Seleno-fused heteroring compound derivatives and their pharmaceutical use

Abstract

Provided herein are novel seleno-fused heteroring compounds, compositions containing the compounds, and preparation methods and uses thereof. The seleno-fused heteroring compounds are represented by Formula (I), 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 polθ, in particular, cancer. (I)

Description

DescriptionTitle of Invention: SELENO-FUSED HETERORINGCOMPOUND DERIVATIVES AND THEIRPHARMACEUTICAL USETechnical Field

[0001] The present disclosure relates to selenium-containing compounds having inhibitory effects on polymerase theta, pharmaceutical compositions containing the same, and preparation methods and uses thereof.Background Art

[0002] DNA double strand breaks (DSBs) are detrimental to cells as they contribute to genome instability, which can induce cell death. To repair DSBs, three pathways are performed in cells: non-homologous end joining (NHEJ), homologous recombination (HR), and theta-mediated end-joining (TMEJ). The NHEJ pathway joins the broken ends of DNA strands together without using a homologous template. The HR and TMEJ pathways have commonality in that they both use a homologous sequence. However, HR is a high-fidelity DNA repair pathway, and TMEJ is an error-prone DNA repair pathway that uses microhomologies.

[0003] The TMEJ pathway involves poly-(ADP-ribose) polymerase PARP1, DNA ligase III, and Polymerase theta. Polymerase theta (PolO, encoded by POLQ) is a 290kDa polymerase A family enzyme, and is known to mediate the TMEJ pathway (Feng et al., 2019, Nature Communication, 10:4286). PolO possesses a N-terminal helicase-like domain and a C-terminal DNA polymerase domain separated by a non- structured central amino acid sequence. In the TMEJ pathway, the helicase domain of PolO acts to displace Replication Protein A (RPA) bound to a single strand DNA overhang and facilitate annealing of micro-homologous sequences that flank a DSB. Then, the polymerase domain of PolO acts to initiate DNA synthesis to fill in gaps (Zatreanu et al., 2021, Nature Communication, 12:3636).

[0004] The TMEJ pathway is also known as alternative NHEJ (alt-NHEJ) pathway or microhomology-mediated end joining (MMEJ) pathway (Zatreanu et al., 2021, NatureCommunication, 12:3636). The TMEJ pathway serves as an essential backup pathway in the event that the NHEJ or HR pathway is compromised (Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218). Accordingly, DNA-repair deficient cancers are dependent on other compensatory repair pathway, and HR- or NHEJ-deficient cancers are dependent on the TMEJ backup pathway. Based on the above mechanism, PARP inhibitors (PARPi) were developed, and HR-deficient tumors have been successfully treated by way of applying PARPi. However, PARPi often face the issue of developing resistance (Drzewiecka et al., 2022, Genes, 13: 1101; and Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218).

[0005] Currently, polO has been identified as another promising therapeutic target for cancers. While polO is overexpressed in various cancers, it is little expressed (largely absent) in normal cells (Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218; and Ceccaldi et al., 2015, Nature, 518:258). Indeed, human neoplasms including those of the lung, stomach, small intestine, rectum, and colon overexpress polO, and the expression level of polO is particularly high in lung cancer, breast cancer, ovarian cancer, colorectal cancer and gastric cancer, etc. (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218). Furthermore, in vivo tests demonstrated HR-deficient tumors are hypersensitive to inhibition of PolO-mediated DNA repair, leading to synthetic lethality (Ceccaldi et al., 2015, Nature, 518:258; and Drzewiecka et al., 2022, Genes, 13: 1101). PolO depletion causes both HR-proficient and HR-deficient tumor cells to become more sensitive to other treatments such as radiation or chemotherapy (Drzewiecka et al., 2022, Genes, 13: 1101, and Goullet de Rugy T et al., 2016, Biology open, 5(10), 1485-1492).

[0006] Therefore, there is a need to develop new polO inhibitors that effectively inhibit the TMEJ pathway and can be used for treating cancer.

[0007] Summary of Invention

[0008] The present disclosure provides novel selenium-containing compounds, compositions comprising the same, and preparation methods and uses thereof. The selenium- containing compounds have an inhibitory activity for polymerase theta, and can be effectively used for treating or preventing various types of cancers.

[0009] In one aspect, the present disclosure relates to a compound of Formula (I):

[0011] wherein:

[0012] each of X1, X2and X3is N or CH;

[0013] X4is C or N, provided that when X4is N, S1and A are absent;

[0014] each of Y1, Y2, and Y3is N or CR1;

[0015] R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0016] A is absent or is selected from R2and a PARP inhibitor moiety;

[0017] R2is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH(3- to 14-membered carbocyclic group), -NH(3- to 14-membered heterocyclic group), halogen, cyano, hydroxy, amino, mercapto, carbamoyl, -NO2, -N3, - SF5, -S(CI-C6alkyl), -C(=O)(Ci-C6alkyl), -C(=O)O(Ci-C6alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-C6alkyl), -NH-(CI-C6alkyl),, and, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylene, a carbocyclic group, a heterocyclic group, aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0018] each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkyl, Ci-Ce alkoxy, 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, cyano, hydroxy, and amino;

[0019] B is selected from the group consisting of 6- to 14-membered aryl and 5- to 14- membered heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;

[0020] C is selected from the group consisting ofand a PARP inhibitor moiety;

[0021] each of n, m, 1 and o is an integer between 0 and 5;

[0022] each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl Ci-Ce alkoxy, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, a carbocyclic group, a heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-Ce alkylene)- OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)- S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), - C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-C6alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, a carbocyclic group, a heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano;

[0023] each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2- Ce alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-Ce alkynylene)-O-, -S(=O)-. -S(=O)2-, -S(=O)2-NH-, -C(=0)-, -C(=0)-0-, -C(=O)-(C1-C6alkylene)-, -NH-, -NH-(CI-C6alkylene)-, -NH-(C=O)-(CI-C6alkylene)-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH- C(=O)-NH-, -C(=NH)-, -C(=N(CI-C6alkyl)), -NH-(CI-C6alkylene)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -(C2-C6 alkenylene)-(3-10 membered heterocyclene)-, -C(=O)-(3-10 membered cycloalkylene)-, -C(=O)-(3-10 membered heterocyclene)-, -NH-(3- 10-membered cycloalkylene), -NH-(3-10 membered heterocyclene)-, -NH-(C=O)-(3-10 membered cycloalkylene)-, -NH-C(=O)-(3-10 membered heterocyclene)-, -NH-C(=O)-C(=O)- (3-10 membered cycloalkylene)-, and - NH-C(=O)-C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocyclene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, oxo, and 3-10 membered cycloalkyl;

[0024] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0025]

[0026] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier(s) 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 polymerase theta, which comprises one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier(s) 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.

[0028] In another aspect, the present disclosure provides the use of the 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, in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by polymerase theta.

[0029] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, in a subject, comprising administering to the subject 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.

[0030] In another aspect, the present disclosure provides the 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, for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta.

[0031] 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.Brief Description of Drawings

[0032] Fig. 1 shows plasma concentration-time profiles of Compound 206 for each administration group.

[0033] Fig. 2 shows plasma concentration-time profiles of Compound 260 for each administration group.

[0034] Fig. 3 shows tumor volume-time profiles of Compound 206 for each administration group.

[0035] Fig. 4 shows body weight-time profiles of Compound 206 for each administration group.

[0036] Fig. 5 shows tumor volume-time profiles of Compound 260 for each administration group.

[0037] Fig. 6 shows body weight-time profiles of Compound 260 for each administration group.

[0038] Description of Embodiments

[0039] Definitions

[0040] Chemical terms

[0041] The definitions of specific functional groups and chemical terms are described in more detail below.

[0042] When a range of values is listed, it is intended to encompass each value and any subrange within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, c3-c5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0043] As used herein (unless otherwise specified), the term “Ci-Ce alkyl” 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 one embodiment, the alkyl group may have 1 to 4 carbon atoms (C1-C4 alkyl) or 3 to 6 carbon atoms (C3-C6 alkyl). Examples of Ci-Ce alkyl 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.

[0044] As used herein (unless otherwise specified), the term “Ci-Ce alkylene” 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-l,3-diyl and the like.

[0045] As used herein (unless otherwise specified), the term “C2-C6 alkenyl” 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 one embodiment, the alkenyl group may have 2 to 4 carbon 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.

[0046] As used herein (unless otherwise specified), the term “C2-C6 alkenylene” refers to a divalent alkenyl linking group, which is a linear or branched, saturated hydrocarbon group having 2 to 6 carbon atoms. An alkenylene group formally corresponds to an alkene with two C-H bonds replaced by points of attachment of the alkenylene group to the remainder of the compound. In one embodiment, the alkenylene group may have 1 to 4 carbon atoms (C1-C4 alkenylene) or 1 to 2 carbon atoms (C1-C2 alkenylene).

[0047] As used herein (unless otherwise specified), the term “C2-C6 alkynyl” 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 one embodiment, the alkynyl group may have 2 to 4 carbon atoms. In one embodiment, the alkynyl group does not contain any double bond. One or more carboncarbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-6 alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0048] As used herein (unless otherwise specified), the term “C2-C6 alkynylene” 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, l-propyn-l,3-diyl, 2- propyn-l,3-diyl, 1 -butyne- 1,4-diyl, 2-butyne-l,4-diyl, 3 -butyne- 1,4-diyl, l-butyne-1,3- diyl, 2 -butyne- 1,4-diyl, 3 -butyne- 1,4-diyl, 3-butyne-2,4-diyl and the like.

[0049] As used herein (unless otherwise specified), the term “Ci-Ce alkoxy” refers to a -OR group, wherein R is substituted or unsubstituted Ci-Ce alkyl. In one embodiment, the alkoxy group may have 1 to 4 carbon atoms. Specifically, Ci-e alkoxyl 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.

[0050] As used herein (unless otherwise specified), the terms “halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In one embodiment, the halo group is F, Cl or Br. In one embodiment, the halo group is F or Cl. In one embodiment, the halo group is F.

[0051] As used herein (unless otherwise specified), the terms “carbocyclic group” refers to a non-aromatic cyclic hydrocarbon group having from 3 to 15 ring carbon and zero heteroatoms in the non-aromatic ring system. In one embodiment, the carbocyclic group may have 3 to 14, 3 to 12, 5 to 14, 5 to 10, 5 to 8, 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.

[0052] As used herein (unless otherwise specified), the terms “heterocarbocyclic group” refers a group or radical of a 3- to 15-membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, silicon, and sulfur. 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 one embodiment, the heterocarbocyclic group may have 4 to 14, 5 to 10, 5 to 8, 5 to 7, or 6 to 7 ring atoms.

[0053] As used herein (unless otherwise specified), the terms “C3-C15 cyclic group”, “3-15 membered cyclic group” or “3- to 15- membered cyclic group” refers to a cyclic hydrocarbon group which is non-aromatic and has 3-15 ring carbon atoms and zero heteroatoms. In one embodiment, the cycloalkyl group may have 3 to 14, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 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.

[0054] As used herein (unless otherwise specified), the terms “C3-10 cycloalkyl” or “3-10 membered cycloalkyl” 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 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 cycloalkyl also includes a ring system in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring. Examples of the cycloalkyl 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, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro- 1H- indenyl, decahydronaphthyl, spiro[4.5]decyl, and the like.

[0055] As used herein (unless otherwise specified), the term “3- to 15-membered heterocyclic group” “3-15 membered heterocyclic group”, “3-15 membered heterocyclyf’or the term “3- to 15-membered heterocyclyl” refers to a radical of a 3- to 15 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, silicon, and phosphorus. The point of attachment of the heroaryl is on carbon or heteroatom. 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 one embodiment, the heterocyclyl group may have 2 to 10, 2 to 7, 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 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- to 14-membered bicyclic spiro heterocyclic group.

[0056] 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 oneheteroatom 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 thiadi azolinyl. 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, pyri dinonyl, 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.

[0057] In one embodiment, the heterocyclic group includes a saturated ring radical that comprises carbon atoms and from heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. In an embodiment, the saturated heterocyclic group may have a 3- to 14- membered heterocyclic group. In an embodiment, the saturated heterocyclic group may have 14-membered bicyclic spiro heterocyclic group. In one embodiment, the saturated heterocyclic group may have 2 to 13, 2 to 12, 2 to 12, 2 to 10, 3 to 13, 3 to 12, 3 to 12, 3 to 11, 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] di thianyl, 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.

[0058] As used herein (unless otherwise specified), the term “Ce-Cu aryl”, “6-14 membered 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- to 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.

[0059] As used herein (unless otherwise specified), the term “Ce-Cu arylene”, “6-14 membered arylene” 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.

[0060] As used herein (unless otherwise specified), the term “5- to 14-membered heteroaryl” or “5-14 membered heteroaryl” refers to any monocyclic or polycyclic (e.g., bi-, or tricyclic) aromatic ring system which has ring carbon atoms and at least one heteroatoms (e.g., nitrogen, oxygen, silicon, and sulfur). The point of attachment of the heroaryl is on carbon or heteroatom. 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 one embodiment, the heteroaryl group may have 3 to 13, 3 to 12, 3 to 10, 3 to 8, 3 to 7, 4 to 7, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.

[0061] 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 groupscontaining 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, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0062] As used herein (unless otherwise specified), the term “5- to 14-membered heteroarylene” or “5-14 membered heteroarylene” refers to a divalent heterocyclic aromatic group, whether or not fused to one or more groups, having 5 to 14 ring atoms including heteroatoms (for example, selected from nitrognen, oxygne, silicon, and sulfur). In one embodiment, the heteroarylene may have 5- to 12- or 5- to 10- or 5- to 8- membered ring atoms. The heteroarylene group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the 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.

[0063] 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 Ci-6 alkyl group.

[0064] As used herein (unless otherwise specified), the term “polycyclic ring” 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 asystem 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 ring includes, but not limited to following groups:

[0066] 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.

[0067] 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, the term “substituted” is contemplated to include all permissible substituents of organic compounds. Exemplary substituents on carbon atoms include, but are not limited to, Ci-Ce alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), 3- to 14-membered (e.g., 3- to 10 membered, 5- to 6-membered, 3- to 5-membered) cycloalkyl, hydroxy, amino, -NH2, - NH(CI-C6alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -(Ci-C6alkylene)-N(Ci-C6alkyl)2, mercapto, -S(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), carbamoyl, oxo, a 3-8 (e.g, 3-6) membered heterocyclic or heteroaryl group, -CORzl(wherein Rzlis selected from the groupconsisting of hydrogen, Ci-Ce alkyl, 3- to 8-membered cycloalkyl, and halogen), and and -CON(Rz2)(Rz3) (wherein each of Rz2and Rz3is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, or halogen, wherein said alkyl is optionally substituted with one or more selected from Ci-Ce 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 Ci-Ce 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 Ci-Ce alkyl 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.

[0068] 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,

[0075] General terms

[0076] 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 one embodiment, the term “about” can mean the numeric value itself.

[0077] 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.

[0078] 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.

[0079]

[0080] Compounds of Formula (I)

[0081] According to an aspect of the present disclosure, provided is a compound of Formula (I), (including subsets of the formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0082] In one embodiment of the compound of Formula (I):

[0084] wherein:

[0085] each of X1, X2and X3is N or CH;

[0086] X4is C or N, provided that when X4is N, S1and A are absent;

[0087] each of Y1, Y2, and Y3is N or CR1;

[0088] R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, preferably, R1is selected from the group consisting ofhydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with a 3 to 6-membered carbocyclic group, more preferably, hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2-C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;

[0089] A is absent or is selected from R2and a PARP inhibitor moiety;

[0090] R2is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH(3- to 14-membered carbocyclic group), -NH(3- to 14-membered heterocyclic group), halogen, cyano, hydroxy, amino, mercapto, carbamoyl, -NO2, -N3, - SF5, -S(CI-C6alkyl), -C(=O)(Ci-C6alkyl), -C(=O)O(Ci-C6alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -N(C1-C6alkyl)-C(=O)-(Ci-C6alkyl), -NH-(CI-C6alkyl), ,, and, preferably, R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, a 5- to 14-membered heterocyclic group, 5- to 14-membered heteroaryl, halogen, cyano, hydroxy, amino,,, , wherein each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or bicyclic group, preferably, each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or spiro bicyclic group, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0091] each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkyl, Ci-Ce alkoxy, 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, cyano, hydroxy, and amino, preferably, each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkoxy, halogen, hydroxy, and amino;

[0092] B is selected from the group consisting of 6- to 14-membered aryl and 5- to 14- membered heteroaryl, preferably, B is selected from the group consisting of 6- to 10- membered aryl and 5- to 10-membered heteroaryl, more preferably, B is selected from the group consisting of 6- to 8-membered aryl and 5- to 8-membered heteroaryl, still more preferably, B is selected from the group consisting of 6-membered aryl and 6-membered heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2- Ce alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;

[0093] C is selected from the group consisting of, and a PARP inhibitor moiety;

[0094] each of n, m, 1 and o is an integer between 0 and 5; preferably, each of n, m, 1 and o is an integer between 0 and 3; more preferably, each of n, m, 1 and o is 0 or 1;

[0095] each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, and hydroxy, preferably, each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3- to 8- membered carbocyclic group, a 3- to 8-membered heterocyclic group, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NH2, halogen, cyano, and hydroxy, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-C6alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH- S(=O)2-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(Ci-Ce alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or bicyclic group, preferably, each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or spiro bicyclic group;

[0096] each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2- Ce alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-Ce alkynylene)-O-, -S(=O)-. -S(=O)2-, - S(=O)2-NH-, -C(=O)-, -C(=O)-O-, -C(=O)-(C1-C6alkylene)-, -NH-, -NH-(CI-C6alkylene)-, -NH-(C=O)-(CI-C6alkylene)-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH- C(=O)-NH-, -C(=NH)-, -C(=N(CI-C6alkyl)), -NH-(CI-C6alkylene)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -(C2-C6 alkenylene)-(3-10 membered heterocyclene)-, -C(=O)-(3-10 membered cycloalkylene)-, -C(=O)-(3-10 membered heterocyclene)-, -NH-(3- 10-membered cycloalkylene), -NH-(3-10 membered heterocyclene)-, -NH-(C=O)-(3-10 membered cycloalkylene)-, -NH-C(=O)-(3-10 membered heterocyclene)-, -NH-C(=O)-C(=O)- (3-10 membered cycloalkylene)-, and - NH-C(=O)-C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocyclene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, oxo, and 3-10 membered cycloalkyl;

[0097] the PARP inhibitor moiety is selected from the group consisting of:

[0100] DI is 5-12 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0101] preferably, DI 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0102] D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0103] preferably, D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0104] C102is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 -f'C102'2alkenylene, C2-C6alkynylene, C102'1, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(CI-C6alkyl)-, and a combination thereof, wherein C102'1and C102'2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring, y ^102-2

[0105] preferably, C102is a direct bond, c102'1Or Ci-Ce alkylene, wherein wherein C102-1and C102-2, taken together with the carbon atom to which they attach, form a 3- to 8- membered carbocyclic ring;

[0106] D3 is 5-12 membered heteroaryl, wherein said heteroaryl is substituted with carbomoyl and is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0107] 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 fromCi-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0108] D4 is a direct 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0109] preferably, D4 is a direct bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0110] D5 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0111] preferably, D5 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0112] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl,halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0113] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen; and

[0114] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0115] 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 Ci- Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci- Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0116] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0117] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0118] D9 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0119] preferably, D9 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0120] D10 is a direct bond or 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0121] preferably, D10 is a direct bond or 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0122] C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof;

[0123] Dl l 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0124] preferably, Dl l 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0125] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0126] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen.

[0127]

[0128] In one embodiment of the compound of Formula (I),

[0129] each of X1, X2and X3is N or CH;

[0130] X4is C or N, provided that when X4is N, S1and A are absent;

[0131] each of Y1, Y2, and Y3is N or CR1;

[0132] R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, preferably, R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with a 3 to 6-membered carbocyclic group, more preferably, hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2-C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;

[0133] A is absent or is selected from the group consisting of R2and a PARP inhibitor moiety;

[0134] R2is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, halogen, cyano, hydroxy, amino, mercapto, carbamoyl, -NO2, -N3, -SF5, -S(Ci-Ce alkyl), -C(=O)(Ci-Ce alkyl), -C(=O)O-(C1-C6 alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -N(CI-C6alkyl)-C(=O)-(Ci-C6alkyl), -NH-(Ci-C6alkyl),, and the following groups:

[0139] wherein each of said alkyl, alkenyl, alkynyl, alkoxy and alkylene is optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0140] each of Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0141] a is an integer between 0 and 10; preferably, a is an integer between 0 and 5; more preferably, a is an integer 0 or 1;

[0142] each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkoxy, halogen, hydroxy, and amino;

[0143] B is selected from the group consisting of:

[0146] wherein each of Rbl, Rb2, Rb3, Rb4and Rb5is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;

[0147] C is selected from the group consisting ofand a PARP inhibitor moiety;

[0148] each of n, m, 1 and o is an integer between 0 and 5; preferably, each of n, m, 1 and o is an integer between 0 and 3; more preferably, each of n, m, 1 and o is 0 or 1;

[0149] each of R3a, R3b, and R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy and the following groups:

[0151]

[0152]

[0153] wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, hydroxy, oxo,-(Ci-C6alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(CI-C6alkyl), -(Ci- Ce alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group and heterocyclic group is a monocyclic or bicyclic group, preferably, each of said carbocyclic group and heterocyclic group is a monocyclic or spiro bicyclic group,

[0154] wherein each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH- S(=O)2-(Ci-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(Ci-Ce alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano;

[0155] preferably, each of Rcl, Rc2, Rc3, Rc4, and Rc5is selected from the group consisting of hydrogen, Ci-Ce alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halogen, cyano, oxo, hydroxy, -(Ci-C6alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, - C(=O)N(Ci-Ce alkyl)(Ci-Ce alkyl), and -NHC(=O)(Ci-Ce alkyl) , wherein each of saidalkyl and alkylene is straight-chained or branched, more preferably, each of Rcl, Rc2, Rc3, Rc4, and Rc5is selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, isopropyl, hydroxy, -CH2OH, -CH2CN, -C(CH3)2-CN, -CH2-S(=O)2-NH2, - C(CH3)2-S(=O)2-NH2, -NH-S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-CH3, -C(=O)NH2, - C(=O)N(CH3)2, -NHC(=O)CH3, and cyclopropyl;

[0156] each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, C2-C6 alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-C6alkynylene)-O-, -S(=O)2-, -S(=O)2-NH-, -C(=O)-, -C(=O)-O-, - NH-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered heterocyclene, and -C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkenylene, alkynylene, arylene, heteroarylene, and heterocyclene is independently optionally substituted with one or more selected from halogen, cyano, oxo, and 3-10 membered cycloalkyl; the PARP inhibitor moiety is selected from the group consisting of:

[0164] C101is CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3,COCH3, and CNH2;

[0165] each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen,

[0166] preferably, each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2,and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0167] D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0168] preferably, D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0169] C102is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6Y'- 'C102-2alkenylene, C2-C6alkynylene, ' C102’1, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(CI-C6alkyl)-, and a combination thereof, wherein C102"1and C102"2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring, y pc102-2

[0170] preferably, C102is a direct bond, c102-1Or Ci-Ce alkylene, wherein wherein C102-1and C102-2, taken together with the carbon atom to which they attach, form a 3- to 8- membered carbocyclic ring;

[0171] each of C103, C104and C105is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[0172] preferably, C103is N, C104is N, and C105is CH; or C103is N, C104is C, and C105is NH; or C103is NH, C104is C, and C105is N;

[0173] each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0174] preferably, each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0175] D4 is a direct 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0176] preferably, D4 is a direct bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0177] D5 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0178] preferably, D5 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0179] each of C106, and C107is independently selected from the group consisting of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHC1, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);

[0180] each of C108, C109, C1010, and C1011is independently selected from the group consisting of N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0181] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0182] 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 Ci- Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci- Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0183] each of C1013, C1014, and C1015is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0184] each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, andalkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen,

[0185] preferably, each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, and Ci-Ce alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0186] D9 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0187] preferably, D9 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0188] D10 is a direct bond or 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0189] preferably, D10 is a direct bond or 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0190] C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof;

[0191] each of C1016, C1017, C1018, and C1019is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0192] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0193] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0194] preferably,

[0195] the PARP inhibitor moiety is selected from the group consisting of:

[0201] In one embodiment of the compound of Formula (I),

[0202] each of X1, X2and X3is N or CH;

[0203] X4is C or N, provided that when X4is N, S1and A are absent;

[0204] each of Y1, Y2, and Y3is N or CR1;

[0205] R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, preferably, R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with a 3 to 6-membered carbocyclic group, more preferably, R1is selected from the group consisting of hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2- C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;

[0206] A is absent or is selected from the group consisting of R2and a PARP inhibitor moiety;

[0207] R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, halogen, hydroxy, amino,and the following groups:

[0212] wherein each of said alkyl, alkenyl, and alkoxy is optionally substituted with one or more selected from halogen, hydroxy, and amino;

[0213] each of Ral, R32, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is selected from the group consisting of hydrogen, Ci-Ce alkyl, -C(=O)O(Ci-Ce alkyl), halogen, amino;

[0214] a is an integer between 0 and 10; preferably, a is an integer between 0 and 5; more preferably a is an integer 0 or 1; and

[0215] preferably, R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl,Ci-Ce alkoxy, halogen, hydroxy, amino,and the following groups:

[0219] more preferably, R2is selected from the group consisting of methyl, methyoxy, chloro, -OH, -CH2OH, -NH2, and the following groups:

[0222]

[0223] B is selected from the group consisting of:

[0226] wherein each of Rbl, Rb2, Rb3, Rb4and Rb5is independently selected from the group consisting of hydrogen, 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, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, secbutoxy, n-pentyloxy, n-hexyloxy, 1,2-dimethylbutoxy, vinyl, 1 -propenyl, 2-propenyl, 1- butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentyl, 2-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, 1,2- dimethylbutoxy, vinyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl is optionally substituted with one or more selected from 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, fluoro, chloro, bromo and iodo, preferably, each of Rbl, Rb2, Rb3, Rb4and Rb5is independently selected from thegroup consisting of hydrogen, methyl, trifluoromethyl, difluoromethyl, methoxy, ethynyl, fluoro, and chloro, more preferably, two of Rbl, Rb2, Rb3, Rb4and Rb5are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, difluoromethyl, methoxy, ethynyl, fluoro, and chloro and the remaining groups are hydrogens;

[0227] more preferably,wherein Rblis methoxy or ethynyl, Rb3is methyl, trifluoromethyl, difluoromethyl, or chloro, Rb2is hydrogen, and Rb4is hydrogen or fluoro; or B is, wherein Rblis methoxy, Rb4is chloro, and each of Rb2,Rb3, and Rb5is hydrogen;

[0228] C is selected from the group consisting ofand a PARP inhibitor moiety;

[0229] each of n, m, 1 and o is an integer between 0 and 5; preferably, each of n, m, 1 and o is an integer between 0 and 3; more preferably, each of n, m, 1 and o is 0 or 1;

[0230] each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, vinyl, 1 -propenyl, 2-propenyl, ethynyl, 1- propynyl, 2-propynyl, methoxy, ethoxy, n-propoxy, iso-propoxy, -NH2, halogen, cyano, hydroxyl, and the following groups:

[0232]

[0233]

[0234] each of said methyl, ethyl, n-propyl, iso-propyl, vinyl, 1 -propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, n-propoxy, iso-propoxy is independently optionally substituted with one or more halogen;

[0235] wherein each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH- S(=O)2-(Ci-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(Ci-Ce alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano;

[0236] preferably, each of Rcl, Rc2, Rc3, Rc4, and Rc5is selected from the group consisting of hydrogen, Ci-Ce alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halogen, cyano, oxo, hydroxy, -(Ci-C6alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, - C(=O)N(Ci-Ce alkyl)(Ci-Ce alkyl), and -NHC(=O)(Ci-Ce alkyl) , wherein each of said alkyl and alkylene is straight-chained or branched, more preferably, each of Rcl, Rc2, Rc3, Rc4, Rc5and Rc6is selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, isopropyl, hydroxy, -CH2OH, -CH2CN, -C(CH3)2-CN, -CH2-S(=O)2-NH2, - C(CH3)2-S(=O)2-NH2, -NH-S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-CH3, -C(=O)NH2, - C(=O)N(CH3)2, -NHC(=O)CH3, and cyclopropyl; preferably,

[0237] each of R3a, R3band R3cis independently selected from the group consisting of ethynyl, cyano, -NH2, chloro, methyl, difuloromethyl, methoxy, hydroxy, and the following groups:

[0242] more preferably,

[0243] C is selected from the group consisting of a PARP inhibitor moiety, ethynyl, cyano, -NH2, chloro, methyl, difluoromethyl, methoxy, hydroxy, and the following groups:

[0248] each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, C2-C6 alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-C6alkynylene)-O-, -S(=O)2-, -S(=O)2-NH-, -C(=O)-, -C(=O)-O-, - NH-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered heterocyclene, and -C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkenylene, alkynylene, arylene, heteroarylene, and heterocyclene is independently optionally substituted with one or more selected from halogen, cyano, oxo, and 3-10 membered cycloalkyl;

[0249] each of S1and S2is absent or is independently selected from the group consisting of a direct bond, ethynylene, propynylene, butynylene, -O-(ethynylene)-, -O-(propynylene)-, -O-(butynylene)-, -O-(ethynylene)-O-, -O-(propynylene)-O-, -O-(butynylene)-O-, -S(=0)2-, -S(=O)2-NH-, -NH-, -C(=0)-, -C(=0)-0-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, and the following groups:

[0254] the PARP inhibitor moiety is selected from the group consisting of:

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] C101is CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2;

[0263] each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0264] D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen; y- c102-2

[0265] C102is a direct bond, c102'1Or Ci-Ce alkylene, wherein wherein C102'1and C102'2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring;

[0266] each of C103, C104and C105is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[0267] preferably, C103is N, C104is N, and C105is CH; or C103is N, C104is C, and C105is NH; or C103is NH, C104is C, and C105is N;

[0268] each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0269] D4 is a direct bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci- Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci- Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy isindependently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0270] D5 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0271] each of C106, and C107is independently selected from the group consisting of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHC1, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);

[0272] each of C108, C109, C1010, and C1011is independently selected from the group consisting of N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0273] D7 is phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0274] each of C1013, C1014, and C1015is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0275] each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, and Ci-Ce alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0276] D9 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0277] DIO is a direct bond or 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0278] C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof;

[0279] each of C1016, C1017, C1018, and C1019is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0280] D12 is 5-6 membered heteroaryl, and D13 is phenyl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen

[0281] preferably,

[0282] the PARP inhibitor moiety is selected from the group consisting of:

[0287] more preferably, the PARP inhibitor moiety is selected from the group consisting of :

[0293] Non-limiting exemplary embodiments of the compounds of Formula (I)

[0294]

[0295] In one embodiment, the present disclosure relates to a compound of Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), and Formula (Ij):

[0305] each of Rla, Rlb>and Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, preferably, each of Rla, Rlband Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with a 3 to 6-membered carbocyclic group, more preferably, each of Rla, Rlb>and Rlcis hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2-C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;

[0306] A is absent or is selected from R2and a PARP inhibitor moiety;

[0307] R2is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH(3- to 14-membered carbocyclic group), -NH(3- to 14-membered heterocyclic group), halogen, cyano, hydroxy, amino, mercapto, carbamoyl, -NO2, -N3, - SF5, -S(CI-C6alkyl), -C(=O)(Ci-C6alkyl), -C(=O)O(Ci-C6alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-C6alkyl), -NH-(CI-C6alkyl),, and, preferabiy, R2isselected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, a 5- to 14-membered heterocyclic group, 5- to 14-membered heteroaryl, halogen, cyano, hydroxy, amino,wherein each of said carbocyclic group, heterocyclic group, aryl, and heteroaryl is a monocyclic orbicyclic group, preferably, each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or spiro bicyclic group, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0308] each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkyl, Ci-Ce alkoxy, 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, cyano, hydroxy, and amino, preferably, each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkoxy, halogen, hydroxy, and amino,

[0309] B is selected from the group consisting of 6- to 14-membered aryl and 5- to 14- membered heteroaryl, preferably, B is selected from the group consisting of 6- to 10- membered aryl and 5- to 10-membered heteroaryl, more preferably, B is selected from the group consisting of 6- to 8-membered aryl and 5- to 8-membered heteroaryl, still more preferably, B is selected from the group consisting of 6-membered aryl and 6-membered heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2- Ce alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;

[0310] C is selected from the group consisting of, and a PARP inhibitor moiety;

[0311] each of n, m, 1 and o is an integer between 0 and 5; preferably, each of n, m, 1 and o is an integer between 0 and 3; more preferably, each of n, m, 1 and o is 0 or 1;

[0312] each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen,cyano, hydroxy, preferably, each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, 6- to 10- membered aryl, 5- to 10-membered heteroaryl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, more preferably, each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, 6-membered aryl, 5- to 6-membered heteroaryl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(C1-C6alkyl), -(Ci-C6alkyl ene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), - C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(Ci- G> alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or bicyclic group, preferably, each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or spiro bicyclic group;

[0313] each of S1and S2is absent or is independently selected from the group consisting of the following and combinations thereof: a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-Ce alkynylene)-O-, -S(=O)-. -S(=O)2-, -S(=O)2-NH-, -C(=O)-, -C(=O)-O-, -C(=O)-(C1-C6alkylene)-, -NH-, -NH-(CI-C6alkylene)-, -NH-(C=O)-(CI-C6alkylene)-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH- C(=O)-NH-, -C(=NH)-, -C(=N(CI-C6alkyl)), -NH-(CI-C6alkylene)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -(C2-C6 alkenylene)-(3-10 membered heterocyclene)-, -C(=O)-(3-10 membered cycloalkylene)-, -C(=O)-(3-10 membered heterocyclene)-, -NH-(3- 10-membered cycloalkylene), -NH-(3-10 membered heterocyclene)-, -NH-(C=O)-(3-10 membered cycloalkylene)-, -NH-C(=O)-(3-10 membered heterocyclene)-, -NH-C(=O)-C(=O)- (3-10 membered cycloalkylene)-, and -NH-C(=0)-C(=0)-(3-10 membered heterocyclene)-, wherein each of said alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocyclene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, oxo, and 3-10 membered cycloalkyl;

[0314] the PARP inhibitor moiety is selected from the group consisting of:

[0317] DI is 5-12 membered nitrogen-containing heterocyclyl, wherein said heterocyclyl is substituted with oxo, and is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0318] preferably, DI 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0319] D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionallysubstituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0320] preferably, D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0321] C102is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 - 'C102-2alkenylene, C2-C6alkynylene, ' C102’1, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(CI-C6alkyl)-, and a combination thereof, wherein C102'1and C102'2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring, y ^?c102-2

[0322] preferably, C102is a direct bond, c102'1Or Ci-Ce alkylene, wherein wherein C102-1and C102-2, taken together with the carbon atom to which they attach, form a 3- to 8- membered carbocyclic ring;

[0323] D3 is 5-12 membered heteroaryl, wherein said heteroaryl is substituted with carbomoyl and is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0324] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0325] D4 is a direct 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0326] preferably, D4 is a direct bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0327] D5 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0328] preferably, D5 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0329] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0330] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen; and

[0331] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0332] 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 Ci- Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci- Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0333] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0334] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0335] D9 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0336] preferably, D9 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0337] DIO is a direct bond or 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0338] preferably, D10 is a direct bond or 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0339] C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof;

[0340] Dl l 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionallysubstituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0341] preferably, Dl l 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0342] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0343] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen.

[0344]

[0345] In one embodiment of the compound of Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), and Formula (Ij),

[0346] each of Rla, Rlb>and Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, preferably, each of Rla, Rlband Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionallysubstituted with a 3 to 6-membered carbocyclic group, more preferably, each of Rla, Rlb’ and Rlcis independently selected from the group consisting of hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2-C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;

[0347] A is absent or is selected from the group consisting of R2and a PARP inhibitor moiety;

[0348] R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, halogen, hydroxy, amino,and the following groups:

[0353] wherein each of said alkyl, alkenyl, and alkoxy is optionally substituted with one or more selected from halogen, hydroxy, and amino;

[0354] each of Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0355] a is an integer between 0 and 10; preferably, a is an integer between 0 and 5; more preferably, a is an integer 0 or 1;

[0356] each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkoxy, halogen, hydroxy, and amino;

[0357] B is selected from the group consisting of:

[0360] wherein each of Rbl, Rb2, Rb3, Rb4and Rb5is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;

[0361] C is selected from the group consisting ofand a PARP inhibitor moiety;

[0362] each of n, m, 1 and o is an integer between 0 and 5; preferably, each of n, m, 1 and o is an integer between 0 and 3; more preferably, each of n, m, 1 and o is 0 or 1;

[0363] each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy and the following groups:

[0367] wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, hydroxy, oxo,-(Ci-C6alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci- Ce alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group and heterocyclic group is a monocyclic or bicyclic group, preferably, each of said carbocyclic group and heterocyclic group is a monocyclic or spiro bicyclic group,

[0368] wherein each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH- S(=O)2-(Ci-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(Ci-Ce alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano;

[0369] preferably, each of Rcl, Rc2, Rc3, Rc4, and Rc5is selected from the group consisting of hydrogen, Ci-Ce alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halogen, cyano, oxo, hydroxy, -(Ci-C6alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, - C(=O)N(Ci-Ce alkyl)(Ci-Ce alkyl), and -NHC(=O)(Ci-Ce alkyl) , wherein each of said alkyl and alkylene is straight-chained or branched, more preferably, each of Rcl, Rc2, Rc3, Rc4, and Rc5is selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, isopropyl, hydroxy, -CH2OH, -CH2CN, -C(CH3)2-CN, -CH2-S(=O)2-NH2, - C(CH3)2-S(=O)2-NH2, -NH-S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-CH3, -C(=O)NH2, - C(=O)N(CH3)2, -NHC(=O)CH3, and cyclopropyl;

[0370] each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, Ci-Ce alkylene, C2-Ce alkenylene, C2- Ce alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-Ce alkynylene)-O-, -S(=O)-. -S(=O)2-, - S(=O)2-NH-, -C(=O)-, -C(=O)-O-, -C(=O)-(C1-C6alkylene)-, -NH-, -NH-(CI-C6alkylene)-, -NH-(C=O)-(CI-C6alkylene)-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH- C(=O)-NH-, -C(=NH)-, -C(=N(CI-C6alkyl)), -NH-(CI-C6alkylene)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -(C2-Ce alkenylene)-(3-10 memberedheterocyclene)-, -C(=O)-(3-10 membered cycloalkylene)-, -C(=O)-(3-10 membered heterocyclene)-, -NH-(3- 10-membered cycloalkylene), -NH-(3-10 membered heterocyclene)-, -NH-(C=O)-(3-10 membered cycloalkylene)-, -NH-C(=O)-(3-10 membered heterocyclene)-, -NH-C(=O)-C(=O)- (3-10 membered cycloalkylene)-, and - NH-C(=O)-C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocyclene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, oxo, and 3-10 membered cycloalkyl;

[0371] the PARP inhibitor moiety is selected from the group consisting of:

[0379] C101is CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3,COCH3, and CNH2;

[0380] each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen,

[0381] preferably, each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0382] D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionallysubstituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0383] preferably, D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0384] C102is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 - 'C102-2alkenylene, C2-C6alkynylene, ' C102’1, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(CI-C6alkyl)-, and a combination thereof, wherein C102'1and C102'2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring, y ^?c102-2

[0385] preferably, C102is a direct bond, c102'1Or Ci-Ce alkylene, wherein wherein C102-1and C102-2, taken together with the carbon atom to which they attach, form a 3- to 8- membered carbocyclic ring;

[0386] each of C103, C104and C105is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[0387] preferably, C103is N, C104is N, and C105is CH; or C103is N, C104is C, and C105is NH; or C103is NH, C104is C, and C105is N;

[0388] each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0389] preferably, each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl,halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0390] D4 is a direct 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0391] preferably, D4 is a direct bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0392] D5 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0393] preferably, D5 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0394] each of C106, and C107is independently selected from the group consisting of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHC1, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);

[0395] each of C108, C109, C1010, and C1011is independently selected from the group consisting of N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0396] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0397] 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 Ci- Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci- Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0398] each of C1013, C1014, and C1015is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0399] each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen,

[0400] preferably, each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, and Ci-Ce alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0401] D9 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl,hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0402] preferably, D9 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0403] DIO is a direct bond or 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0404] preferably, D10 is a direct bond or 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0405] C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof;

[0406] each of C1016, C1017, C1018, and C1019is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0407] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independentlyoptionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0408] 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0409] preferably,

[0410] the PARP inhibitor moiety is selected from the group consisting of:

[0416] In one embodiment of the compound of Formula (la), Formula (lb), Formula (Ic),Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), and Formula (Ij),

[0417] each of Rla, Rlb>and Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, preferably, each of Rla, Rlband Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with a 3 to 6-membered carbocyclic group, more preferably, each of Rla, Rlb>and Rlcis independently selected from the group consisting of hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2-C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;

[0418] A is absent or is selected from the group consisting of R2and a PARP inhibitor moiety;

[0419] R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, halogen, hydroxy, amino,and the following groups:

[0424] wherein each of said alkyl, alkenyl, and alkoxy is optionally substituted with one or more selected from halogen, hydroxy, and amino;

[0425] each of Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; preferably, each of Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, - C(=O)O(Ci-Ce alkyl), halogen, and amino;

[0426] a is an integer between 0 and 10; preferably, a is an integer between 0 and 5; more preferably a is an integer 0 or 1; and

[0427] preferably, R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl,Ci-Ce alkoxy, halogen, hydroxy, amino,and the following groups:[ ]

[0431] more preferably, R2is selected from the group consisting of methyl, methoxy, chloro,-OH, -CH2OH, -NH2, and the following groups:

[0435] B is selected from the group consisting of:

[0438] wherein each of Rbl, Rb2, Rb3, Rb4and Rb5is independently selected from the group consisting of hydrogen, 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, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, secbutoxy, n-pentyloxy, n-hexyloxy, 1,2-dimethylbutoxy, vinyl, 1 -propenyl, 2-propenyl, 1- butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentyl, 2-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, 1,2- dimethylbutoxy, vinyl, 1 -propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl is optionally substituted with one or more selected from 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, fluoro, chloro, bromo and iodo, preferably, each of Rbl, Rb2, Rb3, Rb4and Rb5is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, difluoromethyl, methoxy, ethynyl, fluoro, and chloro, more preferably, two of Rbl, Rb2, Rb3, Rb4and Rb5are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl,difluoromethyl, methoxy, ethynyl, fluoro, and chloro and the remaining groups are hydrogens;

[0439] more preferably,wherein Rblis methoxy or ethynyl, Rb3is methyl, trifluoromethyl, difluoromethyl, or chloro, Rb2is hydrogen, and Rb4is hydrogen or fluoro; or B is, wherein Rblis methoxy, Rb4is chloro, and each of Rb2, Rb3, and Rb5is hydrogen;

[0440] C is selected from the group consisting of,, and a PARP inhibitor moiety;

[0441] each of n, m, 1 and o is an integer between 0 and 5; preferably, each of n, m, 1 and o is an integer between 0 and 3; more preferably, each of n, m, 1 and o is 0 or 1;

[0442] each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, and the following groups:

[0443]

[0444]

[0446] each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-C6alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci- Ce alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group and heterocyclic group is a monocyclic or bicyclic group, preferably, each of said carbocyclic group and heterocyclic group is a monocyclic or spiro bicyclic group;

[0447] wherein each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(CI-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH- S(=O)2-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(Ci-Ce alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano;

[0448] preferably, each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, - S(=O)2-(C1-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), - C(=O)NH2, -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), and -NHC(=O)(CI-C6alkyl) , wherein each of said alkyl and alkylene is straight-chained or branched, more preferably, each of RCIRC2selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, isopropyl, hydroxy, -CH2OH, -CH2CN, - C(CH3)2-CN, -CH2-S(=O)2-NH2, -C(CH3)2-S(=O)2-NH2, -NH-S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-CH3, -C(=O)NH2, -C(=O)N(CH3)2, -NHC(=O)CH3, and cyclopropyl;

[0449] preferably,

[0450] each of R3a, R3band R3cis independently selected from the group consisting of ethynyl, cyano, -NH2, chloro, methyl, difluoromethyl, methoxy, hydroxy, and the following groups:

[0455] more preferably,

[0456] C is selected from the group consisting of a PARP inhibitor moiety, ethynyl, cyano, -NH2, chloro, methyl, difluoromethyl, methoxy, hydroxy, and the following groups:

[0460] each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2- Ce alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-Ce alkynylene)-O-, -S(=O)-. -S(=O)2-, - S(=O)2-NH-, -C(=O)-, -C(=O)-O-, -C(=O)-(C1-C6alkylene)-, -NH-, -NH-(CI-C6alkylene)-, -NH-(C=O)-(CI-C6alkylene)-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH- C(=O)-NH-, -C(=NH)-, -C(=N(CI-C6alkyl)), -NH-(CI-C6alkylene)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -(C2-C6 alkenylene)-(3-10 membered heterocyclene)-, -C(=O)-(3-10 membered cycloalkylene)-, -C(=O)-(3-10 membered heterocyclene)-, -NH-(3- 10-membered cycloalkylene), -NH-(3-10 membered heterocyclene)-, -NH-(C=O)-(3-10 membered cycloalkylene)-, -NH-C(=O)-(3-10 membered heterocyclene)-, -NH-C(=O)-C(=O)- (3-10 membered cycloalkylene)-, and - NH-C(=O)-C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocyclene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, oxo, and 3-10 membered cycloalkyl;

[0461] preferably, each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, C2-C6 alkynylene, -O-(C2-Ce alkynylene)-, -O-(C2-C6alkynylene)-O-, -S(=O)2-, -S(=O)2-NH-, -C(=O)-, -C(=O)-O-, - NH-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, -NH-(C2-C6alkenylene)-NH-, 5-12 membered arylene, 5-12 memebred heteroarylene, 3-10 membered heterocyclene, and -C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkenylene, alkynylene, arylene, heteroarylene, and heterocyclene is independently optionally substituted with one or more selected from halogen, cyano, oxo, and 3-10 membered cycloalkyl;more preferably, each of S1and S2is independently selected from the group consisting of a direct bond, ethynylene, propynylene, butynylene, -O-(ethynylene)-, -O-(propynylene)-, -O- (butynylene)-, -O-(ethynylene)-O-, -O-(propynylene)-O-, -O-(butynylene)-O-, -S(=O)2-, - S(=O)2-NH-, -NH-, -C(=O)-, -C(=O)-O-, -C(=O)-NH-, -C(=O)-C(=O)-NH-, and the following groups:

[0465]

[0466] the PARP inhibitor moiety is selected from the group consisting of:

[0474] C101is CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3,COCH3, and CNH2;

[0475] each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0476] D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;- c102-2

[0477] C102is a direct bond, c102'1Or Ci-Ce alkylene, wherein wherein C102'1and C102'2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring;

[0478] each of C103, C104and C105is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2,

[0479] preferably, C103is N, C104is N, and C105is CH; or C103is N, C104is C, and C105is NH; or C103is NH, C104is C, and C105is N;

[0480] each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0481] D4 is a direct bond, phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci- Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci- Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0482] D5 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0483] each of C106, and C107is independently selected from the group consisting of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHC1, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2);

[0484] each of C108, C109, C1010, and C1011is independently selected from the group consisting of N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0485] D7 is phenylene, or 5-6 membered heteroarylene, wherein each of said phenylene and heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0486] each of C1013, C1014, and C1015is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0487] each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, halogen, cyano, hydroxy, and Ci-Ce alkoxy, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0488] D9 is a direct bond or 5-6 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0489] D10 is a direct bond or 5-6 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen;

[0490] C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-Ce alkenylene, C2-Ce alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof;

[0491] each of C1016, C1017, C1018, and C1019is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2;

[0492] D12 is 5-6 membered heteroaryl, and D13 is phenyl, wherein said phenyl and heteroaryl is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen

[0493] preferably,

[0494] the PARP inhibitor moiety is selected from the group consisting of:

[0499] more preferably, the PARP inhibitor moiety is selected from the group consisting of :

[0505] In one embodiment, the exemplary compounds of Formula (I) are provided below:

[0506]

[0507] 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 via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0508] 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.

[0509] 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.

[0510] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0511] The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0512] 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.

[0513] 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 R 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)).

[0514] 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 allamorphous 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.

[0515] 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 be 2H / D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined by those skilled in the art.

[0516] 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 removed by conventional operations or removed in vivo, to obtain 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.

[0517] 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 humansand lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit / risk ratio.

[0518] 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.

[0519] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. 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, (+)-(lS)-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, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic, valeric acids, and acylated amino acids.

[0520] 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.

[0521] 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.

[0522] The compounds of the invention may exist as mono- or di- salts depending upon the pKa of the acid from which the salt is formed.

[0523] It will be appreciated that for use in medicine the salts of the compounds disclosed herein should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. 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.

[0524] 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, 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+(Cl-4alkyl)4 salts. 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.

[0525] 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.

[0526]

[0527] Preparation Methods

[0528] According to a further aspect of the present disclosure, provided is a process of preparing a compound of Formula (I), 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). 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) 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.

[0529]

[0530] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (I) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of Processes A to M.

[0531]

[0532] Process A

[0533] Process A 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:

[0534] (i) preparing a compound of Formula (A-l)

[0536] (ii) preparing a compound of Formula (A-2)

[0538] (iii) reacting the compound of Formula (A-l) with the compound of Formula (A-2) to obtain the compound of Formula (I);

[0539] wherein X is Se;

[0540] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0541]

[0542] In one embodiment, an exemplary reaction of Process A may be represented by Scheme I shown below:

[0543] Scheme I

[0545] wherein X is Se;

[0546] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0547]

[0548] Process B

[0549] Process B 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:

[0550] (i) preparing a compound of Formula (B-l)

[0552] (ii) preparing a compound of Formula (B-2)

[0553]

[0554] (iii) reacting the compound of Formula (B-l) with the compound of Formula (B-2) to obtain the compound of Formula (I);

[0555] wherein X is Se;

[0556] Hal1is a halogen, preferably a chloro;

[0557] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0558]

[0559] In one embodiment, an exemplary reaction of Process B may be represented by Scheme II shown below:

[0560] Scheme II

[0562] wherein X is Se;

[0563] Hal1is a halogen, preferably a chloro;

[0564] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0565]

[0566] Process C

[0567] Process C-lVN

[0568] Process C-l prepares a compound of Formula (I) where SHs ' , as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0569] (i) preparing a compound of Formula (C-l)

[0570]

[0571] (ii-1) reacting the compound of Formula (C-l) with a compound of Formula (C-2) to obtain a compound of Formula (C-3) and reacting the compound of Formula (C-3) with a compound of Formula (C-4) to obtain the compound of Formula (I)

[0575] (ii-2) reacting the compound of Formula (C-l) with a compound of Formula (C-2’) to obtain the compound of Formula (I)

[0577] wherein X is Se;

[0578] Hal2and Hal3are halogens, preferably each of Hal2and Hal3is a chloro;

[0579] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0580]

[0581] In one embodiment, an exemplary reaction of Process C-l may be represented byScheme III- 1 and Scheme III-2 shown below:

[0582] Scheme III-l

[0583]

[0584] Scheme III-2

[0585]

[0586] wherein X is Se;

[0587] Hal2and Hal3are halogens, preferably each of Hal2and Hal3is a chloro;

[0588] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0589]

[0590] Process C-2 NxN —

[0591] Process C-2 prepares a compound of Formula (I) where S is , as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0592] (i) preparing a compound of Formula (B-l)

[0594] (ii-1) reacting the compound of Formula (B-l) with a compound of Formula (C-2) to obtain a compound of Formula (C-5) and reacting the compound of Formula (C-5) with a compound of Formula (C-6) to obtain a compound of Formula (I)

[0598] (ii-2) reacting the compound of Formula (B-l) with a compound of Formula (C-2”) to obtain the compound of Formula (I)

[0600] wherein X is Se;

[0601] Hal1and Hal3are halogens, preferably each of Hal1and Hal3is a chloro;

[0602] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0603]

[0604] In one embodiment, an exemplary reaction of Process C-2 may be represented by Scheme IV-1 and Scheme IV-2 shown below:

[0609] wherein X is Se;

[0610] Hal1and Hal3are halogens, preferably each of Hal1and Hal3is a chloro;

[0611] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0612]

[0613] Process C-3

[0614] Process C-3 prepares a compound of Formula (I) where S2isherein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0615] (i) preparing a compound of Formula (C-7)

[0616]

[0617] (ii) reacting the compound of Formula (C-7) with a compound of Formula (C-8) to obtain a compound of Formula (C-9)

[0620] (iii) reacting the compound of Formula (C-9) with a compound of Formula (C-2”) to obtain the compound of Formula (I)

[0622] wherein X is Se;

[0623] Hal3is a halogen, preferably a chloro;

[0624] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0625]

[0626] In one embodiment, the compound of Formula (C-7) may be prepared by the processes defined herein.

[0627]

[0628] In one embodiment, an exemplary reaction of Process C-3 may be represented byScheme V shown below:

[0629] Scheme V

[0631] wherein X is Se;

[0632] Hal3is a halogen, preferably a chloro;

[0633] A, B, C, Y1, Y2, Y3, X1, X2, X3, X4, S1, and S2are as defined above.

[0634]

[0635] Process D

[0636] Process D-l

[0637] Process D-l prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0638] (i) preparing a compound of Formula (D-l)

[0640] (ii) reacting the compound of Formula (D-l) with a compound of Formula (D-2) to obtain a compound of Formula (D-3)

[0641] (D-3)

[0643] (iii) reacting the compound of Formula (D-3) with KSeCN to obtain the compound of Formula (A-l);

[0644] wherein Hal4is a halogen, preferably an iodo;

[0645] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0646]

[0647] In one embodiment, an exemplary reaction of Process D-l may be represented by Scheme VI shown below:

[0648] Process VI

[0649]

[0650]

[0651] Process D-2

[0652] Process D-2 prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0653] (i) preparing a compound of Formula (D-l)

[0655] (ii) reacting the compound of Formula (D-l) with KSeCN to obtain a compound of Formula (D-4)

[0657] (iii) reacting the compound of Formula (D-4) with a compound of Formula (D-5) to obtain the compound of Formula (A-l)

[0659] Hal4is a halogen, preferably an iodo;

[0660] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above, preferably, S2comprises carboncarbon triple bond.

[0661]

[0662] In one embodiment, an exemplary reaction of Process D-2 may be represented by Scheme VII shown below:

[0663] Scheme VII

[0665] wherein Hal4is a halogen, preferably an iodo;

[0666] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above, preferably, S2comprises carboncarbon triple bond.

[0667]

[0668] Process E

[0669] Process E prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0670] (i) preparing a compound of Formula (E-l)

[0672] (ii) reacting the compound of Formula (E-l) with KSeCN and benzoyl chloride to obtain a compound of Formula (E-2)

[0674] (iii) reacting the compound of Formula (E-2) with a compound of Formula (E-3) to obtain a compound of Formula (E-4)

[0677] (iv) reacting the compound of Formula (E-4) with NaOH to obtain the compound of Formula (A-l);

[0678] wherein Hal5and Hal6are halogens, preferably Hal5is a bromo and Hal6is a chloro;

[0679] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0680]

[0681] In one embodiment, an exemplary reaction of Process E may be represented by Scheme VIII shown below:

[0682] Scheme VIII

[0684] wherein Hal5and Hal6are halogens, preferably Hal5is a bromo and Hal6is a chloro;

[0685] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0686]

[0687] Process F

[0688] Process F prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0689] (i) preparing a compound of Formula (F-l)

[0691] (ii) reacting the compound of Formula (F-l) with KSeCN to obtain a compound of Formula (F-2)Y1=Y2O2N— / — Hal72^Y3

[0692] NCSe(F-2)

[0693] (iii) reacting the compound of Formula (F-2) with Fe powder to obtain a compound of Formula (F-3)

[0695] (iv) reacting the compound of Formula (F-3) with a compound of Formula (F-4) to obtain a compound of Formula (F-5);

[0698] (v) reacting the compound of Formula (F-5) with NaOH to obtain the compound of Formula (A-l);

[0699] wherein Hal7and Hal8are halogens, preferably a chloro;

[0700] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above, preferably, S2comprises carboncarbon triple bond or heterocyclic ring.

[0701]

[0702] In one embodiment, an exemplary reaction of Process F may be represented by Scheme IX shown below:

[0703] Scheme IXFeAcOH, 120 °C, 16 h

[0704]

[0705] wherein Hal7and Hal8are halogens, preferably a chloro;

[0706] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above, preferably, S2comprises carboncarbon triple bond or heterocyclic ring.

[0707]

[0708] Process G

[0709] Process G prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0710] (i) preparing a compound of Formula (G-l)

[0712] (ii) reacting the compound of Formula (G-l) with KSeCN and Hal10'12 to obtain a compound of Formula (G-2)

[0714] (iii) reacting the compound of Formula (G-2) with a compound of Formula (G-3) to obtain a compound of Formula (G-4)HO. .S2B ( c )

[0715] 0H(G-3)

[0717] (iv) reacting the compound of Formula (G-4) with NaOH to obtain the compound of Formula (A-l);

[0718] wherein Hal9, Hal10and Hal10'1are halogens, preferably, Hal10'1is a bromo;

[0719] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0720]

[0721] In one embodiment, an exemplary reaction of Process G may be represented by Scheme X shown below:

[0722] Scheme X

[0724] wherein Hal9, Hal10and Hal10'1are halogens, and preferably, Hal10'1is a bromo;

[0725] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0726]

[0727] Process H

[0728] Process H prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0729] (i) preparing a compound of Formula (H-l)

[0731] (ii) reacting the compound of Formula (H-l) with tert-butyl carbamate to obtain a compound of Formula (H-2)

[0733] (iii) reacting the compound of Formula (H-2) with a compound of Formula (H-3) to obtain a compound of Formula (H-4)

[0736] (iv) reacting the compound of Formula (H-4) with TFA / H2O to obtain a compound of Formula (H-5)

[0738] (v) reacting the compound of Formula (H-5) with KSeCN to obtain a compound of Formula (H-6)

[0740] (vi) reacting the compound of Formula (H-6) with a compound of Formula (H-7) to obtain a compound of Formula (H-8)

[0743] (vii) reacting the compound of Formula (H-8) with NaOH to obtain the compound ofFormula (A-l);

[0744] wherein Hal11, Hal12, Hal13and Hal14are halogens, preferably, Hal11is a bromo, Hal12is a chloro, Hal13is a bromo and Hal14is a fluoro;

[0745] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0746]

[0747] In one embodiment, an exemplary reaction of Process H may be represented by Scheme XI shown below:

[0748] Scheme XI

[0749]

[0750] wherein Hal11, Hal12, Hal13and Hal14are halogens, preferably, Hal11is a bromo,Hal12is a chloro, Hal13is a bromo and Hal14is a fluoro;

[0751] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0752]

[0753] Process I

[0754] Process I prepares the compound of Formula (A-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0755] (i) preparing a compound of Formula (1-1)

[0757] (ii) reacting the compound of Formula (1-1) with a compound of Formula (1-2) to obtain a compound of Formula (1-3)

[0760] (iii) reacting the compound of Formula (1-3) with KSeCN to obtain a compound ofFormula (1-4)

[0762] (iv) reacting the compound of Formula (1-4) with a compound of Formula (1-5) to obtain a compound of Formula (1-6)

[0765] (v) reacting the compound of Formula (1-6) with NaOH to obtain the compound of Formula (A-l);

[0766] wherein Hal15and Hal16are halogens, preferably, Hal15is a bromo and Hal16is an iodo;

[0767] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0768]

[0769] In one embodiment, an exemplary reaction of Process I may be represented by Scheme XII shown below:

[0770] Scheme XIINaOHTHF / H2O, 25 °C, 4 h

[0771]

[0772] wherein Hal15and Hal16are halogens, preferably, Hal15is a bromo and Hal16is an iodo;

[0773] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0774]

[0775] Process J

[0776] Process J prepares the compound of Formula (B-l) where X is Se, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0777] (i) preparing a compound of Formula (J-l)

[0779] (ii) reacting the compound of Formula (J-l) with a compound of Formula (J-2) to obtain a compound of Formula (J-3)

[0782] (iii) reacting the compound of Formula (J-3) with benzoyl isoselenocyanate to obtain a compound of Formula (J-4)

[0784] (iv) reacting the compound of Formula (J-4) with NaOH to obtain a compound of Formula (J-5)

[0786] (v) reacting the compound of Formula (J-5) with the compound of Formula (A-2) to obtain the compound of Formula (B-l)

[0787] wherein Hal17and Hal18are halogens, preferably, a bromo;

[0788] A, B, C, X1, X2, X3, X4, Y1, Y2, Y3, S1, and S2are as defined above.

[0789]

[0790] In one embodiment, an exemplary reaction of Process J may be represented by Scheme XIII shown below:

[0791] Scheme XIIIh

[0792]

[0793] wherein Hal17and Hal18are halogens, preferably, bromo;

[0794] A, B, C, X1, X2, X3, X4, Y1, Y2, Y3, S1, and S2are as defined above.

[0795]

[0796] Process K

[0797] Process K prepares the compound of Formula (A-l) where X is Se and YHS -C-CN, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0798] (i) preparing a compound of Formula (K-l)

[0800] (ii) reacting the compound of Formula (K-l) with formic acid, followed by triphosgene and Se to obtain a compound of Formula (K-2)

[0802] (iii) reacting the compound of Formula (K-2) with benzylamine to obtain a compound of Formula (K-3)

[0804] (iv) reacting the compound of Formula (K-3) with cesium carbonate to obtain a compound of Formula (K-4)

[0806] (v) reacting the compound of Formula (K-4) with a compound of Formula (K-5) to obtain a compound of Formula (K-6)

[0807]

[0808]

[0809] (vi) reacting the compound of Formula (K-6) with Pd / C to obtain a compound ofFormula (K-7)

[0811] (vii) reacting the compound of Formula (K-7) with Zn(CN)2to obtain the compound of Formula (A-l);

[0812] wherein Hal19, Hal20and Hal21are halogens, preferably, Hal19is a chloro, Hal20is a chloro and Hal21is a bromo;

[0813] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0814]

[0815] A similar process can be used to prepare the compound of Formula (A-l) where X is Se and Y2or Y3is -C-CN.

[0816]

[0817] In one embodiment, an exemplary reaction of Process K may be represented by Scheme XIV shown below:

[0818] Scheme XIVHal191) Formic acid, NaHCO32) Triphosgene, Se BenzylamineDCM, 25 °C, 3 hDio2, ,

[0820] wherein Hal19, Hal20and Hal21are halogens, preferably, Hal19is a chloro, Hal20is a chloro and Hal21is a bromo;

[0821] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0822]

[0823] Process L

[0824] Process L prepares the compound of Formula (A -2), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0825] (i) preparing a compound of Formula (L-l)

[0827] (ii) reacting the compound of Formula (L-l) with a compound of Formula (L-2) obtain a compound of Formula (L-3)

[0830] (iii) reacting the compound of (L-3) with LiOH FLO to obtain the compound of Formula (A-2)

[0831] wherein Hal22is a halogen, preferably, Hal22is a chloro;

[0832] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0833]

[0834] In one embodiment, an exemplary reaction of Process L may be represented by Scheme XV shown below:

[0835] Scheme XV

[0837] wherein Hal22is a halogen, and preferably, Hal22is a chloro;

[0838] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0839]

[0840] Process M

[0841] Process M prepares the compound of Formula (A-l) where Y1is -C-F and Y3is N, as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0842] (i) preparing a compound of Formula (M-l)

[0844] (ii) reacting the compound of Formula (M-l) with potassium fluoride to obtain the compound of Formula (A-l);

[0845] wherein X is Se;

[0846] Hal23is a halogen except a fluoro, and preferably, Hal23is a chloro;

[0847] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0848]

[0849] In one embodiment, an exemplary reaction of Process M may be represented by Scheme XVI shown below:

[0850] Scheme XVI

[0852] wherein X is Se;

[0853] Hal23is a halogen except a fluoro, and preferably, Hal23is a chloro;

[0854] A, B, C, Y1, Y2, Y3, S1, and S2are as defined above.

[0855]

[0856] Therapeutic utilities

[0857] The terms “treat”, “treating”, “treatment” and the like refer to a course of action (such as administering an inhibitor of PolO 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, or 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.

[0858] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a PolO inhibitor or a pharmaceutical composition comprising 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 delaying 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.

[0859] The terms “inhibiting” and “reducing,” or any variation of these terms in relation of PolO, may refer to any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in PolO 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.

[0860] "Disease", "disorder" and "condition" are used interchangeably herein.

[0861] The present disclosure provides a compound that prevents or treats a disease or disorder mediated by PolO or a disease or disorder in which PolO activity is implicated.

[0862] For some embodiments, the disease or disorder mediated by PolO is any of proliferative disorders. The term “proliferative disorders” is used interchangeably herein and pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre- malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis.

[0863] For some embodiments, the disease or disorder mediated by PolO is any of HR- deficient cancers, including BRCA1- and BRCA2-deficient cancer, such as breast cancer, ovarian cancer (J. Med. Chem. 2022, 65, 19, 13198-13215), prostate cancer (Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1; 1866(12): 165954.), pancreatic cancer (Cancers (Basel) 2022 Aug 23;14(17):4077), and lung cancer (Cancers 2019, 77(5), 722). The present compound, composition and method may further enhance the efficacy of cancer therapies with at least one of the following modes of action (MOAs): (1) therapeutic mode that induces DNA damage, (2) therapeutic mode that modulates cell cycles, and (3) therapeutic mode that inhibits components involved in DNA damage responses (DDRs).

[0864] In a cancer treatment, the therapeutically effective amount of the compound of Formula (I) provided herein is an amount sufficient to provide therapeutic benefits during the course of the treatment, or to delay or minimize one or more symptoms associated with cancer. In a cancer treatment, the therapeutically effective amount of a compound is the amount of the therapeutic agent that, when used alone or in combination with other therapies, provides such therapeutic benefits during the course of the treatment.

[0865] Effective amounts of the compound of the present disclosure vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, whether treatment is prophylactic or therapeutic, as well as the specific activity of the composition itself and its ability to elicit the desired response in the individual. In the context of this disclosure, the patient can be a human or non-human mammal. Typically, dosage regimens are adjusted to provide an optimum therapeutic response, i.e., tooptimize safety and efficacy. Accordingly, a therapeutically effective amount is also one of which any undesired collateral effects are outweighed by the beneficial effects of administering the compound as described herein.

[0866] Meanwhile, the compounds of Fomula (I) may be dual targeting compounds. The dual targeting compound may have an inhibitory activity for PolO and also an inhibitory activity for PARP, and can be effectively used for treating various types of cancers.

[0867] DNA repair is essential for the regulation of cell growth and survival. Thus, DNA repair pathways have been targeted for manipulation by medical therapeutics. Singlestrand breaks (SSBs) are the most common type of lesion that occurs in cells. Poly(ADP -ribose) polymerase (PARP) plays a role in repairing DNA damage caused by SSBs.

[0868] 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.

[0869] 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 to 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. Inaddition, 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).

[0870] Furthermore, experimental data has demonstrated the therapeutic efficacy of PARP 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 Cancer108:djwl48; 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 7?G47 -mutant triple-negative breast cancer (TNBC).

[0871] 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.

[0872]

[0873] Pharmaceutical compositions

[0874] The terms "combination", "combined", and related terms refer to the simultaneous, separate or sequential administration of two or more therapeutic agents or therapies. For example, the compound disclosed herein may be administered with another therapeutic agent or therapy simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. The another therapy may be radiotherapy. The another therapeutic agent may be an anti-cancer agent. The anti-cancer agent may include DNA damage response (DDR) targeting anti-cancer agents. DNA damage response (DDR) is a collective term for the plethora of different intra- and inter-cellular signaling events and enzyme activities that result from the induction and detection of DNA damage. There are at least three key aspects of DDR that are different in cancers compared with normal cells, which in turn make DDR an attractive source for drug targets that can (and indeed currently are) being exploited to generate new cancer therapies. Loss of one or more DDR pathways, increased replication stress, and higher levels of endogenous DNAdamage are all differentiating aspects of cancer DDR that can be targeted therapeutically. A number of anti-cancer agents targeting DDR have been known and developed, e.g., PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), AIR 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 (e.g., MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide), etc. (see Mark J. O’Connor, Molecular Cell 60, November 19, 2015, p. 547-560, Choi et al., Int J Mol Sci. 2022 Feb; 23(3): 1701). The compound disclosed herein also belongs to DDR targeting agents.

[0875] In one embodiment, provided is a pharmaceutical composition including the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutical acceptable carrier, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.

[0876] In one embodiment, provided is a method of treating or preventing diseases or disorders mediated by polymerase theta, in a subject, comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the method further comprises administering additional DDR targeting anti -cancer agent described above to the subject.

[0877] In one embodiment, provided is a kit or product comprising:

[0878] - a first pharmaceutical composition or dosage form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers; and

[0879] - a second pharmaceutical composition or dosage form comprising additional DDR targeting anti-cancer agent described above, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.

[0880] In one embodiment, the kit or product is for use in a method of treating and / or preventing diseases or disorders mediated by polymerase theta. In one embodiment, the first pharmaceutical composition or dosage form may be administered simultaneously, separately or sequentially with second pharmaceutical composition or dosage form. In one embodiment, the kit or product may further comprise a package insert comprising an instruction for simultaneous, sequential or separate use in the treatment and / or prevention of diseases or disorders mediated by polymerase theta.

[0881] 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.

[0882]

[0883] Treatment method

[0884] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, in a subject in need of treatment or prevention, comprising administering to the subject 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.

[0885] The terms “human”, “patient” or “subject” are used interchangeably. A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-humananimal, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In one embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0886]

[0887] Administration

[0888] The pharmaceutical composition of the present disclosure can be administered via various routes, including, but not limited to, oral, parenteral (injected), (e.g., intravenous, subcutaneous, intramuscular, intravascular administration, or infusion), sublingual, topical, transdermal, ocular, rectal, nasal, and vaginal.

[0889] The pharmaceutical composition provided herein is administered in a pharmaceutically effective amount. For example, the pharmaceutically effective amount of the pharmaceutical composition may be in the range of about 0.01 mg to about 500 mg / kg of body weight, or about 10 mg to about 500 mg / kg of body weight. In one embodiment, the amount may be in the range of about 0.1 mg to about 250 mg / kg of body weight, or about 0.1 mg to about 10 mg / kg of body weight, or about 0.1 mg to about 1 mg / kg of body weight. In another embodiment, the amount be in the range of about 1 mg to about 100 mg / kg of body weight, preferably, about 10 mg to about 100 mg / kg of body weight. The amount of the composition to be administered will typically be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0890]

[0891] Formulation

[0892] 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 or excipient, and a compound of the presentdisclosure as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0893] 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.

[0894]

[0895] Dosage

[0896] The pharmaceutical composition of the present disclosure may be administered in a single dose or in multiple doses. Dosing may occur one time, two times, three times, four times, five times, six times, or more than six times per day. Dosing may occur once a month, once every two weeks, once a week, or once every other day. In some cases, continuous dosing is achieved and maintained for as long as necessary. In one embodiment, the pharmaceutical composition of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In one embodiment, the pharmaceutical composition of the present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, or2 days, or for less than 1 day. In one embodiment, the pharmaceutical composition of the present disclosure is administered chronically on an ongoing basis.

[0897]

[0898] It is noted that the compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention should be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed herein (including any accompanying claims, and abstract), and / or all of the steps of any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to one that may only include the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed herein (including any accompanying claims, and abstract), or to any novel one, or any novel combination, of the steps of any method or process disclosed herein.

[0899] The contents of the articles and documents referred to herein are incorporated herein by reference in their entireties as if they are all are described in detail herein.

[0900] Examples

[0901] The present disclosure will be further described below with descriptions of specific examples. It should be understood that the following examples are only used to illustrate the present disclosure and not to limit the scope of the present disclosure. The experimental methods without specific conditions used in the following examples are generally performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percent.

[0902] Generally, in the preparation process, each reaction is carried out in an inert solvent at a temperature from room temperature to reflux temperature (e.g., 0 °C to 100 °C, or alternatively 0 °C to 80 °C). The reaction time is usually 0.1-60 hours, or alternatively 0.5-24 hours.

[0903] Abbreviations

[0904] The abbreviations as used herein have the following meanings:

[0905] TEA Triethylamine

[0906] MeOH Methanol

[0907] Na2SO4 Sodium sulfate

[0908] MgSCU Magnesium sulfate

[0909] LCMS Liquid chromatography-mass spectrometry

[0910] HPLC High-performance liquid chromatography

[0911] DCM Dichloromethane

[0912] TFA Trifluoroacetic acid

[0913] THF Tetrahydrofuran

[0914] ACN Acetonitrile

[0915] EtOAc Ethyl acetate

[0916] NaHCCh Sodium bicarbonate

[0917] AcOH Acetic acid

[0918] TLC Thin Layer Chromatography

[0919] PPhs Triphenylphosphine

[0920] HATU 2-(3J / -[l,2,3]triazolo[4,5-Z>]pyridin-3-yl)-l,l,3,3- tetramethylisouronium hexafluorophosphate(V)

[0921] DIEA N, N-Diisopropylethylamine

[0922] DMF Dimethylformamide

[0923] cone. HC1 Concentrated hydrochloric acid

[0924] Cs2CO3Cesium carbonate

[0925] K2CO3 Potassium carbonate

[0926] KseCN Potassium selenocyanate

[0927] Br2Bromine

[0928] Cui Copper(I) iodide

[0929] NaOH Sodium hydroxide

[0930] K3PO4 Potassium phosphate

[0931] TMEDA N, N, N', A'-Tetram ethylethylenediamine

[0932] NH4CI Ammonium chloride

[0933] Se Selenium

[0934] DMA N, A-Di methyl acetamide

[0935] MsCl Methanesulfonyl chloride

[0936] Zn Zinc

[0937] EDCI l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0938] TCFH N, N, N', A -tetramethylchloroformamidinium hexafluorophosphate

[0939]

[0940] Materials and Methods

[0941] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless stated otherwise. All reactions were performed at RT unless stated otherwise. Flash column chromatography was carried out using pre-packed columns filled with Merck flash silica gel 60 (40-63 pm) or Cl 8 flash silica on an ISCO Combiflash Nextgen or a Biotage Selekt.

[0942] Unless stated otherwise, all reagents were used without having been further purified. 'H-NMR spectra were obtained in DMSO-t / 6 or CDC at room temperature on a Bruker 400 MHz instrument. When more than one conformer were detected, the chemical shifts for the most abundant one was reported. Chemical shifts of 'H NMR spectra were recorded in parts per million (ppm) on the 5 scale from an internal standard of residual solvent. LC-MS conditions are described below:

[0943]

[0944] Experimental Procedure:

[0945] Intermediate 1

[0947] Step a. To a mixture of methyl 4-chloro-6-methyl-pyridine-3-carboxylate (1.0 g, 5.39 mmol) and (5-chloro-2-methoxy-phenyl)boronic acid (1.51 g, 8.08 mmol) in dioxane (12 mL) and H2O (4 mL) were added Pd(PPh3)4 (622.58 mg, 538.77 pmol) and K2CO3 (2.23 g, 16.16 mmol) at 25 °C. The suspension was degassed in a vacuum and purged with nitrogen three times. The mixture was heated to 80 °C and stirred at 80 °C under nitrogen for 2 h. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain methyl 4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3- carboxylate (1.39 g, 4.76 mmol, 88.44% yield) as a brown oil.

[0948] 'H NMR (400 MHz, DMSO-d6): 8 = 8.77 (s, 1H), 7.45 (dd, J = 8.8, 2.8 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 3.66 (s, 3H), 3.64 (s, 3H), 2.55 (s, 3H). MS (ESI) m / z = 292.3 [M+H]+

[0949] Step b. To a solution of methyl 4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3- carboxylate (600 mg, 2.06 mmol) in THF (6 mL) and H2O (1.8 mL) was added LiOH H2O (388.38 mg, 9.26 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was heated to 50 °C and stirred at 50 °C for 4 h. The pH of the reaction mixture was adjusted to pH = 4-5 with 1 M HC1 solution (10 mL), then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain 4-(5-chloro-2-methoxy-phenyl)-6-methyl- pyridine-3 -carboxylic acid (420 mg crude) as a white solid.

[0950] 'H NMR (400 MHz, DMSO-d6) 6 = 12.80 (br s, 1H), 8.79 (s, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.24 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.66 (s, 3H), 2.54 (s, 3H). MS (ESI) m / z = 278.0 [M+H]+

[0951]

[0952] Intermediate 2

[0954] Step a. To a mixture of methyl 4-chloro-6-methyl-pyridine-3-carboxylate (500 mg, 2.69 mmol) and K2CO3 (1.12 g, 8.08 mmol) in dioxane (10 mL) and H2O (2 mL) were added (2-chloro-5-methoxy-4-pyridyl)boronic acid (757.20 mg, 4.04 mmol) followed by ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (175.57 mg, 269.39 pmol), then the mixture was stirred at 80 °C for 16 h under nitrogen. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (10 mL x 3) and the filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by column to afford methyl 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3 -carboxylate (515 mg, 1.74 mmol, 64.66% yield, 99% purity) as a white solid.

[0955] MS (ESI) m / z = 292.9 [M+H]+; 'H NMR (400 MHz, CDCh) 8 = 9.06 (s, 1H), 8.05 (s, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.67 (s, 3H).

[0956] Step b. To a solution of methyl 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl- pyridine-3 -carboxylate (200 mg, 683.25 pmol) in THF (2 mL) was added a solution of LiOH H2O (114.69 mg, 2.73 mmol) in H2O (2 mL), then the mixture was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to pH~3 with Citric acid and extracted with EtOAc (10 mL x 3), the combined organic layers were dried over ISfeSCU and filtered. The filtrate was concentrated under reduced pressure to obtain 4-(2-chloro-5-methoxy-4- pyridyl)-6-methyl-pyridine-3-carboxylic acid (214 mg, crude) as a white solid.

[0957] MS (ESI) m / z = 278.9 [M+H]+;'H NMR (400 MHz, DMSO-d6) 6 = 13.07-12.43 (m, 1H), 8.89 (s, 1H), 8.21 (s, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 3.78 (s, 3H), 2.56 (s, 3H).

[0958]

[0959] Intermediate 3

[0961] Intermediate 3 was prepared in the manner described above used for the synthesis of Intermediate 2, except that in step a, (5-chloro-2-methylpyridin-4-yl)boronic acid was used instead of (2-chloro-5-methoxy-4-pyridyl)boronic acid, and the target compound was obtained in the form of a white solid (520 mg, 1.97 mmol, 67% yield, 98% purity). MS (ESI) m / z = 263.7 [M+H]+.

[0962]

[0963] Intermediate 4

[0965] Intermediate 4 was prepared in the manner described above used for the synthesis of Intermediate 2, except that in step a, (5-methoxy-2-(trifluoromethyl)pyridin-4-yl)boronic acid was used instead of (2-chloro-5-methoxy-4-pyridyl)boronic acid, and the target compound was obtained in the form of a white solid (430 mg, 1.38 mmol, 68% yield, 98% purity). MS (ESI) m / z = 313.1 [M+H]+.

[0966]

[0967] Intermediate 5

[0969] Intermediate 5 was prepared in the manner described above used for the synthesis of Intermediate 2, except that in step a, (2-chloro-5-ethynylpyridin-4-yl)boronic acid was used instead of (2-chloro-5-methoxy-4-pyridyl)boronic acid, and the target compound was obtained in the form of a white solid (436 mg, 1.60 mmol, 61% yield, 98% purity) . MS (ESI) m / z = 273.1 [M+H]+.

[0970]

[0971] Intermediate 6

[0972]

[0973] Intermediate 6 was prepared in the manner described above used for the synthesis of Intermediate 2, except that in step a, methyl 3 -chloroisonicotinate was used instead of methyl 4-chloro-6-methylnicotinate, and the target compound was obtained in the form of a white solid (360 mg, 1.36 mmol, 66% yield, 98% purity). MS (ESI) m / z = 265.1 [M+H]+.

[0974]

[0975] Intermediate 7

[0977] Intermediate 7 was prepared in the manner described above for the synthesis of Intermediate 2, except that in step a, ((2-(difluoromethyl)-5-methoxypyridin-4-yl)boronic acid was used instead of (2-chloro-5-methoxy-4-pyridyl)boronic acid, and the target compound was obtained in the form of a white solid (532 mg, 1.81 mmol, 53% yield, 98% purity). MS (ESI) m / z = 295.1 [M+H]+.

[0978]

[0979] Intermediate 8

[0981] Step a. A mixture of tributyl-(2-chloro-3-fluoro-5-methoxy-4-pyridyl)stannane (1 g, 2.22 mmol), methyl 4-bromo-6-methyl-pyridine-3-carboxylate (561.61 mg, 2.44 mmol), Cui (211.33 mg, 1.11 mmol), LiCl (282.25 mg, 6.66 mmol, 136.48 pL) and Pd(PPh3)4 (512.89 mg, 443.85 pmol) in toluene (10 mL) was degassed and purged with N2 threetimes, and then the mixture was stirred at 120 °C for 12 h under an N2 atmosphere. The mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to give methyl 4-(2- chloro-3-fluoro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3-carboxylate (599 mg, 1.74 mmol, 78.18% yield, 90% purity) as a yellow solid.

[0982] 1H NMR (400 MHz, DMSO-d6) 5 = 9.04 (s, 1H), 8.23 (s, 1H), 7.45 (s, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 2.59 (s, 3H). MS (ESI) m / z = 311.1 [M+H]+.

[0983] Step b. To a solution of methyl 4-(2-chloro-3-fluoro-5-methoxy-4-pyridyl)-6- methyl-pyridine-3 -carboxylate (540 mg, 1.74 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH H2O (291.73 mg, 6.95 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and then washed with EtOAc (10 mL x 2). The aqueous phase was adjusted to pH = 5 with IN HC1, then was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. 4-(2-chl oro-3 -fluoro-5 -methoxy -4-pyridyl)-6- methyl-pyridine-3 -carboxylic acid was obtained in the form of a white solid (396 mg, 1.20 mmol, 69.12% yield, 90% purity), which was used into the next step without being further purified.

[0984] 1H NMR (400 MHz, DMSO-d6) 5 = 12.93 (br s, 1H), 8.96 (s, 1H), 8.15 (s, 1H), 7.32 (s, 1H), 3.77 (s, 3H), 2.43 (s, 3H).

[0985]

[0986] Intermediate 9

[0988] Step a. To a stirred solution of 4-chloro-2-(difhioromethyl)-5-methoxy-pyridine (10 g, 51.66 mmol) in toluene (150 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (39.35 g, 154.98 mmol), KOAc (17.74 g, 180.81 mmol) and Pd(dppf)C12 (1.89 g, 2.58 mmol), and the reaction mixture was stirred at 100 °C for 12 h under an N2 atmosphere. The reaction mixture was poured into water (100 mL) and it was extracted with EtOAc (100 mL x 3). The combinedorganic phases were washed with brine (150 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column to obtain 2-(difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (10.13 g, 35.53 mmol, 68.78% yield) as an off-white solid.

[0989] 'H NMR (400 MHz, DMSO-d6) 8 = 8.47 (s, 1H), 7.70 (s, 1H), 6.92 (t, J = 54.8 Hz, 1H), 3.93 (s, 3H), 1.30 (s, 12H). MS (ESI) m / z = 286.2 [M+H]+.

[0990] Step b. To a stirred solution of benzyl 6-chloro-4-iodo-pyridine-3-carboxylate (7 g, 18.74 mmol) in dioxane (100 mL) and H2O (10 mL) were added 2-(difluoromethyl)-5- methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (5.34 g, 18.74 mmol), K2CO3 (5.18 g, 37.48 mmol) and Pd(dppf)C12 (1.37 g, 1.87 mmol), and the reaction mixture was stirred at 80 °C for 1 h under an N2 atmosphere. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column to obtain benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3- carboxylate (2033.85 mg, 4.98 mmol, 26.59% yield, 99.165% purity) as an off-white solid and benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3- carboxylate (3.2 g, 7.91 mmol, 42.19% yield) as an off-white solid.

[0991] 'H NMR (400 MHz, DMSO-d6) 6 = 8.89 (s, 1H), 8.41 (s, 1H), 7.71 (d, J = 2.4 Hz, 2H), 7.32 (d, J = 2.4 Hz, 2H), 7.31-7.26 (m, 1H), 7.14-7.09 (m, 2H), 6.94 (t, J = 51.2 Hz, 1H), 5.15 (s, 2H), 3.73 (s, 3H), MS (ESI) m / z = 405.5 [M+H]+.

[0992]

[0993] Intermediate 10

[0995] Step a. To a solution of 6-chloro-5-fluoro-pyridin-3-ol (4 g, 27.11 mmol) in acetone (50 mL) were added Mel (4.62 g, 32.53 mmol, 2.03 mL) and K2CO3 (7.49 g, 54.22 mmol) at 0 °C under an N2 atmosphere. The mixture was stirred at 20 °C for 12 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (50 mL) andextracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure to obtain 2-chloro-3-fluoro-5-methoxy-pyridine (2.92 g, 16.70 mmol, 77.08% yield, 92.39% purity) as a brown solid, which was used into the next step without being further purified.

[0996] 'H NMR (400 MHz, DMSO ) 3 = 7.93 (d, J = 2.8 Hz, 1H), 7.06 (dd, J = 9.2, 2.8 Hz, 1H), 3.87 (s, 3H). MS (ESI) m / z = 162.1 [M+H]+.

[0997] Step b. To a solution of 2-chloro-3-fluoro-5-methoxy-pyridine (800 mg, 4.95 mmol) in THF (40 mL) was added dropwise n-BuLi (2.5 M, 2.97 mL) (2.5 M in Hexane) at - 78 °C under an N2 atmosphere. After addition, the mixture was stirred at -78 °C for 1 h under an N2 atmosphere, and then tributyl(chloro)stannane (1.93 g, 5.94 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at 20 °C for 2 h under an N2 atmosphere. The reaction mixture was quenched by sat. aq. NH4CI (10 ml) drop by drop under N2 and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column to obtain tributyl-(2-chloro-3-fhioro-5-methoxy-4-pyridyl)stannane (1.6 g, 3.55 mmol, 71.71% yield) as a colorless oil.

[0998] XH NMR (400 MHz, DMSO-t / e) <5 = 7.98 (d, J= 1.6 Hz, 1H), 3.88 (s, 3H), 1.51-1.41 (m, 6H), 1.32-1.25 (m, 6H), 1.18-1.04 (m, 6H), 0.88-0.76 (m, 9H).

[0999] Step c. To a solution of tributyl-(2-chloro-3-fluoro-5-methoxy-4-pyridyl)stannane (800 mg, 1.78 mmol) in toluene (10 mL) were added Pd(PPh3)4 (410.31 mg, 355.08 pmol) and benzyl 6-chloro-4-iodo-pyridine-3-carboxylate (729.56 mg, 1.95 mmol) and Cui (169.06 mg, 887.70 pmol) and LiCl (225.80 mg, 5.33 mmol, 109.19 pL). The mixture was stirred at 120 °C for 16 h under N2. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column to obtain benzyl 6-chloro-4-(2-chloro-3-fluoro-5-methoxy-4-pyridyl)pyridine-3-carboxylate (640 mg, 1.50 mmol, 84.41% yield, 95.357% purity) as a yellow solid.

[1000] 'H NMR (400 MHz, DMSO ) 3 = 9.03 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.35- 7.29 (m, 3H), 7.18-7.14 (m, 2H), 5.18 (s, 2H), 3.74 (s, 3H). MS (ESI) m / z = 407.0 [M+H]+.

[1001]

[1002] Intermediate 11

[1003]

[1004] Intermediate 11 was prepared in the manner described above used for the synthesis of Intermediate 2, except that in step a, methyl 4-chloro-6-(hydroxymethyl)nicotinate was used instead of methyl 4-chloro-6-methylnicotinate, and the target compound was obtained in the form of a white solid.

[1005] 1H NMR (400 MHz, DMSO) 5 9.18 (s, 4H), 8.26 (d, J = 20.3 Hz, 8H), 7.58 (s, 4H), 7.35 - 7.29 (m, 15H), 7.29 - 7.18 (m, 5H), 6.69 (t, J = 57.3 Hz, 4H), 5.45 (s, 8H), 4.99 (s, 8H), 3.99 (s, 4H), 3.79 (s, 12H). MS (ESI) m / z = 401.1 [M+H]+.

[1006]

[1007] Intermediate 12

[1009] Step a. To a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzoic acid (200 mg, 670.53 pmol) and DIEA (260.00 mg, 2.01 mmol) in DMF (5 mL) were added EDCI (124.92 mg, 804.64 pmol) followed by HOBt (108.72 mg, 846.58 pmol) and tert-butyl piperazine- 1 -carboxylate (149.87 mg, 804.64 pmol). The mixture was stirred at 50 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford 4-(2- chloro-5-methoxy-4-pyridyl)-6-methyl-N-[5-(4-tetrahydropyran-2-yloxybut-2-ynoxy)- l,3,4-thiadiazol-2-yl]pyridine-3-carboxamide (237.39 mg, 508.87 pmol, 75.89% yield, 95% purity) as a white solid. MS (ESI) m / z = 510.1 [M+H]+

[1010] Step b. To a solution of tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzoyl)piperazine-l -carboxylate (237.39 mg, 508.86 pmol) in DCM (1.0 mL)was added TFA (447.01 mg, 3.92 mmol, 0.3 mL). The mixture was stirred at 25 °C for 16 h, then was concentrated under reduced pressure to obtain a residue. The residue was purified by acidic prep-HPLC and dried by lyophilization to obtain 4-(4-fluoro-3- (piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (182.94 mg, 499.30 pmol, 98.12% yield, TFA) as a white solid. MS (ESI) m / z = 368.1 [M+H]+[10H]

[1012] Intermediate 13

[1014] Intermediate 13 was prepared in the manner described above used for the synthesis of Int 11, except that in step a, tert-butyl 4-(piperazin-l-ylmethyl)piperidine-l- carboxylate was used instead of tert-butyl piperazine- 1 -carboxylate, and the target compound was obtained in the form of a white solid (1.00 g, 2.16 mmol, 95.88% yield). MS (ESI) m / z = 465.1 [M+H]+.

[1015]

[1016] Intermediate 14

[1018] Intermediate 14 was prepared in the manner described used for the synthesis of Int 11, except that in step a, tert-butyl 8-oxo-4,7-diazaspiro[2.5]octane-7-carboxylate was used instead of tert-butyl piperazine- 1 -carboxylate, and the target compound was obtained in the form of a white solid. MS (ESI) m / z = 407.1 [M+H]+.

[1019]

[1020] Intermediate 15

[1022] Intermediate 15 was prepared in the manner described used for the synthesis of Int 11, except that in step a, tert-butyl 4-(piperidin-4-ylmethyl)piperazine-l -carboxylate was used instead of tert-butyl piperazine- 1 -carboxylate, and the target compound was obtained in the form of a white solid.

[1023] 1H NMR (400 MHz, DMSO) 5 8.15 (dd, J = 7.3, 1.7 Hz, 1H), 8.05 (dd, J = 5.0, 1.4 Hz, 1H), 7.91 (dd, J = 7.3, 1.6 Hz, 1H), 7.66 - 7.42 (m, 3H), 7.16 (t, J = 7.7 Hz, 1H), 3.71 (s, 2H), 3.56 (dt, J = 12.4, 5.2 Hz, 2H), 3.40 (dt, J = 12.4, 5.2 Hz, 2H), 2.70 (t, J = 5.1 Hz, 4H), 2.59 (t, J = 5.1 Hz, 2H), 2.37 (t, J = 5.1 Hz, 2H), 2.28 (d, J = 2.9 Hz, 2H), 1.75 (s, 1H), 1.70 - 1.59 (m, 2H), 1.56 - 1.42 (m, 1H), 1.34 - 1.25 (m, 2H). MS (ESI) m / z = 464.2 [M+H]+.

[1024]

[1025] Intermediate 16

[1026]

[1027] Step a. To a solution of ethyl 6-methyl-5-nitronicotinate (100 mg, 0.48 mmol) in dioxane (0.5 mL) was added SeCh (79.2 mg, 0.71 mmol) at 25 °C. The mixture was stirred at 110 °C for 0.5 h. The reaction mixture was filtered by celite filter and concentrated under reduced pressure to obtain a residue. The residue was purified bycolumn to obtain ethyl 6-formyl-5-nitronicotinate (102.4 mg, 0.46 mmol, 96% yield, 99.5% purity) as a white solid. MS (ESI) m / z = 225.1 [M+H]+.

[1028] Step b. To a solution of NaH (44 mg, 1.10 mmol) in dry THF(1 mL) was added ethyl 2-(diethoxyphosphoryl)butanoate (276.5 mg, 1.10 mmol) at 0 °C and stirred at 0 °C for 20 min. The mixture was stirred at 40 °C for 10 min again. To that mixture was added a solution of ethyl 6-formyl-5-nitronicotinate (102.4 mg, 0.46 mmol) in dry THF (1 mL) at -78 °C and stirred at -78 °C for 1 h. The reaction mixture was quenched by sat. NH4CI and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (20 mL), dried with anhydrous MgSCL, filtered and concentrated under reduced pressure to afford residue. The residue was purified by column to afford ethyl 6-(2- (ethoxycarbonyl)but-l-en-l-yl)-5-nitronicotinate (56.7 mg, 0.18 mmol, 39% yield, 99.2% purity) as a white solid. MS (ESI) m / z = 323.1 [M+H]+.

[1029] Step c. To a solution of ethyl 6-(2-(ethoxycarbonyl)but-l-en-l-yl)-5-nitronicotinate (49.6 mg, 0.15 mmol) in EtOH (1 mL) was added 10 % Pd / C (45.5 mg, 0.02 mmol) and purged with EE gas three times. The mixture was stirred at 25 °C for 15 h and filtered by celite filter. The filtrate was concentrated under reduced pressure to afford residue. The residue was dissolved in dioxane (0.8 mL). To that solution was added 4 M HC1 in dioxane (0.19 mL, 0.77 mmol) at 25 °C. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with diethyl ether to obtain ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-l,5- naphthyridine-3 -carboxylate (26.6 mg, 0.11 mmol, 70% yield, 99.0% purity) as a white solid. MS (ESI) m / z = 249.1 [M+H]+.

[1030] Step d. To a solution of ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-l,5-naphthyridine-3- carboxylate (24.4 mg, 0.10 mmol) in dioxane (0.5 mL) was added DDQ (24.5 mg, 0.11 mmol) at 25 °C. The mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched by sat. NaHCOs and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried with anhydrous MgSO4, filtered and concentrated under reduced pressure to afford residue. The residue was purified by column to afford ethyl 7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridine-3-carboxylate (23.1 mg, 0.09 mmol, 95% yield, 99.7% purity) as a white solid MS (ESI) m / z = 247.1 [M+H]+.

[1031] Step e. To a solution of ethyl 7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridine-3- carboxylate (24.2 mg, 0.10 mmol) in dry THF (1 mL) was added 1 M LAH in THF (0.2mL, 0.20 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by 1 N HC1 in H2O and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried with anhydrous MgSCL, filtered and concentrated under reduced pressure to afford residue. The residue was triturated with diethyl ether / hexane to obtain 3-ethyl-7-(hydroxymethyl)-l,5-naphthyridin-2(177)- one (20.1 mg, 0.10 mmol, 100% yield, 98.9% purity) as a white solid. MS (ESI) m / z = 205.1 [M+H]+.

[1032] Step f. To a solution of 3-ethyl-7-(hydroxymethyl)-l,5-naphthyridin-2(177)-one (40.0 mg, 0.20 mmol) in dry DCM (1 mL) was added SOCh (139.8 mg, 1.18 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain 7-(chloromethyl)-3-ethyl-l,5-naphthyridin-2(177)-one (42.2 mg, 0.19 mmol, 97% yield, 98.1% purity) as a white solid. MS (ESI) m / z = 223.1 [M+H]+.

[1033] Step g. To a solution of tert-butyl 4-(4-bromophenyl)piperazine-l -carboxylate (1.0 g, 2.93 mmol) in DCM (1.0 mL) was added TFA (1.67 g, 14.65 mmol, 1.12 mL). The mixture was stirred at 25 °C for 16 h, then was concentrated under reduced pressure to obtain a residue. The residue was purified by acidic prep-HPLC and dried by lyophilization to obtain l-(4-bromophenyl)piperazine (976.65 mg, 2.89 mmol, 98.56% yield, TFA) as a white solid. MS (ESI) m / z = 242.1 [M+H]+

[1034] Step h. To a solution of l-(4-bromophenyl)piperazine TFA salt (976.65 mg, 2.89 mmol) in ACN was added 7-(chloromethyl)-3-ethyl-l,5-naphthyridin-2-(lH)-one (643.12 mg, 2.89 mmol), KI (47.94 mg, 289 pmol), DIPEA (1.12 g, 8.66 mmol, 1.5 mL), then the mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by acidic prep-HPLC and dried by lyophilization to obtain 7-((4-(4-bromophenyl)piperazin-l-yl)methyl)-3-ethyl-l,5- naphthyridin-2(lH)-one (808.70 mg, 1.89 mmol, 65.52% yield) as a white solid. MS (ESI) m / z = 429.1 [M+H+H]+

[1035] Step i. To a mixture of 7-((4-(4-bromophenyl)piperazin-l-yl)methyl)-3-ethyl-l,5- naphthyridin-2(lH)-one (808.70 mg, 1.89 mmol) and ethynyltrimethylsilane (223.04 mg, 2.27 mmol, 314.6 pL) in DMF (2 mL) were added TEA (574.47 mg, 5.68 mmol, 791.28 pL), Cui (36.04 mg, 189.24 pmol) and Pd(PPh3)4 (25.57 mg, 189.24 pmol). The mixture was degassed and purged with N2 three times. The mixture was heated and stirred at 50 °C under N2 for 12 h. The reaction mixture was diluted with H2O (50 mL). Then themixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column to obtain 3- ethyl-7-((4-(4-((trimethylsilyl)ethynyl)phenyl)piperazin-l-yl)methyl)-l,5-naphthyridin- 2(lH)-one (456.14 mg, 1.89 mmol, 54.24% yield) as a brown solid. MS (ESI) m / z = 445.2 [M+H]+

[1036] Step j. To a solution of 3-ethyl-7-((4-(4-((trimethylsilyl)ethynyl)phenyl)piperazin-l- yl)methyl)-l,5-naphthyridin-2(lH)-one (456.1 mg, 1.89 mmol) in in anhydrous methanol (5 mL) and tetrahydrofuran (5 mL) was added K2CO3 (850 mg, 6.16 mmol). The mixture was stirred at 25 °C for 2 h, diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford 3-ethyl-7-((4-(4- ethynylphenyl)piperazin-l-yl)methyl)-l,5-naphthyridin-2(lH)-one (190.55 mg, 511.59 pmol, 49.87% yield) as a white solid.

[1037] 1H NMR (400 MHz, DMSO) 5 8.45 (d, J = 1.4 Hz, 1H), 7.96 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.30 - 7.15 (m, 3H), 6.57 (d, J = 7.4 Hz, 2H), 3.57 (t, J = 5.2 Hz, 2H), 3.50 - 3.37 (m, 5H), 2.74 (t, J = 5.1 Hz, 2H), 2.65 (qd, J = 6.6, 0.8 Hz, 2H), 2.58 (t, J = 5.2 Hz, 2H), 1.15 (t, J = 6.6 Hz, 3H). MS (ESI) m / z = 327.1 [M+H]+

[1038]

[1041] Intermediate 17 was prepared in the manner described above used for the synthesis of int 15, except that in step h, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzoic acid was used instead of 7-(chloromethyl)-3-ethyl-l,5-naphthyridin- 2(lH)-one, and the target compound was obtained in the form of a white solid.

[1042] 1H NMR (400 MHz, DMSO) 5 8.12 (dd, J = 7.5, 1.6 Hz, 1H), 8.02 (dd, J = 5.0, 1.4 Hz, 1H), 7.61 (dd, J = 7.3, 1.6 Hz, 1H), 7.55 (ddd, J = 7.3, 5.0, 1.5 Hz, 1H), 7.44 (td, J = 7.5, 1.6 Hz, 1H), 7.37 (td, J = 7.5, 1.6 Hz, 1H), 7.29 (d, J = 7.4 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 3.76 (t, J = 5.0 Hz, 2H), 3.71 (s, 2H), 3.56 (dt, J = 12.7, 5.1 Hz, 4H), 3.45 (dd, J = 10.0, 5.1 Hz, 3H). MS (ESI) m / z = 467.1 [M+H]+.

[1043]

[1044] Example 1-1, Compound 1

[1046] Step a. To a solution of 4-iodoaniline (5 g, 22.83 mmol) in dioxane (50 mL) and H2O (10 mL) were added K2CO3 (6.31 g, 45.66 mmol), Pd(dppf)C12 (835.19 mg, 1.14 mmol) and (4-chlorophenyl) boronic acid (4.28 g, 27.39 mmol). The mixture was degassed and purged with N2 three times. The mixture was stirred at 85 °C for 6 h under an N2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford a crude product. The crude product was purified by column to obtain 4-(4- chlorophenyl)aniline (2.2 g, 10.58 mmol, 46.32% yield, 97.901% purity) as a white solid.

[1047] 'H NMR (400 MHz, DMSO-d6) 8 = 7.54 (d, J = 7.6 Hz, 2H), 7.43-7.30 (m, 4H), 6.63 (d, J = 8.4 Hz, 2H), 5.28 (s, 2H). MS (ESI) m / z = 204.01 [M+H]+

[1048] Step b. To a solution of 4-(4-chlorophenyl)aniline (500 mg, 2.45 mmol) in AcOH (5 mL) was added selenocyanatopotassium (1.41 g, 9.82 mmol) at 25 °C. To this mixture was added a solution of Bn (784.65 mg, 4.91 mmol, 252.95 pL) in AcOH (1 mL) at 25 °C, then the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product waspurified by column to obtain 6-(4-chlorophenyl)-l,3-benzoselenazol-2-amine (200 mg, 394.71 pmol, 16.08% yield, 60.714% purity) as a white solid.

[1049] 'H NMR (400 MHz, DMSO-d6) 8 = 8.04-8.00 (m, 1H), 7.65 (br s, 4H), 7.62 (s, 2H), 7.51-7.50 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H). MS (ESI) m / z = 309.01 [M+H]+

[1050] Step c. To a solution of 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3- carboxylic acid (80 mg, 287.06 pmol) in Py (3 mL) were added EDCI (110.06 mg, 574.11 pmol) and 6-(4-chlorophenyl)-l,3-benzoselenazol-2-amine (132.46 mg, 430.59 pmol). The mixture was stirred at 50 °C for 1 h under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC. Most of the CH3CN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to obtain 2'-chloro-N-(6-(4- chlorophenyl)benzo[d][l,3]selenazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxamide (4.72 mg, 8.16 pmol, 2.84% yield, 98.21% purity) as a white solid.

[1051] XH NMR (400 MHz, DMSO-d6) 6 = 13.56-12.71 (m, 1H), 8.91 (br s, 1H), 8.31 (br s, 1H), 8.16 (s, 1H), 7.77-7.68 (m, 4H), 7.56-7.51 (m, 3H), 7.42 (br s, 1H), 3.61 (s, 3H), 2.60 (s, 3H). MS (ESI) m / z = 569.1 [M+H]+

[1052]

[1053] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or example 1-1 referring to the procedure described above.

[1054]

[1055] Example 1-2, Compound 322

[1056]

[1057] Step a. A solution of benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]pyridine-3 -carboxylate (510 mg, 1.2599 mmol), tert-butyl piperazine-1- carboxylate (469.3 mg, 2.5198 mmol), CS2CO3 (1.231 g, 3.7796 mmol) and Pd-PEPPSI-IHeptCl (122.56 mg, 0.126 mmol) in dioxane (5 mL) was stirred at 100 °C for 16 hour under an Ar atmosphere. The mixture was extracted with EA and water. The combined organic layers were washed with brine, dried over MgSCU and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford tert-butyl 4-[5-benzyloxycarbonyl-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]-2-pyridyl]piperazine-l -carboxylate (484 mg, 0.8727 mmol, 69% yield, 99% purity) in the form of a yellow solid.

[1058] Step b. A solution of tert-butyl 4-[5-benzyloxycarbonyl-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-2-pyridyl]piperazine-l -carboxylate (464 mg, 0.8367 mmol) and Pd / C (47 mg) in MeOH (76 mL) was stirred at 25 °C for 1 h under an EE atmosphere. The mixture was celite filtered with MeOH. The filtrate was concentrated under reduced pressure to obtain 6-(4-tert-butoxy carbonylpiperazin- l-yl)-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]pyridine-3-carboxylic acid (385 mg, 0.8289 mmol, 99% yield, 100% purity) in the form of a white solid.

[1059] Step c (Compound 265). A solution of 6-(4-tert-butoxy carbonylpiperazin- l-yl)-4- [2-(difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3-carboxylic acid (58.25 mg, 0.1254 mmol), 4-(2-amino-l,3-benzoselenazol-6-yl)benzonitrile (34 mg, 0.114 mmol), TCFH (38.387 mg, 0.1368 mmol) and NMI (27 uL, 0.342 mmol) in ACN (1 mL) was stirred at 70 °C for 5 hour under an Ar atmosphere. The mixture was filtered, and the filter cake was dried to obtain tert-butyl 4-[5-[[6-(4-cyanophenyl)-l,3-benzoselenazol-2- yl]carbamoyl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-2-pyridyl]piperazine-l- carboxylate (29 mg, 0.0389 mmol, 34% yield, 98% purity) in the form of an ivory solid.

[1060] Step d (Compound 266). A solution of tert-butyl 4-[5-[[6-(4-cyanophenyl)-l,3- benzoselenazol-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-2- pyridyl]piperazine-l -carboxylate (10 mg. 0.0134 mmol) and TFA (55 uL, 0.7252 mmol) in DCM was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue. The residue was precipitated with EA and Ether to obtain compound 266, N-[6-(4-cyanophenyl)-l,3-benzoselenazol-2-yl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-6-piperazin-l-yl-pyridine-3 -carboxamide (7 mg, 0.0109 mmol, 81% yield, 99% purity) as a brown solid.

[1061] Step e. A solution of N-[6-(4-cyanophenyl)-l,3-benzoselenazol-2-yl]-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-6-piperazin-l-yl-pyridine-3-carboxamide (5 mg,0.0078 mmol), 2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic acid (2.78 mg, 0.0093 mmol), TCFH (2.83 mg, 0.0101 mmol) and NMI (1.9 uL, 0.0233 mmol) in DMF (0.8 mL) was stirred at 25 °C for 1 hour under an Ar atmosphere. The mixture was extracted with EA and water, the combined organic layers were washed with brine, dried over MgSCU and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford N-[6-(4-cyanophenyl)-l,3- benzoselenazol-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[4-[2-fluoro-5-[(4- oxo-3H-phthalazin- 1 -yl)methyl]benzoyl]piperazin- 1 -yl]pyridine-3 -carboxamide (4 mg, 0.0043 mmol, 56% yield, 99% purity) in the form of a white solid.

[1062] 'H NMR (400 MHz, DMSO) 5 12.95 (s, 1H), 12.62 (s, 1H), 8.65 (s, 1H), 8.44 (s, 2H), 8.27 (d, J= 7.8 Hz, 1H), 8.01 - 7.70 (m, 10H), 7.48 (d, J= 5.9 Hz, 1H), 7.41 (d, J = 6.4 Hz, 1H), 7.28 (dd, J= 11.4, 6.5 Hz, 1H), 7.16 - 6.82 (m, 2H), 4.36 (s, 2H), 3.79 (d, J = 23.3 Hz, 4H), 3.69 (s, 3H), 3.66 (s, 2H), 3.51 (s, 2H). MS (ESI) m / z = 926.2 [M+H]+.

[1063]

[1064] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or example 1-2 referring to the procedure described above.

[1068] Step a. To a solution of benzoyl chloride (3.0 g, 21.34 mmol) in acetone (45 mL) was added a solution of selenocyanatopotassium (3.07 g, 21.34 mmol) in acetone (75 mL) dropwise. Then the reaction mixture was stirred at 25 °C for 2 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove acetone and obtain a residue. The residue was triturated with DCM (120 mL) and stirred at 25 °C for 1 h, then filtered. The filter cake was washed with DCM (30 mL x 3), and the combined filtrate was concentrated under reduced pressure to obtain benzoylisosel enocyanate (5.02 g, crude) as a brown solid, which was directly used for the next step without being further purified.

[1069] Step b. To a solution of 6-bromo-2-chloro-pyridin-3-amine (0.33 g, 1.59 mmol) in Acetone (6 mL) was added benzoyl isoselenocyanate (1.00 g, crude). Then the reaction mixture was stirred at 70 °C for 2 hr under a nitrogen atmosphere to obtain a yellow suspension. The reaction mixture was evaporated under reduced pressure to remove acetone and obtain a residue. The residue was triturated with EtOAc (10 mL) and stirred at 25 °C for 1 h, then filtered. The filter cake was washed with EtOAc (3 mL x 3) and the filter cake was concentrated under reduced pressure to obtain N-(5-bromo-[1.3]selenazolo[5,4-b]pyridin-2-yl)benzamide (0.52 g, 1.31 mmol, 82.18% yield, 95.8% purity) as a yellow solid, which was directly used for the next step without being further purified. MS (ESI) m / z = 381.9 [M+H]+.

[1070] Step c. A suspension of N-(5-bromo-[l,3]selenazolo[5,4-b]pyridin-2-yl)benzamide (0.5 g, 1.31 mmol) in 70% H2SO4 (5 mL) was stirred at 120 °C for 1 hr. The reaction mixture was cooled to 25 °C and the pH of the mixture was adjusted to pH = 8.0 with 6 M NaOH at 0 °C. The suspension was formed, then filtered. The filter cake was washed with H2O (5 mL x 3) and the filter cake was concentrated under reduced pressure to obtain 5- bromo-[l,3]selenazolo[5,4-b]pyridin-2-amine (303 mg, 1.01 mmol, 77.21% yield, 92.6% purity) as a gray solid, which was directly used for the next step without being further purified.

[1071] Step d. To a solution of 5-bromo-[l,3]selenazolo[5,4-b]pyridin-2-amine (301 mg, 1.09 mmol) in THF (8 mL) were added Boc2O (284.61 mg, 1.30 mmol), TEA (329.89 mg, 3.26 mmol) and DMAP (13.28 mg, 108.67 pmol). Then the reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl N-(5-bromo-[1.3]selenazolo[5,4-b]pyridin-2-yl)carbamate (283 mg, 724.96 pmol, 66.71% yield, 96.6% purity) as a yellow solid. MS (ESI) m / z = 377.8 [M+H]+.

[1072] Step e. To a solution of tert-butyl N-(5-bromo-[l,3]selenazolo[5,4-b]pyridin-2- yl)carbamate (280 mg, 742.52 pmol) in dioxane (10 mL) and H2O (2 mL) were added (4- cyanophenyl)boronic acid (218.21 mg, 1.49 mmol), Cs2CO3 (725.78 mg, 2.23 mmol), XPhos Pd G3 (62.85 mg, 74.25 pmol) and XPhos (35.40 mg, 74.25 pmol) under an nitrogen atmosphere. The reaction mixture was degassed and purged with N2 three times,and the reaction mixture was stirred at 100 °C for 2 hr under an N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tertbutyl N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]carbamate (140 mg, 290.66 pmol, 39.14% yield, 82.9% purity) in the form of a brown solid. MS (ESI) m / z = 401.0 [M+H]+.

[1073] Step f. To a solution of tert-butyl N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4- b]pyridin-2-yl]carbamate (140 mg, 350.61 pmol) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL) under a nitrogen atmosphere, then the reaction mixture was stirred at 25 °C for 1 hr under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reversed phase column to obtain 4-(2-amino-[l,3]selenazolo[5,4-b]pyridin-5-yl)benzonitrile (101 mg, 333.87 pmol, 95.22% yield, 98.9% purity, HC1) in the form of a yellow solid. MS (ESI) m / z = 300.9 [M+H]+.

[1074] Step g. To solution of 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3- carboxylic acid (80 mg, 287.06 pmol) and 4-(2-amino-[l,3]selenazolo[5,4-b]pyridin-5- yl)benzonitrile (85.88 mg, 287.06 pmol, HC1) in DMF (3 mL) and CH3CN (5 mL) were added NMI (141.41 mg, 1.72 mmol) and TCFH (241.63 mg, 861.17 pmol). Then the reaction mixture was stirred at 70 °C for 2 hr to obtain a light brown suspension. The reaction mixture was cooled to 25 °C, then filtered. The filter cake was washed with water (5 mL x 2) and CEECN (3 mL x 3) to obtain a white solid. The white solid was dissolved in CEECN (8 mL) and H2O (8 mL), then freeze-dried to obtain 4-(2-chloro-5- methoxy-4-pyridyl)-N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]-6-methyl- pyridine-3-carboxamide (88.89 mg, 158.77 pmol, 55.31% yield, 100% purity) as a white solid.

[1075] 1H NMR (400 MHz, DMSO-d6) 5 = 13.35 (s, 1H), 8.90 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.21 (br s, 2H), 8.19 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.49 (s, 1H), 3.63 (s, 3H), 2.62 (s, 3H). MS (ESI) m / z = 561.1 [M+H]+.

[1076]

[1077] Example 2-1, Compound 276

[1079] Step a. To a stirred solution of N-(5-bromo-[l,3]selenazolo[5,4-b]pyridin-2-yl)-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-6-methyl-pyridine-3-carboxamide (80 mg, 144.61 pmol) in dioxane (5 mL) and H2O (0.5 mL) were added N,N-bis[(2,4- dimethoxyphenyl)methyl]-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]propane-2-sulfonamide (90.46 mg, 144.61 pmol), XPhos (6.89 mg, 14.46 pmol), CS2CO3 (141.35 mg, 433.83 pmol) and XPhos Pd G3 (12.24 mg, 14.46 pmol), and the reaction mixture was stirred at 100 °C for 12 h under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was purified by column to obtain N-[5-[4-[l-[bis[(2,4-dimethoxyphenyl) methyl]sulfamoyl]- l-methyl-ethyl]phenyl]-[l,3]selenazolo[5,4-b]pyridin-2-yl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-6-methyl-pyridine-3-carboxamide (85 mg, 87.46 pmol, 60.48% yield) as a yellow solid. MS (ESI) m / z = 973.4 [M+H]+.

[1080] Step b. A mixture of N-[5-[4-[l-[bis[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-l- methyl-ethyl]phenyl]-[l,3]selenazolo[5,4-b]pyridin-2-yl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-6-methyl-pyridine-3-carboxamide (85 mg, 40.75 pmol) in TFA (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 20 °C for 10 min under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove TFA. The crude product was purified by prep-HPLC and most of MeCN was removed under reduced pressure. The remaining solvent was removed by lyophilization to obtain 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6- methyl-N-[5-[4-(l-methyl-l-sulfamoyl-ethyl)phenyl]-[l,3]selenazolo[5,4-b]pyridin-2- yl]pyridine-3-carboxamide (15.36 mg, 19.55 pmol, 47.98% yield, TFA) as a yellow solid.

[1081] XH NMR (400 MHz, DMSO-t / e) <5 = 13.29 (br s, 1H), 8.90 (s, 1H), 8.48 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.07 (d, J= 8.4 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J= 8.8 Hz, 2H), 7.52 (s, 1H), 7.01 (t, J= 55.2 Hz, 1H), 6.76 (s, 2H), 3.71 (s, 3H), 2.63 (s, 3H), 1.76 (s, 6H). MS (ESI) m / z = 673.1 [M+H]+.

[1082]

[1083] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or example 2-1 referring to the procedure described above.

[1084]

[1085] Example 2-2, Compound 208

[1087] Step a. To a solution of benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]pyridine-3 -carboxylate (250 mg, 617.60 pmol) and 4,7-diazaspiro[2.5]octan-8- one (93.50 mg, 741.12 pmol) in dioxane (7 mL) were added CS2CO3 (402.45 mg, 1.24 mmol), Pd(OAc)2 (13.87 mg, 61.76 pmol) and Xantphos (71.47 mg, 123.52 pmol) under a nitrogen atmosphere, then the reaction mixture was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 1.5 hr under an N2 atmosphere. The reaction mixture was filtered, the filter cake was washed with EtOAc (10 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(8-oxo-4,7- diazaspiro[2.5]octan-7-yl)pyridine-3-carboxylate (273 mg, 504.05 pmol, 81.62% yield, 91.3% purity) as a light brown solid. MS (ESI) m / z = 495.2 [M+H]+.

[1088] Step b. To a solution of benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(8- oxo-4, 7-diazaspiro[2.5]octan-7-yl)pyridine-3-carboxylate (220 mg, 444.90 pmol) in DCM (6 mL) was added BOC2O (291.30 mg, 1.33 mmol) under a nitrogen atmosphere, then the mixture was stirred at 25 °C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl 7-[5-benzyloxycarbonyl-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-2-pyridyl]-8-oxo-4,7-diazaspiro[2.5]octane-4-carboxylate (189 mg,316.30 pmol, 71.09% yield, 99.51% purity) as a light yellow solid. MS (ESI) m / z = 595.4 [M+H]+.

[1089] Step c. To a solution of tert-butyl 7-[5-benzyloxycarbonyl-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-2-pyridyl]-8-oxo-4,7-diazaspiro[2.5]octane-4-carboxylate (182 mg, 306.09 pmol) in DCM (5 mL) were added TEA (92.92 mg, 918.26 pmol), Et3SiH (71.18 mg, 612.17 pmol) and Pd(OAc)2 (6.87 mg, 30.61 pmol) under a nitrogen atmosphere, then the mixture was stirred at 25 °C for 2 hr under a nitrogen atmosphere. The reaction mixture was filtered, the filter cake was washed MeOH (10 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain 6-(4-tert-butoxycarbonyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3-carboxylic acid (152 mg, 300.09 pmol, 98.04% yield, 99.6% purity) as a light yellow solid. MS (ESI) m / z = 505.2 [M+H]+.

[1090] Step d. To solution of 6-(4-tert-butoxycarbonyl-8-oxo-4,7-diazaspiro[2.5]octan-7- yl)-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3-carboxylic acid (152 mg,301.30 pmol) and 4-(2-amino-[l,3]selenazolo[5,4-b]pyridin-5-yl)benzonitrile (90.15 mg,301.30 pmol) in DMF (6 mL) and CH3CN (9.9 mL) were added NMI (148.42 mg, 1.81 mmol) and TCFH (253.62 mg, 903.90 pmol). Then the mixture was stirred at 70 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reversed phase column to obtain tert-butyl 7-[5-[[5-(4- cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-2-pyridyl]-8-oxo-4,7-diazaspiro[2.5]octane-4-carboxylate (208 mg, 226.89 pmol, 75.30% yield, 85.7% purity) as a light yellow solid. MS (ESI) m / z = 787.2 [M+H]+.

[1091] Step e. To solution of tert-butyl 7-[5-[[5-(4-cyanophenyl)-[l,3]selenazolo[5,4- b]pyridin-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-2-pyridyl]-8-oxo- 4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 254.56 pmol) in DCM (10 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL). Then the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC. to obtain N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4- b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(8-oxo-4,7- diazaspiro[2.5]octan-7-yl)pyridine-3-carboxamide (17.55 mg, 21.46 pmol, 8.43% yield, 97.79% purity, TFA) as an off-white solid.

[1092] 'H NMR (400 MHz, DMSO-t / e) d = 13.43 (s, 1H), 8.94 (s, 1H), 8.51 (s, 1H), 8.35 (d, J= 8.4 Hz, 2H), 8.23 (s, 2H), 8.05 (s, 1H), 7.98 (d, J= 8.4 Hz, 2H), 7.66 (s, 1H), 7.04 (t, J = 55.2 Hz, 1H), 4.30 (t, J = 5.2 Hz, 2H), 3.72 (s, 3H), 3.62 (t, J = 5.2 Hz, 2H), 1.54- 1.48 (m, 2H), 1.36-1.33 (m, 2H). MS (ESI) m / z = 687.2 [M+H]+.

[1093]

[1094] Example 2-2, Compound 327

[1096] Step a. To a mixture of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzoic acid (500 mg, 1.68 mmol), NH4HCO3 (331 mg, 4.19 mmol) in dioxane (4 mL) were added BOC2O (0.42 mL, 1.84 mmol) and pyridine (149 pL, 1.84 mmol) at 25 °C. The mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with EtOAc and washed with H2O to obtain 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzamide (497 mg, 1.67 mmol, 99.7% yield, 98% purity) as a white solid. MS (ESI) m / z = 298.1 [M+H]+.

[1097] Step b. To a mixture of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzamide (110.2 mg, 371 pmol), benzyl 6-chloro-2'-(difluoromethyl)-5'- methoxy-[4,4'-bipyridine]-3-carboxylate (100 mg, 247 pmol), Xantphos (21.4 mg, 37pmol), CS2CO3 (161 mg, 494 pmol) in dioxane (3 mL) was added Pd(OAc)2 (11.1 mg, 49 pmol) and the mixture was degassed with Ar gas at 25°C for 5 mins. The mixture was stirred at 90°C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 2'- (difluoromethyl)-6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzamido)- 5'-methoxy-[4,4'-bipyridine]-3-carboxylate (73.8 mg, 111 pmol, 44.9% yield, 98% purity) as a white solid. MS (ESI) m / z = 666.2 [M+H]+.

[1098] Step c. To a solution of benzyl 2'-(difhioromethyl)-6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzamido)-5'-methoxy-[4,4'-bipyridine]-3-carboxylate (73.8 mg, 111 pmol) in MeOH (4 mL) / THF (2 mL) was added 10% Pd / C (22 mg, 11 pmol) and the mixture was purged with H2 gas 3 times at 25 °C. The mixture was stirred at 25 °C for 2.5 h. The reaction mixture was filtered by celite filter and concentrated under reduced pressure to obtain 2'-(difluoromethyl)-6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzamido)-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (44.8 mg, 78 pmol, 70.2% yield, 99% purity) as a white solid. MS (ESI) m / z = 576.1 [M+H]+.

[1099] Step d. To a mixture of 2'-(difluoromethyl)-6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzamido)-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (40.8 mg, 71 pmol), and TCFH (19.9 mg, 71 pmol) in ACN (4 mL) was added NMI (17 pL, 213 pmol) at 25 °C and the mixture was stirred at 25 °C for 0.5 h. To that mixture was added 4-(2-amino-[l,3]selenazolo[5,4-Z>]pyridin-5-yl)benzonitrile (32.2 mg, 78 pmol, TFA) at 25 °C. The mixture was stirred at 70 °C for 23 h. The reaction mixture was filtered to obtain a residue. The residue was purified by column to obtain A-(5-(4- cyanophenyl)-[l,3]selenazolo[5,4-Z>]pyridin-2-yl)-2'-(difluoromethyl)-6-(2-fluoro-5-((4- oxo-3, 4-dihydrophthal azin-1 -yl)methyl)benzamido)-5'-methoxy-[4,4'-bipyridine]-3- carboxamide (3.5 mg, 4.1 pmol, 5.8% yield, 98% purity) as a white solid.

[1100] XH NMR (400 MHz, DMSO ) 3 = 13.40 (s, 1H), 12.64 (s, 1H), 11.36 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 8.37-8.35 (m, 2H), 8.28-8.27 (m, 2H), 8.22 (s, 2H), 8.03-7.97 (m, 3H), 7.94-7.90 (m, 1H), 7.86-7.83 (m, 1H), 7.77 (s, 1H), 7.70-7.69 (m, 1H), 7.60-7.57 (m, 1H), 7.33-7.29 (m, 1H), 7.19-6.91 (m, 1H), 4.38 (s, 2H), 3.74 (s, 3H). MS (ESI) m / z = 857.1 [M+H]+[HOI]

[1102] Example 2-2, Compound 330

[1104] Step a. A solution of 2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic acid(600 mg, 2.01 mmol), EDCI HC1 (578 mg, 3.02 mmol) and HOBt (462 mg, 3.02 mmol) in DCM (20mL) was stirred at 25 °C for 30 min under an Ar atmosphere. To the solution was added N,O-Dimethylhydroxylamine Hydrochloride (294 mg, 3.02 mmol) and DIPEA(0.70 mL, 4.02 mmol), and then the mixture was stirred at 25 °C for 16 h. The mixture was extracted with DCM and 1 N HC1 solution, The combined organic layers were washed with 1 N NaOH, dried over MgSCE and filtered. The filtrate was concentrated under reduced pressure to obtain a 2-fluoro-N-methoxy-N-methyl-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzamide (680 mg, 1.992 mmol, 99.03% yield, 96% purity) as a white solid.

[1105] 'H NMR (400 MHz, DMSO) 5 12.62 (s, 1H), 8.26 (s, 1H), 8.05 - 7.75 (m, 3H), 7.42 (s, 2H), 7.22 (s, 1H), 4.35 (s, 2H), 3.24 (s, 6H).

[1106] Step b. To a solution of 2-fluoro-N-methoxy-N-methyl-5-[(4-oxo-3H-phthalazin-l- yl)methyl]benzamide (150 mg, 0.439 mmol) in anhydrous THF (3mL) at 0 °C under an Ar atmosphere was added dropwise a lithium aluminum hydride solution in 1.0 M THF(0.66 mL, 0.659 mmol). The mixture was stirred at 0 °C for 20 min. The mixture was extracted with DCM and 1 N HC1 solution. Then, the combined organic layers were washed with brine, dried over MgSCh and filtered. The filtrate was concentrated under reduced pressure to obtain a 2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzaldehyde (43 mg, 0.1523 mmol, 37% yield, 97% purity) as a white solid.

[1107] XH NMR (400 MHz, DMSO) 5 12.61 (s, 1H), 10.19 (s, 1H), 8.27 (d, J= 7.8 Hz, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.91 (t, J= 7.6 Hz, 1H), 7.84 (t, J= 7.5 Hz, 1H), 7.79 (d, J= 5.3 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.40 - 7.32 (m, 1H), 4.40 (s, 2H).

[1108] Step c. A solution of 2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzaldehyde (100 mg, 0.354 mmol), 4,7-diazaspiro[2.5]octan-8-one (49 mg, 0.390 mmol), AcOH (1 drop) in anhydrous THF (4mL) was stirred at 25 °C for 1 hour under an Ar atmosphere. To the solution was added NaBH(OAc)3 (150 mg, 0.709 mmol), and then the mixture was stirred at 40 °C for 16 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford 4-[[4-fluoro-3-[(8-oxo-4,7- diazaspiro[2.5]octan-4-yl)methyl]phenyl]methyl]-2H-phthalazin-l-one (47 mg, 0.1198 mmol, 33% yield, 100% purity) as a white solid.

[1109] 'H NMR (400 MHz, DMSO) 5 12.63 (s, 1H), 8.26 (d, J= 7.5 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.85 (ddd, J = 18.4, 10.9, 6.4 Hz, 2H), 7.69 (s, 1H), 7.39 - 7.30 (m, 1H), 7.29 - 7.17 (m, 1H), 7.12 - 6.98 (m, 1H), 4.29 (s, 2H), 3.79 (s, 2H), 2.82 (t, J= 5.6 Hz, 2H), 1.60 (s, 2H), 1.07 (dd, J= 6.7, 3.6 Hz, 2H), 0.72 (dd, J= 6.7, 3.6 Hz, 2H).

[1110] Step d. A solution of 4-[[4-fluoro-3-[(8-oxo-4,7-diazaspiro[2.5]octan-4- yl)methyl]phenyl]methyl]-2H-phthalazin-l-one (5 mg, 0.0127 mmol), benzyl 6-chloro-4- [2-(difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3-carboxylate (5.16 mg, 0.0127 mmol), CS2CO3 (8.30 mg, 0.0255 mmol), Ruphos (0.59 mg, 0.0013 mmol) and Pd2(dba)3 (1.17 mg, 0.0013 mmol) in dioxane (0.5 mL) was microwaved at 200 °C for 20 min. The mixture was extracted with EA and water. Then, the combined organic layers were washed with brine, dried over MgSCL and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[4-[[2-fluoro-5-[(4-oxo-3H-phthalazin-l- yl)methyl]phenyl]methyl]-8-oxo-4,7-diazaspiro[2.5]octan-7-yl]pyridine-3-carboxylate (2.5 mg, 0.0033 mmol, 26% yield, 100% purity) as a white solid.

[1111] 1H NMR (400 MHz, DMSO) 5 12.59 (s, 1H), 8.96 (s, 1H), 8.40 (s, 1H), 8.26 (d, J = 7.3 Hz, 1H), 8.02 (s, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.57 (s, 1H), 7.41 (d, J= 5.4 Hz, 1H), 7.35 - 7.29 (m, 3H), 7.23 (s, 1H), 7.15 - 7.05 (m, 3H), 5.16 (s, 2H),4.29 (s, 2H), 4.22 (t, J= 5.7 Hz, 2H), 3.92 (s, 2H), 3.73 (s, 3H), 3.13 (t, J = 5.5 Hz, 2H),1.30 (s, 2H), 0.97 (d, J= 2.9 Hz, 2H).

[1112] Step e. A solution of benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[4-[[2- fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]phenyl]methyl]-8-oxo-4,7- diazaspiro[2.5]octan-7-yl]pyridine-3-carboxylate (53.5 mg, 0.0703 mmol) and Pd / C (5.4 mg) in MeOH (2.5 mL) was stirred at 25 °C for 1 h under an H2 atmosphere. The mixture was celite filtered with MeOH, and the filtrate was concentrated under reduced pressure to obtain 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[4-[[2-fluoro-5-[(4-oxo-3H- phthalazin-l-yl)methyl]phenyl]methyl]-8-oxo-4,7-diazaspiro[2.5]octan-7-yl]pyridine-3- carboxylic acid (47.5 mg, 0.0708 mmol, 100% yield, 100% purity) as a white solid.

[1113] Step f. A solution of 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[4-[[2-fluoro-5- [(4-oxo-3H-phthalazin-l-yl)methyl]phenyl]methyl]-8-oxo-4,7-diazaspiro[2.5]octan-7- yl]pyridine-3 -carboxylic acid(19.638 mg, 0.0293 mmol), 4-(2-amino-[l,3]selenazolo[5,4- b]pyridin-5-yl)benzonitrile;2,2,2-trifluoroacetic acid (11 mg, 0.0266 mmol), TCFH (11.203 mg, 0.0399 mmol) and NMI (11 uL, 0.1331 mmol) in ACN (1.2 mL) was stirred at 70 °C for 1 hour under an Ar atmosphere. The solvent was concentrated under reduced pressure to obtain a residue. The residue was purified by column afford N-[5-(4- cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]-6-[4-[[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]phenyl]methyl]-8-oxo-4,7- diazaspiro[2.5]octan-7-yl]pyridine-3-carboxamide (2.3 mg, 0.0024 mmol, 9%, 98% purity) in the form of a white solid.

[1114] 'H NMR (400 MHz, DMSO) 5 13.44 (s, 1H), 12.60 (s, 1H), 8.97 (s, 1H), 8.49 (s, 1H), 8.35 (d, J= 7.8 Hz, 2H), 8.27 (d, J= 7.8 Hz, 1H), 8.11 (d, J= 50.2 Hz, 3H), 7.97 (d, J = 7.9 Hz, 3H), 7.85 (dt, J = 22.2, 7.2 Hz, 2H), 7.66 (s, 1H), 7.45 (d, J = 6.7 Hz, 1H), 7.24 (s, 1H), 7.19 - 6.62 (m, 3H), 4.31 (s, 2H), 4.27 (s, 2H), 3.96 (s, 2H), 3.72 (s, 3H), 3.15 (s, 2H), 1.11 (d, J = 5.7 Hz, 2H), 0.85 (d, J = 6.9 Hz, 2H). MS (ESI) m / z = 953.1 [M+H]+.[1 H5]

[1116] Example 2-2, Compound 334

[1118] Step a. To a solution of 4-(hydroxymethyl)piperidin-2-one (5 g, 38.71 mmol) in DCM (150 mL) were added 4-methylbenzenesulfonyl chloride (11.07 g, 58.07 mmol), TEA (11.75 g, 116.14 mmol, 16.16 mL) and DMAP (945.88 mg, 7.74 mmol). The suspension was degassed and purged with N2 three times. The mixture was stirred at 20 °C for 12 h under an N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (150 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column to obtain (2-oxo-4-piperidyl)methyl 4-methylbenzenesulfonate (8.36 g, 29.50 mmol, 76.22% yield, 100% purity) as an off- white solid. fl 119] 'H NMR (400MHz, DMSO ) 3 = 7.80 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.48-7.43 (m, 1H), 3.97-3.86 (m, 2H), 3.14-2.99 (m, 2H), 2.43 (s, 3H), 2.17-2.05 (m, 2H), 1.89-1.76 (m, 1H), 1.75-1.66 (m, 1H), 1.35-1.21 (m, 1H). MS (ESI) m / z = 284.1 [M+H]+.

[1120] Step b. To a solution of (2-oxo-4-piperidyl)methyl 4-methylbenzenesulfonate (7.76 g, 27.39 mmol) in MeCN (77 mL) were added tert-butyl piperazine- 1 -carboxylate (10.20 g,54.77 mmol) and K2CO3 (7.57 g, 54.77 mmol). The suspension was degassed and purged with N2 three times. The mixture was stirred at 90 °C for 12 h under an N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column to obtain tert-butyl 4-[(2-oxo-4-piperidyl)methyl]piperazine-l- carboxylate (5.71 g, 18.43 mmol, 67.30% yield, 96% purity) as a white solid.

[1121] 'H NMR (400 MHz, MeOD v) d = 3.48-3.37 (m, 4H), 3.36-3.35 (m, 1H), 3.30- 3.21 (m, 1H), 2.49-2.41 (m, 1H), 2.41-2.35 (m, 4H), 2.34-2.22 (m, 2H), 2.19-2.08 (m, 1H), 2.03-1.91 (m, 2H), 1.45 (s, 9H), 1.44-1.36 (m, 1H).

[1122] Step c. To a solution of benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]pyridine-3 -carboxylate (5.61 g, 13.86 mmol) in dioxane (110 mL) were added tert-butyl 4-[(2-oxo-4-piperidyl)methyl]piperazine-l -carboxylate (4.95 g, 16.63 mmol), Pd(OAc)2 (311.14 mg, 1.39 mmol), Xantphos (1.20 g, 2.08 mmol) and CS2CO3 (9.03 g, 27.72 mmol). The suspension was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 1.5 h under an N2 atmosphere. The mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl 4-[[l-[5-benzyloxycarbonyl-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-2-pyridyl]-2-oxo-4-piperidyl]methyl]piperazine- 1-carboxylate (9.01 g, 12.67 mmol, 91.41% yield, 93.6% purity) as a yellow oil. MS (ESI) m / z = 666.5 [M+H]+.

[1123] Step d. To a solution of tert-butyl 4-[[l-[5-benzyloxycarbonyl-4-[2-(difluoromethyl)- 5-methoxy-4-pyridyl]-2-pyridyl]-2-oxo-4-piperidyl]methyl]piperazine-l-carboxylate (8.31 g, 12.48 mmol) in DCM (166 mL) were added Et3SiH (2.90 g, 24.97 mmol, 3.99 mL), TEA (3.79 g, 37.45 mmol, 5.21 mL) and Pd(OAc)2 (280.24 mg, 1.25 mmol). The suspension was degassed and purged with N2 three times. The mixture was stirred at 40 °C for 12 h under an N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) and extracted with DCM (150 mL x 2). The combined organic layers were washed with brine (50 mL), dried over ISfeSCU, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain 6-[4-[(4-tert- butoxycarbonylpiperazin-l-yl)methyl]-2-oxo-l-piperidyl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]pyridine-3-carboxylic acid (5.1 g, 8.86 mmol, 70.98% yield) as a blackish green solid

[1124] 'H NMR (400 MHz, CDCh) (5 = 8.95 (s, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 6.60 (t, J = 56.0 Hz, 1H), 4.18-4.09 (m, 1H), 3.98-3.88 (m, 1H), 3.84 (s, 3H), 3.44-3.39 (m, 4H), 2.78-2.68 (m, 1H), 2.41-2.35 (m, 4H), 2.33-2.21 (m, 4H), 2.17-2.08 (m, 1H), 1.68-1.52 (m, 1H), 1.45 (s, 9H).

[1125] Step e. To a solution of 4-(2-amino-[l,3]selenazolo[5,4-b]pyridin-5-yl)benzonitrile (1.61 g, 5.39 mmol) in DMF (62 mL) and MeCN (31 mL) were added 6-[4-[(4-tert- butoxycarbonylpiperazin-l-yl)methyl]-2-oxo-l-piperidyl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]pyridine-3-carboxylic acid (3.1 g, 5.39 mmol), NMI (1.46 g, 17.77 mmol, 1.42 mL) and TCFH (1.96 g, 7.00 mmol). The suspension was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 2 h under an N2 atmosphere. To the reaction mixture was added water (80 mL) and then the mixture was filtered. The filter cake was washed with water (10 mL x 2), then the filter cake was dried in a vacuum to obtain tert-butyl 4-[[l-[5-[[5-(4-cyanophenyl)-[l,3]selenazolo[5,4- b]pyridin-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-2-pyridyl]-2-oxo- 4-piperidyl]methyl]piperazine-l -carboxylate (2.8 g, 3.17 mmol, 58.92% yield, 97.1% purity) as a yellow solid, which was used into the next step without being further purified. MS (ESI) m / z = 858.4 [M+H]+.

[1126] Step f (Compound 258). To a solution of tert-butyl 4-[[l-[5-[[5-(4-cyanophenyl)-[1.3]selenazolo[5,4-b]pyridin-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]-2-pyridyl]-2-oxo-4-piperidyl]methyl]piperazine-l-carboxylate (4.3 g, 5.02 mmol) in DCM (70 mL) were added TFA (22.00 g, 192.96 mmol, 14.33 mL). The suspension was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 12 h under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC. The remaining solvent was removed by lyophilization to obtain N-[5-(4-cyanophenyl)-[1.3]selenazolo[5,4-b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[2- oxo-4-(piperazin-l-ylmethyl)-l-piperidyl]pyridine-3 -carboxamide (3989.35 mg, 4.51 mmol, 89.83% yield, 98.4% purity, TFA) as a yellow solid.

[1127] 'H NMR (400 MHz, DMSO ) d = 13.38 (br s, 1H), 8.89 (s, 1H), 8.81 (br s, 1H), 8.49 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.21 (s, 2H), 8.04-7.90 (m, 3H), 7.67 (s, 1H), 7.03 (t, J= 55.2 Hz, 1H), 4.13-4.10 (m, 1H), 3.94-3.91 (m, 1H), 3.72 (s, 3H), 3.31-3.17 (m,4H), 3.07-2.75 (m, 4H), 2.74-2.55 (m, 3H), 2.42-2.28 (m, 2H), 2.16-2.05 (m, 1H), 1.69- 1.56 (m, 1H). MS (ESI) m / z = 758.2 [M+H]+.

[1128] Step g. A solution ofN-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-6-[2-oxo-4-(piperazin-l-ylmethyl)-l- piperidyl]pyridine-3-carboxamide;2,2,2-trifluoroacetic acid (5 mg, 0.0057 mmol), 2- fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic acid (1.884 mg, 0.0063 mmol), TCFH (2.417 mg, 0.0086 mmol) and NMI (2.3 uL, 0.0287 mmol) in ACN (0.5 mL) was stirred at 70 °C for 1 hour under an Ar atmosphere. The mixture was extracted with EA and water. Then, the combined organic layers were washed with brine, dried over MgSCE and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4- b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[4-[[4-[2-fluoro-5-[(4-oxo- 3H-phthal azin-1 -yl)methyl]benzoyl]piperazin-l-yl]methyl]-2-oxo-l-piperidyl]pyridine-3- carboxamide (1.4 mg, 0.0014 mmol, 24% yield, 99% purity) as a white solid.

[1129] 'H NMR (400 MHz, CDC13) 5 10.58 (s, 1H), 8.80 (s, 1H), 8.49 - 8.42 (m, 1H), 8.30 (s, 1H), 8.19 (d, J= 8.6 Hz, 2H), 8.12 (s, 1H), 7.88 - 7.69 (m, 7H), 7.66 (s, 1H), 7.31 (dd, J= 6.0, 2.3 Hz, 2H), 7.09 - 6.98 (m, 1H), 6.65 (t, J= 55.6 Hz, 1H), 4.29 (s, 2H), 4.15 (dd,J = 10.3, 6.5 Hz, 1H), 3.88 (dd, J = 23.1, 7.7 Hz, 1H), 3.81 (s, 3H), 3.68 - 3.61 (m, 3H), 3.29 (s, 2H), 2.76 (dd, J = 17.6, 4.8 Hz, 1H), 2.51 (s, 2H), 2.38 - 2.29 (m, 4H), 2.25 - 2.20 (m, 2H). MS (ESI) m / z = 519.7 [M+H]+.

[1130]

[1131] Example 2-2, Compound 336

[1134] Step a. To a mixture of tert-butyl 4-(6-carbam oylpyri din-3 -yl)piperazine-l - carboxylate (50 mg, 163.2 pmol), benzyl 6-chloro-2'-(difluoromethyl)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylate (72.7 mg, 179.5 pmol), Xantphos (14.2 mg, 24.5 pmol), CS2CO3 (106.3 mg, 326.4 pmol) in dioxane (2 mL) was added Pd(OAc)2 (7.3 mg, 32.6 pmol) and the mixture was degassed with Ar gas for 5 mins. The mixture was stirred at 90°C for 1.5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 6-(5-(4-(tert- butoxycarbonyl)piperazin-l-yl)picolinamido)-2'-(difluoromethyl)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylate (67.8 mg, 100.5 pmol, 61.6% yield, 98.2% purity) as a colorless oil. MS (ESI) m / z = 675.1 [M+H]+.

[1135] Step b. To a solution of benzyl 6-(5-(4-(tert-butoxycarbonyl)piperazin-l- yl)picolinamido)-2'-(difluoromethyl)-5'-methoxy-[4,4'-bipyridine]-3 -carboxylate (67.8 mg, 100.5 pmol) in DCM (3 mL) was added TFA (0.23 mL, 3.0 mmol) at 25°C. The mixture was stirred at 25°C for 17 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with DCM / Hex to obtain benzyl 2'-(difluoromethyl)-5'-methoxy-6-(5-(piperazin-l- yl)picolinamido)-[4,4'-bipyridine]-3-carboxylate (57.7 mg, 100.5 pmol, 100% yield, 97.8% purity) as a pale yellow solid. MS (ESI) m / z = 575.1 [M+H]+.

[1136] Step c. To a mixture of benzyl 2'-(difhioromethyl)-5'-methoxy-6-(5-(piperazin-l- yl)picolinamido)-[4,4'-bipyridine]-3-carboxylate (9.2 mg, 16.0 pmol), 5-fluoro-2-methyl- 3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (3.0 mg, 14.6 pmol) in THF (1 mL) was added TIPP (4.5 mg, 16 pmol), a drop of AcOH at 25 °C and the mixture was stirred at 25 °C for 0.5 h. To that mixture was added NaBH(OAc)3 (12.3 mg, 58.2 pmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 2'-(difluoromethyl)-6-(5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6- yl)methyl)piperazin-l-yl)picolinamido)-5'-methoxy-[4,4'-bipyridine]-3-carboxylate (7.8 mg, 10.2 pmol, 70.1% yield, 99.0% purity) as a white solid. MS (ESI) m / z = 765.0 [M+H]+.

[1137] Step d. To a solution of benzyl 2'-(difhioromethyl)-6-(5-(4-((5-fhioro-2-methyl-3- oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-l-yl)picolinamido)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylate (7.8 mg, 10.2 pmol) in THF (1 mL) / H20 (0.5 mL) was added LiOH (1.0 mg, 40.8 pmol) at 25 °C. The mixture was stirred at 25 °C for 19 h. The reaction mixture was concentrated under reduced pressure to obtain an aqueous layer. The aqueous layer was acidified by 1 N HC1 to obtain a pH of pH 2 and the precipitate was filtered off to obtain 2'-(difhioromethyl)-6-(5-(4-((5-fluoro-2-methyl-3-oxo-3,4- dihydroquinoxalin-6-yl)methyl)piperazin-l-yl)picolinamido)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylic acid (6.9 mg, 10.2 pmol, 100% yield, 97.5% purity) as a white solid. MS (ESI) m / z = 675.0 [M+H]+.

[1138] Step e. To a mixture of 2'-(difluoromethyl)-6-(5-(4-((5-fluoro-2-methyl-3-oxo-3,4- dihydroquinoxalin-6-yl)methyl)piperazin-l-yl)picolinamido)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylic acid (5.0 mg, 7.4 pmol), and TCFH (6.2 mg, 22.2 pmol) in ACN (0.5 mL) was added NMI (3.7 mg, 44.5 pmol) at 25 °C and the mixture was stirred at 25 °C for 0.5 h. To that mixture was added 4-(2-amino-[l,3]selenazolo[5,4-Z>]pyridin-5- yl)benzonitrile (2.4 mg, 8.2 pmol) at 25 °C. The mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain A-(5-(4-cyanophenyl)-[l,3]selenazolo[5,4-Z>]pyridin-2- yl)-2'-(difluoromethyl)-6-(5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6- yl)methyl)piperazin-l-yl)picolinamido)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide (1.8 mg, 1.9 pmol, 25.4% yield, 97.0% purity) as a white solid.

[1139] 'H NMR (400 MHz, CDCh) (5 = 10.57 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.19-8.18 (m, 1H), 8.12-8.07 (m, 3H), 7.71-7.67 (m, 5H), 7.61-7.58 (m, 1H), 7.54- 7.35 (m, 2H), 6.82-6.55 (m, 1H), 3.82 (s, 3H), 3.77 (s, 2H), 3.45-3.43 (m, 4H), 2.72-2.70 (m, 4H), 2.61 (s, 3H). MS (ESI) m / z = 957.1 [M+H]+

[1140]

[1141] Example 2-2, Compound 337

[1143] Step a. To a stirred solution of tert-butyl piperazine- 1 -carboxylate (2 g, 10.74 mmol) in MeCN (20 mL) was added TEA (1.63 g, 16.11 mmol, 2.24 mL) at 15 °C. To the mixture was added a solution of ethyl 2-chloro-2-oxo-acetate (1.61 g, 11.81 mmol, 1.32 mL) in MeCN (25 mL) at 0 °C. The reaction mixture was stirred at 15 °C for 12 h under an N2 atmosphere. The desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tertbutyl 4-(2-ethoxy-2-oxo-acetyl) piperazine- 1 -carboxylate (3 g, 10.48 mmol, 97.57% yield) as an off-white solid. MS (ESI) m / z = 309.0 [M+Na]+.

[1144] Step b. A mixture of tert-butyl 4-(2-ethoxy-2-oxo-acetyl) piperazine- 1 -carboxylate (1.5 g, 5.24 mmol) in NH -HzO (30 mL) and EtOH (15 mL) was stirred at 25 °C for 12 h under an N2 atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl 4- oxamoylpiperazine-1 -carboxylate (563 mg, 2.19 mmol, 41.77% yield) as an off-white solid.

[1145] 'H NMR (400 MHz, 400 MHz, CDCI3) 3 = 7.10 (br s, 1H), 5.80 (br s, 1H), 4.07- 4.00 (m, 2H), 3.67-3.59 (m, 2H), 3.52-3.45 (m, 4H), 1.46 (s, 9H). MS (ESI) m / z = 280.0 [M+Na]+.

[1146] Step c. To a stirred solution of benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]pyridine-3 -carboxylate (500 mg, 1.24 mmol) in dioxane (20 mL) were added tertbutyl 4-oxamoylpiperazine-l -carboxylate (349.58 mg, 1.36 mmol), CS2CO3 (804.90 mg, 2.47 mmol), Xantphos (142.94 mg, 247.04 pmol) and Pd(OAc)2 (55.46 mg, 247.04 pmol), and the reaction mixture was stirred at 110 °C for 16 h under an N2 atmosphere. The desired mass was detected. The suspension was filtered through a pad of celite and the filter cake was washed with DCM (20 mL x 2). The combined filtrates were concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl 4-[2-[[5-benzyloxycarbonyl-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-2- pyridyl]amino] -2-oxo-acetyl]piperazine-l -carboxylate (560 mg, 895.11 pmol, 72.47% yield) as a red-brown solid.

[1147] 'H NMR (400 MHz, 400 MHz, DMSO-tL) 3 = 11.74 (br s, 1H), 8.89 (br s, 1H), 8.40 (s, 1H), 8.02 (br s, 1H), 7.63 (s, 1H), 7.34-7.26 (m, 5H), 6.97 (t, J= 55.2 Hz, 1H), 5.14 (s, 2H), 3.74 (s, 3H), 3.53-3.47 (m, 2H), 3.45-3.41 (m, 2H), 3.40-3.35 (m, 4H), 1.41 (s, 9H). MS (ESI) m / z = 626.5 [M+H]+.

[1148] Step d. To a solution of tert-butyl 4-[2-[[5-benzyloxycarbonyl-4-[2-(difluoromethyl)- 5-methoxy-4-pyridyl]-2-pyridyl]amino]-2-oxo-acetyl]piperazine-l-carboxylate (500 mg, 799.21 pmol) in DCM (10 mL) were added Et3SiH (185.86 mg, 1.60 mmol, 255.30 pL), TEA (242.61 mg, 2.40 mmol, 333.72 pL) and Pd(OAc)2(53.83 mg, 239.76 pmol). The suspension was degassed and purged with N2 three times and the mixture was stirred at 40 °C for 12 h under an N2 atmosphere. The reaction mixture was concentrated underreduced pressure to remove DCM. The residue was purified by column to obtain 6-[[2-(4- tert-butoxycarbonylpiperazin-l-yl)-2-oxo-acetyl]amino]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]pyridine-3 -carboxylic acid (620 mg, crude) as an off-white solid. MS (ESI) m / z = 536.3 [M+H]+.

[1149] Step e. To a solution of 6-[[2-(4-tert-butoxy carbonylpiperazin- l-yl)-2-oxo- acetyl]amino]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]pyridine-3-carboxylic acid (200 mg, 373.49 pmol) in DMF (5 mL) and MeCN (1 mL) were added NMI (229.98 mg, 2.80 mmol), 4-(2-amino-[l,3]selenazolo[5,4-b]pyridin-5-yl)benzonitrile (139.68 mg, 466.86 pmol) and TCFH (392.97 mg, 1.40 mmol). The suspension was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 12 h under an N2 atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous ISfeSCU and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl 4-[2-[[5-[[5-(4-cyanophenyl)-[1.3]selenazolo[5,4-b]pyridin-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]-2-pyridyl] amino]-2-oxo-acetyl]piperazine-l -carboxylate (360 mg, 255.67 pmol, 54.76% yield, 58% purity) as a brown solid. MS (ESI) m / z =818.4 [M+H]+.

[1150] Step f (Compound 259). To a stirred solution of tert-butyl 4-[2-[[5-[[5-(4- cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]carbamoyl]-4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-2-pyridyl]amino]-2-oxo-acetyl]piperazine-l-carboxylate (340 mg, 416.32 pmol) in DCM (5 mL) was added TFA (1 mL), and the reaction mixture was stirred at 20 °C for 1 h under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove DCM and TFA. The crude product was purified by prep-HPLC and most of MeCN was removed under reduced pressure. The remaining solvent was removed by lyophilization to obtain N-[5-(4-cyanophenyl)-[1.3]selenazolo[5,4-b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[(2- oxo-2-piperazin-l-yl-acetyl)amino]pyridine-3 -carboxamide (114.16 mg, 159.32 pmol, 38.27% yield, 99.87 % purity, TFA) as a white solid.

[1151] 'H NMR (400 MHz, 400 MHz, DMSO-tL) 3 =13.39 (br s, 1H), 11.72 (br s, 1H), 8.96 (br s, 2H), 8.87 (br s, 1H), 8.51 (s, 1H), 8.35 (d, J= 8.4 Hz, 2H), 8.22 (s, 2H), 8.15 (br s, 1H), 7.97 (d, J= 8.4 Hz, 2H), 7.73 (s, 1H), 7.04 (t, J = 55.2 Hz, 1H), 3.72 (s, 7H), 3.27- 3.14 (m, 4H). MS (ESI) m / z =718.1 [M+H]+.

[1152] Step g. A solution of N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4-b]pyridin-2-yl]-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-6-[(2-oxo-2-piperazin-l-yl- acetyl)amino]pyridine-3-carboxamide;2,2,2-trifluoroacetic acid (5 mg, 0.006 mmol), 2- fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic acid (1.975 mg, 0.0066 mmol), TCFH (2.534 mg, 0.009 mmol) and NMI (2.4 uL, 0.0301 mmol) in ACN (0.5 mL) was stirred at 70 °C for 1 hour under an Ar atmosphere. The mixture was extracted with EA and water. Then, the combined organic layers were washed with brine, dried over MgSC and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford N-[5-(4-cyanophenyl)-[l,3]selenazolo[5,4- b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-[[2-[4-[2-fhioro-5-[(4-oxo- 3H-phthal azin-1 -yl)methyl]benzoyl]piperazin-l-yl]-2-oxo-acetyl]amino]pyridine-3- carboxamide (1.8 mg, 0.0018 mmol, 30% yield, 99% purity) as a white solid.

[1153] 'H NMR (400 MHz, 400 MHz, CDC13) 5 11.05 (s, 1H), 10.00 (d, J = 18.9 Hz, 1H), 8.86 (d, J = 10.4 Hz, 1H), 8.36 (ddd, J = 35.8, 18.1, 10.1 Hz, 3H), 8.18 (d, J = 8.5 Hz, 2H), 8.02 (dd, J= 15.6, 8.4 Hz, 1H), 7.84 (dd, J = 8.5, 3.5 Hz, 1H), 7.81 - 7.62 (m, 6H),7.40 (d, J = 5.4 Hz, 1H), 7.31 (s, 1H), 7.10 (dd, J = 13.9, 8.7 Hz, 1H), 6.62 (dt, J = 55.5, 27.8 Hz, 1H), 4.32 (d, J= 3.4 Hz, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 3.65 (d, J= 1.5 Hz, 4H),3.40 (s, 2H). MS (ESI) m / z = 998.1 [M+H]+.[H54]

[1155] Example 2-2, Compound 339

[1157] Step a. To a mixture of 2-oxopiperidine-4-carboxylic acid (100 mg, 699 pmol), tertbutyl piperazine- 1 -carboxylate (143 mg, 768 pmol), HATU (292 mg, 768 pmol) in ACN (4 mL) was added DIPEA (0.24 mL, 1.40 mmol) at 25 °C. The mixture was stirred at 25 °C for 22 h. The reaction mixture was filtered to obtain tert-butyl 4-(2-oxopiperidine- 4-carbonyl)piperazine-l -carboxylate (73.9 mg, 247 pmol, 35.4% yield, 97% purity) as a white solid. MS (ESI) m / z = 312.2 [M+H]+.

[1158] Step b. To a mixture of tert-butyl 4-(2-oxopiperidine-4-carbonyl)piperazine-l- carboxylate (70.7 mg, 227 pmol), benzyl 6-chloro-2'-(difluoromethyl)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylate (83.5 mg, 206 pmol), Xantphos (17.9 mg, 31 pmol), CS2CO3 (134 mg, 413 pmol) in dioxane (2 mL) was added Pd(OAc)2 (9.3 mg, 41 pmol) and the mixture was degassed with Ar gas for 5 mins. The mixture was stirred at 90°C for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 6-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-2-oxopiperidin-l-yl)-2'-(difluoromethyl)-5'-methoxy-[4,4'-bipyridine]-3- carboxylate (105.8 mg, 156 pmol, 75.5% yield, 97% purity) as a white solid. MS (ESI) m / z = 680.3 [M+H]+.

[1159] Step c. To a solution of benzyl 6-(4-(4-(tert-butoxycarbonyl)piperazine-l-carbonyl)-2-oxopiperidin-l-yl)-2'-(difluoromethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxylate (103 mg, 152 pmol) was added TFA (0.35 mL, 4.57 mmol) at 25°C. The mixture was stirred at 25 °C for 20 h. The reaction mixture was concentrated under reduced pressure to obtain benzyl 2'-(difluoromethyl)-5'-methoxy-6-(2-oxo-4-(piperazine-l-carbonyl)piperidin-l- yl)-[4,4'-bipyridine]-3-carboxylate (86.3 mg, 149 pmol, 97.8% yield, 99% purity) as a white solid. MS (ESI) m / z = 580.3 [M+H]+.

[1160] Step d. To a mixture of benzyl 2'-(difluoromethyl)-5'-methoxy-6-(2-oxo-4- (piperazine-l-carbonyl)piperidin-l-yl)-[4,4'-bipyridine]-3-carboxylate (20 mg, 35 pmol), 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoic acid (11.3 mg, 38 pmol), HATU (14.4 mg, 38 pmol) in DMF (0.5 mL) was added DIPEA (12 pL, 69 mmol) at 25 °C. The mixture was stirred at 25 °C for 21 h. The reaction mixture was diluted with EtOAc (10 mL) and extracted with H2O (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried with anhydrous MgSCL, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 2'-(difluoromethyl)-6-(4-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoyl)piperazine-l-carbonyl)-2-oxopiperidin-l-yl)-5'-methoxy-[4,4'- bipyridine]-3 -carboxylate (22.3 mg, 26 pmol, 75.2% yield, 97% purity) as a white solid. MS (ESI) m / z = 860.2 [M+H]+.

[1161] Step e. To a solution of benzyl 2'-(difhioromethyl)-6-(4-(4-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzoyl)piperazine-l-carbonyl)-2-oxopiperidin-l-yl)-5'- methoxy-[4,4'-bipyridine]-3-carboxylate (22.3 mg, 26 pmol) in MeOH (2 mL) was added 10% Pd / C (5.5 mg, 3 pmol) and the mixture was purged with EE gas three times at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered by celite filter and concentrated under reduced pressure to obtain 2'-(difluoromethyl)-6-(4-(4-(2-fluoro- 5-((4-oxo-3 ,4-dihydrophthalazin- 1 -yl)methyl)benzoyl)piperazine- 1 -carbonyl)-2- oxopiperidin-l-yl)-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (18 mg, 23 pmol, 90.2% yield, 98% purity) as a white solid. MS (ESI) m / z = 770.1 [M+H]+.

[1162] Step f. To a mixture of 2'-(difluoromethyl)-6-(4-(4-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzoyl)piperazine-l-carbonyl)-2-oxopiperidin-l-yl)-5'- methoxy-[4,4'-bipyridine]-3-carboxylic acid (10 mg, 13 pmol), TCFH (10.9 mg, 39 pmol) in ACN (1 mL) was added NMI (6.2 pL, 78 pmol) at 25 °C and stirred at 25 °C for 0.5 h. To the mixture was added 4-(2-amino-[l,3]selenazolo[5,4-b]pyridin-5- yl)benzonitrile (5.9 mg, 14 pmol, TFA) at 25 °C. The mixture was stirred at 70 °C for 20 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain A-(5-(4-cyanophenyl)-[l,3]selenazolo[5,4- Z>]pyridin-2-yl)-2'-(difluoromethyl)-6-(4-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzoyl)piperazine-l-carbonyl)-2-oxopiperidin-l-yl)-5'-methoxy-[4,4'- bipyridine]-3-carboxamide (2.5 mg, 2.4 pmol, 18.3% yield, 98% purity) as a white solid.

[1163] 'H NMR (400 MHz, CDCh) d = 11.86 (s, 1H), 11.26 (s, 1H), 8.78-8.75(m, 1H), 8.45-8.42 (m, 1H), 8.27 (s, 1H), 8.19-8.13 (m, 3H), 7.78-7.75 (m, 7H), 7.63-7.61 (m, 1H), 7.36-7.35 (m, 1H), 7.10-7.06 (m, 1H), 6.98 (s, 1H), 6.76-6.48 (m, 1H), 4.30 (s, 2H), 4.12- 3.99 (m, 3H), 3.77-3.73 (m, 4H), 3.69-3.62 (m, 4H), 3.47 (s, 1H), 3.36 (s, 1H), 3.28-3.11 (m, 2H), 2.62-2.59 (m, 1H), 2.15-2.02 (m, 2H). MS (ESI) m / z = 526.7 [1 / 2M+H]+.

[1164]

[1165] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or example 2-2 referring to the procedure described above.

[1166]

[1167] Example 3-1, Compound 56

[1168]

[1169] Step a. A mixture of 5-bromo-2-chloro-3-fluoropyridine (1 g, 4.75 mmol), Pd2(dba)3 (130.5 mg, 0.14 mmol), Xantphos (110 mg, 0.19 mmol), CS2CO3 (132.7 mg, 0.62 mmol), tert-butyl carbamate (612.4 mg, 5.23 mmol) in dioxane (10 mL) was degassed with nitrogen for 5 mins at 25 °C and stirred at 85 °C for 18 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was used in the next step directly without having been further purified. MS (ESI) m / z = 247.1 [M+H]+.

[1170] Step b. To a mixture of tert-butyl (6-chl oro-5 -fluoropyri din-3 -yl)carbamate (500 mg, 2.03 mmol), TMEDA (707 mg, 6.08 mmol) in Et20 (10 mL) was added dropwise n-BuLi (1.6 M in hexane) (3.8 mL, 6.08 mmol) at -78 °C. The mixture was stirred at -20 °C for 2 h. To that mixture was added dropwise l,2-dibromo-l,l,2,2-tetrafluoroethane (1.63 g, 6.28 mmol) at -78 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by 1 N HC1 (5.0 mL) and extracted with Et20 (50 mL x 2) and H2O (50 mL x2). The combined organic layers were dried over MgSCh, filtered and concentrated under reduced pressure to obtain a residue. The residue was used in the next step directly without being further purified. MS (ESI) m / z = 325.0 [M+H]+.

[1171] Step c. A solution of tert-butyl (4-bromo-6-chloro-5-fluoropyridin-3-yl)carbamate (1 g, 3.07 mmol) in TFA (15 mL) and H2O (7.5 mL) was stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc (50 mL x 2) and aq. NaHCCL (30 mL x 2). The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure to obtain a residue. The residue was used in the next step directly without having been further purified. MS (ESI) m / z = 225.1 [M+H]+.

[1172] Step d. To a mixture of 4-bromo-6-chloro-5-fluoropyridin-3-amine (500 mg, 2.22 mmol), KSeCN (479.3 mg, 3.33 mmol) in AcOH (20 mL) was added Bn (708.8 mg, 4.44 mmol) at 25 °C. The mixture was stirred at 70 °C for 15 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with H2O and filtered to obtain N-(6-chloro-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-yl)acetamide (456 mg, 1.56 mmol, 70% yield, 95% purity) as an orange solid. MS (ESI) m / z = 294.0 [M+H]+.

[1173] Step e. A mixture of N-(6-chloro-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2- yl)acetamide (100 mg, 0.34 mmol), Pd(XPhos)G2 (13.4 mg, 0.02 mmol), K3PO4 (145.1 mg, 0.68 mmol), and (4-cyanophenyl)boronic acid (55.2 mg, 0.38 mmol) in THF (5 mL) / H20 (0.5 mL) was degassed with nitrogen for 5 mins at 25 °C and stirred at 80 °C for 18 h. The reaction mixture was extracted with EtOAc (10 mL x 2) and H2O (10 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain N-(6- (4-cyanophenyl)-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-yl)acetamide (75.8 mg, 0.21 mmol, 62% yield, 97% purity) as a white solid. MS (ESI) m / z = 361.0 [M+H]+.

[1174] Step f. To a solution of N-(6-(4-cyanophenyl)-7-fluoro-[l,3]selenazolo[4,5- c]pyridin-2-yl)acetamide (100 mg, 0.28 mmol) in THF (5 mL) was added NaOH (12.2 mg, 0.31 mmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. The reaction mixture was extracted with EtOAc (20 mL x 2) and H2O (20 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain residue. The residue was used in the next step directly without having been further purified. MS (ESI) m / z = 319.0 [M+H]+.

[1175] Step g. To a mixture of Intermediate 2 (48.3 mg, 0.17 mmol), HATU (65.9 mg, 0.17 mmol), DIEA (40.7 mg, 0.32 mmol) in DMF (2 mL) was added 4-(2-amino-7-fluoro- [l,3]selenazolo[4,5-c]pyridin-6-yl)benzonitrile (50 mg, 0.16 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was extracted with EtOAc (10 mL x 2) and H2O (10 mL x 2). The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure to obtain residue. The residue was purified column to obtain 2'-chloro-N-(6-(4-cyanophenyl)-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-yl)-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (56 mg, 0.10 mmol, 61% yield, 97% purity) as a white solid.

[1176] 1H NMR (400 MHz, DMSO) 5 13.44 (s, 1H), 9.11 (s, 1H), 8.57 (d, J = 5.6 Hz, 2H), 8.23 (s, 1H), 8.13 (d, J = 7.6 Hz, 2H), 7.91 (s, 1H), 7.70 (d, J = 7.6 Hz, 2H), 3.78 (s, 3H), 2.63 (s, 3H). MS (ESI) m / z = 579.1 [M+H]+.

[1177]

[1178] Example 3-1, Compound 60

[1180] Step a. To a solution of 5 -bromo-2-chl oro-3 -fluoro-pyridine (10 g, 47.52 mmol) in dioxane (200 mL) were added tert-butyl carbamate (6.12 g, 52.27 mmol), CS2CO3 (30.97 g, 95.04 mmol), Xantphos (1.10 g, 1.90 mmol) and Pd2(dba)3 (1.31 g, 1.43 mmol). Themixture was degassed with N2 three times, and then stirred at 85 °C for 12 h under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl N-(6-chloro-5-fluoro-3- pyridyl)carbamate (12 g, 38.43 mmol, 80.87% yield, 79% purity) as a yellow solid. MS (ESI) m / z = 247.1 [M+H]+.

[1181] Step b. To a solution of tert-butyl N-(6-chloro-5-fluoro-3-pyridyl)carbamate (4 g, 16.22 mmol) in THF (80 mL) was added TMEDA (5.65 g, 48.65 mmol, 7.34 mL). The mixture was degassed and purged with N2 three times. Then n-BuLi (2.5 M, 19.46 mL in hexane) was added to the mixture slowly at -78 °C. The mixture was stirred at -20 °C under an N2 atmosphere for 1.5 h. Then l,2-dibromo-l,l,2,2-tetrafhioro-ethane (12.64 g, 48.65 mmol) was added to the mixture slowly at -78 °C. The mixture was warmed to 25 °C and stirred at 25 °C under an N2 atmosphere for 1 h. The reaction mixture was quenched by addition 2 M HC1 (~40 mL) under N2, and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl N-(4-bromo-6-chloro-5-fluoro-3- pyridyl)carbamate (4.49 g, 13.52 mmol, 83.35% yield, 98% purity) as a yellow solid.

[1182] 'H NMR (400 MHz, DMSO ) d = 9.24 (s, 1H), 8.36 (s, 1H), 1.46 (s, 9H). MS (ESI) m / z = 325.0 [M+H]+.

[1183] Step c. To a solution of tert-butyl N-(4-bromo-6-chloro-5-fluoro-3- pyridyl)carbamate (6.6 g, 20.27 mmol) in DCM (90 mL) was added TFA (30 mL). The mixture was stirred at 25 °C for 1 h under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in EtOAc (~50 mL) and was neutralized with sat. aq. NaHCOs. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 4-bromo-6-chloro-5-fluoro-pyridin-3-amine (4.08 g, 17.74 mmol, 87.48% yield, 98% purity) as a yellow solid. MS (ESI) m / z = 227.0 [M+H+2]+.

[1184] Step d. To a solution of 4-bromo-6-chl oro-5 -fluoro-pyri din-3 -amine (3.45 g, 15.30 mmol) in acetone (85 mL) was added benzoyl isosel enocyanate (9.65 g, 45.91 mmol). The mixture was heated to 70 °C and stirred at 70 °C for 2 h under a nitrogen atmosphere. The reaction mixture was filtered, and the cake was concentrated under reduced pressureto obtain N-(6-chloro-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-yl)benzamide (5.5 g, crude) as a brown solid. MS (ESI) m / z = 356.0 [M+H]+.

[1185] Step e. Two batches were set up at the same time. The procedure of each batch was as follow: A solution of N-(6-chloro-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2- yl)benzamide (2.75 g, 7.75 mmol) in H2SO4 (126.50 g, 902.88 mmol, 20 mL, 70% purity) was stirred at 120 °C for 1 h under a nitrogen atmosphere. The mixture was neutralized with aq. NaOH. A new solid was appeared. The solid was filtered, washed with H2O (~50 mL x 3) and dried by lyophilization to obtain 6-chloro-7-fluoro-[l,3]selenazolo[4,5- c]pyridin-2-amine (2 g, 5.99 mmol, 38.61% yield, 75% purity) as a brown solid. MS (ESI) m / z = 252.0 [M+H]+.

[1186] 'H NMR (400 MHz, DMSO-tL) 3 = 8.24 (br s, 2H), 8.22 (s, 1H).

[1187] Step f. To a solution of 6-chloro-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-amine (1.5 g, 5.99 mmol) in toluene (75 mL) were added hexane-2, 5-dione (1.37 g, 11.98 mmol, 1.40 mL) and TsOH H2O (227.79 mg, 1.20 mmol). The mixture was degassed and purged with N2 three times. The mixture was stirred at 130 °C for 12 h under an N2 atmosphere. The mixture was added TEA (~2.5 mL) and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain 6-chloro-2-(2,5- dimethylpyrrol-l-yl)-7-fluoro-[l,3]selenazolo[4,5-c]pyridine (1.12 g, 3.34 mmol, 55.78% yield, 98% purity) as a pink solid. MS (ESI) m / z = 330.0 [M+H]+.

[1188] Step g. To a solution of 6-chloro-2-(2,5-dimethylpyrrol-l-yl)-7-fluoro- [l,3]selenazolo[4,5-c]pyridine (100 mg, 304.29 pmol) in dioxane (2.5 mL) and H2O (0.5 mL) were added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (203.64 mg, 912.88 pmol), XPhos (14.51 mg, 30.43 pmol), Cs2CO3(297.43 mg, 912.88 pmol) and XPhos Pd G3 (51.51 mg, 60.86 pmol). The mixture was degassed and purged with N2 three times. The mixture was heated to 100 °C and stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column to obtain 4-[2-(2,5-dimethylpyrrol-l-yl)-7- fluoro-[l,3]selenazolo[4,5-c]pyridin-6-yl]-3,5-dimethyl-isoxazole (89 mg, 217.19 pmol, 71.38% yield, 95% purity) as a white solid.

[1189] XH NMR (400 MHz, CDCh) 3 = 9.17 (d, J = 2.0 Hz, 1H), 6.00 (s, 2H), 2.51 (d, J = 1.6 Hz, 3H), 2.46 (s, 6H), 2.38 (d, J= 1.2 Hz, 3H). MS (ESI) m / z = 391.1 [M+H]+.

[1190] Step h. A solution of 4-[2-(2,5-dimethylpyrrol-l-yl)-7-fluoro-[l,3]selenazolo[4,5- c]pyridin-6-yl]-3,5-dimethyl-isoxazole (300 mg, 770.64 pmol) in 2 M HC1 (8 mL) and THF (8 mL) was heated to 70 °C and stirred at 70 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to remove THF. The mixture was dissolved in MeCN (4 mL) and purified by reversed-phase HPLC to obtain 6-(3,5- dimethylisoxazol-4-yl)-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-amine (233 mg, 726.32 pmol, 94.25% yield, 97% purity) as a light brown solid. MS (ESI) m / z = 313.1 [M+H]+.

[1191] Step i. To a solution of 4-(2-chloro-5-methoxy-4-pyridyl)-6-methyl-pyridine-3- carboxylic acid (53.74 mg, 192.82 pmol) in DMF (1 mL) were added 6-(3,5- dimethylisoxazol-4-yl)-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-amine (40 mg, 128.55 pmol), DIEA (33.23 mg, 257.09 pmol, 44.78 pL) and PYBOP (100.34 mg, 192.82 pmol). The mixture was stirred at 50 °C for 3 h under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in MeCN (2 mL) and purified by Prep-HPLC to obtain 4-(2-chloro-5-methoxy-4-pyridyl)- N-[6-(3,5-dimethylisoxazol-4-yl)-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-2-yl]-6-methyl- pyridine-3-carboxamide (11.65 mg, 20.05 pmol, 15.60% yield, 98.428% purity) as a brown solid.

[1192] XH NMR (400 MHz, DMSO-tL) 3 = 13.80 (s, 1H), 9.03 (s, 1H), 8.90 (s, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 3.59 (s, 3H), 2.62 (s, 3H), 2.43 (s, 3H), 2.26 (s, 3H). MS (ESI) m / z = 573.1 [M+H]+.

[1193]

[1194] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or example 3-1 referring to the procedure described above.

[1195]

[1196] Example 3-2, Compound 157

[1198]

[1199] Step a. To a solution of benzyl 6-chloro-4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]pyridine-3 -carboxylate (400 mg, 988.16 pmol) and 4,7-diazaspiro[2.5]octan-8- one (149.59 mg, 1.19 mmol) in dioxane (10 mL) were added Pd(OAc)2 (22.18 mg, 98.82 pmol), Xantphos (85.76 mg, 148.22 pmol) and CS2CO3 (643.92 mg, 1.98 mmol) under a nitrogen atmosphere. The reaction mixture was degassed and purged with N2 three times, and was stirred at 80 °C for 1.5 hr under an N2 atmosphere. The reaction mixture was filtered, and the filter cake was washed EtOAc (5 mL x 2). Then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(8-oxo-4,7- diazaspiro[2.5]octan-7-yl)pyridine-3-carboxylate (415 mg, 797.29 pmol, 80.68% yield, 95%purity) as a yellow foamy solid.

[1200] 'H NMR (400 MHz, DMSO-d6) 8 = 8.93 (s, 1H), 8.38 (s, 1H), 8.00 (s, 1H), 7.55 (s, 1H), 7.33-7.28 (m, 3H), 7.14-7.10 (m, 2H), 6.95 (t, J = 55.2 Hz, 1H), 5.14 (s, 2H), 4.09 (t, J = 5.2 Hz, 2H), 3.72 (s, 3H), 3.28-3.19 (m, 1H), 3.15-3.07 (m, 2H), 1.24 (q, J = 3.6 Hz, 2H), 0.85 (q, J = 3.6 Hz, 2H).

[1201] Step b. To a solution of benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(8- oxo-4, 7-diazaspiro[2.5]octan-7-yl)pyridine-3-carboxylate (395 mg, 798.80 pmol) in THF (10 mL) were added formaldehyde (1.30 g, 15.98 mmol, 1.19 mL, 37% purity) and NaBH(OAc)3 (507.90 mg, 2.40 mmol). The mixture was stirred at 40 °C for 0.5 h under an N2 atmosphere. The reaction mixture was quenched by addition of aq. NaHCCL (20 mL) and then extracted with EtOAc (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain benzyl 4-[2-(difluoromethyl)-5-methoxy-4- pyridyl]-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)pyridine-3-carboxylate (399 mg, 706.17 pmol, 88.40% yield, 90% purity) as a yellow solid.

[1202] 'H NMR (400 MHz, DMSO-d6) 6 = 8.94 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.34-7.28 (m, 3H), 7.14-7.10 (m, 2H), 6.96 (t, J = 54.8 Hz, 1H), 5.14 (s, 2H), 4.20 (t,J = 5.6 Hz, 2H), 3.72 (s, 3H), 3.26 (t, J = 5.6 Hz, 2H), 2.45 (s, 3H), 1.25 (q, J = 3.6 Hz, 2H), 0.97 (q, J = 3.6 Hz, 2H). MS (ESI) m / z = 509.0 [M+H]+.

[1203] Step c. To a solution of benzyl 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(4- methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)pyridine-3-carboxylate (379 mg, 745.31 pmol) in THF (11.4 mL), MeOH (3.8 mL) and H2O (3.8 mL) was added LiOH H2O (62.55 mg, 1.49 mmol). The mixture was stirred at 40 °C for 1 h under an N2 atmosphere. The reaction mixture was washed with EtOAc (20 mL). The aqueous phase was adjusted to a pH of pH 4 with IN HC1, then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was slurred with DCM (10 mL). The mixture was filtered. The filter cake was washed with DCM (2 mL x 2), and then dried in a vacuum to obtain 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan- 7-yl)pyridine-3-carboxylic acid (273 mg, 606.82 pmol, 81.42% yield, 93% purity) as a white solid.

[1204] 'H NMR (400 MHz, DMSO-d6) 8 = 12.95 (br s, 1H), 8.89 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 6.96 (t, J = 55.2 Hz, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.26 (t, J = 5.6 Hz, 2H), 2.46 (s, 3H), 1.25 (q, J = 3.6 Hz, 2H), 0.97 (q, J = 3.6 Hz, 2H). MS (ESI) m / z = 419.0 [M+H]+.

[1205] Step d. To a solution of 4-(2-amino-7-fluoro-[l,3]selenazolo[4,5-c]pyridin-6- yl)benzonitrile (25 mg, 78.82 pmol) in DMF (1.3 mL) and MeCN (0.65 mL) were added 4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan- 7-yl)pyridine-3-carboxylic acid (39.57 mg, 94.58 pmol) and NMI (38.83 mg, 472.92 pmol, 37.70 pL). The mixture was stirred at 70 °C for 5 min under an N2 atmosphere. Then TCFH (66.35 mg, 236.46 pmol) was added to the reaction mixture at 70 °C. The mixture was stirred at 70 °C for 12 h under an N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford residue. The residue was purified by prep-HPLC. The remaining solvent was removed by lyophilization to obtain N-[6-(4-cyanophenyl)-7-fluoro- [l,3]selenazolo[4,5-c]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-(4- methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)pyridine-3-carboxamide (3.78 mg, 4.55 pmol, 5.77% yield, 100% purity, TFA) as a white solid.

[1206] 1H NMR (400 MHz, CDC13) 5 = 8.85 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.17 (d, J =7.6 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.63 (s, 1H), 6.68 (t, J = 55.6 Hz, 1H), 4.47 (t, J =5.6 Hz, 2H), 3.80 (s, 3H), 3.65 (t, J = 6.0 Hz, 2H), 2.82 (s, 3H), 1.70-1.62 (m, 2H), 1.55- 1.47 (m, 2H). MS (ESI) m / z = 719.1 [M+H]+.

[1207]

[1208] Example 3-2, Compound 331of 4-(2-chloro-3-fluoro-5-methoxy-4-pyridyl)-N-[5-(3,5- dimethylisoxazol-4-yl)-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl]-6-(8-oxo-4,7- diazaspiro[2.5]octan-7-yl)pyridine-3-carboxamide;2,2,2-trifluoroacetic acid (2.4 mg, 0.0029 mmol), 2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic acid (0.967 mg, 0.0032 mmol), TCFH (1.241 mg, 0.0044 mmol) and NMI (1 uL, 0.0147 mmol) in DMF (0.5 mL) was stirred at 40 °C for 16 hour under an Ar atmosphere. The mixture was extracted with EA and water. The combined organic layers were washed with brine, dried over MgSCU and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford 4-(2-chloro-3-fluoro-5-methoxy-4- pyridyl)-N-[5-(3,5-dimethylisoxazol-4-yl)-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl]-6- [4-[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoyl]-8-oxo-4,7- diazaspiro[2.5]octan-7-yl]pyridine-3-carboxamide (1.8 mg, 0.0018 mmol, 62% yield, 98% purity) as a white solid.

[1211] XH NMR (400 MHz, DMSO) 5 13.60 (s, 1H), 12.61 (s, 1H), 9.10 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.19 (s, 1H), 8.13 - 7.75 (m, 5H), 7.49 - 7.16 (m, 3H), 4.35 (s, 2H), 3.92 (dd, J = 89.1, 25.7 Hz, 4H), 3.73 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 0.99 (s, 2H), 0.85 (d, J = 6.8 Hz, 2H). MS (ESI) m / z = 980.9 [M+H]+.

[1212]

[1213] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or example 3-2 referring to the procedure described above.

[1214]

[1215] Example 4-1, Compound 94

[1216]

[1217] Step a. To a solution of 2-bromo-5-fluoropyridin-3-amine (2 g, 10.47 mmol) in ACN (20 mL) was added N-bromosuccinimide (2.05 g, 11.52 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with EtOAc (50 mL x 2) and H2O (50 mL x 2). The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain 2,6-dibromo-5-fhioropyridin-3-amine (2.58 g, 9.56 mmol, 91% yield, 97% purity) as a brown solid. MS (ESI) m / z = 269.0 [M+H]+.

[1218] Step b. To a solution of 2,6-dibromo-5-fluoropyridin-3-amine (1 g, 3.71 mmol) in acetone (7 mL) was added benzoyl isoselenocyanate (1.17 g, 5.56 mmol) at 25 °C. The mixture was stirred at 60 °C for 4 h. The mixture was cooled in an ice bath and filtered to obtain N-((2,6-dibromo-5-fluoropyridin-3-yl)carbamoselenoyl)benzamide (1.5 g, 3.12 mmol, 84% yield, 95% purity) as a white solid. MS (ESI) m / z = 480.0 [M+H]+.

[1219] Step c. To a solution of N-((2,6-dibromo-5-fluoropyridin-3-yl)carbamoselenoyl)- benzamide (1 g, 2.08 mmol) in MeOH (5 mL) was added NaOH (6 M in H2O) (4 mL) at 25 °C. The mixture was stirred at 70 °C for 5 h. The mixture was cooled in an ice bath and filtered to obtain 5-bromo-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-amine (532 mg, 1.80 mmol, 87% yield, 95% purity) as a white solid. MS (ESI) m / z = 296.0 [M+H]+.

[1220] Step d. To a mixture of Intermediate 2 (52.0 mg, 0.19 mmol), HATU (70.9 mg, 0.19 mmol), and DIEA (43.8 mg, 0.34 mmol) in DMF (2 mL) was added 5-bromo-6-fluoro- [l,3]selenazolo[5,4-b]pyridin-2-amine (50 mg, 0.17 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was extracted with EtOAc (10 mL x 2) and H2O (10 mL x 2). The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain N-(5-bromo-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl)-2'-chloro-5'- methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (72 mg, 0.13 mmol, 76% yield, 97% purity) as a white solid. MS (ESI) m / z = 556.1 [M+H]+.

[1221] Step e. A mixture of N-(5-bromo-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl)-2'- chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100 mg, 0.18 mmol), Pd(XPhos)G2 (7.1 mg, 0.01 mmol), K3PO4 (76.4 mg, 0.36 mmol), and (4- cyanophenyl)boronic acid (29.1 mg, 0.20 mmol) in THF (5 mLyELO (0.5 mL) was degassed with nitrogen for 5 mins at 25 °C and stirred at 80 °C for 18 h. The reaction mixture was extracted with EtOAc (10 mL x 2) and H2O (10 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain 2'-chloro-N-(5-(4- cyanophenyl)-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide (54 mg, 0.09 mmol, 52% yield, 97% purity) as a white solid.

[1222] MS (ESI) m / z = 579.1 [M+H]+.

[1223]

[1224] Example 4-1, Compound 335

[1226] Step a. To a solution of tert-butyl 4-(4-bromophenyl)-4-cyano-piperidine-l- carboxylate (300 mg, 821.32 pmol) and 4, 4,5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (417.13 mg, 1.64 mmol) in dioxane (15 mL) were added Pd(dppf)C12-DCM (67.07 mg, 82.13 pmol) and KO Ac (241.82 mg, 2.46 mmol). The mixture was stirred at 100 °C for 12 h under an N2 atmosphere. The reaction mixture was filtered, and the filter cake was washed with EtOAc (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-cyano-4-[4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]piperi dine- 1 -carboxylate (235 mg, crude) as a dark brown oil, which was used for next step without being further purified. MS (ESI) m / z = 413.4 [M+H]+.

[1227] Step b. To a solution of N-(5-bromo-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl)-4- [2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-methyl-pyridine-3-carboxamide (80 mg, 140.05 pmol) in dioxane (5 mL) and H2O (1 mL) were added tert-butyl 4-cyano-4-[4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]piperi dine- 1 -carboxylate (230.99 mg, 560.22 pmol), CS2CO3 (136.90 mg, 420.16 pmol), XPhos (13.35 mg, 28.01 pmol) and XPhos Pd G3 (11.85 mg, 14.01 pmol). The mixture was degassed and purged with N2 three times. Then the mixture was heated to 100 °C and stirred at 100 °C for 2 h under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl 4-cyano-4-[4-[2-[[4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-6-methyl-pyridine-3-carbonyl]amino]-6-fluoro-[1.3]selenazolo[5,4-b]pyridin-5-yl]phenyl]piperidine-l-carboxylate (261.2 mg, crude) as a dark brown solid. MS (ESI) m / z = 778.3 [M+H]+.

[1228] Step c. To a solution of tert-butyl 4-cyano-4-[4-[2-[[4-[2-(difluoromethyl)-5- methoxy-4-pyridyl]-6-methyl-pyridine-3-carbonyl]amino]-6-fluoro-[l,3]selenazolo[5,4- b]pyridin-5-yl]phenyl]piperidine-l -carboxylate (150 mg, 193.13 pmol) in DCM (7.5 mL) was added TFA (2.30 g, 20.19 mmol, 1.50 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC. The remaining solvent was removed by lyophilization to give a crude product. The crude product was further purified by prep- HPLC. The remaining solvent was removed by lyophilization to obtain compound 254, N-[5-[4-(4-cyano-4-piperidyl)phenyl]-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-2-yl]-4-[2- (difluoromethyl)-5-methoxy-4-pyridyl]-6-methyl-pyridine-3-carboxamide (51.38 mg, 64.93 pmol, 33.62% yield, 99.9% purity, TFA) as a yellow solid.

[1229] 'H NMR (400 MHz, DMSO ) d = 13.45 (s, 1H), 8.88 (s, 1H), 8.83-8.73 (m, 1H), 8.63-8.52 (m, 1H), 8.47 (s, 1H), 8.24 (d, J = 12.8 Hz, 1H), 8.08 (d, J = 7.6 Hz, 2H), 7.76 (s, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.50 (s, 1H), 7.01 (t, J= 55.2 Hz, 1H), 3.70 (s, 3H), 3.56 (d, J = 12.0 Hz, 2H), 3.22-3.12 (m, 2H), 2.63 (s, 3H), 2.48-2.42 (m, 2H), 2.32-2.23 (m, 1H). MS (ESI) m / z = 678.1 [M+H]+.

[1230] Step d. A solution of N-[5-[4-(4-cyano-4-piperidyl)phenyl]-6-fluoro-[1.3]selenazolo[5,4-b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6- methyl-pyridine-3-carboxamide;2,2,2-trifluoroacetic acid (5 mg, 0.0063 mmol), 2-fluoro- 5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic acid (2.075 mg, 0.007 mmol), TCFH (2.662 mg, 0.0095 mmol) and NMI (2.5 uL, 0.0316 mmol) in ACN (0.5 mL) was stirred at 70 °C for 1 hour under an Ar atmosphere. The mixture was extracted with EA and water. The combined organic layers were washed with brine, dried over MgSCL and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column to afford N-[5-[4-[4-cyano-l-[2-fluoro-5-[(4-oxo-3H- phthalazin-l-yl)methyl]benzoyl]-4-piperidyl]phenyl]-6-fluoro-[l,3]selenazolo[5,4- b]pyridin-2-yl]-4-[2-(difluoromethyl)-5-methoxy-4-pyridyl]-6-methyl-pyridine-3- carboxamide (1.4 mg, 0.0015 mmol, 23% yield, 98% purity) as a white solid.

[1231] 'H NMR (400 MHz, CDC13) 5 12.63 (s, 1H), 9.07 (s, 1H), 8.47 (d, J = 7.5 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J= 7.9 Hz, 2H), 7.85 (d, J = 9.7 Hz, 3H), 7.66 (s, 1H), 7.60 - 7.33(m, 5H), 7.28 (s, 1H), 7.16 (s, 1H), 7.09 - 6.87 (m, 1H), 6.62 (t, J= 55.5 Hz, 1H), 4.35 (s, 2H), 3.79 (s, 3H), 3.49 (s, 1H), 3.23 (s, 1H), 2.75 (s, 3H), 2.31 - 2.19 (m, 2H), 2.14 (dd, J = 19.7, 6.4 Hz, 2H), 2.01 (d, J= 6.9 Hz, 2H). MS (ESI) m / z = 958.1 [M+H]+.

[1232]

[1233] Example 4-1, Compound 350

[1235] Step a. To a mixture of tert-butyl (5-bromo-6-fluoro-[l,3]selenazolo[5,4-Z>]pyridin- 2-yl)carbamate (10 mg, 25 pmol), 4-(4-fluoro-3 -(piperazine- 1- carbonyl)benzyl)phthalazin-l(2rt)-one (9.3 mg, 25 pmol), Ruphos (7.1 mg, 15 pmol), and Z-BuONa (7.3 mg, 76 pmol) in dioxane (1 mL) was added Pd2(dba)3 (13.9 mg, 15 pmol) at 25°C. The mixture was degassed with Ar gas for 5 mins. The mixture was stirred at 100°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain tert-butyl (6-fluoro-5-(4- (2-fluoro-5-((4-oxo-3 ,4-dihydrophthalazin- 1 -yl)methyl)benzoyl)piperazin- 1 -yl)- [l,3]selenazolo[5,4-Z>]pyridin-2-yl)carbamate (13.1 mg, 19 pmol, 76.0% yield, 99% purity) as a white solid. MS (ESI) m / z = 682.1 [M+H]+.

[1236] Step b. To a solution of tert-butyl (6-fluoro-5-(4-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-l-yl)methyl)benzoyl)piperazin-l-yl)-[l,3]selenazolo[5,4-b]pyridin-2- yl)carbamate (10.6 mg, 16 pmol) in DCM (1 mL) was added TFA (24 pL, 311 pmol) at 25°C. The mixture was stirred at 25°C for 24 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with DCM / Hex to obtain 4-(3-(4-(2-amino-6-fluoro-[l,3]selenazolo[5,4-b]pyridin-5- yl)piperazine-l-carbonyl)-4-fluorobenzyl)phthalazin-l(2H)-one (9 mg, 15 pmol, 99.6% yield, 98% purity) as a pale yellow solid. MS (ESI) m / z = 582.1 [M+H]+.

[1237] Step c. To a mixture of 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxylic acid (5.6 mg, 19 pmol) and TCFH (14.5 mg, 52 pmol) in ACN (1 mL) was added NMI (8.3 pL, 103 pmol) at 25 °C and stirred at 25 °C for 0.5 h. To that mixture was added 4-(3 -(4-(2-amino-6-fluoro-[ 1,3] selenazolo[5,4-Z>]pyridin-5-yl)piperazine- 1 - carbonyl)-4-fluorobenzyl)phthalazin-l(2J7)-one (10 mg, 17 pmol) at 25 °C. The mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column to obtain 2'- (difluoromethyl)-A-(6-fluoro-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l- yl)methyl)benzoyl)piperazin- 1 -yl)-[ 1 ,3 ]selenazolo[5, 4-Z>]pyri din-2 -yl)-5'-methoxy-6- methyl-[4,4'-bipyridine]-3-carboxamide (7.2 mg, 8.4 pmol, 48.8% yield, 99% purity) as a pale yellow solid.

[1238] XH NMR (400 MHz, DMSO ) d = 13.17 (s, 1H), 12.60 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 8.27 (d, J= 7.9 Hz, 1H), 8.03-7.98 (m, 2H), 7.91 (t, J= 7.0 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.74 (s, 1H), 7.48-7.40 (m, 3H), 7.28-7.23 (m, 1H), 7.01 (t, J = 55.1 Hz, 1H), 4.35 (s, 2H), 3.80 (br s, 2H), 3.69 (s, 3H), 3.46 (br s, 2H), 3.32 (br s, 4H), 2.62 (s, 3H). MS (ESI) m / z = 858.0 [M+H]+.

[1239]

[1240] Example 4-1, Compound 262dimethoxyphenyl)methyl]methanesulfonamide (300.00 mg, 545.00 pmol) in dioxane (5 mL) were added Pd(dppf)C12 (39.88 mg, 54.50 pmol), 4,4,5,5-tetramethyl-2- (4, 4, 5, 5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (415.19 mg, 1.63 mmol) andKO Ac (160.46 mg, 1.63 mmol). The mixture was stirred at 100 °C for 16 h under an N2 atmosphere. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic...

Claims

1. CLAIMS

1. A compound of the following Formula (I):wherein: each of X1, X2and X3is N or CH;X4is C or N, provided that when X4is N, S1and A are absent; each of Y1, Y2, and Y3is N or CR1;R1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl;A is absent or is selected from the group consisting of R2and a PARP inhibitor moiety;R2is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, a 3- to 14-membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, -NH(3- to 14-membered carbocyclic group), -NH(3- to 14-membered heterocyclic group), halogen, cyano, hydroxy, amino, mercapto, carbamoyl, -NO2, -N3, -SF5, -S(Ci-Ce alkyl), -C(=O)(Ci-Ce alkyl), - C(=O)O(C1-C6alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-C6alkyl), -NH-(Ci-Ce alkyl),wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, oxo, cyano, hydroxy, amino,mercapto, and carbamoyl; each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkyl, Ci-Ce alkoxy, 3 to 6-membered carbocyclic group, - C(=O)OH, halogen, cyano, hydroxy, and amino;B is selected from the group consisting of 6- to 14-membered aryl and 5- to 14- membered heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;C is selected from the group consisting of ,, and a PARP inhibitor moiety; each of n, m, 1 and o is an integer between 0 and 5; each of R3a, R3band R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl Ci-Ce alkoxy, a 3- to 14- membered carbocyclic group, a 3- to 14-membered heterocyclic group, 6- to 14- membered aryl, 5- to 14-membered heteroaryl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2- NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), - C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano; each of S1and S2is independently selected from the group consisting of the following and combinations thereof: a direct bond, Ci-Ce alkylene, C2-C6alkenylene, C2-C6 alkynylene, -0-(C2-Ce alkynylene)-, -0-(C2-Ce alkynylene)-O-, -S(=0)-. -S(=0)2-, -S(=O)2-NH-, -C(=0)-, -C(=0)-0-, -C(=O)-(C1-C6alkylene)-, -NH-, -NH-(CI-C6alkylene)-, -NH-(C=O)-(CI-C6alkylene)-, -C(=O)-NH-, - C(=O)-C(=O)-NH-, -NH-C(=O)-NH-, -C(=NH)-, -C(=N(CI-C6alkyl)), -NH-(Ci- C , alkylene)-NH-, -NH-(C2-Ce alkenylene)-NH-, 5-12 membered arylene, 5-12 mem ebred heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclene, -(C2-C6 alkenylene)-(3-10 membered heterocyclene)-, -C(=O)-(3- 10 membered cycloalkylene)-, -C(=O)-(3-10 membered heterocyclene)-, -NH-(3- 10-membered cycloalkylene), -NH-(3-10 membered heterocyclene)-, -NH- (C=O)-(3-10 membered cycloalkylene)-, -NH-C(=O)-(3-10 membered heterocyclene)-, -NH-C(=O)-C(=O)- (3-10 membered cycloalkylene)-, and -NH- C(=O)-C(=O)-(3-10 membered heterocyclene)-, wherein each of said alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocyclene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, oxo, and 3-10 membered cycloalkyl; or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. The compound according to claim 1, whereinR1is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkynyl,Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with a 3 to 6-membered carbocyclic group;A is absent or is selected from R2and a PARP inhibitor moiety;R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, a 5- to 14-membered heterocyclic group, 5- to 14-membered heteroaryl, halogen, cyano, hydroxy, amino,wherein each of said carbocyclic group, heterocyclic group, aryl and heteroaryl is a monocyclic or bicyclic group, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, heterocyclic group, aryl and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl,Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkoxy, halogen, hydroxy, and amino;B is selected from the group consisting of:wherein each of Rbl, Rb2, Rb3, Rb4and Rb5is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;C is selected from the group consisting of, and a PARP inhibitor moiety; each of n, m, 1 and o is an integer between 0 and 5; each of R3a, R3b, and R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, -NH2, - NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, and the following groups:wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, - S(=O)2-NH2, -S(=O)2-(CI-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2- (Ci-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-C6alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group and heterocyclic group is a monocyclic or bicyclic group, wherein each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci- Ce alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, 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 (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), and Formula (Ij):wherein each of Rla, Rlb>and Rlcis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, and cyano, wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-membered carbocyclic group, -C(=O)OH, halogen, oxo, cyano, hydroxy, amino, mercapto, and carbamoyl, andA, B, C, S1, and S2are as defined in claim 1, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The compound according to claim 3, wherein each of Rla, Rlb>and Rlcis independently selected from the group consisting of hydrogen, C1-C3 alkyl, cyclopropyl-substituted C2-C3 alkynyl, C1-C3 alkoxy, halogen, and cyano;A is absent or is selected from R2and a PARP inhibitor moiety;R2is selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, halogen, hydroxy, amino,and the following groups:wherein each of said alkyl, alkenyl, and alkoxy is optionally substituted with one or more selected from halogen, hydroxy, and amino, wherein each of Ral, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3 to 6-memberedcarbocyclic group, -C(=O)OH, -C(=O)O(Ci-Ce alkyl), halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, a is an integer between 0 and 10; each of R2a, R2b, R2c, R2d, and R2fis independently selected from the group consisting of Ci-Ce alkoxy, halogen, hydroxy, and amino;B is selected from the group consisting of:wherein each of Rbl, Rb2, Rb3, Rb4and Rb5is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and halogen;C is selected from the group consisting of, and a PARP inhibitor moiety; each of n, m, 1 and o is an integer between 0 and 5; each of R3a, R3b, and R3cis independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, -NH2, - NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)(Ci-Ce alkyl), halogen, cyano, hydroxy, and the following groups:wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, hydroxy, oxo, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, - S(=O)2-NH2, -S(=O)2-(CI-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2- (Ci-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(CI-C6alkyl)C(=O)(Ci-C6alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano, wherein each of said carbocyclic group and heterocyclic group is a monocyclic or bicyclic group, wherein each of Rcl, Rc2, Rc3, Rc4, and Rc5is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, a 3- to 6-membered carbocyclic group, a 3- to 6-membered heterocyclic group, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-C6alkylene)-CN, -S(=O)2-NH2, -S(=O)2-(Ci-C6alkyl), -(Ci- Ce alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -NHC(=O)(CI-C6alkyl), -N(Ci-Ce alkyl)C(=O)(Ci-Ce alkyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkoxy, carbocyclic group, heterocyclic group and alkylene is independently optionally substituted with one or more halogen or cyano; and the PARP inhibitor moiety is selected from the group consisting of:wherein C101is CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2, each of Rcm, RC112, RC113, and RC114is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen,D2 is a direct bond or 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci- Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,C102is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-Ce alkenylene, C2-C6alkynylene,, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, - N(Ci-Ce alkyl)-, and a combination thereof, wherein C102'1and C102'2, taken together with the carbon atom to which they attach, form a 3- to 8-membered carbocyclic ring, each of C103, C104and C105is independently selected from the group consisting of C, N, CH, NH, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CF3, COCH3, and CNH2, each of RC115, RC116, and RC117is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy,NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci- C , alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,D4 is a direct 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci- Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,D5 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl, each of C106, and C107is independently selected from the group consisting of CH2, CO, NH2, CH(OH), CH(CN), CHF, CHC1, CHBr, CHI, CH(CH3), CH(CH2CH3), CH(CH(CH3)2), CH(CF3), CH(OCH3), and CH(NH2), each of C108, C109, C1010, and C1011is independently selected from the group consisting of N, CH, NH, COH, CCN, CF, CC1, 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl, each of C1013, C1014, and C1015is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2,each of RC118, and RC119is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, carbamoyl, acetamido, 3-5 membered cycloalkyl, halogen, cyano, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, and halogen,D9 is a direct bond or 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,DIO is a direct bond or 5-12 membered heteroarylene, wherein said heteroarylene is optionally substituted with one or more selected from Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,C1012is selected from the group consisting of a direct bond, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NH-, -C(=O)-, -S(=O)-. -S(=O)2-, -N(Ci-Ce alkyl)-, and a combination thereof, each of C1016, C1017, C1018, and C1019is independently selected from the group consisting of CH, N, COH, CCN, CF, CC1, CBr, CI, CCH3, CCH2CH3, CCH(CH3)2, CCF3, COCH3, and CNH2, and 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 Ci-Ce alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci- Ce 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.

5. The compound according to claim 4, wherein each of Ral, R32, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, and Ra9is selected from the group consisting of hydrogen, Ci-Ce alkyl, -C(=O)O(Ci-Ce alkyl), halogen, and amino two of Rbl, Rb2, Rb3, Rb4and Rb5are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, difluoromethyl, methoxy, ethynyl, fluoro, and chloro and the remaining groups are hydrogens; each of Rcl, Rc2, Rc3, Rc4, and Rc5is selected from the group consisting of hydrogen, Ci-Ce alkyl, cyclopropyl, cyclobutyl, cyclopentyl, halogen, cyano, oxo, hydroxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -S(=O)2-NH2, -S(=O)2- (Ci-C6alkyl), -(Ci-C6alkylene)-S(=O)2-NH2, -NH-S(=O)2-(CI-C6alkyl), - C(=O)NH2, -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), and -NHC(=O)(CI-C6alkyl), wherein each of said alkyl and alkylene is straight-chained or branched; each of S1and S2is independently selected from the group consisting of a direct bond, ethynylene, propynylene, butynylene, -O-(ethynylene)-, -O-(propynylene)-, -O-(butynylene)-, -O-(ethynylene)-O-, -O-(propynylene)-O-, -O-(butynylene)-O-, -S(=O)2-, -S(=O)2-NH-, -NH-, -C(=O)-, -C(=O)-O-, -C(=O)-NH-, -C(=O)-C(=O)- NH-, and the following groups:the PARP inhibitor moiety is selected from the group consisting of:or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

6. The compound according to claim 1, wherein the compound is selected from the group consisting of the following:seeŌt^e

7. A compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treating or preventing diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer.

8. A method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta in a subject in need of treatment or prevention, comprising administering to the subject at least one compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).

10. A pharmaceutical composition for treating or preventing diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer, comprising thecompound according to any one of claims 1 to 6, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).

11. The pharmaceutical composition according to claim 10, 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 (e.g., 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).

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