Substituted triazine compound derivatives and their pharmaceutical use

Abstract

Provided herein are novel triazine compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The triazine compound derivatives are compounds represented by Formula (I) or (II), or tautomers, stereoisomers, prodrugs, crystal forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds and compositions of the present disclosure can be used to treat diseases or disorders mediated by USP1, in particular, cancer. Formula (I) Formula (II)

Description

1 Description Title of Invention: SUBSTITUTED TRIAZINE COMPOUND DERIVATIVES AND THEIR PHARMACEUTICAL USE Technical Field

[0001] The present disclosure relates to triazine compound derivatives, particularly those with inhibitory effect on USP1, pharmaceutical compositions containing the same, and preparation methods and uses thereof. Background Art

[0002] Ubiquitin is a highly conserved polypeptide composed of 76 amino acids residues. It is conjugated to a substrate protein as part of a post-translational modification, which is known as a ubiquitination process. During the ubiquitination process, ubiquitin is attached to lysine residues on the substrate protein or itself, leading to monoubiqutination or polyubiquitination. Ubiquitination plays a critical role in the regulation of protein stability, function, and localization, and thus, it is involved in various cellular processes, including immune response, cell proliferation, DNA repair, etc.

[0003] Ubiquitination is a reversible process due to the presence of deubiquitination enzymes (DUBs), which can remove ubiquitin from the substrate protein. Ubiquitin specific protease 1 (USP1) is one of deubiquitination enzymes, and is known to play an important role in the regulation of DNA repair processes. In order to gain deubiquitanase activity, USP1 is associated with UAF1 (USP1-associated factor 1) to form a heterodimeric USP1 / UAF1 complex. The USP1 / UAF1 complex regulates the following two cellular pathways: Faconi anemia (FA) pathway and translesion synthesis (TLS) pathway. In the FA pathway, the USP1 / UAF1 complex deubiquitinates monoubiqutinated FANCD2 (Fanconi anemia group complentation group D2) and FANC1 (Fanconi anemia complementation group 1) proteins. In the TLS pathway, the USP1 / UAF1 complex deubiquitinates monoubiqutinated PCNA (proliferating cell nuclear antigen). The above-mentioned two pathways are known to participate in repairing DNA damage caused by DNA interstand crosslink (ICL).2

[0004] Inhibition of USP1 can impair DNA damage response, mainly in the FA and TLS pathways. Based on the above-described mechanism, USP1 has been identified as a promising therapeutic target for various cancers. For example, it has been shown that USP1 inhibitors reverse cisplatin resistance in non-small cell lung cancer (NSCLC) (Chen, J., et al, 2011, Chemistry & biology, 1390-1400). It has also been shown that USP1 inhibition inhibits tumor growth in osteosarcoma cells (Williams, Samuel A., et al., 2011, Cell, 146(6), 918-930; and Lim, K. H & Baek, K. H., 2013, Current pharmaceutical design, 19(22), 4039-4052), and leukemic cells (Mistry, Helena, et al., 2013, Molecular cancer therapeutics 12.12 (2013): 2651-2662).

[0005] Therefore, inhibiting USP1 has potential as a treatment for various cancers, and there is a need to develop novel small molecule compounds that have an inhibitory activity for USP1. Summary of Invention

[0006] The present disclosure provides novel triazine compounds derivatives, compositions comprising the same, and preparation methods and uses thereof. The triazine compound derivatives have an inhibitory activity for USP1, and can be effectively used for treating various types of cancers.

[0007] In one aspect, the present disclosure relates to a compound of the following Formula

[0008]

[0009] wherein:

[0010] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C63 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and - O-(3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), , and

[0011] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0012] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0013] each of x, y, and z is independently an integer between 0 and 3;

[0014] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0015] L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0016] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group,4 wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0017] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0018] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0019] each of n and m is independently an integer between 0 and 3;

[0020] L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[0021] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0022] R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said5 alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6 alkoxy;

[0023] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0024] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0025] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0026] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compounds of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a a pharmaceutically acceptable carrier(s) and / or excipient(s).

[0027] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, which comprises one or more of the compounds of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier(s) and / or excipient(s). In a specific embodiment, the composition comprises one or more of the compounds in a therapeutically effective amount. In a specific6 embodiment, the composition comprises one or more of the compounds in a prophylactically effective amount.

[0028] In another aspect, the present disclosure provides the use of the compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by USP1.

[0029] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, in a subject, comprising administering to the subject at least one compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[0030] In another aspect, the present disclosure provides the compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1.

[0031]

[0032] In another aspect, the present disclosure relates to a compound of the following Formula (II):

[0033]

[0034] wherein:

[0035] each of X1and X2is independently selected from the group consisting of N and CRX;7

[0036] Rxis selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, NH2, NH(C1-C6alkyl), and N(C1-C6alkyl)2;

[0037] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O- (3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3,(C1-C6alkylene)-O-(C1-C6alkyl), , and

[0038] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0039] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0040] each of x, y, and z is independently an integer between 0 and 3;

[0041] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0042] R5is hydrogen or RL2;

[0043] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more8 selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0044] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0045] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0046] each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered, 5-12 membered heteroarylene, 6-10 membered arylene, -(C1-C6 alkylene)-(6-10 membered arylene)-, or -(C1-C6 alkylene)-(6-10 membered arylene)-(C1-C6 alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and hydroxy;

[0047] each of q, r, s and t is independently an integer between 0 and 5;

[0048] each of L4and L5is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -S(=O)-. -S(=O)2-, -C(=O)-, -C(=O)-NH-, -NH-C(=O)- NH-, -C(=NH)-, -C(=N(C1-C6alkyl)), and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6 alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene;9

[0049] each of C1 and C2 is independently selected from the group consisting of hydrogen, a PARP inhibitor moiety, a PARG inhibitor moiety, and an E3 ligase ligand moiety, but C1 and C2 are not both hydrogen;

[0050] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0051] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0052] In another aspect, the present disclosure provides the compounds of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a a pharmaceutically acceptable carrier(s) and / or excipient(s).

[0053] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, particularly, in a subject with a mutation in genes encoding BRCA1 or BRCA2, which comprises one or more of the compounds of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier(s) and / or excipient(s). In a specific embodiment, the composition comprises one or more of the compounds in a therapeutically effective amount. In a specific embodiment, the composition comprises one or more of the compounds in a prophylactically effective amount.

[0054] In another aspect, the present disclosure provides the use of the compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by USP1, particularly, in a subject with a mutation in genes encoding BRCA1 or BRCA2.10

[0055] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, in a subject, particularly, in a subject with a mutation in genes encoding BRCA1 or BRCA2, comprising administering to the subject at least one compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[0056] In another aspect, the present disclosure provides the compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, particularly, in a subject with a mutation in genes encoding BRCA1 or BRCA2.

[0057]

[0058] Furthermore, the present disclosure also provides a novel combination of a USP1 inhibitor and a PARG inhibitor that has a synergistic effect for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, cancers.

[0059] In one aspect, the present disclosure relates to a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2, comprising a USP1 inhibitor, and optionally one or more pharmaceutically acceptable carriers and / or excipients, wherein the USP1 inhibitor is to be used in combination with a PARG inhibitor.

[0060] In another aspect, the present disclosure relates to a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2, comprising a PARG inhibitor, and optionally one or more pharmaceutically acceptable carriers and / or excipients, wherein the PARG inhibitor is to be used in combination with a USP1 inhibitor.11

[0061] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2, in a subject, comprising administering to the subject a USP1 inhibitor and optionally one or more pharmaceutically acceptable carriers and / or excipients, wherein the method further comprising administering to the subject a PARG inhibitor, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0062] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2, in a subject, comprising administering to the subject a PARG inhibitor, and optionally one or more pharmaceutically acceptable carriers and / or excipients, wherein the method further comprising administering to the subject a USP1 inhibitor, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0063] In another aspect, the present disclosure provides a pharmaceutical combination of a USP1 inhibitor and a PARG inhibitor. In one embodiment, the pharmaceutical combination is for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2.

[0064] In another aspect, the present disclosure provides the use of the combination of a USP1 inhibitor and a PARG inhibitor, in the manufacture of a medicament for the treatment or prevention of diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2.

[0065]

[0066] In another aspect, the present disclosure provides a kit or product comprising:

[0067] - a first pharmaceutical composition or dosage form comprising a USP1 inhibitor and, optionally, one or more pharmaceutically acceptable carriers and / or excipients; and

[0068] - a second pharmaceutical composition or dosage form comprising a PARG inhibitor and, optionally, one or more pharmaceutically acceptable carriers and / or excipients.

[0069] 12

[0070] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following specific embodiments, examples, and claims.

[0071]

[0072] Definitions

[0073] Chemical terms

[0074] The definitions of specific functional groups and chemical terms are described in more detail below.

[0075] When a range of values is listed, it is intended to encompass each value and any sub- range within the range. For example, “C1-6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0076] As used herein (unless otherwise specified), the term “C1-6alkyl” refers to a saturated hydrocarbon group which is straight-chained or branched, and has 1 to 6 carbon atoms. It is also referred to herein as a "lower alkyl" group. In some embodiments, the alkyl group may have 1 to 4 carbon atoms (C1-4 alkyl) or 3 to 6 carbon atoms (C3-6 alkyl). Examples of C1-6alkyl group include, but are not limited to methyl, ethyl, n-propyl, iso- propyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentyl, 2-pentyl, neo-pentyl, 3- methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.

[0077] As used herein (unless otherwise specified), the term “C1-6alkylene” refers to a divalent alkyl linking group, which is a linear or branched, saturated hydrocarbon group having 1 to 6 carbon atoms. An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propan-1,3-diyl, propan-1,2-diyl, butan-l,4-diyl, butan-1,3-diyl, butan-l,2-diyl, 2-methyl-propan-1,3-diyl and the like.

[0078] As used herein (unless otherwise specified), the term “C2-6alkenyl” refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, the alkenyl group may have 2 to 4 carbon13 atoms. Examples of C2-6 alkenyl group include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, etc.

[0079] As used herein (unless otherwise specified), the term “C2-6alkynyl” refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2 or 3 carbon-carbon triple bonds) and optionally one or more carbon-carbon double bonds (e.g., 1, 2 or 3 carbon-carbon double bonds). In some embodiments, the alkynyl group may have 2 to 4 carbon atoms. In some embodiments, the alkynyl group does not contain any double bond. One or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1- butynyl). Examples of C2-6alkynyl group include, but are not limited to, ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0080] As used herein (unless otherwise specified), the term “C2-6alkynylene” refers to a divalent alkynyl linking group, which is a linear or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon triple bonds. An alkynylene group formally corresponds to an alkyne with two C-H bonds replaced by points of attachment of the alkynylene group to the remainder of the compound. Examples of alkynylene groups include, but are not limited to, acetylene, 1-propyn-1,3-diyl, 2- propyn-1,3-diyl, 1-butyne-1,4-diyl, 2-butyne-1,4-diyl, 3-butyne-1,4-diyl, 1-butyne-1,3- diyl, 2-butyne-1,4-diyl, 3-butyne-1,4-diyl, 3-butyne-2,4-diyl and the like.

[0081] As used herein (unless otherwise specified), the term “C1-6 alkoxy” refers to a -OR group, wherein R is substituted or unsubstituted C1-6 alkyl. In some embodiments, the alkoxy group may have 1 to 4 carbon atoms. Specifically, C1-6alkoxyl includes, but is not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n- pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

[0082] As used herein (unless otherwise specified), the terms “halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In some embodiments, the halo group is F, Cl or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0083] As used herein (unless otherwise specified), the terms “carbocyclic group” refers to a non-aromatic cyclic hydrocarbon group having from 5 to 10 ring carbon and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic14 group may have 5 to 10, 5 to 8, 5 to 7, or 6 to 7 ring carbon atoms. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0084] As used herein (unless otherwise specified), the terms “heterocarbocyclic group” refers a group or radical of a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, phosphorous, silicon, and selenium. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclic group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. In some embodiments, the heterocarbocyclic group may have 5 to 10, 5 to 8, 5 to 7, or 6 to 7 ring atoms.

[0085] As used herein (unless otherwise specified), the terms “C3-10 cyclic group” or “3-10 membered cyclic group” refers to a cyclic hydrocarbon group which is non-aromatic and has 3-10 ring carbon atoms and zero heteroatoms. In some embodiments, the cycloalkyl group may have 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms. The cyclic group also includes a ring system in which the above cyclic group is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the ring of the cyclic group. Examples of the cyclic group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and the like.15

[0086] As used herein (unless otherwise specified), the term “3-12 membered heterocyclic group”, or the term “3-12 -membered heterocyclyl” refers to a radical of a 3-12 membered saturated or partially unsaturated ring system which is non-aromatic and has ring carbon atoms and at least one ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, phosphorus, silicon, and selenium. Unless stated otherwise specifically in the specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and includes a fused, spiro, or bridged ring system. In some embodiments, the heterocyclyl group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 12, 5 to 8, 5 to 7, 5 to 6, 9 to 11, 9 to 10 ring carbon atoms, and 1 to 4 heteroatoms. In one embodiment, the heterocyclic group may be 7-8 membered bicyclic spiro heterocyclic group.

[0087] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridinonyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, pyridazinonyl triazinanyl. Exemplary 7- membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 10-membered heterocyclyl groups include, without limitation, phthalazinonyl.

[0088] In one embodiment, the heterocyclic group includes a saturated ring radical that comprises carbon atoms and from heteroatoms selected from nitrogen, oxygen, sulfur,16 phosphorus, silicon, and selenium. In an embodiment, the saturated heterocyclic group may have a 3-8 membered heterocyclic group. In an embodiment, the saturated heterocyclic group may have 8 membered bicyclic spiro heterocyclic group. In some embodiments, the saturated heterocyclic group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms, and 1 to 4 heteroatoms. Examples of such saturated heterocyclic group include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of saturated spiro heterocyclic group includes 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0089] As used herein (unless otherwise specified), the term “C6-14 aryl” or “6- to 14- membered aryl” refers to a radical of a carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms. In one embodiment, the aryl may have 6-10 membered ring carbon atoms. The aryl group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the aryl group include, but are not limited to, phenyl, naphtyl, anthracyl, and the like. The aryl group also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the aryl ring.

[0090] As used herein (unless otherwise specified), the term “C6-14arylene” or “6- to 14- membered arylene” refers to a divalent carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms. In one embodiment, the arylene may have 6-10 membered ring carbon atoms. The arylene group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the arylene group include, but are not limited to, phenylene, naphtylene, anthracylene, and the like. The arylene group also includes ring systems wherein the arylene ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the arylene ring.

[0091] As used herein (unless otherwise specified), the term “5- to 12-membered heteroaryl” refers to any monocyclic or polycyclic (e.g., bi-, or tricyclic) aromatic ring system which17 has ring carbon atoms and at least one heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorous, silicon, and selenium). The heteroaryl group also includes ring systems wherein the heteroaryl ring, as defined herein, is fused with one or more cycloalkyl, heterocyclyl or aryl groups wherein the point of attachment is on the heteroaryl ring. In some embodiments, the heteroaryl group may have 3 to 8, 3 to 7, 4 to 7, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.

[0092] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6- membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl (e.g., 1,2,4- triazinyl, 1,3,5-triazinyl), and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0093] As used herein (unless otherwise specified), the term “5-12 membered heteroarylene” refers to a divalent heterocyclic aromatic group, whether or not fused to one or more groups, having 5 to 12 ring atoms including heteroatoms (for example, selected from nitrogen, oxygen, silicon, phosphorous, selenium, and sulfur). In one embodiment, the heteroarylene may have 5-10 or 5-8 or 5-6 membered ring atoms. The heteroarylene group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the18 heteroarylene group include, but are not limited to, pyrrolylene, furanylene, thiophenylene, imidazolylene, pyridinylene, pyrimidinylene, pyrazinylene, tiazolylnylene, and the like. The heteroarylene group also includes ring systems wherein the heteroarylene ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the heteroarylene ring.

[0094] As used herein (unless otherwise specified), the term “carbamoyl” refers to the group -C(=O)- NR’R”, where R’ and R” independently represent a hydrogen or C1-6 alkyl group.

[0095] As used herein (unless otherwise specified), the term “7-11 membered polycylic cycloalkylene” refers to a divalent cycloalkyl linking group, which is a polycyclic (where there are two or more rings) (e.g., bicyclic) hydrocarbon ring system having 7-11 ring carbon. A polycyclic ring system may be a fused ring ring system, a bridged ring system and a spiro ring system. Which system depends on the bridgehead carbon, which is defined as a carbon atom which is shared by at least two rings. A fused ring ring system is a system in which the two or more rings share a covalent bond and have two bridgehead carbons. A bridged ring system is a system in which there is a carbon that is part of two or more rings and the two or more rings are connected by a bridge containing two bridegehead carbons and there are one or more carbons between the two bridegehead carbons. A spiro ring system is a system in which the two or more rings are joined with a single bridgehead carbon. Examples of polycyclic cycloalkylene are cubanylene, bicyclo[2.2.1]heptylene (C7), bicyclo[2.2.2]octylene (C8) and the like.

[0096] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted” refers to the event or circumstance that a chemical group (for example, the groups defined herein) may be substituted as well as the event or circumstance where a chemical group is not substituted.

[0097] The term “substituted” refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein,19 the term “substituted” is contemplated to include all permissible substituents of organic compounds. Exemplary substituents on carbon atoms include, but are not limited to, C1-6alkyl, halogen, cyano, deuterium, C2-6alkenyl, C1-6alkoxy, -(C1-6alkylene)-OH, -(C1-6 alkylene)-O-(C1-6 alkyl), 3-10 membered (e.g., 3-8 membered, 5-6 membered, 3-5 membered) cycloalkyl, hydroxy, amino, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6alkyl), -(C1-C6alkylene)-N(C1-C6alkyl)2, mercapto, -S(C1-6alkyl), -SO2(C1-6alkyl), carbamoyl, oxo, a 3-8 (e.g, 3-6) membered heterocyclic or heteroaryl group, - CORz1(wherein Rz1is selected from the group consisting of hydrogen, C1-6 alkyl, 3-8 membered cycloalkyl, and halogen), and and -CON(Rz2)(Rz3) (wherein each of Rz2and Rz3is independently selected from the group consisting of hydrogen, C1-6alkyl, or halogen, wherein said alkyl is optionally substituted with one or more selected from C1-6 alkyl and halogen; or Rz2and Rz3, taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 3- to 8-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-6 alkyl and halogen), wherein each of said alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic or heteroaryl is independently optionally substituted with one or more selected from C1-6alkyl and halogen. The number of substituents may be any number as long as valence of ths substitued atom and the substituent permit, for example 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, and the like.

[0098] As used herein, the term "PARP inhibitor moiety" refers to a pharmacopore group of a PARP inhibitor compound, or a radical group derived from the PARP inhibitor compound or the pharmacopore group thereof. Examples of PARP inhibitor moiety include, but not limited to,.20

[0100]

[0101] As used herein, the term "PARG inhibitor moiety" refers to a pharmacopore group of a PARG inhibitor compound, or a radical group derived from the PARG inhibitor compound or the pharmacopore group thereof. Examples of PARG inhibitor moiety include, but not limited to,,21

[0106] As used herein, the term "E3 ligase ligand moiety" refers to a pharmacopore group of a E3 ligase ligand compound, or a radical group derived from the E3 ligase ligand compound or the pharmacopore group thereof. Examples of E3 ligase ligand moiety ,

[0107]

[0108] General terms

[0109] The term “about”, when used with a corresponding numeric value, is meant to encompass variations within ± 20% of the numeric value, typically ± 10% of the numeric value, often ± 5% of the numeric value, and most often ± 2% of the numeric value. In some embodiments, the term “about” can mean the numeric value itself.

[0110] Unless particularly stated otherwise, the concept of any expression in singular form should be considered to encompass the concept of the expression in plural form. Therefore, unless particularly stated otherwise, the concept of any article that expresses the concept of singular (for example, “a”, “an”, “the”, and the like in the case of English language) should be considered to encompass the concept of plural.22

[0111] Unless particularly stated otherwise, any term used in the present description should be considered as having the conventional meaning for the relevant technical field. Therefore, unless defined otherwise, all the scientific terms and other technical terms used in the present description have the meaning that is generally understood by those skilled in the art to which the present invention pertains. If there is any conflict in meaning, the present description (including the definitions) takes priority. Description of Embodiments

[0112] Compounds of Formula (I) or Formula (II)

[0113] According to an aspect of the present disclosure, provided is a compound of Formula (I) or Formula (II), (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0114] In one embodiment, the present disclosure relates to a compound of Formula (I):

[0115]

[0116] wherein:

[0117] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O- (3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl,23 oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), , and

[0118] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0119] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0120] each of x, y, and z is independently an integer between 0 and 3;

[0121] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0122] L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0123] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto;24

[0124] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0125] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0126] each of n and m is independently an integer between 0 and 3;

[0127] L3is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[0128] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0129] R2is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein25 each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6alkoxy;

[0130] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0131] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0132] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0133]

[0134] In another embodiment, the present disclosure relates to a compound of Formula (II):

[0136] wherein:

[0137] each of X1and X2is independently selected from the group consisting of N and CRX;

[0138] Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2;26

[0139] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O- (3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl,

[0140] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0141] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0142] each of x, y, and z is independently an integer between 0 and 3;

[0143] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0144] R5is hydrogen or RL2;

[0145] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto;27

[0146] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0147] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0148] each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered, 5-12 membered heteroarylene, 6-10 membered arylene, -(C1-C6alkylene)-(6-10 membered arylene)-, or -(C1-C6alkylene)-(6-10 membered arylene)-(C1-C6alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and hydroxy;

[0149] each of q, r, s and t is independently an integer between 0 and 5;

[0150] each of L4and L5is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -S(=O)-. -S(=O)2-, -C(=O)-, -C(=O)-NH-, -NH-C(=O)- NH-, -C(=NH)-, -C(=N(C1-C6 alkyl)), and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene;

[0151] each of C1 and C2 is independently selected from the group consisting of hydrogen, a PARP inhibitor moiety, a PARG inhibitor moiety, and an E3 ligase ligand moiety, but C1 and C2 are not both hydrogen;28

[0152] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0153] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0154]

[0155] R5

[0156] In one embodiment, R5is hydrogen or RL2; and

[0157] R1, ring A, ring B, n, m, L2, L3, R2, R3, R4, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above and below.

[0158]

[0159] Ring A and L2

[0160] In one embodiment,

[0161] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O- (3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), , and29

[0162] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0163] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0164] each of x, y, and z is independently an integer between 0 and 3;

[0165] L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0166] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto; and

[0167] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0168]

[0169] In one embodiment,

[0170] A is 5-8 membered monocyclic heteroaryl or 8-12 membered bicyclic heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl) wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl,30 oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), , and

[0171] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0172] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0173] each of x, y, and z is independently an integer between 0 and 3; and

[0174] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0175]

[0176] In one embodiment,

[0177] A is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, halogen, cyano, hydroxy, C1-C6alkoxy, amino, mercapto, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl) wherein each of said alkyl, alkoxy, heterocyclyl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6 alkylene)-O-(C1-C6 alkyl), , and

[0178] R13is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;31

[0179] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0180] each of x, y, and z is independently an integer between 0 and 3; and

[0181] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0182]

[0183] In one embodiment,

[0184] A is 5-6 membered monocyclic heteroaryl or 9 membered bicyclic heteroaryl, wherein said heteroaryl contains at least one nitrogen atom or at least one nitrogen atom and at least one sulfur atom as the ring heteroatom and is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, halogen, C1-C6alkoxy, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from ,

[0185] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0186] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0187] each of x, y, and z is independently an integer between 0 and 3; and

[0188] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0189]

[0190] In one embodiment, A is selected from the group consisting of:34

[0198] wherein:

[0199] each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, carbamoyl, halogen, cyano, hydroxy, amino, mercapto, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), ,

[0200] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0201] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;35

[0202] each of x, y, and z is independently an integer between 0 and 3,

[0203] preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, halogen, carbamoyl, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl),

[0204] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0205] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0206] each of x, y, and z is independently an integer between 0 and 2,

[0207] more preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, carbamoyl,36

[0212] (wherein each of Raa1, Raa2, Raa3, Raa4, Raa5, Raa6, and Raais independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, iodo, -S(=O)2-CH3,, , ,37

[0217] wherein each of Ra1, Ra2, and Ra3is independently selected from the group consistingof hydrogen, methyl, isopropyl, trifluoromethyl, and; and

[0218] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0219] In one embodiment, Ra1is methyl, isopropyl or;

[0220] Ra2is trifluoromethyl;

[0221] Ra3is hydrogen; and

[0222] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0223] 38

[0224] In one embodiment, A is

[0225]

[0226] wherein each of Ra2, Ra3, and Ra4is independently selected from the group consisting of hydrogen, methyl, and trifluoromethyl; and

[0227] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0228] In one embodiment,

[0229] Ra2is trifluoromethyl;

[0230] Ra3is hydrogen;

[0231] Ra4is methyl; and

[0232] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0233]

[0234] In one embodiment, A is

[0236] wherein each of Ra2, and Ra3is independently selected from the group consisting of hydrogen, and trifluoromethyl; and

[0237] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0238]

[0239] In one embodiment,

[0240] Ra2is trifluoromethyl;

[0241] Ra3is hydrogen; and39

[0242] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0243]

[0244] In one embodiment, A is

[0245]

[0246] wherein each of Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, and carbamoyl; and

[0247] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0248]

[0249] In one embodiment,

[0250] each of Ra2, Ra3, Ra4, and Ra5is hydrogen;

[0251] Ra6is carbamoyl; and

[0252] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0253]

[0254] In one embodiment, A is

[0256] wherein each of Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, cyclopropyl, n-propyl, fluoro, methoxy,40

[0260] (wherein each of Raa1, Raa2, Raa3, Raa4, Raa5, and Raa6is independently selected from the group consisting of hydrogen, hydroxy, methyl, -S(=O)2-CH3,, , , ,

[0261] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0262]

[0263] In one embodiment,

[0264] Ra2is selected from the group consisting of methyl, trifluoromethyl, cyclopropyl, n- propyl, and fluoro;

[0265] Ra3and Ra4is hydrogen;

[0266] Ra5is selected from the group consisting of methoxy,41

[0270] (wherein each of Raa1, Raa2, Raa3, Raa4, Raa5, and Raa6is independently selected from the group consisting of hydrogen, hydroxy, methyl, -S(=O)2-CH3,, , , ,

[0271] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0272]

[0273] In one embodiment,

[0274] Ra2is selected from the group consisting of methyl, trifluoromethyl, cyclopropyl, n- propyl, and fluoro;

[0275] Ra3and Ra4is hydrogen;

[0276] Ra5is selected from the group consisting of methoxy,42

[0285] L2, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0286]

[0287] In one embodiment, L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene,43 wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0288] ring A, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0289]

[0290] In one embodiment, L2is selected from the group consisting of 6-10 membered arylene, 5-8 membered heteroarylene, and 7-10 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0291] ring A, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0292]

[0293] In one embodiment, L2is selected from the group consisting of 6-10 membered arylene, 5-8 membered heteroarylene, and 7-10 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0294] ring A, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0295] 44

[0296] In one embodiment, L2is selected from the group consisting of 6 membered arylene, 5-6 membered heteroarylene, and 8 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0297] ring A, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0298]

[0299] In one embodiment, L2is

[0300] ,

[0301] wherein:

[0302] each of RL21, RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is45 independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0303] preferably, each of RL21, RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0304] more preferably, each of RL21, RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0305] still more preferably, each of RL21, RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy; and

[0306] ring A, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0307]

[0308] In one embodiment, L2is selected from the group consisting of

[0309] ; and

[0310] ring A, R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0311] 46

[0312] In one embodiment,

[0313] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently substituted with RL1and optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2- C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, oxo, -S(=O)2-CH3, (C1-C6 alkylene)-O-(C1-C6 alkyl), , and

[0314] R13is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0315] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0316] each of x, y, and z is independently an integer between 0 and 3;

[0317] L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently substituted with RL2and optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0318] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-8 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected47 from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2- C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto; and

[0319] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0320]

[0321] In one embodiment,

[0322] A is 5-6 membered monocyclic heteroaryl, wherein said heteroaryl is substituted with RL1and optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0323] L2is phenylene, wherein said phenylene is substituted with RL2and optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0324] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto; and

[0325] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0326]

[0327] In one embodiment,

[0328] A is 5-6 membered monocyclic heteroaryl, wherein said heteroaryl is substituted with RL1and optionally substituted with one or more selected from C1-C6 alkyl, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;48

[0329] L2is phenylene, wherein said phenylene is substituted with RL2and optionally substituted with one or more selected from C1-C6alkyl, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0330] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto; and

[0331] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0332]

[0333] In one embodiment,

[0334] A is selected from the group consisting

[0336] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, methyl, and trifluoromethyl;

[0337] each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, and methoxy;

[0338] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, and mercapto; and

[0339] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.49

[0340]

[0341] In one embodiment,,

[0343] wherein:

[0344] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, methyl, and trifluoromethyl;

[0345] each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, and methoxy;

[0346] each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen and methyl; and

[0347] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0348]

[0349] In one embodiment,selected from the group consisting of:50

[0352] R1, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0353]

[0354] R1

[0355] In one embodiment,

[0356] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0357] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and51

[0358] L2, ring A, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0359]

[0360] In one embodiment,

[0361] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0362] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0363] L2, ring A, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0364]

[0365] In one embodiment,

[0366] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto; and

[0367] L2, ring A, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0368]

[0369] In one embodiment,

[0370] R1is selected from the group consisting of hydrogen, C1-C3 alkyl, NH2, NH(C1-C3 alkyl), and N(C1-C3alkyl)2; and

[0371] L2, ring A, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0372] 52

[0373] In one embodiment,

[0374] R1is selected from the group consisting of hydrogen, methyl, NH2, and N(CH3)2; and

[0375] L2, ring A, ring B, n, m, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0376]

[0377] Ring B

[0378] In one embodiment, B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; and

[0379] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0380]

[0381] In one embodiment, B is 5-8 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; and

[0382] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0383]

[0384] In one embodiment, B is 5-6 membered heteroaryl, wherein said heteroaryl contains at least one nitrogen atom as the ring heteroatom and is optionally substituted with one or more selected from C1-C6 alkyl, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1- C6 alkoxy, and NH2, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and53

[0385] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0386]

[0387] In one embodiment, B is selected from the group consisting of:54

[0393] wherein:

[0394] each of Rb1, Rb2, Rb3, Rb4, and Rb5is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0395] preferably, each of Rb1, Rb2, Rb3, Rb4, and Rb5is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0396] more preferably, each of Rb1, Rb2, Rb3, Rb4, and Rb5is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-6 membered cycloalkyl, halogen, and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,55

[0397] still more preferably, each of Rb1, Rb2, Rb3, Rb4, and Rb5is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n- propoxy, and isopropoxy; and

[0398] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0399]

[0405] wherein each of Rb1, Rb2and Rb3is independently selected from the group consisting of hydrogen, methoxy, chloro, and isopropyl; and

[0406] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0407]

[0408] In one embodiment, Rb1is isopropyl;

[0409] Rb2is hydrogen;

[0410] Rb3is methoxy or chloro; and56

[0411] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0412]

[0413] In one embodiment, B is

[0415] wherein each of Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, methoxy, and cyclopropyl; and

[0416] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0417]

[0418] In one embodiment, Rb2is methoxy;

[0419] Rb3is hydrogen;

[0420] Rb4is cyclopropyl; and

[0421] L2, ring A, n, m, L3, R1, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0422]

[0423] n and m

[0424] In one embodiment, each of n and m is independently an integer between 0 and 3; and

[0425] R1, L2, ring A, ring B, L3, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0426]

[0427] L357

[0428] In one embodiment, L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -,

[0429] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0430] R1, L2, ring A, ring B, n, m, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0431]

[0432] In one embodiment, L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen, and C1-C6alkoxy, ; and

[0433] R1, L2, ring A, ring B, n, m, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0434]

[0435] In one embodiment, L3is selected from the group consisting of a single bond,58

[0438] wherein each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, and iodo; and

[0439] R1, L2, ring A, ring B, n, m, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0440]

[0441] In one embodiment, L3is selected from the group consisting of a single bond,59

[0443] R1, L2, ring A, ring B, n, m, R2, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0444]

[0445] R2

[0446] In one embodiment, R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6alkoxy;

[0447] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0448] R1, L2, ring A, ring B, n, m, L3, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0449] 60

[0450] In one embodiment, R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, mercapto, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-(5-12 membered heterocyclyl), 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6alkoxy; and

[0451] R1, L2, ring A, ring B, n, m, L3, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0452]

[0453] In one embodiment, R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, cyano, hydroxy, NH2, NH(C1-C6 alkyl), N(C1-C6alkyl)2, NH-(5-12 membered heterocyclyl), 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6 alkoxy; and

[0454] R1, L2, ring A, ring B, n, m, L3, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0455]

[0456] In one embodiment, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromehtyl,

[0457]

[0458]

[0459]

[0460]

[0461]

[0462] 64

[0479] wherein each of said R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, and R2iis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, -CH2OCH3, NH2, carbamoyl, hydroxy, fluoro, chloro, bromo, iodo, and cyclopropyl; and

[0480] R1, L2, ring A, ring B, n, m, L3, R3, R4, R5, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0481]

[0482] In one embodiment, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), N(CH3)2, cyano, trifluoromehtyl, hydroxy,[ ]66

[0487]

[0488] R1, L2, ring A, ring B, n, m, L3, R3, R4, R5, X1, X2, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0489]

[0490] R3and R4

[0491] In one embodiment, each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0492] R1, R2, L2, ring A, ring B, n, m, L3, R5, X1, X2, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0493]

[0494] In one embodiment, each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1- C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0495] R1, R2, L2, ring A, ring B, n, m, L3, R5, X1, X2, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0496]

[0497] In one embodiment, each of R3and R4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo; and67

[0498] R1, R2, L2, ring A, ring B, n, m, L3, R5, X1, X2, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0499]

[0500] In one embodiment, each of R3and R4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, and isopropyl,; and

[0501] R1, R2, L2, ring A, ring B, n, m, L3, R5, X1, X2, X1, X2, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0502]

[0503] X1, and X2

[0504] In one embodiment, each of X1and X2is independently selected from the group consisting of N and CRX;

[0505] Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2, NH(C1-C6alkyl), and N(C1-C6alkyl)2; and

[0506] R1, R3, R4, R5, L2, ring A, ring B, n, m, L3, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0507]

[0508] In one embodiment, each of X1and X2is independently selected from the group consisting of N and CRX;

[0509] Rxis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, isopropoxy, NH2, NH(CH3), and N(CH3)2; and

[0510] R1, R3, R4, R5, L2, ring A, ring B, n, m, L3, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0511]

[0512] In one embodiment, each of X1and X2is independently selected from the group consisting of N and CRX;

[0513] Rxis selected from the group consisting of hydrogen, fluoro, methoxy, and NH(CH3); and68

[0514] R1, R3, R4, R5, L2, ring A, ring B, n, m, L3, S1, S2, S3, S4, L4, L5, C1, and C2 are as defined above.

[0515]

[0517] The compound of Formula (II) includes a PARP inhibitor moiety, a PARG inhibitor moiety, or an E3 ligase ligand moiety. The PARP inhibitor moiety, a PARG inhibitor moiety, or an E3 ligase ligand moiety may be connected to the core structure via two spacers and a linker. For example, the compound of Formula (II) including a PARP inhibitor moiety may be represented by the following structure:

[0519] the compound of Formula (II) including a PARG inhibitor moiety may be represented by the following structure ;

[0521] the compound of Formula (II) including an E3 ligase ligand moiety may be represented by the following structure:

[0524] If necessary, the spacer may be omitted. The linker may be a functional group conjugating the core structure (i.e., USP1 inhibitor parts) with C1 / C2 (i.e., a PARP inhibitor / PARG inhibitor / E3 ligase ligand moiety). In some embodiments, the linker may be absent, and a functional group in the inhibitors and / or ligand may participate in conjugating the USP1 inhibitor with the PARP inhibitor / PARG inhibitor / E3 ligase ligand.

[0525] 69

[0526] 1) S1, S2, S3, and S4

[0527] In one embodiment, each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3- 10 membered cycloalkylene,membered heteroarylene, 6-10 membered arylene, -(C1-C6 alkylene)-(6-10 membered arylene)-, or -(C1-C6alkylene)-(6-10 membered arylene)-(C1-C6alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and hydroxy;

[0529] each of q, r, s and t is independently an integer between 0 and 5; and

[0530] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, L4, L5, C1 and C2 are as defined above.

[0531]

[0532] In one embodiment, S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, ,

[0535] each of q, r, s and t is independently an integer between 0 and 5;

[0536] each of Rasand Rbsis independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, and hydroxy;70

[0537] each of Lsaand Lsbis independently selected from a single bond and C1-C6 alkylene; and

[0538] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, L4, L5, C1 and C2 are as defined above.

[0539]

[0540] In one embodiment, each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond,

[0544] p is an integer between 1 and 5;

[0545] each of q, r, s and t is independently an integer between 0 and 5; and

[0546] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, L4, L5, C1 and C2 are as defined above.

[0547] 71

[0548] In one embodiment, each of S1and S3is independently selected from the group consisting of a single bond,

[0552] (wherein p is an integer between 1 and 5, preferably 1 to 3;

[0553] each of q, r, s and t is independently an integer between 0 and 5, preferably 0 to 3);

[0554] each of S2and S4is independently selected from the group consisting of a single bond,

[0556] (wherein p is an integer between 1 and 5, preferably 1 to 3); and

[0557] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, L4, L5, C1 and C2 are as defined above.

[0558]

[0559] In one embodiment, each of S1and S3is independently selected from the group consisting of a single bond,72

[0562]

[0563] (wherein p is 1 or 2; q is 0 or 1; r is 0, 1, or 2; s is 2; t is 1);

[0564] each of S2and S4is independently selected from the group consisting of a single bond,

[0565]

[0566] (wherein p is 2 or 3); and

[0567] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, L4, L5, C1 and C2 are as defined above.

[0568]

[0569] 2) L4and L5

[0570] In one embodiment, each of L4and L5is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -S(=O)-. -S(=O)2-, -C(=O)-, - C(=O)-NH-, -NH-C(=O)-NH-, -C(=NH)-, -C(=N(C1-C6alkyl)), and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6 alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene; and73

[0571] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, S1, S2, S3, S4, C1 and C2 are as defined above.

[0572]

[0573] In one embodiment, each of L4and L5is independently selected from the group consisting of a single bond, C1-C6 alkylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -C(=O)-, -C(=O)-NH-, -NH-C(=O)-NH-, and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6 alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene, and

[0574] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, S1, S2, S3, S4, C1 and C2 are as defined above.

[0575]

[0576] In one embodiment, each of L4and L5is independently selected from the group consisting of of a single bond, -C(=O)-NH-, -NH-C(=O)-NH-, and -C(=O)-Rl45, wherein Rl45is 3-6 membered heterocyclene, and

[0577] R1, R3, R4, R5, ring A, ring B, n, m, L3, X1, X2, S1, S2, S3, S4, C1 and C2 are as defined above.

[0578]

[0579] 3) C1 and C2

[0580] In one embodiment, each of C1 and C2 is independently selected from the group consisting of hydrogen, a PARP inhibitor moiety, a PARG inhibitor moiety, and an E3 ligase ligand moiety, but C1 and C2 are not both hydrogen; and R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0581]

[0582] In one embodiment, at least one of C1 and C2 is a PARP inhibitor moiety.

[0583]

[0584] In one embodiment, the PARP inhibitor moiety is74,

[0586] wherein D1 is 5-12 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0587] preferably, wherein D1 is 5-6 membered monocyclic or 8-12 membered fused bicyclic nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; and

[0588] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0589]

[0590] In one embodiment, the PARP inhibitor moiety is

[0591]

[0592] wherein:

[0593] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, or CNH2;75

[0594] each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0595] preferably, each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0596]

[0597] In one embodiment, the PARP inhibitor moiety is

[0598]

[0599] wherein:

[0600] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, or CNH2;

[0601] each of RC111and RC112is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0602] preferably, each of RC111and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.76

[0603]

[0604] In one embodiment, the PARP inhibitor moiety is

[0605] ,

[0606] wherein:

[0607] D1 is 5-12 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0608] preferably, D1 is 8-12 membered fused bicyclic nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0609] D2 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0610] preferably, D2 is phenylene or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is substituted with oxo, and is optionally substituted with77 one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0611] C102is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof,

[0612] preferably, C102is a single bond or C1-C6 alkylene; and

[0613] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0614]

[0615] In one embodiment, the PARP inhibitor moiety is

[0616] ,

[0617] wherein:

[0618] D2 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0619] preferably, D2 is phenylene or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is substituted with oxo, and is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl,78 halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0620] C102is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof,

[0621] preferably, C102is a single bond or C1-C6 alkylene;

[0622] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2;

[0623] each of RC11, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0624] preferably, each of RC11, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; and

[0625] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0626]

[0627] In one embodiment, the PARP inhibitor moiety is,

[0629] wherein:

[0630] D3 is 5-12 membered heteroaryl, wherein said heteroaryl is substituted with carbomoyl and is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl,79 cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0631] preferably, D3 is 8-10 membered fused bicyclic heteroaryl, wherein said heteroaryl is substituted with carbomoyl and is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0632] D4 is a single bond, 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0633] preferably, D4 is a single bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0634] D5 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0635] preferably, D5 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto,80 wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0636] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0637]

[0638] In one embodiment, the PARP inhibitor moiety is,

[0640] wherein:

[0641] each of C101, C102and C103is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[0642] preferably, C101is N, C102is N, and C103is CH; or C101is N, C102is C, and C103is NH;

[0643] each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0644] each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;81

[0645] D4 is a single bond, 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0646] preferably, D4 is a single bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0647] D5 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0648] preferably, D5 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; and

[0649] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0650]

[0651] In one embodiment, the PARP inhibitor moiety is82

[0653] wherein:

[0654] D6 is 8-15 membered nitrogen-containing bicycylic or tricyclic fused heterocycylyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0655] preferably, D6 is 10-15 membered nitrogen-containing tricyclic fused heterocycylyl, wherein said heterocycylyl is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; and

[0656] D7 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0657] preferably, D7 is phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1- C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1- C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0658] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0659]

[0660] In one embodiment, the PARP inhibitor moiety is83,

[0662] wherein:

[0663] each of C101, and C102is independently selected from the group consisitng of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHCl, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);

[0664] each of C103, C104, C105, and C106is independently selected from the group consisitng of N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0665] D7 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0666] preferably, D7 is phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1- C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1- C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; and

[0667] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0668]

[0669] In one embodiment, the PARP inhibitor moiety is84,

[0671] wherein:

[0672] D8 is 5-12 membered nitrogen-contanining heterocyclyl, wherein said heterocyclyl is substitued with oxo and is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0673] preferably, D8 is 8-12 membered nitrogen-contanining bicyclic fused heterocyclyl, wherein said heterocyclyl is substitued with oxo and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0674] D9 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0675] preferably, D9 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0676] D10 is 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C685 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0677] preferably, D10 is 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0678] C101is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof; and and

[0679] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0680]

[0681] In one embodiment, the PARP inhibitor moiety is,

[0683] wherein:

[0684] each of C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0685] each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,86

[0686] preferably, each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0687] D9 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0688] preferably, D9 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0689] D10 is 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0690] preferably, D10 is 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0691] C101is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof; and

[0692] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.87

[0693]

[0694] In one embodiment, the PARP inhibitor moiety is

[0696] wherein:

[0697] D11 is 8-15 membered nitrogen-containing heterocyclic ring, wherein said heterocyclic ring is substituted with oxo and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0698] preferably, D11 is 12-15 membered nitrogen-containing bicyclic or tricyclic fused heterocyclic ring, wherein said heterocyclic ring is substitued with oxo and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0699] each of D12 and D13 is independently 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0700] preferably, D12 is 5-6 membered heteroaryl, and D13 is phenyl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy,88 NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0701] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0702]

[0703] In one embodiment, the PARP inhibitor moiety is,

[0705] wherein:

[0706] each of C101, C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0707] each of D12 and D13 is independently 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0708] preferably, D12 is 5-6 membered heteroaryl, and D13 is phenyl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and89

[0709] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0710]

[0711] In one embodiment, the PARP inhibitor moiety is selected from the group consisting of:

[0713] R1, R3, R4, R5, L2, ring A, ring B, n, m, L4, X1, X2, S1, and S2are as defined above.

[0714]

[0715] In one embodiment, at least one of C1 and C2 is a PARP inhibitor moiety; the PARP inhibitor moiety is selected from the group consisting of:90

[0716]

[0717] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0718]

[0719] In one embodiment, at least one of C1 and C2 is a PARG inhibitor moiety.

[0720]

[0721] In one embodiment, the PARG inhibitor moiety is

[0723] wherein:

[0724] E1 is 8-15 membered bicyclic or tricyclic fused heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl,91 carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0725] preferably, E1 is 9-13 membered bicyclic or tricyclic fused heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0726] E2 is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0727] preferably, E2 is 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0728] E3 is 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0729] preferably, E3 is 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto,92 wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0730] E4 is 3-10 membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0731] preferably, E4 is 3-6 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0732] each of C201and C202is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. - S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof,

[0733] preferably, C201is a single bond or C1-C6 alkylene, and C202is selected from the group consisting of -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, and a combination thereof,

[0734] more preferably, C201is a single bond or C1-C6alkylene, and C202is selected from the group consisting of -NH-, -S(=O)2-, and a combination thereof; and

[0735] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0736]

[0737] In one embodiment, the PARG inhibitor moiety is selected from the group consisting of:93

[0741] wherein:

[0742] E2 is 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0743] preferably, E2 is 5-6 membered nitrogen containing heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,94

[0744] more preferably, E2 is thiadiazolyl, pyrazolyl, or 1,3,4-selenadiazol-2-yl, wherein said thiadiazolyl, pyrazolyl, and 1,3,4-selenadiazol-2-yl are optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0745] E3 is 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0746] preferably, E3 is 5-6 membered nitrogen containing saturated heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0747] more preferably, E3 is piperazinyl, wherein said piperazynyl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0748] E4 is 3-6 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0749] preferably, E4 is 3-5 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1- C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0750] C201is a single bond or C1-C6alkylene, and C202is selected from the group consisting of -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, and a combination thereof,95

[0751] preferably, C201is a single bond or C1-C6 alkylene, and C202is selected from the group consisting of -NH-, -S(=O)2-, and a combination thereof,

[0752] more preferably, C201is a single bond or C1-C6alkylene, and C202is -NH-S(O)2-;

[0753] each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0754] preferably, each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0755] more preferably, each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; and

[0756] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0757]

[0758] In one embodiment, the PARG inhibitor moiety is selected from the group consisting of:

[0759] , ,96

[0763] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0764]

[0765] In one embodiment, at least one of C1 and C2 is an E3 ligase ligand moiety.

[0766] In one embodiment, the E3 ligase ligand moiety is97

[0767] ,

[0768] wherein F1 is 5-12 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with one or more of oxo and is optionally further substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0769] preferably, F1 is 5-6 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with one or more of oxo and is optionally further substituted with one or more selected from C1-C6 alkyl, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0770] F2 is 5-12 membered heterocyclic ring, wherein said heterocyclic ring is substituted with one or more of oxo and is optionally further substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2- C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0771] preferably,

[0772] F2 is 8-10 membered fused bicyclic heterocyclic ring, wherein said heterocyclic ring is substituted with one or more of oxo and is optionally further substituted with one or more selected from C1-C6 alkyl, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-98 C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0773] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0774]

[0775] In one embodiment, the E3 ligase ligand moiety is

[0777] wherein:

[0778] x is 0 or 1;

[0779] C301is CH2 or NH;

[0780] each of C302and C303is CH or N;

[0781] C304is C(O) or NH;

[0782] each of RC311, RC312and RC313is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy; and

[0783] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0784]

[0785] In one embodiment, the E3 ligase ligand moiety is99

[0787] wherein:

[0788] F3 is 5-12 membered heterocyclic ring, wherein said heterocyclic ring is substituted with one or more of hydroxy and is optionally further substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0789] preferably, F3 is 5-6 membered heterocyclic ring, wherein said heterocyclic ring is substituted with one or more of hydroxy and is optionally further substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[0790] F4 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, hydroxy, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0791] preferably, F4 is phenyl or 5-6 membered heteroaryl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;100

[0792] F5 is 6-10 membered aryl or 5-12 membered heteroaryl, wherein said aryl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, hydroxy, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0793] preferably, F5 is 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0794] each of C305and C306is independently selected from the group consisting of C1-C6alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -N(C1- C6 alkyl)-, and a combination thereof,

[0795] preferably, each of C305and C306is independently selected from the group consisting of C1-C6 alkylene, -NH-, -C(=O)-, and a combination thereof; and

[0796] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0797]

[0798] In one embodiment, the E3 ligase ligand moiety is

[0800] wherein:101

[0801] C305is selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof,

[0802] preferably, C305is selected from the group consisting of C1-C6 alkylene, -NH-, - C(=O)-, and a combination thereof,

[0803] more preferably, C305is -N-(C1-C6alkylene)-C(=O)-,

[0804] still more preferably, C305is -N-CH(tert-butyl)-C(=O)-;

[0805] C307is CH or N;

[0806] C308is C1-C6alkylene, preferably, methylene;

[0807] each of RC314, RC315, RC316, RC317, RC318, RC319, RC320, RC321, RC322, and RC323is independently hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy; and

[0808] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0809]

[0810] In one embodiment, the E3 ligase ligand moiety is

[0811]

[0812] wherein:

[0813] F6 is 5-12 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with one or more of oxo and is optionally further substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,102

[0814] preferably, F6 is 5-6 membered monocyclic or 9-10 membered fused bicyclic heterocyclic ring, wherein said heterocyclic ring is substituted with one or more of hydroxy and is optionally further substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0815] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0816]

[0817] In one embodiment, the E3 ligase ligand moiety is

[0819] wherein

[0820] each of RC324, RC325, RC326, and RC327is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy; and

[0821] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0822]

[0823] In one embodiment, the E3 ligase ligand moiety is selected from the group consisting of:103

[0826] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0827]

[0828] In one embodiment, the E3 ligase ligand moiety is selected from the group consisting of:

[0830] R1, R3, R4, R5, ring A, ring B, n, m, L4, X1, X2, S1, S2, S3, S4, and L5are as defined above.

[0831]

[0832] Non-limiting exemplary embodiments of the compounds of Formula (I)

[0833]

[0834] In one embodiment, the present disclosure relates to a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), or Formula (Ig):

[0838]

[0839]

[0840] 106

[0842] wherein:

[0843] each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6 alkylene)-O-(C1-C6 alkyl),

[0844] R13is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0845] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0846] each of x, y, and z is independently an integer between 0 and 3;

[0847] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;107

[0848] each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0849] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0850] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0851] each of n and m is independently an integer between 0 and 3;

[0852] L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[0853] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto;108

[0854] R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6alkoxy;

[0855] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0856] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0857] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0858]

[0859] In one embodiment,

[0860] each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, carbamoyl, halogen, cyano, hydroxy, amino, mercapto, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino,109 mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), ,

[0861] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0862] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0863] each of x, y, and z is independently an integer between 0 and 3,

[0864] preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, carbamoyl, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, oxo, -S(=O)2-CH3, (C1-C6 alkylene)-O-(C1-C6 alkyl),

[0865] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[0866] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0867] each of x, y, and z is independently an integer between 0 and 3,

[0868] more preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, carbamoyl,110independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, n- propyl, isopropyl, fluoro, chloro, bromom, iodo, -S(=O)2-CH3, , ,111

[0874] still more preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, cyclopropyl, n-propyl, and fluoro, methoxy, [112 [

[0883] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0884] preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0885] more preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-6 membered cycloalkyl, halogen, and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0886] still more preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[0887] each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,113

[0888] preferably, each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0889] more preferably, each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0890] still more preferably, each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy;

[0891] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto, each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1- C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto,

[0892] preferably, R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto,

[0893] more preferably, R1is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromo, iodo, NH2, NH(CH3), and N(CH3)2,

[0894] still more preferably, R1is selected from the group consisting of hydrogen, methyl, NH2, and N(CH3)2.

[0895] each of n and m is independently an integer between 0 and 3;114

[0896] L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen-substitutied C1-C6alkyl, halogen, and C1-C6alkoxy,

[0897] preferably, L3is selected from the group consisting of a single bond,

[0900] wherein each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, fluoro, chloro, bromo, and iodo,115

[0901] more preferably, L3is selected from the group consisting of a single bond,

[0903] R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkynyl, 3- 10 membered cycloalkyl, cyano, hydroxy, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH- (5-12 membered heterocyclyl), 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6 alkoxy,

[0904] preferably, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromehtyl,119

[0927] wherein each of said R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, and R2iis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, -CH2OCH3, NH2, carbamoyl, hydroxy, fluoro, chloro, bromo, iodo, and cyclopropyl,

[0928] more preferably, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), N(CH3)2, cyano, trifluoromehtyl, hydroxy,

[0929] 120

[0934] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0935] preferably, each of R3and R4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo,121

[0936] more preferably, each of R3and R4is hydrogen or C1-C6 alkyl ,

[0937] still more preferably, each of R3and R4is hydrogen or methyl.

[0938]

[0939] In one embodiment, the present disclosure relates to a compound of Formula (Ih), or Formula (Ii):

[0940]

[0941]

[0942] wherein each of Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0943] each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each122 of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0944] each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0945] each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0946] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[0947] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0948] each of n and m is independently an integer between 0 and 3;

[0949] L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[0950] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen,123 and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[0951] R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6 alkoxy;

[0952] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[0953] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0954] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0955]

[0956] In one embodiment,124

[0957] each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0958] preferably, each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0959] more preferably, each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-6 membered cycloalkyl, halogen, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0960] still more preferably, each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[0961] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, halogen, cyano, hydroxy, amino, mercapto, and 3-6 membered heterocyclyl, wherein each of said alkyl, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0962] preferably, each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, carbamoyl, and 3-6 membered heterocyclyl, wherein each of said alkyl, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[0963] more preferably, each of Ra2and Ra3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,125 tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, carbamoyl,

[0964]

[0965] Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo,

[0966] still more preferably, each of Ra2and Ra3is independently selected from the group consisting of hydrogen, and trifluoromethyl;

[0967] each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, amino, and mercapto,

[0968] preferably, each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen, methyl, ethhyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl,

[0969] more prefeably, each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen and methyl;

[0970] each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano,126 C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0971] preferably, each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1- C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0972] more preferably, each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0973] still more preferably, each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy,

[0974] still more preferably, each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, and methoxy;

[0975] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto, each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1- C6alkyl, halogen, cyano, hydroxy, NH2and mercapto,

[0976] preferably, R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), N(C1-C6alkyl)2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto,127

[0977] more preferably, R1is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromo, iodo, NH2, NH(CH3), and N(CH3)2,

[0978] still more preferably, R1is selected from the group consisting of hydrogen, methyl, NH2, and N(CH3)2.

[0979] each of n and m is independently an integer between 0 and 3;

[0980] L3is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen, and C1-C6 alkoxy,

[0981] preferably, L3is selected from the group consisting of a single bond,

[0982] 128,

[0984] wherein each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, fluoro, chloro, bromo, and iodo,

[0985] more preferably, L3is selected from the group consisting of a single bond,

[0986]

[0987] R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkynyl, 3- 10 membered cycloalkyl, cyano, hydroxy, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH- (5-12 membered heterocyclyl), 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6alkoxy,

[0988] preferably, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromehtyl,

[9660] L£ L132,

[0998] wherein each of said R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, and R2iis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, -CH2OCH3, NH2, carbamoyl, hydroxy, fluoro, chloro, bromo, iodo, and cyclopropyl,

[0999] more preferably, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), N(CH3)2, cyano, trifluoromehtyl, hydroxy,[ ]134

[1005] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1006] preferably, each of R3and R4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo,

[1007] more preferably, each of R3and R4is hydrogen or methyl.

[1008]

[1009] In one embodiment, the present disclosure relates to a compound of Formula (Ij), Formula (Ik), or Formula (Im):135

[1013] wherein:

[1014] each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl)

[1015] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;136

[1016] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[1017] each of x, y, and z is independently an integer between 0 and 3;

[1018] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1019] R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1020] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1021] each of n and m is independently an integer between 0 and 3;

[1022] L3is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[1023]

[1024] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently137 selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1025] R2is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6 alkoxy;

[1026] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[1027] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[1028] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1029]

[1030] In one embodiment, the present disclosure relates to a compound of Formula (In), Formula (Io), or Formula (Ip):138

[1034] wherein:

[1035] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1036] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl,139 halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1037] L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1038] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1039] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[1040] each of n and m is independently an integer between 0 and 3;

[1041] L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[1042] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently140 selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1043] R2is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6 alkoxy;

[1044] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[1045] each of R2a, R2b, R2d, R2e, R2f, R2g, R2h, and R2iis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, and mercapto, wherein said alkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6 alkoxy,

[1046] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1047]

[1048] In one embodiment, the present disclosure relates to a compound of Formula (Iq), Formula (Ir) or Formula (Is):141

[1052] wherein:

[1053] each of Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1054] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently142 optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1055] RL11is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto;

[1056] each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1057] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[1058] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1059] each of n and m is independently an integer between 0 and 3;

[1060] L3is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -S(=O)2-, -,

[1061] wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently143 selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1062] R2is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6 alkoxy;

[1063] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and

[1064] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1065]

[1066] In one embodiment, the exemplary compounds of Formula (I) are provided below:152

[1067] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1068]

[1069] In another embodiment, the exemplary compounds of Formula (I) are provided below:170

[1070] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1071]

[1072] Non-limiting exemplary embodiments of the compounds of Formula

[1073]

[1074] In one embodiment, the present disclosure relates to a compound of Formula (IIa-1), Formula (IIa-2), Formula (IIb) or Formula (IIc):171

[1080] wherein:

[1081] each of X1and X2is independently selected from the group consisting of N and CRX;

[1082] Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2;

[1083] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6172 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O- (3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), , and

[1084] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[1085] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[1086] each of x, y, and z is independently an integer between 0 and 3;

[1087] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1088] R5is hydrogen or RL2;

[1089] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto;

[1090] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl,173 alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[1091] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1092] each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene,, 5-12 membered heteroarylene, 6-10 membered arylene, -(C1-C6alkylene)-(6-10 membered arylene)-, or -(C1-C6 alkylene)-(6-10 membered arylene)-(C1-C6 alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and hydroxy;

[1093] each of q, r, s and t is independently an integer between 0 and 5;

[1094] each of L4and L5is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -S(=O)-. -S(=O)2-, -C(=O)-, -C(=O)-NH-, -NH-C(=O)- NH-, -C(=NH)-, -C(=N(C1-C6 alkyl)), and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene; and

[1095] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,174

[1096] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1097]

[1098] In one embodiment,

[1099] each of X1and X2is independently selected from the group consisting of N and CRX;

[1100] Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2;,

[1102] Ra1is independently selected from the group consisting of RL1, hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1103] each of Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1104] , each of Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is175 independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1105] R5is hydrogen or RL2;

[1106] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto;

[1107] R1is hydrogen;

[1108] each of S1and S3is independently selected from the group consisting of a single bond,

[1110] (wherein p is an integer between 1 and 5, preferably 1 to 3;

[1111] each of q, r, s and t is independently an integer between 0 and 5, preferably 0 to 3);

[1112] each of S2and S4is independently selected from the group consisting of a single bond,

[1114] (wherein p is an integer between 1 and 5, preferably 1 to 3);176

[1115] each of L4and L5is independently selected from the group consisting of a single

[1116] each of R3and R4is hydrogen;

[1117] the PARP inhibitor moiety is

[1119] wherein:

[1120] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2;

[1121] each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1122] preferably, each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1123] or

[1124] the PARP inhibitor moiety is177

[1125]

[1126] wherein:

[1127] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, or CNH2;

[1128] each of RC111and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1129] preferably, each of RC111and RC112is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1130] or

[1131] the PARP inhibitor moiety is,

[1133] wherein:

[1134] D2 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl,178 cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1135] preferably, D2 is phenylene or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is substituted with oxo, and is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1136] C102is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof,

[1137] preferably, C102is a single bond or C1-C6alkylene;

[1138] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2;

[1139] each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1140] preferably, each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1141] or

[1142] the PARP inhibitor moiety is179,

[1144] wherein:

[1145] each of C101, C102and C103is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[1146] preferably, C101is N, C102is N, and C103is CH; or C101is N, C102is C, and C103is NH;

[1147] each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1148] each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1149] D4 is a single bond, 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,180

[1150] preferably, D4 is a single bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1151] D5 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1152] preferably, D5 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1153] or

[1154] the PARP inhibitor moiety is,

[1156] wherein:

[1157] each of C101, and C102is independently selected from the group consisitng of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHCl, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);181

[1158] each of C103, C104, C105, and C106is independently selected from the group consisitng of N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[1159] D7 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1160] preferably, D7 is phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1- C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1- C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1161] or

[1162] the PARP inhibitor moiety is,

[1164] wherein:

[1165] each of C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[1166] each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano,182 hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1167] preferably, each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1168] D9 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1169] preferably, D9 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1170] D10 is 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1171] preferably, D10 is 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;183

[1172] C101is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof;

[1173] or

[1174] the PARP inhibitor moiety is

[1176] wherein:

[1177] each of C101, C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[1178] each of D12 and D13 is independently 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1179] preferably, D12 is 5-6 membered heteroaryl, and D13 is phenyl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1180] preferably, the PARP inhibitor moiety is selected from the group consisting of:184

[1181] ;

[1182]

[1183] the PARG inhibitor moiety is selected from the group consisting of:, and185,

[1187] wherein:

[1188] E2 is 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1189] preferably, E2 is 5-6 membered nitrogen containing heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1190] more preferably, E2 is thiadiazolyl, pyrazolyl, or 1,3,4-selenadiazol-2-yl, wherein said thiadiazolyl, pyrazolyl, and 1,3,4-selenadiazol-2-yl are optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1191] E3 is 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1192] preferably, E3 is 5-6 membered nitrogen containing saturated heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and186 alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1193] more preferably, E3 is piperazinyl, wherein said piperazynyl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1194] E4 is 3-6 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1195] preferably, 3-5 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1- C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1196] C201is a single bond or C1-C6alkylene, and C202is selected from the group consisting of -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, and a combination thereof,

[1197] preferably, C201is a single bond or C1-C6 alkylene, and C202is selected from the group consisting of -NH-, -S(=O)2-, and a combination thereof,

[1198] more preferably, C201is a single bond or C1-C6 alkylene, and C202is -NH-S(O)2-;

[1199]

[1200] each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1201] preferably, each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto,187 wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1202] more preferably, each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1203] preferably, the PARG inhibitor moiety is selected from the group consisting of: ,188

[1208] the E3 ligase ligand moiety is

[1210] wherein:

[1211] x is 0 or 1;

[1212] C301is CH2or NH;

[1213] each of C302and C303is CH or N;

[1214] C304is C(O) or NH;

[1215] each of RC311, RC312and RC313is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy;

[1216] or

[1217] the E3 ligase ligand moiety is189

[1219] wherein:

[1220] C305is selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof,

[1221] preferably, C305is selected from the group consisting of C1-C6 alkylene, -NH-, - C(=O)-, and a combination thereof,

[1222] more preferably, C305is -N-(C1-C6alkylene)-C(=O)-,

[1223] still more preferably, C305is -N-CH(tert-butyl)-C(=O)-;

[1224] C307is CH or N;

[1225] C308is C1-C6 alkylene, preferably, methylene;

[1226] each of RC314, RC315, RC316, RC317, RC318, RC319, RC320, RC321, RC322, and RC323is independently hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy;

[1227] or

[1228] the E3 ligase ligand moiety is

[1229] 190

[1230] wherein

[1231] each of RC324, RC325, RC326, and RC327is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy;

[1232] preferably, the E3 ligase ligand moiety is selected from the group consisting of:

[1236] In one embodiment, the present disclosure relates to a compound of Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg), or Formula (IIh):191

[1242] wherein:

[1243] each of X1and X2is independently selected from the group consisting of N and CRX;192

[1244] Rxis selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, NH2, NH(C1-C6alkyl), and N(C1-C6alkyl)2;

[1245] A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O- (3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl), , and

[1246] R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;

[1247] each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[1248] each of x, y, and z is independently an integer between 0 and 3;

[1249] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1250] R5is hydrogen or RL2;

[1251] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more193 selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[1252] R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto;

[1253] each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto;

[1254] each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered, 5-12 membered heteroarylene, 6-10 membered arylene, -(C1-C6 alkylene)-(6-10 membered arylene)-, or -(C1-C6 alkylene)-(6-10 membered arylene)-(C1-C6 alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and hydroxy;

[1255] each of q, r, s and t is independently an integer between 0 and 5;

[1256] each of C1 and C2 is independently selected from the group consisting of a PARP inhibitor moiety, a PARG inhibitor moiety, and an E3 ligase ligand moiety;

[1257] C' is selected from the group consisting of a PARP inhibitor moiety, a PARG inhibitor moiety, and an E3 ligase ligand moiety, wherein the moiety includes a nitrogen radiacal to which S1group is attached, preferably, wherein the moiety includes piperidinylene or piperazinylene, and the rest of the moiety is attached to S1group via the piperidinylene or piperazinylene as a linker; and194

[1258] each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[1259] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1260]

[1261] In one embodiment,

[1262] each of X1and X2is independently selected from the group consisting of N and CRX;

[1263] Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2, NH(C1-C6alkyl), and N(C1-C6alkyl)2;,

[1265] Ra1is independently selected from the group consisting of RL1, hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1266] each of Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;195

[1267] , each of Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[1268] R5is hydrogen or RL2;

[1269] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto;

[1270] R1is hydrogen;

[1271] each of S1and S3is independently selected from the group consisting of a single bond,

[1273] (wherein p is an integer between 1 and 5, preferably 1 to 3;

[1274] each of q, r, s and t is independently an integer between 0 and 5, preferably 0 to 3);196

[1275] each of S2and S4is independently selected from the group consisting of a single bond,

[1277] (wherein p is an integer between 1 and 5, preferably 1 to 3);

[1278] each of R3and R4is hydrogen;

[1279] the PARP inhibitor moiety is

[1280]

[1281] wherein:

[1282] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2;

[1283] each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1284] preferably, each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1285] or

[1286] the PARP inhibitor moiety is197

[1287]

[1288] wherein:

[1289] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, or CNH2;

[1290] each of RC111and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1291] preferably, each of RC111and RC112is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1292] or

[1293] the PARP inhibitor moiety is,

[1295] wherein:

[1296] D2 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one198 or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1297] preferably, D2 is phenylene or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is substituted with oxo, and is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1298] C102is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof,

[1299] preferably, C102is a single bond or C1-C6alkylene;

[1300] C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2;

[1301] each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1302] preferably, each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1303] or

[1304] the PARP inhibitor moiety is199,

[1306] wherein:

[1307] each of C101, C102and C103is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[1308] preferably, C101is N, C102is N, and C103is CH; or C101is N, C102is C, and C103is NH;

[1309] each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1310] each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1311] D4 is a single bond, 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,200

[1312] preferably, D4 is a single bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1313] D5 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1314] preferably, D5 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1315] or

[1316] the PARP inhibitor moiety is,

[1318] wherein:

[1319] each of C101, and C102is independently selected from the group consisitng of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHCl, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);201

[1320] each of C103, C104, C105, and C106is independently selected from the group consisitng of N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[1321] D7 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1322] preferably, D7 is phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from C1- C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1- C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1323] or

[1324] the PARP inhibitor moiety is,

[1326] wherein:

[1327] each of C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[1328] each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano,202 hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1329] preferably, each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1330] D9 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1331] preferably, D9 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1332] D10 is 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1333] preferably, D10 is 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;203

[1334] C101is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6alkyl)-, and a combination thereof;

[1335] or

[1336] the PARP inhibitor moiety is,

[1338] wherein:

[1339] each of C101, C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[1340] each of D12 and D13 is independently 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1341] preferably, D12 is 5-6 membered heteroaryl, and D13 is phenyl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1342] preferably, the PARP inhibitor moiety is selected from the group consisting of:204 ;

[1345] the PARG inhibitor moiety is selected from the group consisting of:205,

[1349] wherein:

[1350] E2 is 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1351] preferably, E2 is 5-6 membered nitrogen containing heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1352] more preferably, E2 is thiadiazolyl, pyrazolyl, or 1,3,4-selenadiazol-2-yl, wherein said thiadiazolyl, pyrazolyl, and 1,3,4-selenadiazol-2-yl are optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1353] E3 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1354] preferably, E3 is a 5-6 membered nitrogen containing saturated heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and206 alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1355] more preferably, E3 is piperazinyl, wherein said piperazynyl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, and C1-C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1356] E4 is 3-6 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,

[1357] preferably, E4 is 3-5 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, and C1- C6 alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1358] C201is a single bond or C1-C6alkylene, and C202is selected from the group consisting of -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, and a combination thereof,

[1359] preferably, C201is a single bond or C1-C6 alkylene, and C202is selected from the group consisting of -NH-, -S(=O)2-, and a combination thereof,

[1360] more preferably, C201is a single bond or C1-C6 alkylene, and C202is -NH-S(=O)2-;

[1361] each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1362] preferably, each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen,207

[1363] more preferably, each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen;

[1364] preferably, the PARG inhibitor moiety is selected from the group consisting of: ,208

[1369] the E3 ligase ligand moiety is

[1371] wherein:

[1372] x is 0 or 1;

[1373] C301is CH2or NH;

[1374] each of C302and C303is CH or N;

[1375] C304is C(O) or NH;

[1376] each of RC311, RC312and RC313is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy;

[1377] or

[1378] the E3 ligase ligand moiety is209

[1380] wherein:

[1381] C305is selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof,

[1382] preferably, C305is selected from the group consisting of C1-C6 alkylene, -NH-, - C(=O)-, and a combination thereof,

[1383] more preferably, C305is -N-(C1-C6alkylene)-C(=O)-,

[1384] still more preferably, C305is -N-CH(tert-butyl)-C(=O)-;

[1385] C307is CH or N;

[1386] C308is C1-C6 alkylene, preferably, methylene;

[1387] each of RC314, RC315, RC316, RC317, RC318, RC319, RC320, RC321, RC322, and RC323is independently hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy;

[1388] or

[1389] the E3 ligase ligand moiety is

[1390] 210

[1391] wherein

[1392] each of RC324, RC325, RC326, and RC327is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy;

[1393] preferably, the E3 ligase ligand moiety is selected from the group consisting of:

[1397] In one embodiment, the exemplary compounds of Formula (II) are provided below:221

[1398] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1399]

[1400] In another embodiment, the exemplary compounds of Formula (II) are provided below:231, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1402]

[1403] As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via232 migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[1404] As used herein, the term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[1405] As used herein, the term “diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may be separated into each stereoisomer under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[1406] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[1407] The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[1408] It will be understood by those skilled in the art that the organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as “hydrate.” The present disclosure encompasses all solvates of the compounds disclosed herein. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvates will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvate” means both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[1409] The term “hydrate” refers to a compound that is associated with water. Generally, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, hydrates of a compound can be represented, for example, by a general formula R∙x H2O, wherein R233 denotes the compound, and x is a number greater than 0. Given compounds can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, for example, hemihydrates (R∙ 0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R∙2 H2O) and hexahydrates (R∙6 H2O)).

[1410] Compounds disclosed herein may be in an amorphous or crystalline form (crystal form or polymorph). Furthermore, the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of the present disclosure includes all amorphous or crystalline forms of the compounds disclosed herein. The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, rate of crystallization, storage temperatures, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[1411] As used herein, the term “isotopically labeled form” of a compound that contains an isotopic form of one or more atoms in the compound that is different from the naturally occurring isotopic distribution of the atom in nature. All isotopic forms are included as options, unless a specific isotopic form is indicated. An “isotopically label form” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be2H / D, any carbon may be13C, or any nitrogen may be15N, and that the presence and placement of such atoms may be determined by those skilled in the art.

[1412] As used herein, the term “prodrug” refers to substances that can be converted, under physiological conditions or through solvolysis, into the compound of the present disclosure having biological activity. The prodrug of the present disclosure is prepared by modifying the functional groups in the compound, and the modification can be removed234 by conventional operations or removed in vivo, to produce the compound of the present disclosure. The prodrug includes a compound which is formed by connecting a hydroxyl group or amino group in the compound of the present disclosure to any group. When the prodrug of the compound of the present disclosure is administered to a mammalian individual, the prodrug is dissociated to form a free hydroxyl or amino group.

[1413] The term “pharmaceutically acceptable salt” refers to a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit / risk ratio.

[1414] Certain compounds disclosed herein can exist in the form of salts, for example acid addition salts, or salts with organic or inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds disclosed herein include the salt forms of the compounds.

[1415] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of the parent compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts (e.g., mono - or di- salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di- salts formed with an acid selected from the group consisting of acetic, 2,2- dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)- camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2- sulfonic, naphthalene-1, 5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic,235 salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic, valeric acids, and acylated amino acids.

[1416] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is a hydrochloride salt.

[1417] Where the compounds disclosed herein contain an amine function, the compound may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein.

[1418] The compounds of the invention may exist as mono- or di- salts depending upon the pKaof the acid from which the salt is formed.

[1419] Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric acid, phosphoric acid sulfuric acid, and perchloric acid and organic acids e.g., succinic, maleic, acetic, oxalic, malonic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g., oxalates or formates may be used, for example in the isolation of compounds disclosed herein and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[1420] Salts formed using conventional methods in the art such as ion exchange are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,236 lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[1421] The compounds disclosed herein may form acid addition salts with one or more equivalents of the acid. The scope of the present invention includes all possible stoichiometric and non-stoichiometric forms.

[1422]

[1423] Preparation Methods

[1424] According to a further aspect of the present disclosure, provided is a process of preparing an intermediate of the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof. According to a further aspect of the present disclosure, provided is a process of preparing a compound of Formula (I) or (II) , or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof. The following schemes are examples of synthetic schemes that may be used to synthesize the compound of Formula (I) or (II). In the following schemes, reactive groups can be protected with protecting groups and de- protected by well-established techniques in the art. The compound of Formula (I) or (II) described in the present disclosure may be prepared by those skilled in the organic synthesis field by using a standard method, which is discussed below in detail.

[1425]

[1426] According to a further aspect of the present disclosure, a process of preparing an intermediate of the compound of Formula (I) or (II) as herein defined or a tautomer,237 stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of the following General Procedure aA and aB:

[1427]

[1428] General Procedure aA:

[1429] General Procedure aA prepares an intermediate of the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1430] (a) reacting a compound of Formula (aa) with a compound of Formula (ab) to produce a compound of Formula (1a):

[1434] (b) reacting a compound of Formula (1a) with a compound of Formula (ac) to produce a compound of Formula (2a):

[1435] (ac)238

[1437] (c) reacting a compound of Formula (2a) with Raney Ni under H2 atmosphere to produce a compound of Formula (3a):

[1438]

[1439] wherein each of R1 and R2 is independently hydrogen or any functional group such as C1-C6alkyl or C1-C6alkoxy.

[1440] Exemplary reaction conditions for each step of General Procedure aA are described in the description below of the Example of intermediate A-1.

[1441] In one embodiment, an exemplary reaction scheme may be Scheme aA shown below:

[1442] Scheme aA

[1443]

[1444]

[1445] General Procedure aB:239

[1446] General Procedure aB prepares an intermediate for the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises reacting a compound of Formula (ba) with a compound of Formula (bb) to produce a compound of Formula (1b)::

[1449] (1b)

[1450] wherein R1 is hydrogen or any functional group such as C1-C6alkyl or C1-C6alkoxy; R2 is hydrogen or halogen, and ring A is as defined herein.

[1451] Exemplary reaction conditions for each step of General Procedure aB are described in the description below of the Example of intermediate B-1.

[1452] In one embodiment, an exemplary reaction scheme may be Scheme aB shown below:

[1453] Scheme aB240

[1454]

[1455]

[1456] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of the following methods:

[1457]

[1458] Method 1: General Procedure A

[1459] Method 1 prepares a compound of Formula (I), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[1460] reacting a compound of Formula (A-1) with a compound of Formula (A-2) to produce a compound of Formula (A-3):241

[1463]

[1464] wherein ring A is as defined herein and each of R1, R2, and R3 is independently hydrogen or any functional group such as C1-C6 alkyl or C1-C6 alkoxy.

[1465]

[1466] In one embodiment, the step is performed at a suitable temperature such as from 80 to 120oC, in the presence of a suitable inorganic base such as K3PO4or K2CO3or Cs2CO3, and in a suitable organic solvent such as THF / H2O or 1,4-Dioxane / H2O, and in a suitable palladium catalyst such as Xphos PdG3 or Pd(dtbpf)Cl2.

[1467]

[1468] In one embodiment, an exemplary reaction scheme may be Scheme A shown below:

[1469] Scheme A

[1472] Method 2: General Procedure B

[1473] Method 2 prepares a compound of Formula (I), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[1474] 242

[1475] (i) preparing a compound of Formula (B-1):

[1478] (ii) reacting the compound of Formula (B-1) with a compound of Formula (B-2) to produce a compound of Formula (B-3):

[1482] (iii) reacting the compound of Formula (B-3) with halomethylbenzene (e.g., bromomethylbenzene) to produce a compound of Formula (B-4):

[1485] (iv) reacting the compound of Formula (B-4) with a compound of Formula (B-5) to produce a compound of Formula (B-6):

[1486] 243

[1490] (v) reacting the compound of Formula (B-6) with H2gas in the presence of a catalyst (e.g., Pd / C) to produce a compound of Formula (B-7): (B-7);

[1493] (vi) reacting the compound of Formula (B-7) with PPh3 / DEAD to produce a compound of Formula (B-8):

[1496] (vii) reacting the compound of Formula (B-8) with a reducing agent (e.g., LiAlH4) to produce a compound of Formula (B-9):244

[1499] (viii) reacting the compound of Formula (B-9) with methylsulfonyl methanesulfonate / triethylamine (TEA) to produce a compound of Formula (B-10):

[1502] (ix) reacting the compound of Formula (B-10) with tert-butyl N-tert- butoxycarbonylcarbamate to produce a compound of Formula (B-11):

[1505] (x) reacting the compound of Formula (B-11) with tert-butyl N-tert- butoxycarbonylcarbamate to produce a compound of Formula (B-12):

[1506]

[1507]

[1508] (xi) reacting the compound of Formula (B-12) with a compound of Formula (B-13) to produce a compound of Formula (B-14):245

[1512] (xii) reacting the compound of Formula (B-14) with a compound of Formula (B-15) to produce a compound of Formula (I) or (II):

[1514] wherein ring B, R1, Ra2, Ra3, RL11, RL22, RL23, and RL25are as defined above; and

[1515] each of Hal3and Hal4is a halide (e.g., chloride and bromide).

[1516]

[1517] In one embodiment, an exemplary reaction scheme may be Scheme B shown below:

[1518] Scheme B

[1519]

[1520] 247

[1528] Method 3: General Procedure C

[1529] Method 3 prepares a compound of Formula (I) or (II), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting the compound of Formula (C-1) with a compound of Formula (C-2) to produce a compound of Formula (C- 3):

[1533] wherein each of R1 and R2 is independently hydrogen or any functional group such as C1-C6 alkyl or C1-C6 alkoxy, and R3 is any functional group such as heteroaryl.248

[1534]

[1535] In one embodiment, the step is performed at a suitable temperature such as from -78 oC to room temperature, in the presence of a suitable base such as LiHMDS or 60% NaH,

[1536]

[1537] In one embodiment, an exemplary reaction scheme may be Scheme C shown below:

[1538] Scheme C

[1541] Method 4: General Procedure D

[1542] Method 4 prepares a compound of Formula (I) or (II), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting the compound of Formula (D-1) with a compound of Formula (D-2) to produce a compound of Formula (D-3):

[1544] (D-2)249

[1547] In one embodiment, the step is performed at a suitable temperature such as room temperature to 100oC, in the presence of a suitable organic base such as triethyl amine or diisopropylethylamine, and in a suitable organic solvent such as THF or DMF.

[1548]

[1549] In one embodiment, an exemplary reaction scheme may be Scheme D shown below:

[1550] Scheme D

[1553] Method 5: General Procedure E

[1554] Method 5 prepares a compound of Formula (I) or (II), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[1555] (a) reacting the compound of Formula (E-1) with a compound of Formula (E-2) to produce a compound of Formula (E-3):250

[1559] (b) reacting the compound of Formula (E-3) with sodium acetate and acid to produce the compound of Formula (E-4):

[1562] In one embodiment, step a is performed at a suitable temperature such as from 0oC to room temperature, in the presence of a suitable base such as LiHMDS or 60% NaH, and in a suitable organic solvent such as THF or DMF.

[1563]

[1564] In one embodiment, an exemplary reaction scheme may be Scheme E shown below:251

[1565] Scheme E

[1568] A process of preparing the present compound is not limited to the general procedures described above. The present compound can be prepared by processes exemplified in Examples, for example, Example 8 (General Procedure F), Example 162 (General Procedure J), Example 61 (General Procedure G), Example 84 (General Procedure H), Example 190 (General Procedure I), etc. Further, the present compound may be prepared by those skilled in the organic synthesis field by using a standard method.

[1569]

[1570] Pharmaceutical combination

[1571] The present disclosure provides a novel combination of a USP1 inhibitor and a PARG inhibitor that has a synergistic effect for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, cancers, preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, prostate cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.252

[1572] In one embodiment, the USP1 inhibitor may be a compound / drug that can inhibit USP1 or reduce USP1 activity. For example, the USP1 inhibitor may be any compound / drug(s) that are known to inhibit USP1 in the art.

[1573] In one embodiment, the USP1 inhibitor may be a compound of Formula (X):

[1575] wherein:

[1576] ring H is phenyl or 6 membered heteroaryl, which is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, deuterium, and halogen,

[1577] preferably, ring H is selected from the group consisting of:,

[1579] more preferably, ring H is seleced from the group consisting of:

[1581] ring I is 6-13 membered heteroaryl or heterocyclyl, which is optionally substituted with one or more selected from oxo, C1-C6 alkyl, halogen, C1-C6 alkoxy, cyano, =NH, - C(=O)-CH3, -NH2, -P(=O)-(CH3)2, and -C(=O)-NHCH3, wherein said alkyl is optionally substituted halogen,253

[1582] preferably, ring I is 6-13 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocyclyl, which contains 1-6 nitrogen, or 1-6 nitrogen and oxygen, sulfur, or Si as the ring heteroatom, which is optionally substituted with one or more selected from oxo, C1- C6 alkyl, halogen, C1-C6 alkoxy, cyano, =NH, -C(=O)-CH3, -NH2, -P(=O)-(CH3)2, and - C(=O)-NHCH3, wherein said alkyl is optionally substituted halogen,

[1583] more preferably, ring I is selected from the group consisting of:

[1584]

[1585] J is selected from the group consisting of a single bond, C1-C6 alkylene, -NH-(C1-C6 alkylene)-, -N(C2-6alkynyl)-(C1-C6alkylene)-, and -N(6-13 membered heteroary)- (C1-C6alkylene)-,

[1586] preferably, J is selected from the group consisting of a single bond,

[1588] more preferably, J is selected from the group consisting of:

[1590] ring K is selected from the group consisting of phenyl, 6 membered heteroaryl, and 6-13 membered cycloalkyl, which is optionally substituted with one or more selected254 from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1591] preferably, ring K is selected from the group consisting of phenyl, 6 membered heteroaryl, and 6-13 membered cycloalkyl, which is optionally substituted with one or more halogens,

[1592] more preferably, ring K is selected from the group consisting of:

[1593] ,

[1594] still more preferably, ring K is;

[1595] ring M is 5-13 membered heteroaryl, which is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, and 5-13 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is independently optionally substituted with one or more selected from halogen, C1-C6 alkyl, deuterium, - CO-(C1-C6 alkyl)-, and :

[1596] preferably, ring M is selected from the group consisting of:

[1597] 255

[1598] wherein RMis selected from the group consisting of C1-C6 alkyl and 3-10 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionallysubstituted with one or more selected from C1-C6 alkyl, deuterium, and ,

[1599] preferably, RMis selected from the group consisting of methyl, ethyl, isopropyl, trideuteriomethyl, cyclobutyl, and,

[1600] more preferably, ring M isor ;

[1601]

[1602] wherein RKM2, RKM3, RKM11, RKM12, RKM13, RKM22, RKM23, and RKM25are independently selected from hydrogen, halogen, C1-C6 alkyl, and halogen-substituted C1- C6alkyl,

[1603] preferably,,

[1604] wherein RKMis hydrogen or C1-C6 alkyl,

[1605] preferably, RKMis hydrogen or methyl,

[1606] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1607] 256

[1608] In one embodiment, the USP1 inhibitor may be any of the compounds disclosed herein (e.g., the compounds of Formulae (I) or (II)).

[1609]

[1610] In one embodiment, the USP1 inhibitor may be selected from the group consisting of the compounds shown in the table below. The documents mentioned in the below table are sources of the USP1 inhibitor compounds, and are incorporated herein by reference in their entirety.257258259260261262263264265266267268269

[1611] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1612] 270

[1613] In one embodiment, the USP1 inhibitor may be selected from the group consisting of:275

[1614] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1615]

[1616] In one embodiment, the PARG inhibitor may be a compound / drug that can inhibit PARG or reduce PARG activity. For example, the PARG inhibitor may be any compound / drug(s) that are known to inhibit PARG in the art.

[1617] 276

[1618] In one embodiment, the PARG inhibitor may be a compound of Formula (XI):

[1620] wherein:

[1621] ring N is 9-13 membered heteroaryl or heterocyclyl, which is optionally substituted with one or more selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, 6-14 membered aryl, 5-12 membered heteroaryl, C1-C6 alkylene-O-C1-C6 alkyl, oxo, -NH-O-C1-C6alkyl, carbamoyl, acetamido, NH2, mercapto, hydroxyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkoxy, cyano, and 3-10 membered saturated heterocyclyl, wherein each of said alkyl, alkoxy, aryl, heteroaryl, alkenyl, alkynyl, haloalkoxy, cycloalkyl, and heterocylyl is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-10 membered cycloalkyl, halogen, cyano, hydroxyl, NH2, mercapto, and carbamoyl,

[1622] preferably, ring N is 9-13 membered heteroaryl or heterocyclyl, which is optionally substituted with one or more selected from C1-C6alkyl, halogen, 3-10 membered cycloalkyl, phenyl, C1-C6 alkylene-O-C1-C6 alkyl, oxo, -NH-O-C1-C6 alkyl, carbamoyl, acetamido, NH2, mercapto, hydroxyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkoxy, cyano, and 3-10 membered saturated heterocyclyl, wherein each of said alkyl, phenyl, alkenyl, alkynyl, haloalkoxy, cycloalkyl, and heterocylyl is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-10 membered cycloalkyl, halogen, cyano, hydroxyl, NH2, mercapto, and carbamoyl,

[1623] more preferably, ring N is 9-13 membered heteroaryl or heterocyclyl, which is optionally substituted with one or more selected from C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, phenyl, C1-C6alkylene-O-C1-C6alkyl, oxo, -NH-O-C1-C6alkyl, and tetrahydrofuranyl, wherein each of said alkyl and phenyl is independently optionally substituted with one or more selected from halogen,

[1624] still more preferably, ring N is 9-13 membered bicyclic or tricyclic fused heteroaryl or heterocyclyl, which contains 1-4 nitrogen, or 1-4 nitrogen and oxygen or sulfur as the ring heteroatom and is optionally substituted with one or more selected from methyl,277 ethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, cyclopropyl, 4-fluorophenyl, - (CH2)2-O-CH3, oxo, -NH-O-CH3, and tetrahydrofuranyl,

[1625] still more preferably, ring N is selected from the group consisting of:

[1628] ROais selected from the following:

[1630] wherein Y is absent or oxygen,

[1631] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen,

[1632] Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl,

[1633] Rx3is selected from the group consisting of hydrogen and halogen,

[1634] RObis hydrogen or C1-C6alkyl;

[1635] preferably, ROis methyl or

[1636] ROais selected from the group consisting of:278;

[1638] RObis hydrogen or methyl,

[1639] more preferably, ROis

[1640] ROais selected from the group consisting of:

[1641] ;

[1642] RObis hydrogen;

[1643] RPis selected from the group consisting of C1-C6alkyl, 3-14 membered heterocyclyl, -(C1-C6 alkylene)-(3-14 membered heterocyclyl), 5-14 membered heteroaryl, -(C1-C6 alkylene)-(5-14 membered heteroaryl), 5-14 membered aryl, and –(C1-C6 alkylene)-(5-14 membered aryl), wherein each of said heterocyclyl, heteroaryl, or aryl is independently optionally substituted with one or more selected from C1-C6 alkyl, C1-C6 alkylene-O-C1- C6 alkyl, halogen, oxo, =N-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl),, and, wherein said alky is optionally substituted with OH or halogen,279

[1644] each of RPa, RPb, and RPcis independently selected from the group consisting of 3-10 membered cycloalkyl, C1-C6alkyl, 3-10 membered heterocyclyl, and -O-(C1-C6alkyl)- N(C1-C6alkyl), wherein each of said cycloalkyl, alkyl, and heterocyclyl is independently optionally substituted with one or more selected from OH, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with deuterium;

[1645] preferably, RPis selected from the group consisting of methyl, 6-8 membered heterocyclyl, -CH2-(5 membered heteroaryl), or -CH2-phenyl, wherein each of said heterocyclyl, heteroaryl, or phenyl is independently optionally substituted with one or more selected from C1-C6alkyl, C1-C6alkylene-O-C1-C6alkyl, halogen, oxo, =N-CH3, - S(=O)2-CH-(CH3)2, -S(=O)2-CH3,, a , wherein said alky is optionally substituted with OH or halogen,

[1646] each of RPa, RPb, and RPcis independently selected from the group consisting of 3-10 membered cycloalkyl, C1-C6 alkyl, 3-10 membered heterocyclyl, and -O-(CH2)2-N(CH3)2, wherein each of said cycloalkyl, alkyl, and heterocyclyl is independently optionally substituted with one or more selected from OH, C1-C6alkyl, and C1-C6alkoxy optionally substituted with deuterium,

[1647] more preferably, RPis selected from the group consisting of methyl, 6 membered monocyclic or 8 membered bicyclic heterocyclyl, -CH2-(5 membered heteroaryl), or - CH2-phenyl, wherein said heteroaryl is optionally substituted with methyl, wherein said phenyl is optionally substituted with methyl, wherein said heterocyclyl is optionally substituted with one or more selected from methyl, hydroxymethyl, fluoromethyl, trifluoromethyl, CH2-O-CH3, CH2-O-CHF2, fluoro, oxo, =N-CH3, -S(=O)2-CH-(CH3)2, -

[1648] each of RPa, RPb, and RPcis independently selected from the group consisting of 3-10 membered cycloalkyl, C1-C6 alkyl, 3-10 membered heterocyclyl, and -O-(CH2)2-N(CH3)2, wherein each of said cycloalkyl, alkyl, and heterocyclyl is independently optionally280 substituted with one or more selected from OH, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with deuterium,

[1649] still more preferably, RPis selected from the group consisting of

[1651] RSis selected from the group consisting of C1-C6alkyl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, -(C1-C6 alkylene)-(5-12 membered heteroaryl), -(C1-C6 alkylene)-(5-12 membered heterocyclyl), -C(=O)-(5-12 membered heteroaryl), -(C=O)- (5-12 membered heterocyclyl), -NH-(C=O)-(5-12 membered heteroaryl), -NH-(C=O)-(5- 12 membered heterocyclyl), -S-(C1-C6alkylene)-(5-12 membered heteroaryl), and -S-(C1- C6 alkylene)-(5-12 membered heterocyclyl), wherein each of said alkyl, alkylene, heteroaryl, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2- C6 alkynyl, acryl, hydroxy, C1-C6 alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deutrinum, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1652] preferably, Rsis selected from the group consisting of C1-C6 alkyl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, -(C1-C6alkylene)-(5-12 membered heteroaryl), - (C=O)-(5-12 membered heterocyclyl), -NH-(C=O)-(5-12 membered heterocyclyl), and - S-(C1-C6 alkylene)-(5-12 membered heterocyclyl), wherein each of said alkyl, alkylene, heteroaryl, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2- C6 alkynyl, acryl, hydroxy, C1-C6 alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deutrinum, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[1653] more preferably, RSis selected from the group consisting of:281

[1656] wherein RSais S, O, or Se,

[1657] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1658]

[1659] In one embodiment, the PARG inhibitor may be any of the compounds disclosed herein (e.g., the compounds of Formula (IIb)).

[1660]

[1661] In one embodiment, the PARG inhibitor may be selected from the group consisting of the compounds shown in the table below. The documents mentioned in the below table are sources of the PARG inhibitor compounds, and are incorporated herein by reference in their entirety.282283284285286287288289290291292293294295296297298299ed form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1663]

[1664] In one embodiment, the PARG inhibitor may be selected from the group consisting of:307

[1665] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[1666]

[1667] Therapeutic utilities

[1668] The terms “treat”, “treating”, “treatment” and the like refer to a course of action (such as administering an inhibitor of USP1 or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject. Thus, “treatment” may also refer to inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[1669] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a USP1 inhibitor or a pharmaceutical composition comprising the same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying308 the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression of the disease, disorder or condition such that it does not reach a harmful or otherwise undesired state.

[1670] The terms “inhibiting” and “reducing,” or any variation of these terms in relation of USP1, may refer to any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in USP1 activity, PARP activity, or PARG activity of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, compared to a control group. The term “about” as used herein means variations within ± 20%, preferably, within ± 10%, more preferably within ± 5% of a given value.

[1671] "Disease", "disorder" and "condition" are used interchangeably herein.

[1672]

[1673] The present disclosure provides a compound that prevents or treats a disease or disorder mediated by USP1 or a disease or disorder in which USP1 activity is implicated. The present disclosure also provides a compound that selectively inhibits USP1 enzyme activity in vitro or in vivo.

[1674] In some embodiments, the disease or disorder mediated by USP1 is cancer. In some embodiments, the disease or disorder mediated by USP1 is a hematological cancer, a lymphatic cancer, and a DNA damage repair pathway deficient cancer. In some embodiments, the cancer comprises cancer cells with a mutation in genes encoding BRCA1 or BRCA2. In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the mutation in the gene encoding p53 is a germline mutation. In some embodiments, the mutation in the gene encoding p53 is a somatic mutation. In some embodiments, the cancer comprises cancer cells with a loss of function mutation in the gene encoding p53. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, prostate cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma,309 glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer (García-Santisteban et al. Molecular Cancer 2013, 12:91), colon cancer, osteosarcoma (Int J Biol Sci. 2022; 18(8): 3122–3136.), triple negative breast cancer (Cancers (Basel). 2020 Nov; 12(11): 3090), pancreatic cancer (iScience. 2018 Mar 23; 1: 72–86), bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; and uterine cancer. In some embodiments, the cancer comprises cancer cells with a mutation in genes encoding BRCA1 or BRCA2.

[1675]

[1676] Meanwhile, the compound of Fomula (II) may be a dual targeting compound. The dual targeting compound may have an inhibitory activity for USP1 and also i) an inhibitory activity for PARP, or ii) an inhibitory activity for PARG, or iii) a binding activity for E3 ligase, and can be effectively used for treating various types of cancers.

[1677] DNA repair is essential for the regulation of cell growth and survival. Thus, DNA repair pathways have been targeted for manipulation by medical therapeutics. Single- strand breaks (SSBs) are the most common type of lesion that occurs in cells. Poly(ADP-ribose) glycohydrolase (PARG) and poly(ADP-ribose) polymerase (PARP) play roles in repairing DNA damage caused by SSBs.

[1678] At an early stage of single-strand DNA repair, PARP detects single-strand breaks and begins to synthesize poly ADP-ribose (PAR) itself. Such poly ADP-ribosylation (PARylation) serves as a signal to recruit DNA repair proteins, such as XRCC1(X-ray repair cross-complementing protein 1), and the DNA repair proteins subsequently proceed to repair the SSBs. Then, PARG reverses the action of PARP enzymes by hydrolysing ribose-ribose bonds present in PAR, which is a process referred to as depoly(ADP-ribosyl)ation (dePARylation). When PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalytically active form (Curtin, N. J., & Szabo, C., 2013, Molecular aspects of medicine, 34(6), 1217-1256). Therefore, a sequential event of PARylation and dePARylation should be well-regulated since imbalance between PARylation and dePARylation can lead to DNA damage.

[1679] Cancer is a result of uncontrolled and unregulated cellular proliferation. A rapid proliferation can cause a high level of oxidative stress within tumor cells, which leads to310 DNA damage and increased rate of mutation. The mutation can cause deficiencies in DNA repair mechanisms, and accordingly, cancer cells with the deficiencies tend to heavily rely on specific DNA repair mechanisms. To date, several therapeutic agents have been developed to target cancer cells that rely on specific DNA repair mechanisms. For example, it has been shown that tumor cells carrying a mutation in BRCA1 and BRCA2 genes often harbor defects in DNA double brand break (DSB) repair and such BRCA1 / BRCA2 deficient tumor cells are more sensitive to PARP inhibitors. In addition, there is some evidence suggesting that defects in DSB repair can also sensitize tumor cells to PARG inhibition, and PARG inhibitors can specifically kill BRCA2- deficient tumors (Fathers, Catherine, et al., 2012, Cell cycle, 11.5: 990-997).

[1680] Furthermore, experimental data has demonstrated the therapeutic efficacy of PARP and PARG inhibitors in the treatment of cancer. For example, the efficacy of PARPi monotherapy in HR deficient (HRD) cancers carrying BRCA1 / 2 mutations was first demonstrated in cancer cell lines, and later confirmed in patient-derived xenograft (PDX) models. Treatment with olaparib resulted in significant tumor graft regression (Ter Brugge P, et al., Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J Natl Cancer Inst 2016; 108:djw148; Park  HS, et al., Establishment of chemosensitivity tests in triple-negative and BRCA-mutated breast cancer patient-derived xenograft models. PLoS One  2019; 14: e0225082) in PDX tumors of BRCA1-mutant triple-negative breast cancer (TNBC). Moreover, in vivo tests showed that PARG inhibitors have efficacy against various types of cancers, including breast cancer and cervical cancer (Blenn, C., W`yrsch, P., & Althaus, F. R., 2011, Molecules, 16(2), 1854-1877). Another PARG inhibitor, adenosine diphosphate (hydroxymethy1)pyrrolidinediol (ADP-HPD), which is an analog of ADP-ribose, showed good selectivity in inhibiting PARG at a low concentration (Slama, J. T., Aboul-Ela, N., & Jacobson, M. K. (1995)., Journal of medicinal chemistry, 38(21), 4332-4336).

[1681] Meanwhile, ubiquitination is catalyzed by the signaling cascades of ubiquitin- activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) and leads to the covalent binding of ubiquitin to the target protein. Ubiquitin is activated in an ATP-dependent manner and binds to the cysteine residue on E1 through a thioester bond. Subsequently, the activated ubiquitin molecule is transferred to the cysteine active site of E2 and then recruited into E3 ligases. Finally, E3 ligases bind the E2-Ub311 complex to the target protein and promote the binding of ubiquitin to the lysine residues of the substrate. Ubiquitin molecules can not only undergo monoubiquitination with seven lysine residues but also form polyubiquitin chains based on the original target substrate. In addition to serving as a signal for specific subcellular localization and mediating protein–protein interactions, monoubiquitination is also related to the degradation of a few proteins. Monoubiquitination targets proteins with less than 150 amino acids and low structural disorder, while polyubiquitination recognizes proteins of any size with a highly disordered structure. Ubiquitination is closely related to various biological processes, including internalization and lysosomal targeting, protein interaction regulation, changes in subcellular distribution, transcriptional regulation, growth response, innate immune response, DNA repair and replication, and transmembrane signal transduction, particularly in the regulation of the nuclear factor kappa B (NF-κB) pathway.

[1682] E3 ubiquitin ligases, critical enzymes in the ubiquitination reaction, mediate the recognition of the substrate in the ubiquitin–proteasome system and determine the specificity of the ubiquitination reaction. On the basis of their structural characteristics and action mechanism, they are classified into three families: the really interesting new gene (RING) domain, the homologous to the E6-associated protein carboxyl terminus (HECT) domain, and the RING-between-RING (RBR) types of E3 ligases (Deng L., Meng T., Chen L., Wei W., Wang P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct. Target. Ther.2020; 5:11). After the E3 ligases bind to the E2-Ub complex and the substrate, the RING-type E3 ligases catalyze the direct transfer of ubiquitin from E2 to the lysine residue of the substrate. However, HECT and RBR E3 ligases catalyze the transfer of ubiquitin from E2 to cysteine, the active site of E3 ligases. Subsequently, ubiquitin is transferred to substrate proteins. E3 ligases play a vital role in the occurrence and progression of human cancer (Mohammed A Mansour, Int J Biochem Cell Biol.2018 Aug:101:80-93).

[1683] Targeting E3 ligases can enhance antitumor immunity in cancer immunotherapy. For example, ARV-110 (DC50 ~ 1 nM) and ARV-471 (DC50 ~ 1 nM) are targeting AR and estrogen receptors (ER), respectively and are currently in phase two of clinical trials for prostate cancer or breast cancer (Gao, X. et al. Phase 1 / 2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol.2022, 40, 17; Hamilton, E.P. et al., ARV-471, an312 estrogen receptor (ER) PROTACdegrader, combined with palbociclib in advanced ER+ / human epidermal growth factor receptor 2–negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1 / 2 study. J. Clin. Oncol.2022, 40).

[1684] For treating or preventing cancer, the dual targeting compound may be more advantageous than a single targeting compound, when they are administered at the same dosage.

[1685]

[1686] Pharmaceutical compositions / formulation

[1687] The present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and a pharmaceutically acceptable carrier(s) and / or excipient(s). The composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.

[1688] The present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the USP1 inhibitors and / or PARG inhibitors disclosed herein, and a pharmaceutically acceptable carrier(s) and / or excipient(s). The composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.

[1689] The pharmaceutical composition may, for example, be in a form suitable for oral administration such as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection such as a sterile solution, suspension or emulsion, for topical administration such as an ointment or cream, or for rectal administration such as a suppository. The pharmaceutical composition will include a conventional pharmaceutical carrier and / or excipient, and a compound of the present313 disclosure as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[1690] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. For oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in the art.

[1691]

[1692] Treatment method

[1693] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, in a subject in need of treatment or prevention, comprising administering to the subject the at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[1694] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, in a314 subject in need of treatment or prevention, comprising administering to the subject the USP1 inhibitor disclosed herein, or a pharmaceutical composition disclosed herein, wherein the method further comprises administering to the subject the PARG inhibitor disclosed herein, or a pharmaceutical composition disclosed herein.

[1695] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, in a subject in need of treatment or prevention, comprising administering to the subject the PARG inhibitor disclosed herein, or a pharmaceutical composition disclosed herein, wherein the method further comprises administering to the subject the USP1 inhibitor disclosed herein, or a pharmaceutical composition disclosed herein.

[1696] The terms “human”, “patient” or “subject” are used interchangeably. A “subject” to which admi...

Claims

484 CLAIMS

1. A compound of the following Formula (I):wherein: A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O-(3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl),R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl; each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring; each of x, y, and z is independently an integer between 0 and 3; B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-485 C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; L2is selected from the group consisting of 6-14 membered arylene, 5-12 membered heteroarylene, and 7-11 membered polycyclic cycloalkylene, wherein each of said arylene, heteroarylene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- 10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of n and m is independently an integer between 0 and 3; L3is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6486 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6alkoxy; each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto,487 wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. A compound of the following Formula (II):wherein: each of X1and X2is independently selected from the group consisting of N and CRX; Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2; A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O-(3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl),R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl;488 each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring; each of x, y, and z is independently an integer between 0 and 3; B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1- C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; R5is hydrogen or RL2; RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered489 cycloalkylene,, membered heteroarylene, 6-10 membered arylene, -(C1-C6 alkylene)-(6-10 membered arylene)-, or -(C1-C6alkylene)-(6-10 membered arylene)-(C1-C6alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and hydroxy; each of q, r, s and t is independently an integer between 0 and 5; each of L4and L5is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -S(=O)-. -S(=O)2-, -C(=O)-, - C(=O)-NH-, -NH-C(=O)-NH-, -C(=NH)-, -C(=N(C1-C6 alkyl)), and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6 alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene, each of C1 and C2 is independently selected from the group consisting of hydrogen, a PARP inhibitor moiety, a PARG inhibitor moiety, and an E3 ligase ligand moiety, but C1 and C2 are not both hydrogen; and each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), and Formula (Ig):492wherein: each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl; each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring; each of x, y, and z is independently an integer between 0 and 3; each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is493 independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1- C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of n and m is independently an integer between 0 and 3; L3is selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said494 alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6alkyl, halogen, and C1-C6alkoxy; each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of Formula (Ih) and Formula (Ii):495wherein each of Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and496 mercapto; each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto; each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2and mercapto; each of n and m is independently an integer between 0 and 3; L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally497 substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2and mercapto; R2is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, mercapto, NR21R22, 5-12 membered monocyclic or bicyclic heterocyclyl, 6-14 membered aryl, and 5-12 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, carbamoyl, oxo, 3-10 membered cycloalkyl, and mercapto, wherein each of said alkyl and cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, and C1-C6 alkoxy; each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, mercapto, and 5-12 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2 and mercapto; and each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

5. The compound according to claim 3, wherein each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, carbamoyl, 3-6 membered heterocyclyl, and -O-(3-6 membered heterocyclyl), wherein each of said alkyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, oxo, -S(=O)2-CH3, (C1-C6498 alkylene)-O-(C1-C6alkyl),R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl; each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring; each of x, y, and z is independently an integer between 0 and 3; each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; each of RL22, RL23, RL24, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1- C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, NH(C1-C6alkyl), N(C1- C6 alkyl)2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2and mercapto; each of n and m is independently an integer between 0 and 3; L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl,499 halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen, and C1-C6alkoxy, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromehtyl,502, wherein each of said R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, and R2iis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, -CH2OCH3, NH2, carbamoyl, hydroxy, fluoro, chloro, bromo, iodo, and cyclopropyl; and each of R3and R4is hydrogen or C1-C6 alkyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.503

6. The compound according to claim 4, wherein each of Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-6 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, carbamoyl, and 3-6 membered heterocyclyl, wherein each of said alkyl, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; each of RL11, RL12, and RL13is independently selected from the group consisting of hydrogen, methyl, ethhyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl; each of RL22, RL23, and RL25is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), N(C1- C6 alkyl)2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto; each of n and m is independently an integer between 0 and 3; L3is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, -C(=O)-, -S(=O)-. -, wherein each of said alkylene, alkenylene, alkynelene, and cycloalkylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, and 3-10 membered cycloalkyl, and each of RLa, RLb, RLc, and RLdis504 independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen-substituted C1-C6alkyl, halogen, and C1-C6alkoxy, R2is selected from the group consisting of hydrogen, ethynyl, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromehtyl,507, wherein each of said R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, and R2iis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, -CH2OCH3, NH2, carbamoyl, hydroxy, fluoro, chloro, bromo, iodo, and cyclopropyl; and each of R3and R4is hydrogen or C1-C6 alkyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

7. The compound according to claim 2, wherein the compound is selected from the group consisting of compounds of Formula (IIa-1), Formula (IIa-2), Formula (IIb), and Formula (IIc):508wherein: each of X1and X2is independently selected from the group consisting of N and CRX; Rxis selected from the group consisting of hydrogen, halogen, C1-C6alkoxy, NH2,509 NH(C1-C6 alkyl), and N(C1-C6 alkyl)2; A is 5-12 membered monocyclic or bicyclic heteroaryl or 5-12 membered monocyclic or bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, -O-(3-6 membered heterocyclyl), and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, oxo, -S(=O)2-CH3, (C1-C6alkylene)-O-(C1-C6alkyl),R13is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, - S(=O)2-CH3, and 3-6 membered heterocyclyl; each of R14and R15is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and 3-6 membered heterocyclyl, or R14and R15, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring; each of x, y, and z is independently an integer between 0 and 3; B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1- C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; R5is hydrogen or RL2; RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy,510 amino, and mercapto; R1is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6 alkoxy, NR11R12, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2 and mercapto; each of R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2and mercapto; each of S1, S2, S3, and S4is independently selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-6 alkynylene, 3-10 membered cycloalkylene,, 5-12 membered heteroarylene, 6-10 membered arylene, -(C1-C6alkylene)-(6-10 membered arylene)-, or -(C1-C6 alkylene)-(6-10 membered arylene)-(C1-C6 alkylene)-, wherein each of said alkylene, alkenylene, alkynylene, cycloalkylene, heteroarylene, and arylene is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and hydroxy; each of q, r, s and t is independently an integer between 0 and 5; each of L4and L5is independently selected from the group consisting of a single bond, C1-C6alkylene, C2-C6alkenylene, C2-6alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -S(=O)-. -S(=O)2-, -C(=O)-, - C(=O)-NH-, -NH-C(=O)-NH-, -C(=NH)-, -C(=N(C1-C6 alkyl)), and -C(=O)-Rl45, wherein Rl45is selected from the group consisting of C1-C6alkylene, 3-10 membered cycloalkylene, and 3-10 membered heterocyclene; and each of R3and R4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano,511 C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The compound according to claim 7, wherein the PARP inhibitor moiety iswherein: C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2; each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; or the PARP inhibitor moiety iswherein: C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, or CNH2; each of RC111and RC112is independently selected from the group consisting of512 hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; or the PARP inhibitor moiety is, wherein: D2 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; C102is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof; C101is CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2; each of RC111, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; or the PARP inhibitor moiety is513, wherein: each of C101, C102and C103is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2; each of RC111, RC112, and RC113is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; D4 is a single bond, 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1- C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; D5 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; or the PARP inhibitor moiety is514, wherein: each of C101, and C102is independently selected from the group consisitng of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHCl, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2); each of C103, C104, C105, and C106is independently selected from the group consisitng of N, CH, NH, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2; D7 is 6-10 membered arylene or 5-12 membered heteroarylene, wherein each of said arylene and heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; or the PARP inhibitor moiety is, wherein: each of C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;515 each of RC111, and RC112is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; D9 is a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; D10 is 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; C101is selected from the group consisting of a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof; or the PARP inhibitor moiety is, wherein:516 each of C101, C102, C103, and C104is independently selected from the group consisting of CH, N, COH, CCN, CF, CCl, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2; each of D12 and D13 is independently 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1- C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; the PARG inhibitor moiety is selected from the group consisting of:, wherein: E2 is 5-6 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered517 cycloalkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; E3 is a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; E4 is 3-6 memebered cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, and halogen; C201is a single bond or C1-C6 alkylene, and C202is selected from the group consisting of -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, and a combination thereof; each of RC211, RC212, RC213, RC214, RC215, and RC216is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1- C6 alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl; the E3 ligase ligand moiety is518 wherein: x is 0 or 1; C301is CH2or NH; each of C302and C303is CH or N; C304is C(O) or NH; each of RC311, RC312and RC313is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy; or the E3 ligase ligand moiety iswherein: C305is selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-, -S(=O)2-, -N(C1-C6 alkyl)-, and a combination thereof; C307is CH or N; C308is C1-C6 alkylene, preferably, methylene; each of RC314, RC315, RC316, RC317, RC318, RC319, RC320, RC321, RC322, and RC323is independently hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy; or the E3 ligase ligand moiety is519wherein each of RC324, RC325, RC326, and RC327is independently selected from the group consisting of hydrogen, F, Cl, Br, I, methyl, ethyl, isopropyl, carbamoyl, hydroxy, cyano, and methoxy, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

9. The compound according to claim 1, wherein the compound is selected from the group consisting of the following:536, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.537

10. The compound according to claim 2, wherein the compound is selected from the group consisting of the following:546, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. A pharmaceutical composition for preventing or treating diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non- small cell lung cancer (NSCLC), ovarian cancer, breast cancer, prostate cancer,547 bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer, comprising the compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and optionally a pharmaceutically acceptable carrier(s) and / or excipient(s).

12. The pharmaceutical composition according to claim 11, wherein the composition is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS- 1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

13. A pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, diseases or disorders caused by a mutation in genes encoding BRCA1 or BRCA2, comprising a USP1 inhibitor and optionally one or more pharmaceutically acceptable carriers and / or excipients, wherein the USP1 inhibitor is to be used in combination with a PARG inhibitor.548

14. A pharmaceutical composition according to claim 13, wherein the USP1 inhibitor is the compound of claim 1 or 2.

15. A combination of a USP1 inhibitor and a PARG inhibitor for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1 and / or PARG, particularly, cancers.

16. The combination according to claim 15, wherein the USP1 inhibitor is a compound of Formula (X):wherein: ring H is phenyl or 6 membered heteroaryl, which is optionally substituted with one or more selected from C1-C6 alkyl, 3-10 membered cycloalkyl, and C1-C6 alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, deuterium, and halogen; ring I is 6-13 membered heteroaryl or heterocyclyl, which is optionally substituted with one or more selected from oxo, C1-C6 alkyl, halogen, C1-C6 alkoxy, cyano, =NH, -C(=O)-CH3, -NH2, -P(=O)-(CH3)2, and -C(=O)-NHCH3, wherein said alkyl is optionally substituted halogen; J is selected from the group consisting of a single bond, C1-C6 alkylene, -NH-(C1- C6 alkylene)-, -N(C2-6 alkynyl)-(C1-C6 alkylene)-, and -N(6-13 membered heteroary)- (C1-C6alkylene)-; ring K is selected from the group consisting of phenyl, 6 membered heteroaryl, and 6-13 membered cycloalkyl, which is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, C1-C6alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or549 more selected from C1-C6 alkyl, and halogen: ring M is 5-13 membered heteroaryl, which is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, and 5-13 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is independently optionally substituted with one or more selected from halogen, C1- C6 alkyl, deuterium, -CO-(C1-C6 alkyl)-, and : ;wherein RKM2, RKM3, RKM11, RKM12, RKM13, RKM22, RKM23, and RKM25are independently selected from hydrogen, halogen, C1-C6 alkyl, and halogen-substituted C1-C6 alkyl,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

17. The combination according to claim 15, wherein the PARG inhibitor is a compound of Formula (XI):wherein: ring N is 9-13 membered heteroaryl or heterocyclyl, which is optionally substituted with one or more selected from C1-C6alkyl, C1-C6alkoxy, halogen, 3- 10 membered cycloalkyl, 6-14 membered aryl, 5-12 membered heteroaryl, C1-C6 alkylene-O-C1-C6 alkyl, oxo, -NH-O-C1-C6 alkyl, carbamoyl, acetamido, NH2, mercapto, hydroxyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkoxy, cyano, and 3-10 membered saturated heterocyclyl, wherein each of said alkyl, alkoxy, aryl, heteroaryl, alkenyl, alkynyl, haloalkoxy, cycloalkyl, and heterocylyl is550 independently optionally substituted with one or more selected from C1-C6 alkyl, 3-10 membered cycloalkyl, halogen, cyano, hydroxyl, NH2, mercapto, and carbamoyl;ROais selected from the following:wherein Y is absent or oxygen, Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen, Rx2is selected from the group consisting of hydrogen and C1-C6alkyl Rx3is selected from the group consisting of hydrogen and halogen; RObis hydrogen or C1-C6 alkyl; RPis selected from the group consisting of C1-C6 alkyl, 3-14 membered heterocyclyl, -(C1-C6alkylene)-(3-14 membered heterocyclyl), 5-14 membered heteroaryl, -(C1-C6 alkylene)-(5-14 membered heteroaryl), 5-14 membered aryl, and –(C1-C6 alkylene)-(5-14 membered aryl), wherein each of said heterocyclyl, heteroaryl, or aryl is independently optionally substituted with one or more selected from C1-C6alkyl, C1-C6alkylene-O-C1-C6alkyl, halogen, oxo, =N-(C1-C6alkyl), -S(=O)2-(C1-C6alkyl),, wherein said alky is optionally substituted with OH or halogen, each of RPa, RPb, and RPcis independently selected from the group consisting of 3- 10 membered cycloalkyl, C1-C6alkyl, 3-10 membered heterocyclyl, and -O-(C1- C6 alkyl)-N(C1-C6 alkyl), wherein each of said cycloalkyl, alkyl, and heterocyclyl is independently optionally substituted with one or more selected from OH, C1-C6 alkyl, and C1-C6alkoxy optionally substituted with deuterium; Rsis selected from the group consisting of C1-C6 alkyl, 5-12 membered551 heteroaryl, 5-12 membered heterocyclyl, -(C1-C6 alkylene)-(5-12 membered heteroaryl), -(C1-C6alkylene)-(5-12 membered heterocyclyl), -C(=O)-(5-12 membered heteroaryl), -(C=O)-(5-12 membered heterocyclyl), -NH-(C=O)-(5-12 membered heteroaryl), -NH-(C=O)-(5-12 membered heterocyclyl), -S-(C1-C6 alkylene)-(5-12 membered heteroaryl), and -S-(C1-C6 alkylene)-(5-12 membered heterocyclyl), wherein each of said alkyl, alkylene, heteroaryl, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, acryl, hydroxy, C1-C6alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deutrinum, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

18. The combination according to claim 15, wherein the USP1 inhibitor is the compound selected from the group consisting of the following:565, pharmaceutically acceptable salt, hydrate or solvate thereof.

19. The combination according to claim 15, wherein the PARG inhibitor is the compound selected from the group consisting of the following:VLS582or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

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