R' is selected from 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 .

252. The compound of claim 238, wherein R' is selected from halogen, -CN, -N02, optionally substituted C 3-6 cycloalkyl-substituted C 1-6 alkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 1-6 heteroalkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkenyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

253. The compound of claim 238, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

254. The compound of claim 238, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

255. The compound of claim 238, wherein R’ is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

256. The compound of claim 238, wherein R’ is Cl.

257. The compound of claim 238, wherein R5is selected from H, F, Cl, and Br.

258. The compound of claim 238, wherein R5is H.

259. The compound of claim 238, wherein R6is selected from H, F, Cl, and Br.

260. The compound of claim 238, wherein R6is H or F.

261. The compound of claim 238, wherein each R a is independently selected from H and C 1-6 alkyl.

262. The compound of claim 238, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

263. The compound of claim 238, wherein R b each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

264. The compound of claim 238, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

265. The compound of claim 238, wherein each R d is independently selected from H and C 1-6 alkyl.

266. The compound of claim 238, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

267. The compound of Claim 238, wherein the term "optionally substituted" preceding a chemical group for which substitution is not specified indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

268. The compound of claim 238, wherein the term “optionally substituted” preceding a chemical group for which no substituents are designated means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

269. The compound of claim 238, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified indicates that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

270. A compound according to claim 238, wherein Ph represents 271. The compound of claim 238, wherein m is selected from 0, 1, and 2.

272. The compound of claim 238, wherein m is 0 or 1.

273. The compound of claim 1, wherein the compound is selected from the group consisting of:

274. The compound of claim 1, wherein the compound is selected from the group consisting of:

275. The compound of claim 8, wherein the Formula I is represented by Formula (13): wherein: ♦ indicates a point of attachment to the Formula II; each of R46and R47is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cyc Q is selected from the group consisting of 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 selected from aryl, C 3-12 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 selected from a bond, -(CH2) a C(R1)(R2)(CH2) b -, -N(R1)-, -0-, -S-, -C(=0)-, -C(=S)-, -S(=0)-, and -S(=0)2-; X1, X2, and X3are each independently selected from CR, S, or N; with the proviso that at least one of X1, X2, and X3is N, and one of X1, X2, and X3is S; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R' is selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b and each of R c is independently selected from 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 can together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclyl; Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, with the proviso that a + b < 5; and The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

276. The compound of claim 275, wherein Q is selected from optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c and Cy.

277. The compound of claim 275, wherein Q is selected from C 1-6 alkyl, -SR a and Cy.

278. The compound of claim 275, wherein Q is selected from methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, and Cy.

279. The compound of claim 275, wherein Q is selected from isopropyl, isopropylthio, and Cy.

280. The compound of claim 275, wherein Q is Cy.

281. The compound of claim 275, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

282. The compound of claim 275, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R'.

283. The compound of claim 275, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridinyl, indolinyl, indolyl, 6,7-dihydro-5H- cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

284. The compound of claim 275, wherein Cy is phenyl or pyridinyl optionally substituted with 1, 2, 3, or more R’.

285. The compound of claim 275, wherein Q is selected from:

286. The compound of claim 275, wherein Q is selected from:

287. The compound of claim 275, wherein L A is selected from the group consisting of a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

288. The compound of claim 275, wherein L A is selected from the group consisting of a bond, -CH2-, -CF2-, -CC12-, -CBr2-, -CFCl-, -CFBr-, -CClBr-, -NH-, -0-, -S-, -C(=0)-, and -C(=S)-.

289. The compound of claim 275, wherein L A is selected from the group consisting of a bond, -CH2-, -CF2-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

290. The compound of Claim 275, wherein L A is -CH2-.

291. The compound of claim 275, wherein X1 is CR or N.

292. The compound of claim 275, wherein X2 is S or N.

293. The compound of claim 275, wherein X3 is S or N.

294. The compound of claim 275, wherein is selected from:

295. The compound of claim 275, wherein R is selected from 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 .

296. The compound of claim 275, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

297. The compound of claim 275, wherein R is selected from H, 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.

298. The compound of claim 275, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

299. The compound of claim 275, wherein R is selected from H, methyl, and -OH.

300. The compound of claim 275, wherein R is H.

301. The compound of claim 275, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

302. The compound according to claim 275, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

303. The compound of claim 275, wherein 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.

304. The compound of claim 275, wherein each of R1 and R2 is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

305. The compound of claim 275, wherein each of R1 and R2 is independently selected from H and F.

306. The compound of claim 275, wherein both R1 and R2 are H.

307. The compound of claim 275, wherein both R1 and R2 are F.

308. The compound of claim 275, wherein R' is selected from 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 .

309. The compound of claim 275, wherein R' is selected from halogen, -CN, -N02, optionally substituted C 3-6 cycloalkyl-substituted C 1-6 alkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 1-6 heteroalkyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkenyl, optionally substituted with 1, 2, or 3 halogen or C 3-6 cycloalkyl-substituted C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

310. The compound of claim 275, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

311. The compound of claim 275, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

312. The compound of claim 275, wherein R’ is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

313. The compound of claim 275, wherein R’ is Cl or F.

314. The compound of claim 275, wherein each R a is independently selected from H and C 1-6 alkyl.

315. The compound of claim 275, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

316. The compound of claim 275, wherein each R a is independently H or isopropyl.

317. The compound according to claim 275, wherein R b and R c Each of them is independently selected from H and C. 1-6 Alkyl and C 3-6 Cycloalkyl.

318. The compound of Claim 275, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

319. The compound of Claim 275, wherein R b is H and R c is cyclopropyl, or R b is cyclopropyl and R c is H.

320. The compound of claim 275, wherein each R d is independently selected from H and C 1-6 alkyl.

321. The compound of claim 275, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

322. The compound of claim 275, wherein each R d is independently H or methyl.

323. 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 compound of Claim 275, wherein the term "optionally substituted" preceding a chemical group for which substitution is not specified indicates that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

326. The compound of claim 275, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

327. The compound of claim 275, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, and cyclopropyl.

328. The compound of claim 8, wherein the Formula I is represented by Formula (14A), (14B), or (14C): wherein: ♦ represents the point of attachment to the Formula II; a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5; and ♦ represents the point of attachment to the Formula II; a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5; and 331. The compound of claim 328, wherein each of R1and R2is 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. 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 Alkyne, -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 Optional substitution of C 3-6 Carbocyclic groups and optionally substituted 3- to 6-membered heterocyclic groups, or R1 and R2 together with the atoms they are attached to form optionally substituted C groups. 3-12 Carbocyclic or optionally substituted 3- to 12-membered heterocyclic groups; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 selected from the group consisting of 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 selected from aryl, C 3-12 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 selected from the group consisting of a bond, -(CH2) a C(R1)(R2)(CH2) b - N(R1)-, -0-, -S-, -C(=0)-, -C(=S)-, -S(=0)-, and -S(=0)2-; R' is selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b each of R c is independently selected from 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 can form, together with the nitrogen atom to which they are attached, an optionally substituted 3- to 12-membered heterocyclyl; Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; 332. The compound of claim 328, wherein each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl. The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

329. The compound of claim 328, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

330. The compound according to claim 328, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

333. The compound of claim 328, wherein each of R1and R2is independently selected from H and F.

334. The compound of claim 328, wherein both R1and R2are H.

335. The compound of claim 328, wherein both R1and R2are F.

338. The compound of claim 328, wherein R is selected from H, 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.

339. The compound of claim 328, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

336. The compound of claim 328, wherein R is selected from 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 .

337. The compound of claim 328, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR b R c .

340. The compound of claim 328, wherein R is selected from H, methyl, and -OH.

341. The compound of claim 328, wherein R is H. ​ ​ 342. The compound of claim 328, wherein Q is selected from the group consisting of optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c and Cy.

343. The compound of claim 328, wherein Q is selected from C 1-6 alkyl, -SR a and Cy.

344. The compound of claim 328, wherein Q is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, and Cy.

345. The compound of claim 328, wherein Q is selected from the group consisting of i-propyl, i-propylthio, and Cy.

346. The compound of claim 328, wherein Q is Cy.

347. The compound of claim 328, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

348. The compound of claim 328, wherein Cy is selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

349. The compound of claim 328, wherein Cy is selected from the group consisting of phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolizinyl, indolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

350. The compound of claim 328, wherein Cy is phenyl or pyridyl, optionally substituted with 1, 2, 3, or more R’.

351. The compound of claim 328, wherein Q is selected from the group consisting of:

352. The compound of claim 328, wherein Q is selected from:

353. The compound of claim 328, wherein L A is selected from the group consisting of a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

354. The compound of claim 328, wherein L A is selected from the group consisting of a bond, -CH2-, -CF2-, -CC12-, -CBr2-, -CFCl-, -CFBr-, -CClBr-, -NH-, -0-, -S-, -C(=0)-, and -C(=S)-.

355. The compound of claim 328, wherein L A is selected from the group consisting of a bond, -CH2-, -CF2-, -NH-, -0-, -S-, -C(=0)-, and -C(=S)-.

356. The compound of claim 328, wherein L A is -CH2-.

357. The compound of claim 328, wherein R' is selected from 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 .

358. The compound according to claim 328, wherein R' is selected from halogens, -CN, -NO2, optionally surrounded by one, two, or three halogens or C. 3-6 Cycloalkyl-substituted C 1-6 Alkyl group, optionally with one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 1-6 Heteroalkyl groups, optionally with one, two, or three halogens or C atoms. 3-6 Cycloalkyl-substituted C 2-6 Alkenyl group, optionally surrounded by one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

359. The compound of claim 328, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

360. The compound of claim 328, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

361. The compound of claim 328, wherein R’ is selected from the group consisting of F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

362. The compound of claim 328, wherein R’ is Cl or F.

363. The compound of claim 328, wherein each R a is independently selected from H and C 1-6 alkyl.

364. The compound of claim 328, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

365. The compound of claim 328, wherein each R a is independently H or isopropyl.

366. The compound of claim 328, wherein R b each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

367. The compound of claim 328, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

368. The compound of claim 328, wherein R b is H and R c is cyclopropyl, or R b is cyclopropyl and R c is H.

369. The compound of claim 328, wherein each R d is independently selected from H and C 1-6 alkyl.

370. The compound of claim 328, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

371. The compound of claim 328, wherein each R d is independently H or methyl.

372. The compound of claim 328, wherein a is selected from the group consisting of 0 and 1, and b is selected from the group consisting of 0 and 1.

373. The compound of claim 328, wherein a is 0 and b is 0.

374. The compound of claim 328, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

375. The compound of claim 328, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

376. The compound of claim 328, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means 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.

377. The compound of claim 1, wherein the DT is a moiety represented by formula (15A), (15B), (15C), or (15D): wherein U is independently selected from a bond, -CH2-, -NH-, and -O-; represents the point of attachment to said formula II; each of V and W is independently selected from -C(=O)- and -CH2-; each of X, Y, and Z is independently selected from CR6and N; R5is selected from H, halogen, and optionally substituted C1-C6alkyl; and R6is selected from H, halogen, and optionally substituted C1-C6alkyl.

378. The compound of claim 377, wherein U is a bond.

379. The compound of claim 377, wherein U is -CH2-.

380. The compound of claim 377, wherein V is -C(=O)- and W is -CH2-.

381. The compound of claim 377, wherein V is -CH2- and W is -C(=O)-.

382. The compound of claim 377, wherein both V and W are -C(=O)-.

383. The compound of claim 377, wherein each of X, Y, and Z is independently selected from CR6.

384. The compound of claim 377, wherein R5is selected from H, F, Cl, and Br.

385. The compound of claim 377, wherein R5is H.

386. The compound of claim 377, wherein R6is selected from H, F, Cl, and Br.

387. The compound of claim 377, wherein R6is H or F.

388. The compound of claim 377, wherein the DT is a moiety selected from:

389. The compound of claim 377, wherein the DT is a moiety selected from:

390. The compound of claim 1, wherein the compound is represented by formula (16A) or (16B) wherein: each of X1, X2, and X3is independently selected from CR, S, or N; each of R1, R2, R3, and R4is independently H or C1-6alkyl; Q is selected from the group consisting of 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 selected from aryl, C 3-12 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 selected from the group consisting of a bond, -(CH2) a C(R1)(R2)(CH2) b - N(R1)-, -0-, -S-, -C(=0)-, -C(=S)-, -S(=0)-, and -S(=0)2-; provided that at least one of X1, X2, and X3is N, and one of X1, X2, and X3is S; U is independently selected from a bond, -CH2-, -NH-, and -O-; A is selected from C 1-20 Alkylene, -O-, -S-, -N(R) e - and -N(R) e )-C 1-20 alkylene-, and optionally wherein the C 1-20 One, two, three or more methylene groups in the alkylene group are independently selected from -O-, -S-, -N(R) e Substitution of groups with -, -C(=O)- and -C(=S)-; B is a bond or selected from arylene, C 3-12 carbocyclylene, 5- to 12-membered heteroarylene, and 3- to 12-membered heterocyclylene, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of halogen, -CN, -NO2, C1-C6alkyl, 1-6 alkyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 1-6 heteroalkyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 2-6 alkenyl, C1-C6alkyl optionally substituted with 1, 2, or 3 halogens, 2-6 alkynyl, -OR a , -SR a , and -NR b R c ; each of V and W is independently selected from -C(=O)- and -CH2-; each of X, Y, and Z is independently selected from CR6and N; R5is selected from H, halogen, and optionally substituted C1-C6alkyl; each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, -CN, -NO2, -OR 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 R1and R2can form, together with the atoms to which they are attached, an optionally substituted C 3-12 carbocyclyl or optionally substituted 3- to 12-membered heterocyclyl; R is selected from the group consisting of H, halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), 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 selected from the group consisting of halogen, -CN, -N(=0), -N02, -ON(=0), 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(=0)R a , -C(=S)R a , -C(=0)OR a , -OC(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -NR b R c , -C(=0)NR b R c , -S(=0)NR b R c , -S(=0)2NR b R c , -NR d C(=0)R a , -NR d C(=0)OR a , -NR d C(=0)NR b R c , -NR d S(=0)R a , -NR d S(=0)2R a , -NR d S(=0)NR b R c , -NR d S(=0)2NR b R c , -SN(=0), -NR d N(=0), optionally substituted aryl, optionally substituted C 3-12 carbocyclyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl; R6is selected from H, halogen, and optionally substituted C1-C6alkyl; a is selected from 0, 1, 2, 3, 4, and 5, b is selected from 0, 1, 2, 3, 4, and 5, provided that a + b < 5; Each R a Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R b and each of R c is independently selected from 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 can together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclyl; Each R d Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; R e selected from H and optionally substituted C 1-6 alkyl; e is 0 or 1; f is selected from 0, 1, 2, and 3; and g is selected from 0, 1, 2, and 3. The term "optionally substituted" preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

391. The compound of claim 390, wherein Q is selected from optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c and Cy.

392. The compound of claim 390, wherein Q is selected from C 1-6 alkyl, -SR a and Cy.

393. The compound of claim 390, wherein Q is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, and Cy.

394. The compound of claim 390, wherein Q is selected from i-propyl, i-propylthio, and Cy.

395. The compound of claim 390, wherein Q is Cy.

396. The compound of claim 390, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'.

397. The compound of claim 390, wherein Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolinyl, isoindolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, pteridinyl, purinyl, triazolyl, tetrazolyl, triazinyl, cinnolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, benzothienyl, imidazopyridinyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthrydinyl, furopyridinyl, and indazolyl, each of which is optionally substituted with 1, 2, 3, or more R’.

398. The compound of claim 390, wherein Cy is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, pyridyl, indolizinyl, indolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, phthalazinyl, benzimidazolyl, pyrrolopyridinyl, benzofuranyl, and tetrahydrobenzofuranyl, each of which is optionally substituted with 1, 2, 3, or more R’.

399. The compound of claim 390, wherein Cy is phenyl or pyridyl, optionally substituted with 1, 2, 3, or more R’.

400. The compound of claim 390, wherein Q is selected from:

401. The compound of claim 390, wherein Q is selected from:

402. The compound of claim 390, wherein L A is selected from the group consisting of a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-.

403. The compound of claim 390, wherein L A is selected from a bond, -CH2-, -CF2-, -CC12-, -CBr2-, -CFCl-, -CFBr-, -CClBr-, -NH-, -0-, -S-, -C(=0)-, and -C(=S)-.

404. The compound of claim 390, wherein L A is selected from the group consisting of a bond, -CH2-, -CF2-, -NH-, -O-, -S-, -C(=O)-, and -C(=S)-.

405. The compound of claim 390, wherein L A is -CH2-.

406. The compound of claim 390, wherein X1 is CR or N.

407. The compound of claim 390, wherein X2 is S or N.

408. The compound of claim 390, wherein X3 is S or N.

409. The compound of claim 390, wherein is selected from:

410. The compound of claim 390, wherein A is selected from C 1-8 alkylene, -0-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein 1, 2, 3 or more methylenes in said C 1-8 alkylene are independently replaced with a group selected from -0- and -C(=0).

411. The compound of claim 390, wherein A is selected from -CH2-, -O-, -NH-, -NH-(CH2)3-, -NH-(CH2)5-, and -NH-C(=O)-(CH2)3-O-(CH2)3-.

412. The compound of claim 390, wherein A is selected from -CH2-, -O-, and -NH-.

413. The compound of claim 390, wherein A is -NH-.

414. The compound of claim 390, wherein B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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.

415. The compound of claim 390, wherein B is a bond or is selected from phenylene, pyrrolylene, furanylene, thienylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiazolylene, isothiazolylene, thiadiazolylene, pyridinylene, pyrylylene, 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.

416. 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. The compound of claim 390, wherein B is a bond or phenylene.

418. The compound of claim 390, wherein is a moiety selected from the group consisting of:

419. The compound of claim 390, wherein is a moiety selected from the group consisting of:

420. The compound of claim 390, wherein U is a bond.

421. The compound of claim 390, wherein U is -CH2-.

422. The compound of claim 390, wherein V is -C(=O)- and W is -CH2-.

423. The compound of claim 390, wherein V is -CH2- and W is -C(=O)-.

424. The compound of claim 390, wherein V and W are both -C(=O)-.

425. The compound of claim 390, wherein each of X, Y, and Z is independently selected from CR6.

426. The compound of claim 390, wherein is a moiety selected from the group consisting of:

427. The compound of claim 390, wherein is a moiety selected from the group consisting of:

428. The compound of claim 390, wherein each of R1and R2is independently selected from H, halogen, optionally substituted C1-C6alkyl, 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 .

429. The compound according to claim 390, wherein each of R1 and R2 is independently selected from H, halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c .

430. The compound of claim 390, wherein each of R1and R2is 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.

431. The compound of claim 390, wherein each of R1and R2is independently selected from H, F, Cl, Br, methyl, ethyl, and propyl.

432. The compound of claim 390, wherein each of R1and R2is independently selected from H and F.

433. The compound of claim 390, wherein both R1and R2are H.

434. The compound of claim 390, wherein both R1and R2are F.

435. The compound of claim 390, wherein R is selected from 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 .

436. The compound of claim 390, wherein R is selected from H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , and -NR bRc .

437. The compound of claim 390, wherein R is selected from H, 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.

438. The compound of claim 390, wherein R is selected from H, F, Cl, Br, methyl, ethyl, propyl, -OH, -O(CH3), and -NH2.

439. The compound of claim 390, wherein R is selected from H, methyl, and -OH.

440. The compound of claim 390, wherein R is H.

441. The compound of claim 390, wherein R' is selected from 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 .

442. The compound according to claim 390, wherein R' is selected from halogens, -CN, -NO2, optionally surrounded by one, two, or three halogens or C. 3-6 Cycloalkyl-substituted C 1-6 Alkyl group, optionally with one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 1-6 Heteroalkyl groups, optionally with one, two, or three halogens or C atoms. 3-6 Cycloalkyl-substituted C 2-6 Alkenyl group, optionally surrounded by one, two, or three halogens or C 3-6 Cycloalkyl-substituted C 2-6 alkynyl group, -OR a -SR a and -NR b R c .

443. The compound of claim 390, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, -0(CH3), -0(C 3-6 cycloalkyl), -NH2, -NH(CH3), -N(CH3)2, and -NH(C 3-6 cycloalkyl).

444. The compound of claim 390, wherein R' is selected from the group consisting of halogen, -CH2(C 3-6 cycloalkyl), -OH, and -NH(C 3-6 cycloalkyl).

445. The compound of claim 390, wherein R' is selected from F, Cl, cyclopropylmethyl, -OH, and cyclopropylamino.

446. The compound of claim 390, wherein R' is Cl or F.

447. The compound according to claim 390, wherein... In It is a single key.

448. The compound according to claim 390, wherein... In It is a double bond.

449. The compound of claim 390, wherein R" is selected from 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 .

450. The compound according to claim 390, wherein R” is selected from halogens, -CN, -NO2, C1-C6 alkyl groups optionally substituted with one, two, or three halogens, C1-C6 alkyl groups optionally substituted with one, two, or three halogens. 1-6 Heteroalkyl groups, C14 groups optionally substituted with one, two, or three halogens. 2-6 Alkenyl group, C substituted with one, two or three halogens. 2-6 alkynyl group, -OR a -SR a and -NR b R c .

451. The compound of claim 390, wherein 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.

452. The compound of claim 390, wherein R" is selected from F, Cl, Br, methyl, ethyl, propyl, -OH, and -NH2.

453. The compound of claim 390, wherein R5is selected from H, F, Cl, and Br.

454. The compound of claim 390, wherein R5is H.

455. The compound of claim 390, wherein R6is selected from H, F, Cl, and Br.

456. The compound of claim 390, wherein R6is H or F.

457. The compound of claim 390, wherein each R a is independently selected from H and C 1-6 alkyl.

458. The compound of claim 390, wherein each R a is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

459. The compound of claim 390, wherein each R a is independently H or isopropyl.

460. The compound of claim 390, wherein R b each of R c is independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

461. The compound of Claim 390, wherein R b and each of R c is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

462. The compound of Claim 390, wherein R b is H and R c is cyclopropyl, or R b is cyclopropyl and R c is H.

463. The compound of claim 390, wherein each R d is independently selected from H and C 1-6 alkyl.

464. The compound of claim 390, wherein each R d is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

465. The compound of Claim 390, wherein R e is H.

466. 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.

471. The compound of Claim 390, wherein is a moiety selected from the group consisting of:

472. The compound of claim 390, wherein the term “optionally substituted” preceding a chemical group for which no substituents are specified means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

473. The compound of claim 390, wherein the term "optionally substituted" preceding a chemical group for which no substituents are designated means that said chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -OH, -NH2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

474. The compound of claim 390, wherein the term "optionally substituted" preceding a chemical group for which no substituents are specified means 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.

475. The compound of claim 1, wherein the compound is represented by formula (17A) or (17B) wherein: each of R19and R20is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cyc Q is selected from the group consisting of optionally substituted C 1-6 alkyl, -OR a , -SR a , -NR b R c and Cy; Cy is selected from phenyl, naphthyl, anthryl, phenanthryl, C 3-8 carbocyclyl, 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and 5- to 10-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more R'; L A is selected from the group consisting of a bond, -C(R1)(R2)-, -N(R1)-, -O-, -S-, -C(=O)-, and -C(=S)-; selected from the group consisting of: A is selected from C 1-8 alkylene, -0-, -NH-, -N(CH3)-, -N(C2H5)-, -NH-C 1-8 alkylene, and optionally wherein said C 1-8 1, 2, 3 or more methylenes in said alkylene are independently replaced by a group selected from -0- and -C(=0)-; B is a bond or is selected from arylene and 5- or 6-membered heteroarylene comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of 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; U is independently selected from a bond, -CH2-, -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 Alkyne, -CN, -NO2, -OR a -SR a and -NR b R c ; R is selected from 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 ; R' is selected from the group consisting of 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 ; R5is selected from H, F, Cl, and Br; R6is selected from H, F, Cl, and Br; Each R a Independently selected from H and C 1-6 alkyl; R b and each of R c is independently selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; e is 0 or 1; and The term "optionally substituted" preceding a chemical group for which no substitution is specified indicates that the chemical group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH, -NH2, -NO2, -CN, and C 3-6 cycloalkyl.

476. The compound of claim 1, wherein the compound is selected from the group consisting of:

477. A pharmaceutical composition comprising a compound of any one of claims 1-476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, and one or more pharmaceutically acceptable excipients.

478. A kit comprising a compound of any one of claims 1-476, 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. A method for preventing or treating a disease or condition in 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 any one of claims 1-476, 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 the condition is selected from the group consisting of a hyperproliferative disease, a cardiovascular disease, a hematologic disease, an infectious disease, an endocrine disease, a metabolic disease, a gastrointestinal disease, a respiratory disease, inflammation, opioid addiction, and a urologic disease.

481. The method of claim 479, wherein the disease or the 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 carcinoma or a sarcoma.

484. The method of claim 483, wherein the carcinoma is a hematopoietic cancer or a solid tumor.

485. The method of claim 484, wherein the hematopoietic system cancer is selected from leukemia, lymphoma, heavy chain disease, myeloproliferative disorder, multiple myeloma, plasmacytoma, common eosinophilia, 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 system cancer, genitourinary system cancer, gynecological cancer, skin cancer, soft tissue cancer, oral cavity cancer, head and neck cancer, esophageal cancer, liver cancer, and pancreatic cancer.

487. The method of claim 479, wherein the disease or the 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, heart valve disease, stenosis, restenosis, in-stent stenosis, angina, 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.

489. The method of claim 479, wherein the disease or the condition is pulmonary hypertension.

490. The method of claim 489, wherein the disease or the condition is pulmonary arterial hypertension.

491. The method of claim 490, wherein the disease or the condition is selected from idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, drug or toxin-induced pulmonary arterial hypertension, idiopathic pulmonary veno-occlusive disease, heritable pulmonary veno-occlusive disease, drug, toxin, or radiation-induced pulmonary veno-occlusive disease, idiopathic pulmonary capillary hemangiomatosis, heritable pulmonary capillary hemangiomatosis, drug, toxin, or radiation-induced pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.

492. A method for inhibiting tumor growth or preventing tumor recurrence in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477.

493. A method for degrading 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 any one of claims 1-476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477.

494. A compound of any one of claims 1-476, or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or a pharmaceutical composition of claim 477, for use in therapy.

495. The compound of any one of claims 1-476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or the pharmaceutical composition of claim 477, for use in preventing or treating a disease or condition in which degradation of GRK2 is beneficial in a subject.

496. The compound of any one of claims 1-476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or the pharmaceutical composition of claim 477, and one or more pharmaceutically acceptable excipients, for use in inhibiting tumor growth or preventing tumor recurrence in a subject.

497. The compound of any one of claims 1-476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or the pharmaceutical composition of claim 477, for use in degrading GRK2 or inhibiting the activity of GRK2 in a subject.

498. Use of a compound of any one of claims 1-476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or the pharmaceutical composition of claim 477, for the manufacture of a medicament for preventing or treating a disease or condition in which degradation of GRK2 is beneficial in a subject.

499. Use of a compound of any one of claims 1-476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or the pharmaceutical composition of claim 477, for the manufacture of a medicament for inhibiting tumor growth or preventing tumor recurrence in a subject.

500. Use of a compound of any one of claims 1-476 or a pharmaceutically acceptable salt, isomer, isotope, prodrug, solvate, or polymorph thereof, or the pharmaceutical composition of claim 477, for the manufacture of a medicament for degrading GRK2 or inhibiting the activity of GRK2 in a subject.

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