PARP1 inhibitor compounds

Abstract

A PARP1 inhibitor compound having the following structure: 【Chemical 1】 TIFF2026522578000315.tif38169R 1 and R 4 is independently selected from H and an organic group. R 2 and R 3 is independently absent, H or an organic group. Z 1 and Z 2 is independently C or N. L has the following structure: 【Chemical 2】 TIFF2026522578000316.tif61169X 1 Each of which is independently selected from C and N. X 2 Each of which is independently selected from C, N, O and S. n, m, p, q, r, and s are each in the range of 0 to 6. m + n, p + q, r + s are each in the range of 2 to 6. R[[ID=二十五]] 5A [[ID=二十六]],R 5B , R 5C , and, R 6 Each of which is independently absent, H or an organic group. Qa, Qb, and Qc are each independently a bond or an organic linker. The compound is used in medicine (for example, used in the treatment of cancer). A composition and a kit comprising the compound, and a method for synthesizing the compound are also provided.

Description

[Technical Field]

[0001] The present invention relates to PARP1 inhibitor compounds, and more particularly to PARP1 inhibitor compounds for use in pharmaceuticals. The inhibitors according to the present invention can be used in pharmaceutical compositions, in particular pharmaceutical compositions for treating cancer. The present invention also relates to methods for producing such inhibitors and therapeutic methods using such inhibitors. [Background technology]

[0002] The poly(ADP-ribose) polymerase (PARP) family consists of 17 PARP proteins that catalyze a post-translational process called polyADP-ribosylation, which involves the transfer of ADP-ribose to target proteins. Modification of target proteins by polyADP-ribosylation causes significant changes in their function. Therefore, PARPs play crucial roles in many cellular processes, including chromatin remodeling, transcription, replication, recombination, cell cycle progression, and DNA damage repair (Non-Patent Literature 1).

[0003] PARP1 and 2 are the most widely studied PARP enzymes, primarily for their role in DNA damage repair, particularly in the base excision repair (BER) process of single-strand breaks (SSBs) (Non-Patent Literature 2). PARP1 is activated by DNA damage breaks, and subsequent poly-ADP ribosylation of target proteins leads to the recruitment of additional factors to initiate DNA damage repair. Self-poly-ADP ribosylation of PARP triggers the dissociation of bound PARP from DNA, thereby allowing other DNA repair proteins to access and complete the repair of the damage. This highlights the important role that PARP plays in enabling cancer cells to repair DNA damage caused by exogenous agents such as radiation therapy and chemotherapy.

[0004] Inhibition of the PARP enzyme has been used as a strategy to selectively kill cancer cells with genetic defects in the complementary DNA damage repair pathway (Non-Patent Literature 3). This synthetic lethal approach has been successfully demonstrated in tumors with epigenetic modifications or harmful mutations in BRCA1 and BRCA2, two tumor suppressor proteins with functional redundancy involved in the repair of double-strand breaks (DSBs) by homologous recombination (HR) (Non-Patent Literature 4). Such tumors with homologous recombination repair deficiency (HRD) depend on PARP function for their survival. When PARP is inhibited in such tumors, DSB breaks are processed by error-prone alternative repair pathways, leading to genomic instability and cancer cell death.

[0005] By inhibiting PARP, inactivated PARP can be trapped at DNA damage sites. This causes replication forks to stall and subsequently disintegrate when they reach the trapped PARP site during the S phase, resulting in genotoxic DNA double-strand breaks. This PARP1-DNA trapping is thought to lead to the selective death of cancer cells with HRD (Non-Patent Literature 3).

[0006] This strategy has led to the approval of several PARP inhibitors for the treatment of cancers with HRD, including breast, ovarian, and prostate cancers with BRCA1 / 2 mutations, ovarian and prostate cancers with genomic effects due to HRD, and maintenance therapy for ovarian cancer in which platinum sensitivity acts as a surrogate for HRD (Non-Patent Literature 5).

[0007] In recent years, genomic instability has been shown to activate the innate immune system in the form of unrepaired DNA double-strand breaks or micronuclear collapse, through the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS), leading to the production of cyclic guanosine-monophosphate·adenosine-monophosphate (cGAMP) and the induction of dimerization of stimulator of interferon genes (STING). STING then moves from the endoplasmic reticulum to the Golgi apparatus, where it recruits and activates TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory factor 3 (IRF3), which induces the production of type I interferons and supports the induction of an adaptive immune response (Non-Patent Document 6).

[0008] For example, the activation of the STING pathway and anti-tumor immune responses induced by PARP inhibitors have been demonstrated in multiple tumor models, providing a basis for using combinations of PARP inhibitors and immunotherapies to improve therapeutic efficacy (Non-Patent Document 7). For example, the PARP inhibitor olaparib has also been shown to induce a synthetic lethal effect in combination with a synthetic cyclic dinucleotide STING agonist in DNA damage repair-deficient cancer cells and BRCA-deficient breast cancer models in recent years (Non-Patent Document 8).

[0009] Overall, in various cell and animal models, regulation of nucleic acid recognition pathways through multiple mechanisms has been shown to promote anti-tumor effects, indicating the potential for therapies that enhance the effects of immunotherapy or overcome resistance to immune checkpoint inhibitors through the use of PARP inhibitors. Numerous clinical trials combining PARP inhibitors and immunotherapy are underway (reviewed in Non-Patent Document 9).

[0010] In recent years, PARP1 has been shown to bind to the Epstein-Barr virus (EBV) genome, and PARP1 inhibitors have been shown to alter EBV chromatin structure and the expression of latent genes (Non-Patent Document 10). Therefore, PARP1 inhibitors may play a role in EBV-related cancers such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal cancer, and gastrointestinal cancer. Interestingly, EBV has also been shown to be a causative factor in multiple sclerosis (MS), where EBV infection significantly increases the subsequent risk of MS (Non-Patent Document 11).

[0011] First-generation PARP inhibitors generally exhibit non-selective activity against PARP1 and 2. The clinical use of these molecules is associated with hematotoxicities such as anemia, neutropenia, and thrombocytopenia, and dose-limiting cytopenia restricts their combination with cytotoxic chemotherapy and other targeted agents (Non-Patent Document 12). Evidence from preclinical mouse studies strongly suggests that inhibition of PARP2 is a major factor in these hematotoxicities, indicating that PARP2 is particularly involved in erythropoiesis in mice (Non-Patent Document 13). Furthermore, PARP2 function has been shown not to be essential for antitumor activity in HRD mouse cancer models (Non-Patent Document 14). Taken together, these data suggest an unmet medical need for the development of inhibitors with improved selectivity for PARP1 over PARP2 and other PARPs, which would provide expanded therapeutic utility (1) as monotherapy and (2) in combination with other anticancer agents.

[0012] To date, two PARP1 selective inhibitors, AZD5305 and AZD9574, are in clinical development. AZD5305 is a potent PARP1 inhibitor and trapper with 500-fold selectivity over PARP2, and is reported to have lower off-target activity against secondary pharmacological targets than first-generation PARP inhibitors (Non-Patent Literature 15). Importantly, in rodent models, AZD5305 showed significantly lower hematological toxicity than first-generation PARP inhibitors, confirming the pathogenic role of PARP2 in reported hematological toxicity (Non-Patent Literature 16). [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Kamaletdinova, T. et al. Cell. 2019;8:1625. [Non-Patent Document 2] Ngoi, YL. et al. Cancer J. 2021;27:521-528. [Non-Patent Document 3] Farmer, H. et al. Nature. 2005;434:917-921. [Non-Patent Document 4] Lord, C.J. and Ashworth, A. Science. 2017;355:1152-1158. [Non-Patent Document 5] Fong, PC. et al. N. Engl. J. Med. 2009;361:123-134. [Non-Patent Document 6] Zhu,Y. et al. Mol. Cancer. 2019,18:152. [Non-Patent Document 7] Sen, T. et al. Cancer Discov. 2019;9:646-661. [Non-Patent Document 8] Pantelidou, C. et al. 2021: bioRxiv 2021.01.26.428337v1.

Non-licensed literature 9

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Non-Patent Document 20

Summary of the Invention

Problems to be Solved by the Invention

[0014] In view of the above, one object of the present invention is to provide a PARP1 inhibitor, particularly a PARP1 inhibitor for use in medicine. It is a further object to provide a pharmaceutical composition comprising such an inhibitor, particularly a compound and a pharmaceutical composition for treating cancer. It is also an object to provide a method for synthesizing the said compound.

Means for Solving the Problems

[0015] [Summary] In one aspect, a PARP1 inhibitor compound for use in medicine is provided. The PARP1 inhibitor has the following structure:

Chemical Formula

Chemical Formula

Chemical formula

[0016] Typically, p+q is a number selected from 2, 3, 4, 5, and 6. Arbitrarily, p+q is a number selected from 2, 3, 4, 5, and 6, and m+n is a number selected from 2, 3, 4, 5, and 6.

[0017] In another aspect, a pharmaceutical composition comprising a PARP1 inhibitor compound as defined in this disclosure is provided.

[0018] In a further aspect, a pharmaceutical kit for treating cancer is provided. The kit comprises a PARP1 inhibitor compound as defined in this disclosure, and a further agent for treating cancer. The compound and the further agent are suitable for simultaneous, sequential, or separate administration.

[0019] In another aspect, a method is provided for treating a disease and / or condition and / or disorder, comprising administering a compound, composition, or kit provided in this disclosure to a patient.

[0020] In another aspect, the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound selected from the above is provided.

[0021] In another aspect, a method for synthesizing PARP1 inhibitor compounds provided in this disclosure is provided. The method comprises reacting a first reactant comprising a ring E having a first portion of group L with a second reactant comprising the remaining portion of group L to form a PARP1 inhibitor compound.

[0022] This summary is provided to introduce, in a simplified form, some of the concepts selected from those further explained in the detailed description below. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Nor is the claimed subject matter limited to any way of resolving some or all of the disadvantages described herein. [Modes for carrying out the invention]

[0023] Detailed explanation

[0024] General definition In this disclosure, the verb "to include" is used as an abbreviation for "to contain" or "to consist of." In other words, the verb "to include" is intended to be an open-ended term, but its substitution with the closed-ended term "to consist of" is explicitly anticipated, particularly when used in relation to chemical composition.

[0025] It will be understood that some of the compounds disclosed herein may be ionizable, that is, some compounds may be weak acids, weak bases, or amphoteric electrolytes. The designation of an ionizable compound in its free form is intended to encompass the corresponding ionized form. Ionizable compounds may exist in their free form or in the form of pharmaceutically acceptable salts.

[0026] A compound is considered a PARP1 inhibitor if, compared to the same process in its absence, its presence prevents or reduces the ability of immobilized PARP1 to undergo auto-poly-ADP-ribosylation (autoPARylation) after incubation with biotinylated-NAD+. Typically, a compound is considered a PARP1 inhibitor if its IC50 < 10 μM in a suitable assay. A suitable assay may be performed using an assay solution containing 2 nM PARP1 and 2 μM biotin-NAD+ in an assay buffer of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v). Poly-ADP-ribosylation (PARylation) may be performed at room temperature for 2 hours and may be detected using a readout from a dissociation-enhanced lantanide fluorescence immunoassay (DELFIA). Particularly suitable assays are described in the following examples. In a PARP1 inhibitor assay, the compound exhibits an IC50 < 10 μM. 50 Preferably, <1 μM, IC 50 It is more preferable that the impedance is <100nM, IC 50 A molecular weight of <10 nM is most preferable.

[0027] A compound is considered a selective PARP1 inhibitor if its presence can substitute or reduce the ability of a high-affinity Cy5 fluorescent dye-labeled chemical probe to bind to PARP1, while its activity in substituting the ability of the same chemical probe to bind to PARP2 is at least 10 times weaker. Typically, in this assay, IC for PARP1... 50A compound is considered a selective PARP1 inhibitor if it is <10 μM and exhibits at least 10-fold selectivity compared to PARP2. Such a suitable assay may be performed at room temperature for 1 hour using 10 nM PARP1 or PARP2, Tb-cryptate antibody, and a PARP1 / 2 conjugated probe in an assay buffer of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v). Probe-binding substitution may be detected using homogeneous time-resolved fluorescence. Particularly suitable assays are described in the following examples. The selectivity for PARP1 over PARP2 is preferably at least 50-fold, and more preferably at least 100-fold.

[0028] Furthermore, the compound showed IC15 for PARP1 in the NanoBRET assay, which demonstrates engagement with cellular targets. 50 A selective PARP1 inhibitor is considered to have a concentration of <10 μM and at least 10 times the selectivity for PARP2. These assays are based on bioluminescence resonance energy transfer (BRET) between a nano-luc labeled protein (e.g., PARP1 or PARP2) and a fluorescent group on a high-affinity NAD+ competitively binding probe. Such cell probe substitution assays can be used to measure the affinity and selectivity of inhibitors for PARP1 and PARP2. Particularly suitable assays are described in the examples below. A selectivity of at least 50 times, and more preferably at least 100 times, for PARP1 over PARP2 is preferred.

[0029] In this disclosure, the expression "substituted or unsubstituted organic group" is used as a synonym for "substituent." Examples of organic groups are described in more detail below.

[0030] When an organic group is described as "substituted," it means that a hydrogen atom (H) in that organic group has been replaced by another organic group.

[0031] In structural formulas, dotted lines represent covalent bonds of an appropriate bond order other than zero, most typically representing single or double bonds. As is to be understood, systems with multiple double bonds may be conjugated or aromatic systems.

[0032] Unless the stereochemistry of a particular bond is directly illustrated, all chemical formulas in this disclosure are represented in nonstereoisomer form and are intended to represent all stereoisomers of a particular structure. This includes all possible isolated enantiomers, all possible mixtures of enantiomers, all possible mixtures of diastereomers, all possible mixtures of epimers, and all possible racemic mixtures. Furthermore, all chemical formulas in this disclosure are also intended to represent all tautomers equivalent to the corresponding chemical formula.

[0033] In this disclosure, the term "aliphatic ring" is used in a broad sense to refer to a ring in which all bonds between the atoms constituting the ring are single bonds. The aliphatic ring may be a carbocyclic or heterocyclic ring, and may be substituted or unsubstituted.

[0034] Numbering of compounds Various compounds in this disclosure are enantiomers or diastereomers. If a compound number is followed by a suffix, the suffix indicates stereochemistry. Compound numbers without a suffix refer to compounds having the given structural formula without specifying stereochemistry.

[0035] The suffix "rac" in compound numbers indicates a racemic mixture.

[0036] The suffixes "cis" and "trans" refer to compounds in which ring A is in the cis and trans configurations, respectively, as described in detail in the "Stereochemistry" section below. In the case of diastereomer compounds, the suffixes "cis" and "trans" may refer to a pair of diastereomers having the configurations shown for ring A. Nuclear Overhauser effect nuclear magnetic resonance spectroscopy (NOE NMR) may be used to determine the stereochemistry of a compound, as described in this disclosure.

[0037] The suffix "a" attached to the compound number refers to the enantiomer that elutes as the first fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography (SFC) using a chiral column.

[0038] The suffix "b" attached to the compound number indicates the enantiomer that elutes as the second fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography (SFC) using a chiral column.

[0039] Some of the structural formulas shown in this disclosure represent the stereochemistry assigned by the applicant. In the event of any inconsistency between the elution order (indicated by compound number) and the assigned stereochemistry, the elution order shall prevail.

[0040] As an example, Example 3 below describes the synthesis of compound 6. Compound 6 is obtained as a mixture of diastereomers. In the first separation step, the diastereomers are separated into two fractions by preparative HPLC. The first fraction to elute contains the pair of enantiomers 6cis-a and 6cis-b. The second fraction contains the pair of enantiomers 6trans-a and 6trans-b. In the second separation step, the mixture of 6cis-a and 6cis-b is passed through a REGIS(R,R)-Whelk-O chiral chromatography column under the conditions shown above. In the second separation step, the first fraction to elute contains compound 6cis-a, and the second fraction contains compound 6cis-b. On the other hand, the mixture of 6trans-a and 6trans-b is passed through a Daicel CHIRALPAK chiral chromatography column under the conditions shown above to obtain compound 6trans-a (first to elute) and compound 6trans-b (second to elute).

[0041] discussion This disclosure provides PARP1 inhibitor compounds having a monocyclic head group. Also provided are kits and compositions comprising these compounds, as well as medical applications of the compounds, compositions, and kits.

[0042] The PARP1 inhibitor compound has the structure shown by the following general formula: [ka] (In the formula, R 1 This is selected from H and substituted or unsubstituted organic groups; R 2 It is either absent or selected from H and substituted or unsubstituted organic groups; R 3 It is either absent or selected from H and substituted or unsubstituted organic groups; R 4 This is selected from H and substituted or unsubstituted organic groups; Z1 and Z 2 Each is independently selected from C and N; and, L is a group having the following structure: [ka] (In the formula, X 1 Each of these is selected independently from C and N; X 2 Each of these is independently selected from C, N, O, and S; Given that n+m is a number selected from 1, 2, 3, 4, 5, and 6, n is a number selected from 0, 1, 2, 3, 4, 5, and 6, and m is a number selected from 0, 1, 2, 3, 4, 5, and 6; Given that p+q is a number selected from 1, 2, 3, 4, 5, and 6, p is a number selected from 0, 1, 2, 3, 4, 5, and 6, and q is a number selected from 0, 1, 2, 3, 4, 5, and 6; Given that r+s is a number selected from 2, 3, 4, 5, and 6, r is a number independently selected from 0, 1, 2, 3, 4, 5, and 6, and s is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; R 5A , R 5B , and R 5C Each of these is independently either absent or selected from H and substituted or unsubstituted organic groups; R 6 It is either absent or selected from H and substituted or unsubstituted organic groups; The lines forming rings A, B, and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; Each of Qa, Qb, and Qc is independently selected from a bond or group having a structure independently selected from the following: [ka] (In the formula, Given that t+u is a number selected from 0, 1, 2, 3, 4, 5, and 6, t is a number selected from 0, 1, 2, 3, 4, and 5, and u is a number independently selected from 0, 1, 2, 3, 4, and 5; R 7 and R 8 Each of these is independently selected from H and substituted or unsubstituted organic groups.

[0043] Typically, p+q is a number selected from 2, 3, 4, 5, and 6. Optionally, p+q is a number selected from 2, 3, 4, 5, and 6, and m+n is a number selected from 2, 3, 4, 5, and 6.

[0044] The PARP1 inhibitor compounds provided in this disclosure may be selective to PARP1 compared to PARP2. By selectively inhibiting PARP1 compared to PARP2, PARP2-related side effects, including one or more hematological toxicities such as anemia, neutropenia, and thrombocytopenia, can be reduced. This may make it possible to treat cancer patients while reducing hematological side effects. Alternatively or additionally, PARP1 inhibitors may be administered to patients at higher doses, or in combination with chemotherapeutic agents.

[0045] The PARP1 inhibitor compounds provided in this disclosure have a monocyclic head group. On the other hand, the comparative compounds have a bicyclic head group, R 1 and R 2 The groups at the position fuse to form a ring. While not intended to be theoretically constrained, PARP1 inhibitor compounds having a monocyclic head group are thought to have improved physicochemical and pharmacokinetic properties and potential for penetration into the central nervous system (CNS). Therefore, the compounds provided in this disclosure may be particularly useful in the treatment of brain cancers (e.g., glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, astrocytoma, etc.) and spinal cord cancers.

[0046] The improvements in pharmacokinetic properties and permeability into the central nervous system (CNS) are thought to be at least partially due to improved physicochemical properties of the molecule and modifications to its three-dimensional structure compared to molecules with a bicyclic head group. Specifically, the head group of a bicyclic head group tends to be flatter and more lipophilic.

[0047] substituent "R 5 The expression "base" is generally used in R 5A , R 5B , and R 5C It refers to the base. 5A The "group" is R bonded to ring A. 5 It refers to the base, "R 5B " and "R 5C Similarly, the R group is bonded to the corresponding ring. 5 It refers to a base. In some of the chemical formulas shown in this disclosure, R 5 More specific identifiers are used for the base. For example, "R 5A1 " is R 5A Identify a subset of the original.

[0048] In the structural formulas shown in this disclosure, the dotted lines represent covalent bonds of any non-zero bond order, and in the compounds provided in this disclosure, R 2 , R 3 , and R 5 Some of the groups may be absent. As you can understand, the number of ring bonds and substituents are Z 1 , Z 2 , X 1 , and X 2 Atoms are selected to maintain a stable valency. "Maintaining a stable valency" means that the atoms have the normal (most commonly found) valencies in organic compounds (i.e., 2 for oxygen; 2 or 6 for sulfur; 3 or 4 for nitrogen; and 4 for carbon).

[0049] X 1 or X 2 When the atom is nitrogen (N), the atom most preferably has a valence of 3. Also, X1 or X 2 Compounds in which the atom is tetravalent nitrogen are also considered. Tetravalent nitrogen is positively charged, and such compounds may have counterions.

[0050] Typically, each of rings A, B, and C contains at most one tetravalent nitrogen atom. Preferably, the PARP1 inhibitor compound contains at most one tetravalent nitrogen atom, and more preferably does not contain tetravalent nitrogen.

[0051] Each R 5 The base may or may not exist. Also, each R 5 The groups may be the same or different. To avoid any ambiguity, R depends on the selection of the corresponding X group. 5 When the number of bases changes, the following conditions typically apply: i)X 1 If N, then the corresponding R 5 The base does not exist; ii)X 1 If is C and forms a double bond with an adjacent ring atom, then the corresponding R 5 The base does not exist; iii)X 1 If is C and does not form a double bond with an adjacent ring atom, then the corresponding R 5 The basis exists; iv)X 2 If O, then the corresponding R 5 and R 6 None of the bases exist; v)X 2 If S, then the corresponding R 5 and R 6 Either neither base exists, or both are =O or =NR 10 Selected from; here R 10 is H or a substituted or unsubstituted organic group, preferably a C1-C3 alkyl group; vi)X 2 If is N and forms a double bond with an adjacent ring atom, then the corresponding R 5 and / or R 6 The base does not exist; vii) X 2 is N and does not form a double bond with an adjacent ring atom, only one corresponding R 5 and / or R 6 group exists; viii) X 2 is C and forms a double bond with an adjacent ring atom, only one corresponding R 5 and / or R 6 group exists; ix) X 2 is C and does not form a double bond with an adjacent ring atom, both corresponding R 5 groups, or both the corresponding R 5 group and / or R 6 groups exist.

[0052] Substituents (i.e., R groups: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 ) are not particularly limited as long as they do not prevent the PARP1 inhibitory effect from occurring. The substituents are selected from H and substituted or unsubstituted organic groups. Therefore, in the above and below, the terms "substituent" and "organic group" are not particularly limited and can be any functional group or atom, particularly any functional group or atom common in organic chemistry.

[0053] Any R 5 or R 6 group may form a ring with any other R 5 or R 6 group on adjacent and / or neighboring atoms, but this is not preferred in many embodiments unless explicitly stated. Therefore, the following substituents may combine to form a ring: one R 5A and another one R 5A ; one R 5B and another one R 5B ; one R 5C and another one R 5C ; or one R 5Cand R 6 In the context of this disclosure, adjacent and / or near atoms may mean another atom directly bonded to an atom (adjacent), or two atoms separated by only one atom (near); or two atoms sterically close enough to form a ring (near). 5 / R 6 While it is preferable that the groups do not come together to form a ring, this embodiment is not excluded.

[0054] The PARP1 inhibitor compounds provided in this disclosure have a monocyclic head group. 1 , R 2 , R 3 , and R 4 None of them form a ring with any other R group.

[0055] A single R on one atom 5 or R 6 A group, or two R groups on the same atom 5 and / or R 6 The group may form a single group that double bonds to that atom. Therefore, one R bonded to the same atom 5 or R 6 A group, or two R groups bonded to the same atom 5 or R 6 The groups may combine to form a C=O group or a C=C(R')² group. Here, each of the R' groups may be the same or different, and is either H or an organic group, preferably H or a linear or branched C1-C6 alkyl group. This is more typical when the R groups bonded to the C atom are bonded to the C atom so that the R groups bonded to the C atom combine to form a C=O group or a C=C(R')² group. Therefore, in some cases, X is C. 2 The group may have an O group.

[0056] The terms "substituent" and "organic group" may have any of the following meanings:

[0057] The organic group may comprise one or more atoms from any of groups IIIA, IVA, VA, VIA, or VIIA of the periodic table, for example, B, Si, N, P, O, or S atoms (e.g., OH, OR, NH2, NHR, NR2, SH, SR, SO2R, SO3H, PO4H2) or halogen atoms (e.g., F, Cl, Br, or I), where R is a linear or branched lower hydrocarbon (containing 1 to 6 carbon atoms) or a linear or branched higher hydrocarbon (containing 7 or more carbon atoms, for example, 7 to 40 carbon atoms).

[0058] The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may be linear, branched, or cyclic. Independently, the hydrocarbon group may comprise an aliphatic group or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated group or an unsaturated group.

[0059] If the hydrocarbon has an unsaturated group, it may have one or more alkene functionalities and / or one or more alkyne functionalities. If the hydrocarbon has a linear or branched group, it may have one or more primary, secondary, and / or tertiary alkyl groups.

[0060] If the hydrocarbon comprises a cyclic group, it may also comprise an aromatic ring, an aromatic ring, an aliphatic ring, a heterocycle, and / or fused cyclic derivatives of these groups. The ring may be fully saturated, partially saturated, or completely unsaturated.Therefore, the cyclic groups are benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluorantene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole Isooxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolan, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-azathiopyran N, Chian, Indole, Indazole, Benzimidazole, 4-Azaindole, 5-Azaindole, 6-Azaindole, 7-Azaindole, Isoindole, 4-Azaisoindole, 5-Azaisoindole, 6-Azaisoindole, 7-Azaisoindole, Indoridine, 1-Azaindinidine, 2-Azaindinidine, 3-Azaindinidine, 5-Azaindinidine, 6-Azaindinidine, 7-Azaindinidine, 8-Azaindinidine, 9-Azaindinidine, Purine, Carbazole, Cal The compounds may include borin, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene, phenoxanthiine, and / or thianthlene, as well as positional isomers of the above groups. These groups may generally be bonded at any point on the group, and may be bonded at heteroatoms or carbon atoms.In some examples, specific binding sites are preferred, such as 1-yl and 2-yl, and where appropriate, these are explicitly specified. All tautomer ring forms are included in these definitions. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole, and 3H-pyrrole.

[0061] The number of carbon atoms in a hydrocarbon group is not particularly limited, but it is preferable that the hydrocarbon group has 1 to 40 carbon atoms. Therefore, the hydrocarbon group may be a lower hydrocarbon (1 to 6 carbon atoms) or a higher hydrocarbon (7 or more carbon atoms, for example, 7 to 40 carbon atoms). The lower hydrocarbon group may be a methyl group, ethyl group, propyl group, butyl group, pentyl group, or hexyl group, or positional isomers of these groups, such as an isopropyl group, isobutyl group, or tert-butyl group. The number of atoms in the ring of a cyclic group is not particularly limited, but it is preferable that the ring of a cyclic group has 3 to 10 atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 atoms.

[0062] The group comprising the heteroatoms described above may, like the other groups defined above, comprise one or more heteroatoms from any of the groups IIIA, IVA, VA, VIA, or VIIA of the periodic table, such as B, Si, N, P, O, S atoms, or halogen atoms (e.g., F, Cl, Br, or I). Therefore, the substituent may comprise one or more of the common functional groups in organic chemistry, such as hydroxyl groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulfate groups, sulfonic acid groups, sulfonyl groups, and phosphate groups. The substituent may also comprise derivatives of these groups, such as carboxylic acid anhydrides and carboxylic acid halides.

[0063] Furthermore, any substituent may comprise two or more combinations of substituents and / or functional groups as defined above.

[0064] Typically, R 1 , R 2 , R 3 , R4 , R 5A (For example, R 5A1 , R 5A2 , and R 5A3 ), R 5B , R 5C (For example, R 5C1 ), R 6 , R 7 , R 51 , and R 52 If one or more of the organic groups are substituted or unsubstituted, then the substituted or unsubstituted organic groups are independently selected from the following: -deuterium; - Halogens (-F, -Cl, -Br, and -I, etc.); - Nitrile group; - Substituted or unsubstituted linear or branched C1-C6 alkyl groups (methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group, etc.); - Substituted or unsubstituted linear or branched C1-C6 alkyl-aryl groups (-CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph, etc.); - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (-CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CI3, etc.); --NH2, or substituted or unsubstituted linear or branched primary, secondary, or tertiary C1-C6 amine groups (-NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, -CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and -CH2-NPrEt, etc.); - Substituted or unsubstituted amino-aryl groups (-NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)Cl-Ph, -NH-(2,3 or 4)Br-Ph, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph, -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, -NH-(2,3 or 4)OMe-Ph, -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4) OPr-Ph, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F2-Ph, -NH-2,(3,4,5 or 6)Cl2-Ph, -NH-2,(3,4,5 or 6)Br2-Ph, -NH-2,(3,4,5 or 6)I2-Ph, -NH-2,(3,4,5 or 6)Me2-Ph, -NH-2,(3,4,5 or 6)Et2-Ph, -NH-2,(3,4,5 or 6)Pr2-Ph, and -NH-2,(3,4,5 or 6)Bu2-Ph, etc. - Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); - Substituted or unsubstituted cyclic C3-C8 alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); --OH group; - Substituted or unsubstituted linear or branched C1-C6 alcohol groups (-CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH, etc.); - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid groups (-COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH, etc.); -Substituted or unsubstituted linear or branched carbonyl groups (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl, -(CO)N H2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2, etc. - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe, etc.); - Substituted or unsubstituted linear or branched C1-C6 amide groups (-CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt, etc.); - Substituted or unsubstituted linear or branched C1-C7 aminocarbonyl groups (-NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, and -NMe-CO-Ph, etc.); - Substituted or unsubstituted linear or branched C1-C7 alkoxy or aryloxy groups (-OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-Cl-Ph, -CH2OMe, -CH2OEt, -CH2OPr, -CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe, and -CH2CH2CH2CH2CH2OMe, etc.); - Substituted or unsubstituted linear or branched aminoalkoxy groups (-OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2, etc.); - Substituted or unsubstituted sulfonyl groups (-SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe, etc.); - Substituted or unsubstituted aminosulfonyl groups (-NHSO2Me, -NHSO2Et, -NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, and -NHSO2CH2CH2OCH3, etc.); - Substituted or unsubstituted aromatic groups (Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3, 4, 5 or 6)-Pr2-Ph-, 2,(3, 4, 5 or 6)-Bu2-Ph-, 2,(3, 4, 5 or 6)-(CN)2-Ph-, 2,(3, 4, 5 or 6)-(NO2)2-Ph-, 2,(3, 4, 5 or 6)-(NH2)2-Ph-, 2,(3, 4, 5 or 6)-(MeO)2-Ph-, 2,(3, 4, 5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-E t2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph- , 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-);-Optionally, saturated or unsaturated, substituted or unsubstituted heterocyclic groups (pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1 ,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl, 2-Azapiperidine-4-yl, 3-Azapiperidine-1-yl, 3-Azapiperidine-2-yl, 3-Azapiperidine-4-yl, 3-Azapiperidine-5-yl, Piperazine-1-yl, Piperazine-2-yl, Furan-2-yl, Furan-3-yl, Pyran-2-yl, Pyran-3-yl, Pyran-4-yl, 2-Azapyran-2-yl, 2-Azapyran-3-yl, 2-Azapyran-4-yl, 2-Azapyran-5-yl, 2-Azapyran-6-yl, 3-Azapyran-2-yl, 3-Azapyran-4-yl, 3-Azapyran-5-yl, 3- Azapiran-6-yl, 4-azapiran-2-yl, 4-azapiran-3-yl, 4-azapiran-4-yl, 4-azapiran-5-yl, 4-azapiran-6-yl, oxetane-2-yl, oxetane-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl,3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza- Tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophene-2-yl, thiophene-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2 -Azathiopyran-3-yl, 2-Azathiopyran-4-yl, 2-Azathiopyran-5-yl, 2-Azathiopyran-6-yl, 3-Azathiopyran-2-yl, 3-Azathiopyran-4-yl, 3-Azathiopyran-5-yl, 3-Azathiopyran-6-yl, 4-Azathiopyran-2-yl, 4-Azathiopyran-3-yl, 4-Azathiopyran-4-yl, 4-Azathiopyran-5-yl, 4-Azathiopyran-6-yl, Thioran-2-yl, Thioran-3-yl, Chian-2-yl, Chian-3-yl (e.g., thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl, and tetrazole-1-yl, tetrazole-2-yl, and tetrazole-5-yl).

[0065] A pair of R atoms bonded to different atoms 5AThe groups may come together to form a ring with the atoms that make up ring A.

[0066] A pair of R atoms bonded to different atoms 5B The groups may come together to form a ring with the atoms that make up ring B.

[0067] A pair of R atoms bonded to different atoms 5C The groups may come together to form a ring with the atoms that make up the ring C.

[0068] R bonded to different atoms 5C Base and R 6 The groups may come together to form a ring with the atoms that make up the ring C.

[0069] R 5 Group(R 5A1 , R 5A2 , and R 5A3 R such as 5A ;R 5B ; or, R 5C1 R such as 5C ) may not exist, or may be selected from the following: -hydrogen; -deuterium; -Halogens (-F, -Cl, -Br, and -I, etc.; preferably F or Cl); - Nitrile group; - Substituted or unsubstituted C1-C6 alkyl groups; - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (preferably CF3 or CHF2); -Cyclopropyl group; --OH group; - Substituted or unsubstituted linear or branched C1-C6 alcohol groups; - Substituted or unsubstituted linear or branched C1-C7 aminocarbonyl groups (e.g., -NH-CO-Me); --NH2 group; - Substituted or unsubstituted C1-C6 amino groups; - A substituted or unsubstituted C1-C6 alkoxy group.

[0070] A pair of R atoms bonded to different atoms 5A When the groups come together to form a ring with the atoms that make up ring A; and / or when a pair of R groups bonded to different atoms 5B When the groups come together to form a ring with the atoms that make up ring B; and / or when a pair of R groups bonded to different atoms 5C When the groups come together and form a ring with the atoms that make up the ring C, the pair of R 5A Group, R 5B Base, or R 5C Each of the groups independently comprises -CH2- or -CH2CH2-, or the pair of groups together comprises -CH=CH-CH=CH- or -NH-CO-NH-.

[0071] Ring E The ring E (sometimes referred to as the "head group") of the compound provided in this disclosure has the following structure: [ka] (In the formula, Z 1 and Z 2 These are independently selected from C and N; R 1 This is selected from H and substituted or unsubstituted organic groups; R 2 It is either absent or selected from H and substituted or unsubstituted organic groups; R 3 is either absent or selected from H and substituted or unsubstituted organic groups; and, R 4 (These are selected from H and substituted or unsubstituted organic groups.)

[0072] Ring E may have the following structure: [ka] (In the formula, R 1 , R 2 , and R 4Each of these is independently selected from H and a substituted or unsubstituted organic group.

[0073] Alternatively, ring E may have the following structure: [ka] (In the formula, R 1 , R 3 , and R 4 Each of these is independently selected from H and a substituted or unsubstituted organic group.

[0074] In some other possibility, ring E may have the following structure: [ka] (In the formula, R 1 , R 2 , R 3 , and R 4 Each of these is independently selected from H and a substituted or unsubstituted organic group.

[0075] In general, R 2 and R 3 The following conditions apply to your selection: -Z 1 If R is N, 2 It does not exist. Z 1 If C, then R 2 This is selected from H and substituted or unsubstituted organic groups, and is preferably H. -Z 2 If R is N, 3 It does not exist. Z 2 If C, then R 3 This is selected from H and substituted or unsubstituted organic groups, and is preferably H.

[0076] R 1 and R 2 Each of these can be independently selected from the following: -H; -C1-C6 alkyl, aminoalkyl, alkoxy, or haloalkyl groups; -C3~C6 cycloalkyl groups; -Halogen group; and, [ka] (In the formula, R 22 R is selected from H, C1-C6 alkyl, cycloalkyl, alkoxy, or haloalkyl groups, and halogen groups; R 23 Each of these is independently selected from H and a substituted or unsubstituted organic group; R 23 Each of these is preferably selected from H, C1-C6 alkyl, aminoalkyl, alkoxy, or haloalkyl groups, and halogen groups. Typically, at least one R 23 (is H.)

[0077] In most embodiments, R 1 and R 2 At least one of them is not H. Preferably, R 1 R is a substituted or unsubstituted organic group. 2 H is H.

[0078] Preferably, R 1 , R 2 , R 3 , and R 22 At least one of the groups is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, or cyclopropylmethyl group.

[0079] R 1 and R 2 At least one of them may be a group having the following structure: [ka] (In the formula, R 23 Each of these is independently selected from H, F, C1-C3 alkyl groups, and C1-C3 fluoroalkyl groups.

[0080] Optionally, R 3 This is further defined below, R 1 , R 2 , and R 22 At least one of the groups is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, or cyclopropylmethyl group.

[0081] R 1 This can be selected from H, C1-C3 alkyl groups, C1-C3 alkoxy groups, and C1-C3 haloalkyl groups.

[0082] Alternatively, R 1 This can be selected from a halogen group (which may optionally be Cl), a C1-C4 alkyl group, and a C1-C4 haloalkyl group (which may optionally be a C1-C4 fluoroalkyl group). For example, R 1 -CH2CH3, -CF3, [ka] -CH2CH2F, -Cl, and -CH2CF3 may be selected.

[0083] Most preferably, R 1 It is an ethyl group.

[0084] R 2 In particular, may be selected from H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, and cyclopropylmethyl group. Most preferably, R 2 H is H.

[0085] R 3This may be selected in particular from H, halogens, C1-C3 alkyl groups, C1-C3 haloalkyl groups, C1-C3 alcohol groups, and C1-C3 aminoalkyl groups. Most preferably, R 3 H is H.

[0086] R 4 This may be selected in particular from H, C1-C3 alkyl groups, and C1-C3 haloalkyl groups. Most preferably, R 4 H is H.

[0087] In one example of a group of compounds, Z 1 and Z 2 C is C, and R is R. 2 and R 3 Each of these is independently selected from H, halogen, C1-C3 alkyl groups, and C1-C3 haloalkyl groups. Optionally, R 2 and R 3 Each of these is independently selected from H, a C1-C3 alkyl group, and a C1-C3 haloalkyl group. In the compounds of this group, R 2 and R 3 These can optionally be H.

[0088] Ring E is as follows: [ka] [ka] It may have a structure selected from among the following.

[0089] In one other possibility, ring E has the following structure: [ka] It may have.

[0090] Preferably, ring E is: [ka] Selected from.

[0091] Most preferably, ring E has the following structure: [ka] It has.

[0092] Rings A, B, and C - General Matters - Rings A and C are independently either carbocyclic or heterocyclic structures.

[0093] The variable atoms that are part of the framework of rings A, B, and C are collectively referred to as "X" atoms. 1 Each atom is independently selected from C and N. 2 Each atom is independently selected from C, N, O, and S, with C and N being particularly preferred.

[0094] X 1 and X 2 Each atom is selected independently. One or more of the following conditions, most preferably all of the following conditions, may apply: Typically, each ring has at least one X group that is carbon. If rings A, B, or C are four-membered rings, they typically contain at most one heteroatom. If rings A, B, or C are five-membered or six-membered rings, they typically contain at most three heteroatoms, and optionally at most two. Each of rings A, B, and C may individually contain up to three heteroatoms. -The aforementioned compounds are typically not quaternary ammonium compounds. X is N. 1 Atoms are typically R 5 It has no base. X is N. 2 Atoms typically have at most one R 5 It has a base. -The aforementioned compound is X 2 It does not have OO bonds, SS bonds, or SO bonds between atoms. 2If is O or S, the adjacent ring atom is C or N. More generally, the compound may not have OO bonds or SS bonds.

[0095] Ring A Ring A of a PARP1 inhibitor compound has the following general structure: [ka] It holds.

[0096] X 1AE X is bonded to ring E via linker Qa. 1 It is an atom. X 1AB X is bonded to ring B via linker Qb. 1 It is an atom. X 2A X is part of ring A. 2 It refers to an atom.

[0097] X 1AE This may be C or N, and is preferably C.

[0098] Qa, [ka] And if u=0, then X 1AE X is C. 1AE If R is N, 5A1 They typically do not exist.

[0099] X 1AB This may be C or N, and is preferably C.

[0100] Rings A and B are not typically linked via an NN bond. Therefore, Qb is either a bond or [ka] And if t=0, then X 1AB X is C. 1AB If R is N, 5A3They typically do not exist.

[0101] X 2A Each atom is independently selected from C, N, O, and S, with C and N being particularly preferred. 2A The group is selected such that ring A does not have OO bonds, OS bonds, and SS bonds. Particularly preferred is all X 2A The atom is C.

[0102] Ring A is typically a 4, 5, 6, 7, or 8-membered ring. Therefore, n is either 0 or an integer between 1 and 6; m is either 0 or an integer between 1 and 6; and the sum of n and m is an integer between 2 and 6.

[0103] In particular, ring A may be a 4, 5, or 6-membered ring, and is preferably a 5 or 6-membered ring. In other words, the sum of n and m may be an integer in the range of 2 to 4.

[0104] Preferably, both n and m are at least 1. In other words, X 1AE and X 1AB It is preferable that they are not adjacent to each other.

[0105] According to another possibility, ring A may be a three-membered ring. For example, ring A is: [ka] That's fine.

[0106] If ring A is a three-membered ring, Qb is preferably not a bond. For example, if ring A is a three-membered ring, Qb may be -CH2-.

[0107] R 5A Group(R 5A1 , R 5A2 , and R 5A3 Each of the R groups is independently selected from those that are absent or from H and substituted or unsubstituted organic groups. Ring A is the present R group. 5ADepending on the number of groups, it may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring.

[0108] In most embodiments, R is a substituted or unsubstituted organic group. 5A There is one or fewer bases.

[0109] R 5A If a base exists, its R 5A The most preferred group is H.

[0110] Ring A may have the following structure: [ka] (In the formula, n is 1, 2, or 3; m is 0, 1, or 2; X 1 is C or N; X 2 Each of these is independently selected from C, O, and N; R 5A1 , R 5A2 , and R 5A3 Each of these is independently either absent or selected from H and substituted or unsubstituted organic groups; however, X 1 If R is N, 5A1 It does not exist, and the corresponding X 2 If R is O, 5A2 (Assuming it does not exist.)

[0111] Optionally, R 5A1 and R 5A3 Each of them is either H or does not exist. Optionally, R 5A2 Each of these is either absent, H, an oxo group, or a methyl group, independently of the others.

[0112] Furthermore, optionally, R 5A1 , R 5A2 , and R 5A3 Each of these is either H independently, or does not exist. For example, R 5A1 , R5A2 , and R 5A3 Each of these can be H.

[0113] Alternatively, R 5A1 , R 5A2 , and R 5A3 The two groups selected from the group may together represent a C1-C3 alkyl group that bridges ring A. For example, R 5A1 , R 5A2 , and R 5A3 Two groups selected from the group may together represent a -CH2- group. In such a compound, R 5A1 , R 5A2 , and R 5A3 The remaining group is preferably H.

[0114] Examples of the structure of a bridged ring A include: [ka] It includes.

[0115] Alternatively, adjacent X 2 Two Rs on an atom 5A2 The groups may together represent a phenyl group. For example, ring A has the following structure: [ka] It may have.

[0116] Preferably, ring A is monocyclic. For example, ring A may have the following structure: [ka] (In the formula, m is either 1 or 2; n is either 1 or 2; R 5A2 and R 5A3 Each of these is either absent or selected from H and substituted or unsubstituted organic groups; and, (i)X 1 C is R5A1 It does not exist, or it is selected from H and substituted or unsubstituted organic groups; or (ii)X 1 N is R 5A1 It does not exist. In such compounds, ring A is preferably an aliphatic ring (i.e., all bonds between X atoms are single bonds), and R 5A3 is H. Optionally, R 5A2 Each of them is H.

[0117] Optionally, ring A is as follows: [ka] It may have a structure selected from among the following.

[0118] According to another possibility, ring A is as follows: [ka] It may have a structure selected from among the following.

[0119] For example, ring A is as follows: [ka] That's fine.

[0120] In other examples, ring A is a substituted or unsubstituted 7-membered aliphatic carbon ring or heterocycle, optionally a cycloheptane, and further optionally a cycloheptane having a structure selected from the following: [ka] (In the formula, R 5A and R 5A3 Each of these is independently selected from H and a substituted or unsubstituted organic group, where R 5A3 H is the most preferred value.

[0121] Alternatively, ring A is a substituted or unsubstituted 6-membered aliphatic carbocyclic or heterocyclic ring, optionally cyclohexane or tetrahydropyran, and further optionally having a structure selected from the following: [ka] [ka] (In the formula, R 5A and R 5A3 Each of these is independently selected from H and a substituted or unsubstituted organic group, where R 5A3 H is the most preferred value.

[0122] According to another possibility, ring A is a substituted or unsubstituted five-membered aliphatic carbocyclic or heterocyclic ring, optionally cyclopentane, cyclopentene, or tetrahydrofuran, and further optionally having a structure selected from the following: [ka] Or, [ka] (In the formula, R 5A and R 5A3 Each of these is independently selected from H and a substituted or unsubstituted organic group, where R 5A3 H is the most preferred value.

[0123] In further examples, ring A may be a five-membered aromatic ring, optionally pyrrole or pyrazole, and optionally having a structure selected from the following: [ka] (In the formula, R 5A Each of these is independently selected from H and substituted or unsubstituted organic groups.

[0124] Other examples of compounds include compounds in which ring A is substituted or unsubstituted cyclobutane, and which optionally have the following structures: [ka] (In the formula, R 5A and R 5A3 Each of these is independently selected from H and a substituted or unsubstituted organic group, where R 5A3 H is the most preferred value.

[0125] Alternatively, substituted or unsubstituted cyclobutanes have the following structures: [ka] It may have.

[0126] Examples of the structure of ring A are as follows: [ka] It includes the following.

[0127] Ring B Ring B of the PARP1 inhibitor compound has the following structure: [ka] It holds.

[0128] X 1BC X is bonded to ring C via linker Qc. 1 It is an atom. X 2B X is part of ring B. 2 It refers to an atom.

[0129] X 1BC X may be C or N, and is preferably N. 1BC If R is N, 5B3 They typically do not exist.

[0130] Rings B and C are not typically linked via NN bonds. Qc is [ka] And if t=0, then X 1BC is C. If Qc is a bond, then X 1BC and X1 CB Of these, one or fewer is N.

[0131] X 2B Each atom is independently selected from C, N, O, and S, preferably C and N. 2B The atoms are selected such that ring B does not have OO bonds, OS bonds, and SS bonds. Particularly preferred are all X 2B The atom is C.

[0132] Ring B may be a 4, 5, 6, 7, or 8-membered ring. Therefore, p is either 0 or an integer between 1 and 6; q is either 0 or an integer between 1 and 6; and the sum of p and q is an integer between 2 and 6.

[0133] In particular, ring B may be a 5-membered ring or a 6-membered ring, and is especially preferably a 6-membered ring. In other words, the sum of p and q may be 3 or 4, and is preferably 4.

[0134] Preferably, both p and q are at least 1. In other words, X 1BC It is preferable that the N atom bonded to linker Qa is not adjacent to it.

[0135] If ring B is a 6-membered ring, it is preferable that p is 2 and q is 2.

[0136] R 5B Group(R 5B2 , R 5B3 Each of the following is independently either absent or selected from H and a substituted or unsubstituted organic group. Ring B is present R 5B Depending on the number of bases Ring B may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring. Ring B is preferably a saturated heterocycle.

[0137] In most embodiments, R is a substituted or unsubstituted organic group. 5B There is one or fewer bases.

[0138] R 5B If a base exists, its R 5B The group is most preferably H. Preferably all R 5B The base exists, and all R 5B The base is H.

[0139] Two R's 5B The bases may work together to bridge ring B.

[0140] Ring B may be a 7-membered saturated heterocycle, and may optionally be a homopiperazine having the following structure: [ka] (In the formula, R 5B Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5B Each of these is H.

[0141] Alternatively, ring B may be a 6-membered saturated heterocycle, optionally a piperazine, and further optionally a piperazine having the following structure: [ka] (In the formula, R 5B Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5B Each of these is H.

[0142] According to another possibility, ring B may be a 5-membered saturated heterocycle, optionally an imidazolidine, and further optionally an imidazolidine having the following structure: [ka] (In the formula, R 5B Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5B Each of these is H.

[0143] Alternatively, ring B may be azepane and may optionally have the following structure: [ka] (In the formula, R 5B Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5B Each of these is H.

[0144] In one other possibility, ring B may be piperidine and may optionally have the following structure: [ka] (In the formula, R 5B Each of these is independently selected from H and substituted or unsubstituted organic groups, where each R is optionally 5B (is H.)

[0145] Alternatively, ring B may be pyrrolidine and may optionally have the following structure: [ka] (In the formula, R 5B Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5B Each of these is H.

[0146] Furthermore, according to other possibilities, ring B may have the following structure: [ka] (In the formula, R 5BEach of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5B Each of these is H.

[0147] Preferably, ring B is as follows: [ka] It may have a structure selected from among the following.

[0148] Ring B has the following structure: [ka] It is particularly preferable to have this feature.

[0149] Ring C The ring C of PARP1 inhibitor compounds has the following structure: [ka] It has.

[0150] X 1CB X is bonded to ring B via linker Qc. 1 Refers to an atom. X 2C X of ring C 2 It refers to an atom.

[0151] X 1CB X may be C or N, and is preferably C. 1CB If R is N, 5C1 They typically do not exist.

[0152] Qc, [ka] And if u=0, then X 1CB is C. X of ring B 1BC If the atom is N and Qc is the bond, then X 1CB C is C.

[0153] The ring C may be a 4, 5, 6, 7, or 8-membered ring. Therefore, r is either 0 or an integer between 1 and 6; s is either 0 or an integer between 1 and 6; and the sum of r and s is an integer between 2 and 6.

[0154] Preferably, r and s are at least 1 each.

[0155] In particular, ring C may be a 5- or 6-membered ring, and is especially preferably a 6-membered ring. In other words, the sum of p and q may be 3 or 4, and is preferably 4.

[0156] Ring C may be a six-membered aliphatic ring, and may optionally be a six-membered aliphatic ring having the following structure: [ka] (In the formula, R 5C and R 5C1 Each of these is independently selected from H and a substituted or unsubstituted organic group, where preferably R 5C1 is H, and more preferably R 5C1 and R 5C Each of these is H.

[0157] Alternatively, ring C may be a 6-membered aromatic ring, and may be optionally selected from the following: iia) Phenyl group, optionally having the following formula: [ka] (In the formula, R 5C Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5C Each of them is H. iib) A pyridine group, which may optionally have a formula selected from the following: [ka] (In the formula, R 5CEach of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5C Each of them is H. ); and, iic) Diazine group, optionally having a formula selected from the following: [ka] (In the formula, R 5C Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5C Each of these is H.

[0158] In further examples, ring C may be a five-membered aromatic ring, and can be arbitrarily selected from the following: iiia) The imidazole group may optionally have the following structure: [ka] (In the formula, R 5C Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5C Each of them is H. iiib) The thiophene group may optionally have a structure selected from the following: [ka] (In the formula, R 5C Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5C Each of them is H. iiic) The thiazole group may optionally have a structure selected from the following: [ka] (In the formula, R 5C Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally selected. 5C Each of them is H. ); and, iiid) A triazole group, optionally a triazole group having the following structure: [ka] (In the formula, R 5C R is selected from H and substituted or unsubstituted organic groups, where R is optionally selected. 5C (is H.)

[0159] For example, ring C is as follows: [ka] [ka] It may have a structure selected from among the following.

[0160] Preferably, ring C is a six-membered aromatic ring. For example, ring C may have the following structure: [ka] (In the formula, X C Each of these is independently selected from C and N; X C If N, then the corresponding R 5CO or R 5CM The base does not exist; and, X C If C, then the corresponding R 5CO or R 5CM The group is H, or an organic group selected from a halo group, -CN, a C1-C2 alkyl group, and a C1-C2 haloalkyl group.

[0161] X C If C, then the corresponding R 5CO or R 5CM The group may be H, or an organic group selected from H, -Cl, -F, and -CN.

[0162] The ring C may have exactly one substituent. In other words, exactly one R5CO Base or exactly one R 5CM The group may be an organic group.

[0163] Optionally, X is N. C Atoms consist of two or fewer people.

[0164] In particular, ring C may have the following structure: [ka] (In the formula, R C2о is selected from H and halogen; and, i)X 2CM is C, and R 5C2 Is it H; or, ii)X 2CM is N, and R 5C2 It does not exist.

[0165] Preferably, R C2о F is a halogen, and the preferred halogen is F.

[0166] Ring C is as follows: [ka] It may have a structure selected from among the following.

[0167] According to another possibility, ring C is as follows: [ka] That's fine.

[0168] In a further example, ring C is as follows: [ka] [ka] [ka] You may choose from the following.

[0169] Substituent R 6 In the PARP1 inhibitor compounds provided in this disclosure, R 6 It is either absent or selected from H and substituted or unsubstituted organic groups. Preferably, R 6 H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 , -NR 51 COR 52 -SO2NR 51 R 51 , -NR 51 SO2R 52 , -O-CR 52 R 52 R 52 ,-CR 52 R 52 NR 51 R 51 , and one of the following structures: [ka] (In the formula, R 51 and R 52 Each of these is independently selected from H and substituted or unsubstituted organic groups. 51 and R 52 Preferably, each is independently selected from H, halogen, C1-C3 alkyl groups, and C1-C3 haloalkyl groups. For example, R 51 and R 52 These can each be H.

[0170] R 6 -F, -Cl, -CN, -CONH2, -CONHMe, -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me, -SO2NHMe, -CONHSO2Me, and the following: [ka] You may choose from the following.

[0171] According to another possibility, R 6 The following structure may be present: [ka] (In the formula, R 51 The following can be selected: -C1-C6 alkyl groups, optionally C3-C6 cycloalkyl groups, C1-C3 alkyl groups, or C1-C3 deuterated alkyl groups; -C1-C3 haloalkyl groups, optionally C1-C3 fluoroalkyl groups; and, - A saturated heterocyclic group with 4, 5, 6, or 7 members, optionally a cyclic ether group with 4, 5, or 6 members.

[0172] For example, R 6 The following: [ka] You may choose from the following.

[0173] Or, R 6 The following: [ka] You may choose from the following.

[0174] Preferred R 6 The basis is as follows: [ka] That is the case.

[0175] Most preferred R 6 The base is -CONHMe(i.e., [ka] ), and the following: [ka] That is the case.

[0176] The structure of the compound, L group, or ring C is R 6 If it is depicted as having CONHMe, then R 6 The basis is as follows: [ka] Substitution with is being considered.

[0177] Similarly, if the structure of the compound, L group, or ring C is R 6 As follows: [ka] If it is depicted as having R 6 Substituting the base with CONHMe is being considered.

[0178] Alternatively, R 6 The following structure may be present: [ka] (In the formula, X 6 Each of these is independently selected from C, N, and O; R 61 It either does not exist or is H; R 62 Each of these is either absent or contains H, a halo group (e.g., F), an oxo group, a C1-C3 alkyl group, a C1-C3 haloalkyl group (optionally a C1-C3 fluoroalkyl group), and -NHR 63 (Here, R 63 (is selected from H or C1-C3 alkyl groups.)

[0179] Such R 6 The following is an example of the basis: [ka] Includes.

[0180] In other examples, R 6 Base and one R 5C The groups may come together to form a ring. For example, ring C is as follows: [ka] It may have a structure selected from among the following.

[0181] However, typically, ring C is not a fused ring system, and any R 5C Also, other R 5C Base or R 6 It does not form a ring with the base.

[0182] According to other possibilities, R 6 -H, -F, -Cl, and -CN may be selected.

[0183] Linker (Q base) The following formula: [ka] As shown, rings E, A, B, and C are connected by linkers Qa, Qb, and Qc.

[0184] In this disclosure, the linker may be collectively referred to as the "Q group." Qa, Qb, and Qc, and rings A-C, as a whole, may be referred to as the "L group."

[0185] Each linker is independently selected from groups having a bond and a structure independently selected from the following: [ka] (In the formula, Given that t+u is a number selected from 0, 1, 2, 3, 4, 5, and 6, t is a number selected from 0, 1, 2, 3, 4, and 5, and u is independently a number selected from 0, 1, 2, 3, 4, and 5; and R 7 and R 8 Each of these is independently selected from H and substituted or unsubstituted organic groups.

[0186] Q group, [ka] In this case, t and u are selected such that the Q group is bonded to the ring via a CN bond rather than an NN bond. Typically, t is at least 1 and u is at least 1.

[0187] For example, at least one of Qa, Qb, and Qc may be: [ka] (In the formula, t+u is at least 1; R 7 This is selected from H, halogens (e.g., -F, -Cl, -Br, and -I, preferably -F), substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (preferably CF3), -NH2 groups or substituted or unsubstituted C1-C6 amino groups, -OH groups or substituted or unsubstituted linear or branched C1-C6 alcohol groups, and substituted or unsubstituted C1-C6 alkoxy groups.

[0188] In particular, R 7 This may be selected from H, halogens (preferably F), substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups.

[0189] At least one of Qa, Qb, and Qc has the following structure: [ka] If R is provided, 8 You may choose from the following: -H; - Substituted or unsubstituted linear or branched C1-C6 alkyl groups (methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group, etc.); - Substituted or unsubstituted linear or branched C1-C6 alkyl-aryl groups (-CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph, etc.); - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (-CH2F, -CF3, -CH2CH2F, and -CH2CF3, etc.); - Substituted or unsubstituted cyclic amine or amide groups (e.g., pyrrolidine-3-yl, piperidine-3-yl, piperidine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); - Substituted or unsubstituted C3-C8 cyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); - Substituted or unsubstituted linear or branched C2-C6 alcohol groups (-CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH, etc.); - Substituted or unsubstituted linear or branched C2-C6 carboxylic acid groups (-CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH, etc.); - Substituted or unsubstituted linear or branched carbonyl groups (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl, -( CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2, etc. - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe, etc.); - Substituted or unsubstituted linear or branched C1-C6 amide groups (-CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt, etc.); - Substituted or unsubstituted sulfonyl groups (-SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe, etc.); - Substituted or unsubstituted aromatic groups (Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4 ,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et 2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2- (CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-, etc.); and,- Substituted or unsubstituted heterocyclic groups (pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyridazine-4-yl, pyridazine-2-yl, pyrimidine-4-yl, pyridazine-4-yl, pyridazine-2-yl, pyrimidine-4-yl, pyridazine-4-yl) Limidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, fran-2-yl, fran-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran -5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-4-yl, 2-azapyran-tetrahydrofuran-5-yl, 3-azapyran-tetrahydrofuran-2-yl, 3-azapyran-tetrahydrofuran-4- Il, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl,Morpholin-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathio Pyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thian-2-yl, thian-3-yl, thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl, and tetrazole-5-yl, etc.

[0190] In particular, R 8 This may be selected from H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group.

[0191] Optionally, Qa is a bond or a -CH2-, preferably Qa is a bond. The L group has the following structure: [ka] It may also be equipped with.

[0192] The L group can optionally have the following structure: [ka] It may also be equipped with.

[0193] Optionally, Qb is a bond or -CH2-, preferably a bond. If ring A is a 5, 6, or 7-membered ring, Qb is preferably a bond. If ring A is a 3-membered ring, Qb is preferably -CH2-. If ring A is a 4-membered ring, Qb is -CH2- or a bond.

[0194] Optionally, Qc is a bond or a -CH2-, preferably a bond. In particular, if ring B is a 5, 6, or 7-membered ring, Qc may be a bond.

[0195] If ring B is a 3- or 4-membered ring, Qc is -CH2-, -O-, and -NR 8 -You may choose from the following. 8 is H, or a substituted or unsubstituted organic group, and optionally H, or a C1-C3 alkyl group.

[0196] In particular, if ring B is a 3- or 4-membered ring, Qc may be -O- or -NH-.

[0197] Preferably, Qa, Qb, and Qc are each independently selected from a bond and -CH2-. Most preferably, Qa, Qb, and Qc are each a bond.

[0198] Stereochemistry Many of the PARP1 inhibitor compounds provided in this disclosure may contain one or more chiral centers.

[0199] While not intended to be constrained by theory, it is believed that the arrangement of rings E and B relative to ring A may influence the activity of PARP1 inhibitor compounds.

[0200] In the context of this disclosure, when a PARP1 inhibitor compound is described as "A ring cis" or having a cis configuration of ring A, it means that the L group of the compound has the following structure: [ka] (In the formula, ring A is a saturated or unsaturated aliphatic carbocyclic or heterocyclic ring.)

[0201] When a PARP1 inhibitor compound is described as "A ring trans" or having a trans configuration of ring A, it means that the L group of the compound has the following structure: [ka] (In the formula, ring A is a saturated or unsaturated aliphatic carbocyclic or heterocyclic ring.)

[0202] If the PARP1 inhibitor compound is ring A trans and ring A is cyclopentane (for example, if ring A has the structure "A9"), then X of ring A 1 Both atoms have an R configuration, or the X of ring A. 1 Both atoms may have an S configuration. In other words, ring A may have an (R,R) configuration or an (S,S) configuration. In some examples, the (S,S) enantiomer may have higher activity than the (R,R) enantiomer.

[0203] In some of the compounds provided in this disclosure, ring A is an aromatic ring. When ring A is an aromatic ring, the PARP1 inhibitor compound is neither ring A cis nor ring A trans.

[0204] The PARP1 inhibitor compounds described herein may be provided in the form of isolated enantiomers, mixtures of two or more enantiomers, mixtures of two or more diastereomers and / or epimers, or racemic mixtures.

[0205] Example of L-base In particular, the L group may have the following structure: [ka] (In the formula, m is either 1 or 2; n is either 1 or 2; X 1AE is C, and R 5A1 is H or X 1AE is N, and R 5A1 It does not exist; R 5A2 Each of them is either nonexistent or H, independently of each other; R 5A3 is either nonexistent or H; p is either 1 or 2; q is either 1 or 2; X 1BC is C, and R 5B3 is H or X 1BC is N, and R 5B3 It does not exist; R 5C2о is H or a halogen, and may optionally be F; X 2CM is N, and R 5C2M It does not exist, or X 2CM is C, and R 5C2M is H; R 6 The following can be selected: [ka] ).

[0206] In the modified example, R 5A1 Base, multiple R 5A2 Base, and R 5A3 The two groups selected from the group represent the -CH2- groups that bridge ring A.

[0207] Optionally, R 6 The following: [ka] You may choose from the following.

[0208] Ring L has the following structure: [ka] p may be 2 and q may also be 2, such that the condition is met.

[0209] Preferably, X 1BC is N, and R 5B3 It does not exist.

[0210] Preferably, ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl.

[0211] The L group is as follows: [ka] [ka] [ka] [ka] [ka] [ka] You may choose from the following.

[0212] The L group, in particular, i) Below: [ka] , optionally, the following: [ka] ; ii) Below: [ka] , optionally, the following: [ka] ; iii) Below: [ka] ; iv) Below: [ka] , optionally, the following: [ka] ; v) Below: [ka] ; vi) Below: [ka] , optionally, the following: [ka] ; vii) Below: [ka] , optionally, the following: [ka] ; or, viii) Below: [ka] , optionally, the following: [ka] You may choose from the following.

[0213] Compound example Specific examples of PARP1 inhibitor compounds provided in this disclosure include compounds having the following structures: [ka] (In the formula, R 23 Each of these is independently selected from H or a halogen (e.g., F); R 22 This is selected from H, a methyl group, and a halomethyl group (e.g., CH2F, CHF2, and CF3); Z 2 is C, and R 3 is H, or Z 2 is N, and R 3 It does not exist; m is either 1 or 2; n is either 1 or 2; X 1AE is C, and R 5A1 It does not exist or is H; or, X 1AE is N, and R 5A1 It does not exist; R 5A2 Each of them either does not exist independently or is H; R 5A3 It does not exist or is H; p is either 1 or 2; q is either 1 or 2; X 1BC is C, and R 5B3 is H; or, X 1BC is N, and R 5B3 It does not exist; R 5C2о is H or a halogen, and may optionally be F; X 2CM is N, and R 5C2M It does not exist; or, X 2CM is C, and R 5C2M is H; R 6 The following can be selected: [ka] . ) .

[0214] In the modified example, R 5A1 Base, multiple R 5A2 Base, and R 5A3 The two groups selected from the group represent the -CH2- groups that bridge ring A.

[0215] Optionally, R 6 The following: [ka] You may choose from the following.

[0216] Preferably, R 23 Each of them is H, and R 22 It is a methyl group.

[0217] Preferably, Z 2 is C, and R 3 H is H.

[0218] Preferably, X 1AE is C, and R 5A1 H is H.

[0219] Ring A is preferably selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl.

[0220] Ring B is preferably piperazine: [ka]

[0221] Further examples of PARP1 inhibitor compounds provided in this disclosure include compounds having the following structures: [ka] (In the formula, Z 1 and Z 2These are independently selected from C and N, Z 1 If R is N, 2 It does not exist; Z 1 If C, then R 2 is H; Z 2 If R is N, 3 It does not exist; Z 2 If C, then R 3 is H; X C Each of them is independently selected from C and N; and, X C If N, then the corresponding R 5CO or R 5CM The basis does not exist; X C If C, then the corresponding R 5CO or R 5CM The group is either H, or an organic group selected from a halo group, -CN, a C1 or C2 alkyl group, and a C1 or C2 haloalkyl group; Two R's 5A The conditions are that the groups together represent -CH2- and ring A is non-aromatic, and other R 5A Each of the elements is independently either H or nonexistent; or Preferably, ring A is non-aromatic, R 5A Each element is either independently H, or does not exist.

[0222] R 6 This is as already defined in this disclosure. For example, R 6 The following: [ka] You may choose from the following.

[0223] PARP1 inhibitor compounds include the following: [ka]

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[0224] Pharmaceutical use The compounds described herein may be provided for pharmaceutical use. In the context of the present invention, pharmaceutical uses are not particularly limited, as long as they are uses facilitated by the PARP1 inhibitory effect of the compounds. Accordingly, the compounds of the present invention may be used for any disease, condition or disorder that can be prevented, improved or treated with PARP1 inhibitors.

[0225] In particular, PARP1 inhibitor compounds may be used to treat cancer. The nature of the cancer is not particularly limited, insofar as it can be treated, prevented, or improved with PARP1 inhibitors. Cancer can be a solid tumor or a humoral tumor.

[0226] For example, cancers may be selected from the following: cancers of the eye, brain (glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma, etc.), spinal cord, kidney, mouth, lips, pharynx, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gallbladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchi, liver, skin, ureter, urethra, testicle, vagina, anus, laryngeal gland, ovary, thyroid gland, esophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, and adrenal gland; endometrial cancer, oral cancer, malignant melanoma, neuroblastoma, gastric cancer, hemangioma, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, and PTEN hamartomatosis. Syndrome (PHTS) (Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome, etc.), leukemia and lymphoma (acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prelymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary exudative lymphoma, AIDS-associated lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal cancer, and gastrointestinal cancer).

[0227] In addition, the compounds described herein may be used for cancers associated with Epstein-Barr virus (EBV), such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal cancer, and gastrointestinal cancer.

[0228] The compounds described herein may be used to treat cancers lacking DNA damage response repair pathways, particularly cancers lacking homologous recombination (HR)-dependent DNA double break (DSB) repair activity. Components of the homologous recombination-dependent DNA double break (DSB) repair pathway and other DNA damage response pathways include, but are not limited to, the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP(SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, and BLM. Other components involved in homologous recombination (HR)-dependent DNA double-strand breaks (DSBs) include regulatory factors such as ESMY (Non-Patent Literature 17). Cancers lacking the ability to repair homologous recombination (HR)-dependent DNA double-strand breaks (DSBs) typically become dependent on alternative DSB repair pathways. Such cancers include, but are not limited to, ovarian, prostate, breast, lung, gastrointestinal, hematological, and pancreatic cancers.

[0229] Cancer cells may have a phenotype lacking BRCA1 and / or BRCA2, that is, cancer cells may lack the function of BRCA1 and / or BRCA2. Such deficiencies can result from mutations, polymorphisms, or epigenetic silencing of the nucleic acids encoding BRCA1 and / or BRCA2, or from amplification, polymorphisms, or mutations of genes encoding regulatory factors (e.g., the ESMY gene encoding the BRCA2 regulator; Non-Patent Literature 17). Amplification of the ESMY gene has been associated with breast and ovarian cancer. Carriers of mutations in the tumor suppressor genes BRCA1 and / or BRCA2 are known to be at high risk of developing certain cancers, including ovarian, prostate, and breast cancer. Wild-type alleles of BRCA1 and / or BRCA2 are frequently lost in tumors of heterozygous carriers (Non-Patent Literature 18), and their detection is well known in the art as a means of patient selection (Non-Patent Literature 19; Non-Patent Literature 20).

[0230] The compounds provided in this disclosure may be administered to patients undergoing radiotherapy and / or chemotherapy with further agents for treating cancer.

[0231] For example, the PARP1 inhibitor compound may be used in combination with further agents for treating cancer.

[0232] Further agents for treating cancer may be selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapies, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors.

[0233] In particular, the agent may comprise an immunotherapy agent selected from the following: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T-cell therapy); small molecule immunomodulators; and tumor microenvironment modifiers.

[0234] Pharmaceutical composition In other respects, a pharmaceutical composition comprising the PARP1 inhibitor compound defined above is provided.

[0235] Typically, the composition contains pharmaceutically acceptable additives and / or excipients.

[0236] In a pharmaceutical composition, the PARP1 inhibitor compound as defined above may exist in the form described above, or alternatively, in a form suitable for improving bioavailability, solubility and / or activity, and / or in a form suitable for improving formulation. Accordingly, the compound may be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other suitable alternative form.

[0237] Typically, pharmaceutical compositions are used for medical purposes, for example, to treat the diseases, conditions, or disorders defined above.

[0238] For example, a pharmaceutical composition may be used to treat cancer. The pharmaceutical composition may further comprise a further agent for treating cancer. The further agent for treating cancer is not particularly limited, as long as it provides some usefulness in treating cancer.

[0239] Further agents for treating cancer may comprise one or more chemotherapeutic agents such as microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors.

[0240] In particular, the further agents for treating cancer may comprise immunotherapeutic agents selected from the following: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T-cell therapy); small molecule immunomodulators and tumor microenvironment modifiers.

[0241] kit In other respects, a pharmaceutical kit for treating cancer is provided. The pharmaceutical kit comprises the PARP1 inhibitor compound defined above and further agents for treating cancer. The compound and further agents are suitable for simultaneous, sequential, or separate administration.

[0242] Further agents for treating cancer may be any of the further agents for treating cancer identified in the description of the above pharmaceutical composition.

[0243] In particular, further agents for treating cancer may comprise one or more chemotherapeutic agents selected from the following: microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapies, radioligand therapies, angiogenesis inhibitors, and immunotherapeutic agents (antitumor vaccines; tumor lysis). Sexual viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T cell therapy); small molecule immunomodulators, and tumor microenvironment modifiers, etc.; apoptosis inducers, and cell cycle signaling inhibitors.

[0244] Treatment method Another aspect of the present invention provides a method for treating a disease and / or condition and / or disorder, comprising administering a PARP1 inhibitor compound, composition, or kit as appropriate in this disclosure to a patient (or subject). Such a method is typically for treating any disease, condition, or disorder mentioned in this disclosure. In a typical embodiment, such a method is for treating cancer.

[0245] The patient may be any animal, but preferably a mammal. For example, the patient may be a human, dog, horse, or cat, but preferably a human.

[0246] The treatment method may include administering to the patient (or subject) the compound or composition defined above and further agents for treating the cancer defined above. The compound, composition, and further agents may be administered simultaneously, sequentially, or separately, depending on the drugs, the patient, and the disease being treated (e.g., the type of cancer being treated).

[0247] The patient may be one who is receiving treatment using ionizing radiation.

[0248] Method for synthesizing PARP1 inhibitor compounds Furthermore, a method for synthesizing PARP1 inhibitor compounds as defined in this disclosure is provided. Generally, the method comprises a reaction between (i) a first reactant comprising a ring E having a portion of an L group and (ii) a second reactant comprising the remainder of the L group, thereby forming a PARP1 inhibitor compound. Those skilled in the art may select reaction conditions by reference to known synthetic techniques, depending on suitable starting materials. The method may include one or more additional steps. Exemplary synthetic methods are shown in the examples of this disclosure described later.

[0249] In one exemplary method, the first reactant comprises ring E and ring A, the second reactant comprises a Qb precursor having a reactive group, and the method comprises bonding ring A to the Qb precursor. In the method, the reactive group of the Qb precursor may comprise a carbonyl group, an alkyl halide, or an alkyl sulfonate. The reaction may comprise alkylation, reductive amination, or amidation to form an L group.

[0250] In another exemplary method, the first reactant comprises ring E, ring A, Qa, and ring B, and the second reactant comprises a derivative of ring C having a leaving group, such as a halide or a sulfonic acid ester. In this method, the reaction may include a nucleophilic substitution reaction, such as an aromatic nucleophilic substitution reaction, to form the L group.

[0251] A particularly preferred method is one in which L has the following structure: [ka] This is a method for synthesizing PARP1 inhibitor compounds that have a group containing [a specific group].

[0252] In the preferred method described above, the first reactant has the following structure: [ka] (In the formula, R 9 R is a protecting group. 9 The most typical protecting group is the methyl group. Other examples of protecting groups include acetyl, t-butyl, benzoyl, benzyl, p-methoxybenzyl, p-methoxyphenyl, methoxymethyl, ethoxyethyl, methoxyethoxymethyl, methylthiomethyl, trityl, methoxytrityl, dimethoxytrityl, pivaloyl, tetrahydropyranyl, tetrahydrofuran, and silyl groups (e.g., trimethylsilyl, t-butyldimethylsilyl, triisopropylsilyloxymethyl, and triisopropylsilyl).

[0253] In the preferred method described above, the second reactant has the following structure: [ka]

[0254] In the preferred embodiment described above, carrying out the reaction comprises (i) and (ii) below: (i) Using a reducing agent in the presence of an acid, the first reactant and the second reactant are coupled to obtain an intermediate product having the following structure: [ka] (ii) Subsequently, deprotect the ring E' to form a PARP1 inhibitor compound.

[0255] The reducing agent and acid used in step (i) can be selected as appropriate. Examples of suitable reducing agents include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. The acid may be a weak acid, and optionally a weak organic acid such as acetic acid.

[0256] (ii) The conditions used for deprotection in step (ii) are the protecting group R 9 It can be appropriately selected depending on its properties. For example, R 9 In embodiments where is a methyl group, deprotection may be carried out by using trimethylsilyl iodide (TMSI) or boron tribromide in a suitable solvent (e.g., dichloromethane, acetonitrile, or chloroform). Other acids or Lewis acids may also be used.

[0257] In some embodiments of the preferred method described above, rings A, B', and B are all saturated rings, and optionally X of rings B and B'. 1 It is N.

[0258] The PARP1 inhibitor compound may be obtained in the form of a mixture of two or more structural isomers. The method may further include separating these structural isomers. For example, the method may further include separating the structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography (SFC) and / or chiral high-performance liquid chromatography (HPLC).

[0259] If the PARP1 inhibitor compound is a diastereomer, the separation may be carried out in two steps. In the first step, two pairs of stereoisomers may be isolated by HPLC. In the second step, individual stereoisomers may be isolated from the pairs of stereoisomers by SFC.

[0260] example

[0261] Example 1: Synthesis of 3rac [ka]

[0262] Preparation of 6-bromo-3-iodo-2-methoxypyridine (1002) The following three types of solutions, A to C, were prepared. A: A solution of NaNO2 (3.4g, 0.049mol) in H2O (100mL). B: A solution of 6-bromo-2-methoxypyridine-3-amine (1001) (10g, 0.049mol) in concentrated hydrochloric acid:H2O=1:1 (80mL). C:KI (24.56 g, 0.15 mol) in H2O (450 mL) solution. At 0°C, "A" was added dropwise to "B". The reaction mixture was stirred at 0°C for 20 minutes. Then, at 0°C, the reaction mixture was added dropwise to "C". The mixture was heated at 60°C for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with toluene (500 mL x 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (toluene / PE, eluting from 0% to 50%) to obtain 6-bromo-3-iodo-2-methoxypyridine (1002) (8.9 g, purity 90%, yield 58%) as a white solid. LCMS(ESI) C6H5BrINO [M+H] + m / z calculated value: 313.86, measured value: no signal detected.

[0263] Preparation of 6-bromo-2-methoxy-3-vinylpyridine (1004) To a 50 mL DMF / H2O = 5:1 solution of 6-bromo-3-iodo-2-methoxypyridine (1002) (1 g, 0.0032 mol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1003) (0.50 g, 0.0032 mol), Na2CO3 (1.01 g, 0.0096 mol), and Pd(dppf)Cl2·DCM (0.26 g, 0.00032 mol) were added under a nitrogen atmosphere. The mixture was heated at 65°C for 2 hours. The resulting mixture was diluted with water (100 mL) and extracted using ELISA (100 mL x 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with 0% to 100% Â1 / PE) to obtain 6-bromo-2-methoxy-3-vinylpyridine (1004) (600 mg, purity 90%, yield 78%) as a white solid. LCMS(ESI)C8H8BrNO [M+H] + m / z Calculated value: 213.98, Measured value: No signal detected.

[0264] Preparation of 7-(6-methoxy-5-vinylpyridine-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1006) In a sealed tube, tBuONa (0.89 g, 0.0084 mol) and RuPhos Pd G3 (0.24 g, 0.00024 mol) were added to a 20 mL solution of 6-bromo-2-methoxy-3-vinylpyridine (1004) (600 mg, 0.0028 mol) and 1,4-dioxa-7-azaspiro[4.4]nonane (1005) (0.41 g, 0.0031 mol) in dioxane (20 mL). The mixture was heated at 100 °C for 2 hours. The resulting mixture was concentrated and purified by silica gel chromatography (eluting with 0% to 100% siRNA / PE) to obtain 7-(6-methoxy-5-vinylpyridine-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1006) (250 mg, purity 90%, yield 30%) as a white solid. LCMS(ESI) C 14 H 18 N2O3[M+H] + m / z Calculated value: 263.13, Measured value: 262.92.

[0265] Preparation of 7-(5-ethyl-6-methoxypyridine-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1007) 7-(6-methoxy-5-vinylpyridine-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1006) (250 mg, 0.96 mmol) was dissolved in MeOH (20 mL) and 10% Pd / C (25 mg) was added. The mixture was degassed and refilled with hydrogen three times. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then filtered through Celite and concentrated under reduced pressure to obtain the crude product of 7-(5-ethyl-6-methoxypyridine-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1007) (250 mg, purity 90%, yield 90%). The crude product was used directly in the next step without further purification. LCMS(ESI) C 14 H 20 N2O3[M+H] + m / z Calculated value: 265.15, Measured value: 264.95.

[0266] Preparation of 1-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-3-one (1008) A solution of 7-(5-ethyl-6-methoxypyridine-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1007) (200 mg, 0.76 mmol) in concentrated hydrochloric acid (conc. HCl) (12 mL) was stirred at 50°C for 12 hours. The pH of the resulting mixture was then adjusted to pH 7-8 with aqueous NaHCO3 solution and extracted with siRNA (30 mL x 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated to obtain the crude product of 1-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-3-one (1008) (130 mg, purity 90%, yield 70%) as a white solid. LCMS(ESI) C 12 H 16 N2O2[M+H] + m / z Calculated value: 221.12, Measured value: 221.20.

[0267] Preparation of 5-(4-(1-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-3-yl)piperazine-1-yl)-N-methylpicolinamide (1010) 1-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-3-one (1008) (120 mg, 0.45 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide (1009) (117 mg, 0.45 mmol) were dissolved in MeOH (10 mL) and AcOH (0.1 mL) was added. Then, NaBH3CN (29 mg, 0.45 mmol) was added to the mixture. The mixture was heated at 50 °C for 1 hour. The resulting mixture was quenched with water (1 mL), concentrated, and then purified by silica gel chromatography (eluting with 0% to 10% MeOH / DCM) to obtain 5-(4-(1-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-3-yl)piperazine-1-yl)-N-methylpicolinamide (1010) (100 mg, purity 90%, yield 38%) as a white solid. LCMS(ESI) C 23 H 32 N6O2[M+H] + m / z Calculated value: 425.26, Measured value: 425.25.

[0268] Preparation of 5-(4-(1-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)pyrrolidine-3-yl)piperazine-1-yl)-N-methylpicolinamide (3rac) To a solution of 5-(4-(1-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-3-yl)piperazine-1-yl)-N-methylpicolinamide (1010) (100 mg, 0.24 mmol) in DCM (10 mL), BBr3 (118 mg, 0.47 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (10 mL) and then extracted with ELISA (50 mL x 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate, concentrated, and purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 5% to 95% MeCN / H2O (0.1% FA)) to obtain 5-(4-(1-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)pyrrolidine-3-yl)piperazine-1-yl)-N-methylpicolinamide (3rac) (11.9 mg, purity 99%, yield 13%) as a white solid. 1H NMR (400MHz, DMSO-d6, ppm) δ:10.20(s,1H),8.44-8.36(m,1H),8.28(d,J=2.4Hz,1H),7.83(d,J=8.8Hz,1H),7.44-7.37(m,1H ),7.11(d,J=7.6Hz,1H),5.39(s,1H),3.65-3.57(m,1H),3.52-3.42(m,1H),3.37-3.33(m,3H),3.3 0-3.22(m,2H),3.19-3.09(m,1H),2.94(d,J=4.8Hz,1H),2.78(d,J=4.8Hz,3H),2.68-2.60(m,2H), 2.60-2.53(m,2H),2.34-2.25(m,2H),2.23-2.14(m,1H),1.89-1.77(m,1H),1.03(t,J=7.4Hz,3H). LCMS(ESI) C 22 H 30 N6O2[M+H] + m / z measured value: 411.24, actual value: 411.25.

[0269] Example 2: Synthesis of 4cis

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[0270] Preparation of 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-ol (1103) To a solution of 6-bromo-3-ethyl-2-methoxypyridine (1101) (800 mg, 12.41 mmol) in THF (15 mL), n-BuLi (2.5 M in hexane, 2.22 mL, 5.55 mmol) was added dropwise under a nitrogen atmosphere at -78°C. The solution was then stirred at -78°C for 30 minutes. Next, 3-(benzyloxy)cyclobutan-1-one (1102, 984 mg, 5.55 mmol) was added dropwise. The resulting solution was gradually heated to room temperature and stirred for 2 hours. The resulting mixture was quenched with saturated NH4Cl aqueous solution and extracted with RINKAN (20 mL x 3). The combined organic groups were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (eluting at PE / Â=100:0 to 80:20) to obtain 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-ol (1103) (400 mg, yield 32%) as a colorless oil. LCMS(ESI) C 19 H 24 NO3 [M+H] + m / z Calculated value: 314.17, Measured value: 314.10.

[0271] Preparation of 6-(3-(benzyloxy)cyclobuta-1-en-1-yl)-3-ethyl-2-methoxypyridine (1104) 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-ol (1103, 400 mg, 1.27 mmol) and TEA (257 mg, 2.54 mmol) were dissolved in DCM (10 mL) and MsCl (292 mg, 2.54 mmol) at 0°C. The resulting solution was gradually heated to room temperature and stirred for 2 hours. The reaction mixture was added to water and then extracted with siRNA (10 mL x 3). The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 90:10) to obtain 6-(3-(benzyloxy)cyclobuta-1-en-1-yl)-3-ethyl-2-methoxypyridine (1104) (120 mg, yield 30%) as a colorless oil. LCMS(ESI) C 19 H 22 NO2 [M+H] + m / z: Calculated value: 296.16, Measured value: 296.05.

[0272] Preparation of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-ol (1105) Pd / C (5 mg, 0.04 mmol) was added to a solution of 6-(3-(benzyloxy)cyclobuta-1-en-1-yl)-3-ethyl-2-methoxypyridine (1104) (120 mg, 0.40 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-ol (1105) (70 mg, yield 60%) as a yellow solid. LCMS(ESI) C 12 H 18 NO2 [M+H] + m / z Calculated value: 208.13, Measured value: 208.05.

[0273] Preparation of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-one (1106) Dess Martin's reagent (368 g, 0.87 mmol) was added to a solution of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-ol (1105) (60 mg, 0.29 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After adding the reaction mixture to a sodium hypochlorite solution, it was extracted with  (5 mL x 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE /  = 100:0 to 80:20) to obtain 3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-one (1106) (35 mg, yield 37%) as a yellow oil. LCMS(ESI) C 12 H 16 NO2 [M+H] + m / z Calculated value: 206.11, Measured value: 205.94.

[0274] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutyl)piperazine-1-yl)-N-methylpicolinamide (1107) 3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutan-1-one (1106) (30 mg, 0.15 mmol) and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (1009) (32 mg, 0.15 mmol) were dissolved in MeOH (5 mL), to which sodium triacetoxyborohydride (77 mg, 0.37 mmol) was added. The mixture was stirred at 50°C for 1 hour. Sodium cyanoborohydride (11 mg, 0.18 mmol) was added at 50°C. The mixture was stirred at 50°C for 3 hours. Saturated NH4Cl aqueous solution (2 mL) was added. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 97:3) to obtain 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutyl)piperazin-1-yl)-N-methylpicolinamide (1107) (40 mg, yield 7%) as a white solid. LCMS(ESI) C 23 H 32 N5O2[M+H] + m / z Calculated value: 409.25, Measured value: 410.72.

[0275] Preparation of 5-(4-((1s,3s)-3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclobutyl)piperazine-1-yl)-N-methylpicolinamide (4cis) 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclobutyl)piperazine-1-yl)-N-methylpicolinamide (1107) (40 mg, 0.10 mmol) was dissolved in ACN (5 mL) and TMSI (58.65 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5 μm C18 150 × 21.2 mm; mobile phase: ACN / H2O [0.1% FA] = 20 / 80) to obtain 5-(4-((1s,3s)-3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclobutyl)piperazine-1-yl)-N-methylpicolinamide (4cis) (5 mg, yield 13%) as a white solid. 1HNMR(400MHz,DMSO-d6) δ 11.53(s,1H),8.40(q,J=4.4Hz,1H),8.29(d,J=2.4Hz,1H),7.84(d,J=8.8Hz,1H),7.4 1(dd,J=8.8,2.4Hz,1H),7.19(d,J=7.2Hz,1H),5.98(d,J=6.8Hz,1H),3.49-3.37(m,4 H),3.05-2.97(m,1H),2.87-2.74(m,4H),2.59-2.52(m,2H),2.48-2.40 (m,4H),2.34(q,J=7.2Hz,2H),2.08-1.84(m,2H),1.06(t,J=7.2Hz,3H). LCMS(ESI) C 22 H 30 N5O2[M+H] + m / z calculated value: 396.23, measured value: 396.25.

[0276] Example 3: Synthesis of 6cis-a, 6cis-b, 6trans-a, and 6trans-b

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[0277] Preparation of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1203) To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1201) (200 mg, 0.96 mmol) and 6-chloro-3-ethyl-2-methoxypyridine (1202) (197 mg, 1.15 mmol) in dioxane (5 mL) / water (0.5 mL), Pd(dppf)Cl2 (70 mg, 0.10 mmol) and sodium carbonate (255 mg, 2.40 mmol) were added at room temperature. The reaction mixture was stirred at 95 °C for 6 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 85:15) to obtain 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1203) (90 mg, yield 43%) as a white solid. LCMS(ESI) C 13 H 15 NO2 [M+H] + m / z Calculated value: 218.12, Measured value: 218.00.

[0278] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-N-methylpicolinamide (1204) To a 5 mL solution of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1203) (90 mg, 0.42 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide (1009) (110 mg, 0.50 mmol) in MeOH, two drops of acetic acid were added at room temperature and the mixture was stirred for 10 minutes. NaBH(OAc)3 (220 mg, 1.04 mmol) was added to the reaction mixture and the mixture was stirred at 60°C for 1 hour. NaBH3CN (261 mg, 4.15 mmol) was added to the reaction mixture and the mixture was stirred at 60°C for 15 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 95:5) to obtain 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-N-methylpicolinamide (1204) (85 mg, yield 49%) as a pale yellow oil. LCMS(ESI) C 24 H 31 N5O2[M+H] + m / z Calculated value: 422.26, Measured value: 422.25.

[0279] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (1205) 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-N-methylpicolinamide (1204) (85 mg, 0.20 mmol) was dissolved in MeOH (5 mL) and Pd(OH)2 / C (20 mg) was added. The mixture was degassed and refilled with hydrogen three times, and then hydrogen was refilled. The resulting mixture was stirred at 50°C for 3 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain the crude product 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (1205) (80 mg, yield 93%) as a pale yellow oil. LCMS(ESI) C 24 H 33 N5O2[M+H] +m / z Calculated value: 424.27, Measured value: 424.15.

[0280] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (6cis-a,6cis-b,6trans-a,6trans-b) TMSI (113 mg, 0.57 mmol) was added to a solution of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (1205) (80 mg, 0.19 mmol) in ACN (4 mL). The mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5μm C18 150×21.2mm, mobile phase: ACN-H2O (0.1% FA), gradient: 2%~95%), and the first fraction was obtained as a 6cis-a / 6cis-b racemic mixture (the stereochemistry of the cis group in cyclopentane was estimated based on NOE experiments) (10 mg, purity 95%, white solid), and the second fraction was obtained as a 6trans-a / 6trans-b racemic mixture (the stereochemistry of the trans group in cyclopentane was estimated based on NOE experiments) (3 mg, purity 95%, white solid). 6cis-a / 6cis-b racemic mixture 1 1H NMR (400MHz, CDCl3, ppm) δ 8.19(d,J=2.4Hz,1H),8.10(d,J=8.8Hz,1H),7.83(d,J=4.8Hz,1H),7.69(d,J=7 .2Hz,1H),7.29(d,J=2.4Hz,1H),6.82(d,J=7.2Hz,1H),4.20-3.36(m,8H),3.24 (dt,J=14.8,10.8Hz,2H),3.02(d,J=5.2Hz,3H),2.66-2.54(m,3H),2.39(dd,J= 22.0,11.2Hz,2H),2.31-2.19(m,2H),2.10-2.00(m,1H),1.22(t,J=7.4Hz,3H). LCMS(ESI) C 23 H 31 N5O2[M+H] + m / z Measured value: 410.26, Actual measured value: 410.20. 6trans-a / 6trans-b racemic mixture 1 H NMR(400MHz,CDCl3,ppm) δ 11.74(s,1H),8.17(s,1H),8.06(dd,J=8.4,2.4Hz,1H),7.78(s,1H),7.25-7.15(m,2H),6.02(dd,J=6.4,2.0Hz,1H),3.37(s ,3H),3.22-2.96(m,5H),2.71(s,3H),2.57-2.48(m,2H),2.27-1.98(m,4H),1.86-1.58(m,4H),1.18(td,J=7.2,2.4Hz,3H). LCMS(ESI) C 23 H 31 N5O2[M+H] + m / z Calculated value: 410.26, Measured value: 410.40.

[0281] A 6cis-a / 6cis-b racemic mixture was processed using SFC (column: Regis(R,R)-Whelk-O 1,250mm × 20mm ID, 5μm; mobile phase: CO2). 2 The mixture was separated using MeOH [0.1% (NH3) (7M MeOH solution)] = 65 / 35, and concentrated under reduced pressure to obtain 6cis-a (white solid) as the first fraction and 6cis-b (white solid) as the second fraction.

[0282] A racemic mixture of 6trans-a and 6trans-b was separated by SFC (column: Daicel CHIRALPAK IJ SFC 250mm x 20mm ID, 5μm; mobile phase: CO2 / MeOH [0.1% (NH3) (7M MeOH solution)] = 60 / 40), and concentrated under reduced pressure to obtain 6trans-a (white solid) as the first fraction and 6trans-b (white solid) as the second fraction.

[0283] Example 4: Synthesis of 7cis-a, 7cis-b, 7trans-a, and 7trans-b [ka]

[0284] Preparation of 3-oxocyclopenta-1-en-1-yl pivalate (1302) To a solution of cyclopentane-1,3-dione (1301) (8 g, 81.6 mmol) and DIPEA (21.09 g, 163.2 mmol) in DCM (160 mL), pivaloyl chloride (10.77 g, 89.8 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (400 mL) and extracted with siRNA (400 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product, which was purified by flash column chromatography (PE / siRNA = 100:0 to 70:30) to obtain 3-oxocyclopenta-1-en-1-yl pivalate (1302) (12 g, yield 81%) as a pale yellow oil. LCMS(ESI) C 10 H 14 O3[M+H] + m / z Calculated value: 183.12, Measured value: 183.00.

[0285] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) 3-Oxocyclopenta-1-en-1-yl 2,2-dimethylpropanoate (1302) (8g, 43.9 mmol), B2Pin2 (22.3g, 87.9 mmol), palladium(II) acetate (863 mg, 3.52 mmol), and tri-o-tolylphosphine (1.2g, 3.9 mmol) were dissolved in acetone (80 mL) / water (8 mL), to which 1,3,5-trimethoxybenzene (3.7g, 22.0 mmol) was added. The reaction mixture was stirred at 60°C for 18 hours. After cooling to room temperature, the reaction mixture was added to water (800 mL). The aqueous layer was washed three times with RINKAN (600 mL). The aqueous layer was concentrated under reduced pressure to obtain 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) (2g, yield 22%) as a white solid. LCMS(ESI) C 24 H 31 N5O2[M-72+H] + m / z Calculated value: 126, Measured value: N / A.

[0286] Preparation of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1305) To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) (2.0 g, 9.6 mmol) and 6-chloro-3-ethyl-2-methoxypyridine (1304) (1.6 g, 9.6 mmol) in dioxane (50 mL) / water (5 mL), Pd(dppf)Cl2 (351 mg, 0.48 mmol) and sodium carbonate (2.5 g, 24.0 mmol) were added at room temperature. The reaction mixture was stirred at 95 °C for 8 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting at PE / Â=100:0 to 85:15) to obtain 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1305) (450 mg, yield 22%) as a white solid. LCMS(ESI) C 13 H 15 NO2 [M+H] + m / z Calculated value: 218.12, Measured value: 218.00.

[0287] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1307) To a 5 mL solution of 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1305) (186 mg, 0.85 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (1306) (243 mg, 1.02 mmol) in MeOH, two drops of acetic acid were added at room temperature and the mixture was stirred for 10 minutes. NaBH(OAc)3 (433 mg, 2.04 mmol) was added to the reaction mixture and the mixture was stirred at 60°C for 1 hour. NaBH3CN (534 mg, 8.5 mmol) was added to the reaction mixture and the mixture was stirred at 60°C for 2 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 95:5) to obtain the crude product of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1307) (200 mg, yield 54%) as a pale yellow oil. LCMS(ESI) C 24 H 30 FN5O2[M+H] + m / z Calculated value: 440.25, Measured value: 440.20.

[0288] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1308) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1307) (200 mg, 0.46 mmol) in MeOH (5 mL), Pd(OH)2 / C (80 mg) was added. The mixture was degassed and refilled with hydrogen three times, and then refilled with hydrogen. The resulting mixture was stirred at 50°C for 5 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 95:5) to obtain 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1308) (125 mg, yield 63%) as a pale yellow oil. LCMS(ESI) C 24 H 32 FN5O2[M+H] + m / z Calculated value: 442.26, Measured value: 442.25.

[0289] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (7trans-a / 7trans-b / 7cis-a / 7cis-b) 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1308) (125 mg, 0.283 mmol) was dissolved in ACN (5 mL) and TMSI (170 mg, 0.85 mmol) was added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN-water (0.05% aqueous ammonia), gradient: 25%-95%) to obtain a racemic mixture of 7trans-a and 7trans-b as the first fraction (23 mg, white solid) and a racemic mixture of 7cis-a and 7cis-b as the second fraction (33 mg, white solid). 7trans-a / 7trans-b LCMS(ESI) C 23 H3FN5O2[M+H] + m / z: Calculated value: 428.25, Measured value: 428.20. 7cis-a / 7cis-b LCMS(ESI) C 23 H3FN5O2[M+H] + m / z: Calculated value: 428.25, Measured value: 428.20.

[0290] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (7trans-a, 7trans-b, 7cis-a, and 7cis-b) A racemic mixture of 7trans-a and 7trans-b was separated by SFC (column: Daicel CHIRALPAK IH SFC 250mm x 20mm ID, 5μm; mobile phase: CO2 / MeOH [0.1% (NH3) (7M MeOH solution)] = 70 / 30) and concentrated under reduced pressure to obtain 7trans-a as the first fraction (3.85 mg, purity 99%, ee%: 100, white solid) and 7trans-b as the second fraction (5.43 mg, purity 99%, ee%: 100, white solid). 7trans-a 1 H NMR(400MHz,MeOD,ppm) δ 7.90(dd,J=8.0,1.2Hz,1H),7.52(dd,J=10.4,8.4Hz,1H),7.35(d,J=7.2Hz,1H),6.23(d,J=7.2Hz,1H),3.29-3.24(m,4H),3.17-3.09(m,1H) ,2.96-2.87(m,4H),2.79-2.68(m,4H),2.48(q,J=7.6Hz,2H),2.18-2. 04(m,3H),2.00-1.92(m,1H),1.78-1.59(m,2H),1.16(t,J=7.6Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 23 H3FN5O2[M+H] + m / z Calculated value: 428.25, Measured value: 428.20. 7trans-b 1H NMR(400MHz,MeOD,ppm) δ 7.90(d,J=8.0Hz,1H),7.61-7.42(m,1H),7.35(d,J=7.2Hz,1H),6.22(d,J=6.8Hz,1H),3.29-3.22(m,4H),3.17-3.08(m,1H),2.99-2 .83(m,4H),2.80-2.65(m,4H),2.48(q,J=7.6Hz,2H),2.20-2.04(m,3H),2.00-1.91(m,1H),1.78-1.58(m,2H),1.16(t,J=7.6Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 23 H3FN5O2[M+H] + m / z Calculated value: 428.25, Measured value: 428.20.

[0291] A racemic mixture of 7cis-a and 7cis-b was separated by SFC (column: Daicel CHIRALPAK IH SFC 250mm × 20mm ID, 5μm; mobile phase: CO2 / MeOH [0.1% (NH3) (7M MeOH solution)] = 70 / 30) and concentrated under reduced pressure to obtain the first fraction, 7cis-a (6.20 mg, purity 98%, ee%: 100, white solid), and the second fraction, 7cis-b (5.34 mg, purity 98%, ee%: 99, white solid). 7cis-a 11H NMR (400MHz, MeOD, ppm) δ 7.91(dd,J=8.0,1.2Hz,1H),7.57(dd,J=10.4,8.2Hz,1H),7.31(d,J=6.8Hz,1H ),6.21(d,J=6.8Hz,1H),3.54-3.42(m,2H),3.40-3.33(m,2H),3.19-3.11(m,1 H),2.91(s,3H),2.84-2.72(m,5H),2.46(q,J=7.6Hz,2H),2.25-2.14(m,2H),2 .05-1.98(m,1H),1.90-1.79(m,2H),1.76-1.65(m,1H),1.14(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 23 H3FN5O2[M+H] + m / z Calculated value: 428.25, Measured value: 428.20. 7cis-b 1 1H NMR (400MHz, MeOD, ppm) δ 7.91(d,J=8.0Hz,1H),7.57(dd,J=10.4,8.2Hz,1H),7.31(d,J=6.8Hz,1H),6 .21(d,J=6.8Hz,1H),3.52-3.42(m,2H),3.40-3.33(m,2H),3.19-3.11(m,1H) ,2.91(s,3H),2.84-2.74(m,5H),2.46(q,J=7.6Hz,2H),2.25-2.14(m,2H),2. 05-1.98(m,1H),1.89-1.79(m,2H),1.76-1.64(m,1H),1.14(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 23 H3FN5O2[M+H] + m / z Calculated value: 428.25, Measured value: 428.20.

[0292] Example 5: Synthesis of 12cis-a, 12cis-b, 12trans-a, and 12trans-b [ka]

[0293] Preparation of methyl 5-bromo-6-methoxypicolinate (1402) To a solution of 5-bromo-6-methoxypicolinic acid (1401) (5.00 g, 21.65 mmol) in MeOH (200 mL), SOCl2 (7.67 g, 64.47 mmol) was added dropwise. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, then adjusted to pH 9 with Na2CO3 aqueous solution, and the aqueous layer was extracted with siRNA (300 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 80:20) to obtain methyl 5-bromo-6-methoxypicolinate (1402) (4.50 g, yield 85%) as a white solid. LCMS(ESI) C8H8BrNO3[M+H] + m / z Calculated value: 245.97, Measured value: 245.95.

[0294] Preparation of methyl 5-ethyl-6-methoxypicolinate (1403) To a solution of methyl 5-bromo-6-methoxypicolinate (1402) (4.50 g, 18.29 mmol) in 1,4-dioxane (200 mL), diethylzinc (1 M, 90 mL) and Pd(dppf)Cl2 (1.34 g, 1.83 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 80°C for 18 hours under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl (300 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (PE / ethyl = 100:0 to 80:20) to obtain methyl 5-ethyl-6-methoxypicolinate (1403) (2.30 g, yield 64%) as a yellow solid. LCMS(ESI) C 10 H 13 NO3 [M+H] +m / z Calculated value: 196.09, Measured value: 196.05.

[0295] Preparation of (5-ethyl-6-methoxypyridine-2-yl)methanol (1404) To a solution of methyl 5-ethyl-6-methoxypicolinate (1403) (2.30 g, 11.78 mmol) in THF (100 mL), LiAlH4 (11.8 mL, 11.78 mmol, 1 M) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with cold water and then extracted with ELISA (200 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / ELISA = 100:0 to 60:40) to obtain (5-ethyl-6-methoxypyridine-2-yl)methanol (1404) (1.70 g, yield 86%) as a colorless oil. LCMS(ESI) C9H 13 NO2 [M+H] + m / z Calculated value: 168.09, Measured value: 168.05.

[0296] Preparation of 5-ethyl-6-methoxypicolinaldehyde (1405) Dess-Martin reagent (6.47 g, 15.25 mmol) was added to a solution of (5-ethyl-6-methoxypyridine-2-yl)methanol (1404) (1.70 g, 10.17 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and then extracted with DCM (100 mL x 3). The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / siRNA = 100:0 to 80:20) to obtain 5-ethyl-6-methoxypicolinealdehyde (1405) (1.50 g, yield 89%) as a colorless oil. LCMS(ESI) C9H 11 NO2 [M+H] + m / z Calculated value: 166.08, Measured value: 166.05.

[0297] Preparation of 1-(5-ethyl-6-methoxypyridine-2-yl)buta-3-en-1-ol (1406) To a solution of 5-ethyl-6-methoxypicolinealdehyde (1405) (1.50 g, 9.08 mmol) in THF (50 mL), bromo(propa-2-en-1-yl)magnesium (1.45 g, 9.99 mmol) was added dropwise at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 0°C for 2 hours. The mixture was diluted with water (50 mL) and extracted with Â(100 mL × 3). The combined organic layers were washed with saturated brine (100 mL × 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (PE / Â(1406) (1.40 g, yield 74%) as a yellow oil. LCMS(ESI) C 12 H 17 NO2 [M+H] + m / z Calculated value: 208.13, Measured value: 208.05.

[0298] Preparation of 4-(5-ethyl-6-methoxypyridine-2-yl)butan-1,2,4-triol (1407) To a solution of 1-(5-ethyl-6-methoxypyridine-2-yl)butan-3-en-1-ol (1406) (1.40 g, 6.75 mmol) in THF / water (5:1, 48 mL), K2OsO4·2H2O (124 mg, 0.34 mmol) and NMO (7.92 g, 67.54 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (50 mL) and extracted with ELISA (100 mL x 3). The combined organic layers were washed with saturated brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain 4-(5-ethyl-6-methoxypyridine-2-yl)butan-1,2,4-triol (1407) (1.00 g, yield 61%) as a yellow oil. LCMS(ESI) C 12 H 19 NO4 [M+H] + m / z Calculated value: 242.13, Measured value: 242.05.

[0299] Preparation of 5-(5-ethyl-6-methoxypyridine-2-yl)tetrahydrofuran-3-ol (1408) PTSA (2.26 g, 12.43 mmol) was added to a solution of 4-(5-ethyl-6-methoxypyridine-2-yl)butan-1,2,4-triol (1407) (1.00 g, 4.14 mmol) in toluene (50 mL) at room temperature. The reaction mixture was stirred at 120 °C for 6 hours. The reaction mixture was quenched with cold water and then extracted with DCM (80 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain 5-(5-ethyl-6-methoxypyridine-2-yl)tetrahydrofuran-3-ol (1408) (450 mg, yield 49%) as a colorless oil. LCMS(ESI) C 12 H 17 NO3 [M+H] + m / z Calculated value: 224.12, Measured value: 224.05.

[0300] Preparation of 5-(5-ethyl-6-methoxypyridine-2-yl)dihydrofuran-3(2H)-one (1409) To a solution of 5-(5-ethyl-6-methoxypyridine-2-yl)tetrahydrofuran-3-ol (1408) (450 mg, 2.01 mmol) in DCM (30 mL), Dess-Martin reagent (1.28 g, 3.02 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and then extracted with DCM (100 mL x 3). The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / Â=100:0 to 80:20) to obtain 5-(5-ethyl-6-methoxypyridine-2-yl)dihydrofuran-3(2H)-one (1409) (220 mg, yield 49%) as a colorless oil. LCMS(ESI) C 12 H 15 NO3 [M+H] + m / z Calculated value: 222.11, Measured value: 222.05.

[0301] Preparation of 5-(4-(5-(5-ethyl-6-methoxypyridine-2-yl)tetrahydrofuran-3-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1410) To a solution of 5-(5-ethyl-6-methoxypyridine-2-yl)dihydrofuran-3(2H)-one (1409) (110 mg, 0.50 mmol) in MeOH (20 mL), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (1306) (1306) (130 mg, 0.55 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH(OAc)3 (211 mg, 1.00 mmol) at room temperature. The reaction mixture was stirred for 1 hour, after which NaBH3CN (16 mg, 0.25 mmol) was added. The reaction mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain 5-(4-(5-(5-ethyl-6-methoxypyridine-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1410) (120 mg, yield 54%) as a yellow solid. LCMS(ESI) C 23 H 30 FN5O3[M+H] + m / z Calculated value: 444.23, Measured value: 444.24.

[0302] Preparation of 5-(4-(5-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)tetrahydrofuran-3-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (12cis-a / 12cis-b / 12trans-a / 12trans-b) 5-(4-(5-(5-ethyl-6-methoxypyridine-2-yl)tetrahydrofuran-3-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1410) (120 mg, 0.27 mmol) was dissolved in ACN (30 mL) and TMSI (162 mg, 0.81 mmol) was added at room temperature. The mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was collected in C 18The solution was purified using a column (mobile phase: ACN-water (0.1% FA), gradient: 10-95) to obtain 5-(4-(5-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (a mixture of 12cis-a / 12cis-b / 12trans-a / 12trans-b) (70 mg, yield 60%) as a yellow solid. LCMS(ESI) C 22 H 28 FN5O3[M+H] + m / z Calculated value: 430.22, Measured value: 430.20.

[0303] Chiral separation of 5-(4-(5-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)tetrahydrofuran-3-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (12cis-a / 12cis-b / 12trans-a / 12trans-b) A mixture of 12cis-a / 12cis-b / 12trans-a / 12trans-b was separated by SFC (column: Daicel Chiralpak AS-H-30% D 250mm×20mm ID, 5μm; mobile phase: CO2 / MeOH[0.1%NH3]=70 / 30), concentrated under reduced pressure, and obtained the following fractions: 12cis-rac (32.4 mg, racemic mixture of 12cis-a and 12cis-b, white solid) as the first fraction; 12trans-a (6.2 mg, purity 98%, ee%:100, white solid) as the second fraction; and 12trans-b (6.0 mg, purity 99%, ee%:100, white solid) as the third fraction. 12cis-rac 1 H NMR(400MHz,MeOD-d4,ppm) δ:7.91(d,J=8.0Hz,1H),7.59-7.55(m,1H),7.34(d,J=6.8Hz,1H),6.30(d,J=6.8Hz,1H),4.83-4.81(m,1H),4.32(d,J=10.4Hz,1H),3.81-3 .77(m,1H),3.57-3.51(m,4H),3.05(s,1H),2.91(s,3H),2.83(t,J=4. 8Hz,4H),2.56-2.44(m,3H),2.19-2.14(m,1H),1.15(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 22 H 28 FN5O3[M+H] + m / z Calculated value: 430.22, Measured value: 430.25. 12trans-a 1 H NMR(400MHz,MeOD-d4,ppm) δ:7.90(dd,J=7.0Hz,1.0Hz,1H),7.58-7.47(m,1H),7.38(d,J=7.2Hz,1H),6.31(d,J=7.0Hz,1H),4.97-4.91(m, 1H),4.28-4.21(m,1H),3.83-3.79(m,1H),3.26(t,J=5.0Hz,4H),3.18-3.13(m,1H),2.91(s,3H),2.78-2.72(m,2 H),2.66-2.61(m,2 H),2.52-2.47(m,2 H),2.43-2.35(m,1H),2.16-2.08(m,1H),1.17(t,J=7.6Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 22 H 28 FN5O3[M+H] + m / z Calculated value: 430.22, Measured value: 430.25. 12trans-b 1H NMR(400MHz,MeOD-d4,ppm) δ:7.90(d,J=8.0Hz,1H),7.53-7.49(m,1H),7.38(d,J=7.2Hz,1H),6.31(d,J=7. 2Hz,1H),4.97-4.91(m,1H),4.27-4.23(m,1H),3.86-3.78(m,1H),3.26(t,J=4. 8Hz,4H),3.18-3.13(m,1H),2.91(s,3H),2.79-2.72(m,2H),2.68-2.61(m,2H), 2.52-2.47(m,2H),2.43-2.35(m,1H),2.16-2.09(m,1H),1.16(t,J=7.6Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 22 H 28 FN5O3[M+H] + m / z Calculated value: 430.22, Measured value: 430.20.

[0304] Example 6: Synthesis of 17cis-a, 17cis-b, 17trans-a, and 17trans-b [ka]

[0305] Preparation of 2,4-dichloro-5-ethylpyrimidine (1502) DIEA (23.00 g, 0.18 mol) was added to a solution of 5-ethyl-1,3-dihydropyrimidine-2,4-dione (1501) (10.00 g, 0.07 mol) in POCl3 (55.00 g, 0.36 mol) at 0°C. The mixture was then stirred at 120°C for 2 hours. The reaction mixture was poured into ice water, and the aqueous layer was extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / ELISA = 100:0 to 92:8) to obtain 2,4-dichloro-5-ethylpyrimidine (1502) (4.80 g, yield 38%) as a white solid. LCMS(ESI) C6H6C l2N2[M+H]+ m / z Calculated value: 176.99, Measured value: 177.20.

[0306] Preparation of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (1504) To a solution of (4-methoxyphenyl)methanol (1503) (4.54 g, 32.90 mmol) in THF (20 mL), tBuOLi (2.30 g, 28.75 mmol) was added over 15 minutes at 70°C. Then, 2,4-dichloro-5-ethylpyrimidine (1502) (4.80 g, 27.27 mmol) was added to the reaction mixture at 0°C. The mixture was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 93:7) to obtain 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (1504) (4.00 g, yield 53%) as a white solid. LCMS(ESI) C 14 H 15 ClN2O2[M+H] + m / z Calculated value: 279.08, Measured value: 279.25.

[0307] Preparation of 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)cyclopenta-2-en-1-one (1505) To a 1,4-dioxane:water = 5:1 (25 mL) solution of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (1504) (400 mg, 1.43 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) (447 mg, 2.15 mmol) was added. Then, at room temperature, Pd(dppf)Cl2 (105 mg, 0.14 mmol) and Na2CO3 (608 mg, 5.7 mmol) were added. The mixture was then stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 80:20) to obtain 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)cyclopenta-2-en-1-one (1505) (400 mg, yield 85%) as a white solid. LCMS(ESI) C 19 H 20 N2O3[M+H] + m / z Calculated value: 325.15, Measured value: 325.20.

[0308] Preparation of 5-(4-(3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1506) To a solution of 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)cyclopenta-2-en-1-one (1505) (400 mg, 1.23 mmol) in EtOH (10 mL), 4-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (1306) (323 mg, 1.35 mmol) was added. Then, at room temperature, 2 drops of acetic acid and NaBH(OAc)3 (1.3 g, 6.15 mmol) were added. After stirring at 90°C for 30 minutes, NaBH3CN (772 mg, 12.32 mmol) was added. The reaction mixture was stirred at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain 5-(4-(3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1506) (200 mg, yield 29%) as a white solid. LCMS(ESI) C 30 H 35 FN6O3[M+H] + m / z Calculated value: 547.28, Measured value: 547.30.

[0309] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (17cis-a / 17cis-b / 17trans-a / 17trans-b) 5-(4-(3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1506) (200 mg, 0.36 mmol) was dissolved in MeOH (10 mL) and Pd / C (51.18 mg, 0.36 mmol) was added. The reaction mixture was stirred at 50°C for 3 hours under a hydrogen atmosphere. The solution was filtered and concentrated under reduced pressure to obtain 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (a mixture of 17cis-a / 17cis-b / 17trans-a / 17trans-b) (100 mg, yield 64%) as a white solid. LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z Calculated value: 429.23.16, Measured value: 429.20.

[0310] Chiral separation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (17cis-a / 17cis-b / 17trans-a / 17trans-b) A mixture of 17cis-a / 17cis-b / 17trans-a / 17trans-b was separated by SFC (column: DAIEL IJ 4.6mm ID*250mmL 5μm; mobile phase: CO2 / MeOH[0.1%NH3]=65 / 35), concentrated under reduced pressure, and obtained the following fractions: 17cis-rac (52mg, 99% purity, white solid), a racemic mixture of 17cis-a and 17cis-b, as the first fraction; 17trans-a (12mg, 99% purity, ee%:100, white solid), as the second fraction; and 17trans-b (11mg, 99% purity, ee%:99, white solid), as the third fraction. 17cis-rac 1H NMR (400MHz, DMSO) δ 12.49(s,1H),8.44-8.31(m,1H),7.85(d,J=8.0Hz,1H),7.72(s,1H),7.56 (m,1H),3.24-3.14(m,4H),3.08-2.98(m,1H),2.77(d,J=4.8Hz,3H),2.71- 2.66(m,1H),2.65-2.55(m,4H),2.34-2.28(m,2H),2.18-2.08(m,1H),2.02 -1.92(m,1H),1.85-1.73(m,3H),1.73-1.62(m,1H),1.07(t,J=7.2Hz,3H). LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z calculated value: 429.23, measured value: 429.15. 17trans-a 1 H NMR (400MHz, DMSO) δ 12.27(s,1H),8.45-8.31(m,1H),7.94-7.79(m,1H),7.72(s,1H),7.61-7.51(m,1H),3.20-3.12(m,4H),3.12-3.06(m,1H ),2.85-2.72(m,4H),2.61-2.53(m,4H),2.34-2.28(m,2H),2.06-1.76(m,5H),1.54-1.44(m,1H),1.07(t,J=7.6Hz,3H). LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z calculated value: 429.23, measured value: 429.25. 17trans-b 1H NMR(400MHz,DMSO) δ 12.28(s,1H),8.51-8.25(m,1H),7.84(d,J=8.0Hz,1H),7.73(s,1H),7.60-7.51(m,1H),3.18-3.13(m,4H),3.12-3.07(m, 1H),2.79-2.73(m,4H),2.60-2.54(m,4H),2.34-2.29(m,2H),2.05-1.75(m,5H),1.52-1.44(m,1H),1.07(t,J=7.6Hz,3H). LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z Calculated value: 429.23, Measured value: 429.25.

[0311] Example 7: Synthesis of 28cis-a, 28cis-b, 28trans-a, and 28trans-b [ka]

[0312] Preparation of 3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopenta-2-en-1-one (1602) To a 15 mL solution of 6-chloro-2-methoxy-3-(trifluoromethyl)pyridine (1601) (700 mg, 60% purity, 1.99 mmol) in a dioxane:water ratio of 5:1, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) (900 mg, 4.33 mmol), Pd(dppf)Cl2 (70 mg, 0.10 mmol), and K2CO3 (700 mg, 5.07 mmol) were added. The reaction mixture was stirred at 90°C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 85:15) to obtain 3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopenta-2-en-1-one (1602) (400 mg, yield 78%) as a yellow solid. LCMS(ESI) C 12 H 10 F3NO2[M+H] +m / z Calculated value: 258.07, Measured value: 257.89.

[0313] Preparation of 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-N-methylpicolinamide (1603) To a solution of 3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopenta-2-en-1-one (1602) (400 mg, 1.55 mmol) in MeOH (20 mL), N-methyl-5-(piperazin-1-yl)picolinamide (1009) (800 mg, 3.63 mmol) and 3 drops of HOAc were added. After 10 minutes, NaBH3CN (900 mg, 14.51 mmol) was added. The reaction mixture was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 92:8) to obtain 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-N-methylpicolinamide (1603) (600 mg, yield 83%) as a yellow solid. LCMS(ESI) C 23 H 26 F3N5O2[M+H] + m / z Calculated value: 462.20, Measured value: 462.20.

[0314] Preparation of 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (1604) 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-N-methylpicolinamide (1603) (600 mg, 1.30 mmol) was dissolved in MeOH (100 mL) and Pd(OH)2 / C (200 mg, 1.42 mmol) was added. The reaction mixture was stirred at 50°C for 15 hours under a hydrogen atmosphere. After cooling to room temperature, the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (1604) (550 mg, yield 91%) as a yellow solid. LCMS(ESI) C 23 H 28 F3N5O2[M+H] + m / z Calculated value: 464.22, Measured value: 464.20.

[0315] Preparation of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)picolinamide (28-cis racemic mixture and 28-trans racemic mixture) 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridine-2-yl)cyclopentyl)piperazine-1-yl)-N-methylpicolinamide (1604) (550 mg, 1.18 mmol) was dissolved in ACN (20 mL) and TMSI (550 mg, 2.75 mmol) was added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5μm C18 150×21.2mm, mobile phase: ACN-water (0.1% FA), gradient: 10-25) to obtain a 28-cis racemic mixture of 6-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-3-ethylpyridine-2(1H)-one (60 mg, purity 99%, yield 11%) and a 28-trans racemic mixture of 6-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-3-ethylpyridine-2(1H)-one (40 mg, purity 99%, yield 7%) as white solids. LCMS(ESI) C 22 H 26 F3N5O2[M+H] + m / z Calculated value: 450.20, Measured value: 450.09.

[0316] Preparation of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)picolinamide (28cis-a and 28cis-b) A 28-cis racemic mixture (60 mg, 0.13 mmol) of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)picolinamide was separated by SFC (column: DAIEL AD-H 4.6 mm * 250 mm L 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M MeOH solution)] = 60 / 40), concentrated under reduced pressure, and obtained two fractions: 28cis-a (11 mg, purity 99%, ee%: 100, white solid) as the first fraction, and 28cis-b (11 mg, purity 99%, ee%: 100, white solid) as the second fraction. 28cis-a 1 H NMR(400MHz,MeOD) δ 8.31(d,J=2.8Hz,1 H),7.91(d,J=8.8Hz,1H),7.83(d,J=7.6Hz,1H),7.40(dd,J=8.8,2.8Hz,1H),6.33(d,J=7.6Hz,1H),3.68-3.58(m,2H),3.55-3.45(m ,2H),3.27-2.21(m,1H),2.93(s,3H),2.89-2.74(m,5H),2.30-2.20(m,2H),2.13-2.04(m,1H),1.98-1.81(m,1H),1.80-1.66(m,1H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 22 H 26 F3N5O2[M+H] + m / z Calculated value: 450.20, Measured value: 450.15. 28cis-b 1H NMR(400MHz,MeOD) δ 8.33(d,J=2.8Hz,1H),7.93(d,J=8.8Hz,1H),7.85(d,J=7.6Hz,1H),7.42(dd,J=8.8,2.8Hz,1H),6.35(d,J=7.2Hz,1H),3.68-3.59(m,2H),3.5 7-3.48(m,2H),3.31-3.23(m,1H),2.95(s,3H),2.89-2.76(m,5H),2.33 -2.21(m,2H),2.17-2.05(m,1H),2.01-1.82(m,1H),1.81-1.69(m,1H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 22 H 26 F3N5O2[M+H] + m / z Calculated value: 450.20, Measured value: 450.20.

[0317] Preparation of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)picolinamide (28trans-a and 28trans-b) A 28-trans racemic mixture (40 mg, 0.09 mmol) of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)picolinamide was separated by SFC (column: DAIEL IH 4.6 mm * 250 mm L 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M MeOH solution)] = 70 / 30), concentrated under reduced pressure, to obtain the first fraction 28-trans-a (9 mg, purity 99%, ee%: 100, white solid) and the second fraction 28-trans-b (8 mg, purity 99%, ee%: 100, white solid). 28trans-a 1H NMR(400MHz,MeOD) δ 8.29(d,J=2.4Hz,1H),7.95-7.84(m,2H),7.38(dd,J=8.8,2.8Hz,1H),6.35(d,J=7.2Hz,1H),3.43-3.36(m,4H),3 .23-3.14(m,1H),2.98-2.86(m,4H),2.78-2.68(m,4H),2.26-2.08(m,3H),2.07-1.94(m,1H),1.83-1.60(m,2H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 22 H 26 F3N5O2[M+H] + m / z Calculated value: 450.20, Measured value: 450.20. 28trans-b 1 H NMR(400MHz,MeOD) δ 8.29(d,J=2.8Hz,1H),7.94-7.84(m,2H),7.38(dd,J=8.8,2.8Hz,1H),6.35(d,J=7.6Hz,1H),3.46-3.37(m,4H),3 .24-3.14(m,1H),2.96-2.87(m,4H),2.76-2.69(m,4H),2.24-2.08(m,3H),2.05-1.95(m,1H),1.83-1.60(m,2H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 22 H 26 F3N5O2[M+H] + m / z Calculated value: 450.20, Measured value: 450.25.

[0318] Example 8: Synthesis of 51cis-a, 51cis-b, 51trans-a, and 51trans-b [ka]

[0319] Preparation of tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate (1702) To a solution of methyl tert-butyl 4-(2-bromo-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate (1701) (10.00 g, 25.00 mmol) in DMSO (100 mL), CsF (15.19 g, 100.00 mmol) and 18-crown-6 (13.20 g, 50.00 mmol) were added. The reaction mixture was stirred at 100 °C for 5 hours. The mixture was diluted with water (200 mL) and extracted with Âx (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL x 3), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (PE / siRNA = 100:0 to 46:54) to obtain tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate (1702) (7.00 g, yield 82%) as a yellow solid. LCMS(ESI) C 16 H 22 FN3O4[M+H] + m / z Calculated value: 340.16, Measured value: 340.20.

[0320] Preparation of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid (1703) To a 10 mL THF / water = 1:1 solution of tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate (1702) (1.00 g, 2.95 mmol), LiOH (140 mg, 5.90 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 6 with 1 M HCl. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (PE / Â=100:0 to 50:50) to obtain 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid (1703) (950 mg, yield 99%) as a yellow solid. LCMS(ESI) C 15 H 20 FN3O4[M+H] + m / z Calculated value: 326.14, Measured value: 326.15.

[0321] Preparation of tert-butyl 4-(2-fluoro-6-((2-fluoroethyl)carbamoyl)pyridine-3-yl)piperazine-1-carboxylate (1704) 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid (1703) (950 mg, 2.92 mmol) and 2-fluoroethaneamine (275 mg, 4.36 mmol) were dissolved in DMF (20 mL), to which HATU (1.66 g, 4.37 mmol) and DIEA (1.50 g, 11.60 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (PE / siRNA = 100:0 to 50:50) to obtain tert-butyl 4-(2-fluoro-6-((2-fluoroethyl)carbamoyl)pyridine-3-yl)piperazine-1-carboxylate (1704) (1.00 g, yield 99%) as a yellow oil. LCMS(ESI) C 17 H 24 F2N4O3[M+H] + m / z Calculated value: 371.18, Measured value: 371.30.

[0322] Preparation of 6-fluoro-N-(2-fluoroethyl)-5-(piperazin-1-yl)picolinamide (1705) tert-butyl 4-(2-fluoro-6-((2-fluoroethyl)carbamoyl)pyridine-3-yl)piperazine-1-carboxylate (1704) (1.00 g, 2.70 mmol) was added to a solution of HCl dioxane (10 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain 6-fluoro-N-(2-fluoroethyl)-5-(piperazine-1-yl)picolinamide (1705) (790 mg, yield 99%) as a yellow solid. LCMS(ESI) C 12 H 16 F2N4O [M+H] + m / z Calculated value: 271.13, Measured value: 271.20.

[0323] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (1706) Two drops of acetic acid were added to a 20 mL solution of 6-fluoro-N-(2-fluoroethyl)-5-(piperazin-1-yl)picolinamide (1705) (790 mg, 2.93 mmol), 3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1305) (300 mg, 1.38 mmol), and NaBH(OAc)3 (439 mg, 6.99 mmol) in MeOH (20 mL) at room temperature, and the mixture was stirred for 10 minutes. Then, NaBH3CN (434 mg, 2.05 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (1706) (650 mg, yield 99%) as a yellow oil. LCMS(ESI) C 25 H 31 F2N5O2[M+H] + m / z Calculated value: 472.25, Measured value: 474.45.

[0324] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (1707) A mixture of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (1706) (650 mg, 1.38 mmol) and Pd / C (270 mg) in methanol (5 mL) was degassed with hydrogen and stirred at room temperature under a hydrogen atmosphere for 5 hours. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (1707) (650 mg, yield 99%) as a yellow oil. LCMS(ESI) C 25 H 33 F2N5O2[M+H] + m / z Calculated value: 474.26, Measured value: 474.20.

[0325] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (51cis-a / 51cis-b / 51trans-a / 51trans-b) TMSI (825 mg, 4.13 mmol) was added to a solution of 5-(4-(3-(5-ethyl-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (1707) (650 mg, 1.37 mmol) in ACN (30 mL). The reaction mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was collected in C 18 The mixture was purified by column chromatography (mobile phase: ACN-water (0.05% NH3), gradient: 30-95) to obtain a 51cis-a / 51cis-b racemic mixture (110 mg, yield 32%) and a 51trans-a / 51trans-b racemic mixture (90 mg, yield 32%) of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide as white solids. LCMS(ESI) C 24 H 31 F2N5O2[M+H] +m / z Calculated value: 460.24, Measured value: 460.80.

[0326] Chiral separation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (51cis-a / 51cis-b racemic mixture and 51trans-a / 51trans-b racemic mixture) The 51cis-a / 51cis-b racemic mixture was separated by SFC (column: IB N-5 4.6 mm × 250 mm L, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 60 / 40), concentrated under reduced pressure, and obtained 51cis-a as the first fraction (31 mg, purity 98%, ee%: 100, white solid) and 51cis-b as the second fraction (28 mg, purity 99%, ee%: 100, white solid).

[0327] The 51trans-a / 51trans-b racemic mixture was separated by SFC (column: (R,R)-Whelk-O1 4.6 mm × 250 mm L, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 60 / 40), concentrated under reduced pressure, and obtained 51trans-a (31 mg, purity 99%, ee%: 100, white solid) as the third fraction and 51trans-b (31 mg, purity 97%, ee%: 100, white solid) as the first fraction. 51cis-a 1 H NMR(400MHz,MeOD-d4,ppm) δ:7.93(dd,J=8.0,1.2Hz,1H),7.61-7.55(m,1H),7.31(d,J=7.2Hz,1H),6.21(d,J=7.2Hz,1H), 4.60(t,J=5.2Hz,1H),4.48(t,J=5.2Hz,1H),3.71(t,J=5.2Hz,1H),3.64(t,J=5.2Hz,1H),3.51- 3.45(m,2H),3.41-3.34(m,2H),3.19-3.12(m,1H),2.83-2.76(m,5H),2.46(q,J=7.2Hz,2H),2. 25-2.14(m,2H),2.06-1.99(m,1H),1.88-1.80(m,2H),1.75-1.66(m,1H),1.14(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 24 H 31 F2N5O2[M+H] + m / z Calculated value: 460.24, Measured value: 460.45. 51cis-b 1 H NMR(400MHz,MeOD-d4,ppm) δ:7.93(dd,J=8.0,1.2Hz,1H),7.62-7.54(m,1H),7.31(d,J=6.8Hz,1H),6.21(d,J=7.2Hz,1H),4.60(t,J=5.2Hz,1H),4.48(t,J=5.2Hz,1H), 3.71(t,J=5.2Hz,1H),3.64(t,J=5.2Hz,1H),3.52-3.45(m,2H),3.41-3.34(m,2H),3.19-3.11(m,1H),2.83-2.76(m,5H),2.46(q,J=7.6Hz,2 H),2.25-2.15(m,2H),2.04-1.98(m,1H),1.89-1.80(m,2H),1.75-1.65(m,1H),1.14(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 24 H 31 F2N5O2[M+H] + m / z Calculated value: 460.24, Measured value: 460.45. 51trans-a 1H NMR(400MHz,MeOD-d4,ppm) δ:7.92(dd,J=8.0,0.8Hz,1H),7.58-7.49(m,1H),7.35(d,J=6.8Hz,1H),6.23(d,J=7.2Hz,1H),4.59 (t,J=5.2Hz,1H),4.47(t,J=4.8Hz,1H),3.70(t,J=5.2Hz,1H),3.64(t,J=4.8Hz,1H),3.29-3.23(m,4 H),3.16-3.09(m,1H),2.96-2.88(m,1H),2.77-2.70(m,4H),2.48(q,J=7.2Hz,2 H),2.19-2.05(m,3H),2.00-1.92(m,1H),1.79-1.60(m,2H),1.16(t,J=7.2Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 24 H 31 F2N5O2[M+H] + m / z Calculated value: 460.24, Measured value: 460.45. 51trans-b 1 H NMR(400MHz,MeOD-d4,ppm) δ:7.92(dd,J=8.0,1.2Hz,1H),7.53(dd,J=10.0,8.0Hz,1 H),7.35(d,J=7.2Hz,1H),6.23(d,J=7.2Hz,1H),4.59(t,J=5.2Hz,1H),4.47(t,J=5.2Hz,1H),3.70(t,J=5.2Hz,1H),3.64(t,J=5.2Hz,1H),3.29- 3.23(m,4H),3.17-3.09(m,1H),2.96-2.87(m,1H),2.77-2.69(m,4H),2. 48(q,J=7.6Hz,2H),2.19-2.05(m,3H),2.00-1.92(m,1H),1.77-1.58(m,2 H),1.16(t,J=7.2Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C24 H 31 F2N5O2[M+H] + m / z Calculated value: 460.24, Measured value: 460.45.

[0328] Example 9: Synthesis of 79cis-a, 79cis-b, 79trans-a, and 79trans-b [ka]

[0329] Preparation of 6-bromo-3-chloro-2-methoxypyridine (1802) The following solutions A and B were prepared: A: NaNO2 (3.4g, 0.049mol) solution in 100mL of water; B: A solution of 6-bromo-2-methoxypyridine-3-amine (1801) (5g, 0.025mol) in concentrated hydrochloric acid / water = 1:1 (80mL). At 0°C, A was added dropwise to B, and the reaction mixture was stirred at 0°C for 20 minutes. Then, at 0°C, CuCl (4.87 g, 0.049 mol) was added to the mixture. The mixture was stirred at 0°C for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with  (500 mL × 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluted with  / PE, 0 to 50%) to obtain 6-bromo-3-chloro-2-methoxypyridine (1802) (3 g, purity 90%, yield 49%) as a white solid. LCMS(ESI) C6H5BrClNO [M+H] + m / z calculated value: 221.92, measured value: no signal detected.

[0330] Preparation of 3-(5-chloro-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1803) To a 100 mL solution of 6-bromo-3-chloro-2-methoxypyridine (1802) (2.8 g, 0.013 mol) in a dioxane / water ratio of 5:1, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) (2.62 g, 0.013 mol), Na2CO3 (2.67 g, 0.025 mol), and Pd(dppf)Cl2·DCM (1.03 g, 0.0012 mol) were added under a nitrogen atmosphere. The mixture was heated at 100 °C for 5 hours. The resulting mixture was diluted with water (100 mL) and extracted with ELISA (100 mL x 3). The combined organic phases were washed with saturated saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (elution with Â1 / PE, 0 to 100%) to obtain 3-(5-chloro-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1803) (1.2 g, purity 90%, yield 38%) as a white solid. LCMS(ESI) C 11 H 10 ClNO2[M+H] + m / z Calculated value: 224.04, Measured value: 223.75.

[0331] Preparation of 5-(4-(3-(5-chloro-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1804) To a solution of 3-(5-chloro-6-methoxypyridine-2-yl)cyclopenta-2-en-1-one (1803) (500 mg, 2.23 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (1306) (586 mg, 2.46 mmol) in EtOH (20 mL), AcOH (0.1 mL) and NaBH(OAc)3 (946 mg, 4.46 mmol) were added. The mixture was heated at 50 °C for 10 minutes. Then, NaBH3CN (211 mg, 3.35 mol) was added to the mixture. The mixture was heated at 90 °C for 15 hours. The resulting mixture was quenched with water (1 mL), concentrated, and purified by silica gel column chromatography (eluted with MeOH / DCM, 0 to 10%) to obtain 5-(4-(3-(5-chloro-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1804) (700 mg, purity 90%, yield 63%) as a white solid. LCMS(ESI) C 22 H 25 ClFN5O2[M+H] + m / z Calculated value: 446.17, Measured value: 446.10.

[0332] Preparation of 5-(4-(3-(5-chloro-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1805) 5-(4-(3-(5-chloro-6-methoxypyridine-2-yl)cyclopenta-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1804) (700 mg, 1.57 mmol) was dissolved in toluene (20 mL) and Rh(PPh3)3Cl2 (145 mg, 0.16 mmol) was added. The mixture was degassed and refilled with hydrogen three times, and then hydrogen was refilled. The resulting mixture was stirred at 100 °C for 18 hours. The mixture was then purified by silica gel column chromatography (eluted with MeOH / DCM, 0 to 10%) to obtain 5-(4-(3-(5-chloro-6-methoxypyridine-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1805) (500 mg, purity 90%, yield 64%) as a white solid. LCMS(ESI) C 22 H 27 ClFN5O2[M+H] + m / z Calculated value: 448.18, Measured value: 448.15.

[0333] Preparation of 5-(4-(3-(5-chloro-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (79cis-a / 79cis-b / 79trans-a / 79trans-b) 5-(4-(3-(5-chloro-6-methoxypyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1805) (500 mg, 1.12 mmol) was dissolved in ACN (20 mL) and TMSI (894 mg, 4.46 mmol) was added. The mixture was heated at 50°C for 2 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10%), followed by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 5% to 95% α-MeCN / H2O containing 0.1% FA) to obtain 5-(4-(3-(5-chloro-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (79cis-a / 79cis-b / 79trans-a / 79trans-b) (50 mg, purity 99%, yield 9%) as a white solid.

[0334] Chiral separation of 5-(4-(3-(5-chloro-6-oxo-1,6-dihydropyridine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (79cis-a / 79cis-b / 79trans-a / 79trans-b) The 79 stereoisomers were separated by SFC (column: DAIEL IH 20mm ID×250mmL, 5μm; mobile phase: CO2 / MeOH [0.1% NH3 (7M MeOH solution)] = 80 / 20), concentrated under reduced pressure, and obtained the following fractions: 79cis-a (13.4 mg, purity 99.64%, ee%: 100, white solid) as the first fraction, 79cis-b (10.7 mg, purity 99.72%, ee%: 100, white solid) as the second fraction, and 79trans-rac (12.3 mg, purity 99.94%, white solid), a racemic mixture of 79trans-a and 79trans-b, as the third fraction. 79cis-a 1H NMR(400MHz,DMSO-d6,ppm) δ:12.57(s,1 H),8.45-8.35(m,1H),7.86(d,J=8.0Hz,1H),7.63-7.54(m,2H),6.11(d,J=7.6Hz,1H),3.32-3.26(m,2H),3.25-3.16(m,2 H),3.10-3.01(m,1H),2.77(d,J=4.8Hz,3H),2.71-2.59(m,5H),2.17-2.02(m,2H),1.86-1.66(m,3H),1.64-1.52(m,1H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 21 H 25 ClFN5O2[M+H] + m / z Calculated value: 434.17, Measured value: 433.94. 79cis-b 1 H NMR(400MHz,DMSO-d6,ppm) δ:12.58(s,1H),8.45-8.36(m,1H),7.86(d,J=8.0Hz,1H),7.66-7.51(m,2H),6.11(d,J=7.6Hz,1H),3.31-3.26(m,2H),3.24-3. 18(m,2H),3.11-3.00(m,1H),2.77(d,J=4.8Hz,3H),2.71-2.60(m,5H),2.15-2.01(m,2H),1.87-1.67(m,3H),1.65-1.54(m,1H). The stereochemistry of cis was assigned based on NOE experiments. LCMS(ESI) C 21 H 25 ClFN5O2[M+H] + m / z Calculated value: 434.17, Measured value: 433.97. 79trans-rac 1H NMR(400MHz,DMSO-d6,ppm) δ:12.07(s,1 H),8.46-8.35(m,1H),7.84(d,J=8.0Hz,1H),7.63(d,J=7.6Hz,1H),7.58-7.50(m,1H),6.08(d,J=7.6Hz,1H),3.19-3.10(m,4H),3.0 5-2.97(m,1H),2.87-2.80(m,1H),2.76(d,J=4.8Hz,3H),2.61-2.52(m,4H),2.06-1.89(m,3H),1.80-1.70(m,1H),1.66-1.43(m,2H). The stereochemistry of the trans group was assigned based on NOE experiments. LCMS(ESI) C 21 H 25 ClFN5O2[M+H] + m / z Calculated value: 434.17, Measured value: 433.95.

[0335] Example 10: Synthesis of 75cis-a, 75cis-b, 75trans-a, and 75trans-b [ka]

[0336] Preparation of 5-bromo-3-methoxy-2-vinylpyrazine (1903) To a solution of 5-bromo-2-iodo-3-methoxypyrazine (1901) (30 g, 95.3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1902) (22 g, 142.8 mmol) in dioxane / water (500 mL, v / v=10:1), Pd(dppf)Cl2·DCM (6.98 g, 9.5 mmol) and K2CO3 (39.45 g, 285.9 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / Â = 100:0 to 90:10) to obtain 5-bromo-3-methoxy-2-vinylpyrazine (1903) (15g, purity 90%, yield 65%) as a yellow oil. LCMS(ESI) C7H7BrN2O [M+H] + m / z Calculated value: 214.97, Measured value: 214.95.

[0337] Preparation of 5-bromo-2-ethyl-3-methoxypyrazine (1904) To a solution of 5-bromo-3-methoxy-2-vinylpyrazine (1903) (15 g, 69.8 mmol) in siRNA (500 mL), PtO2 (1.59 g) was added at room temperature. The mixture was degassed and refilled with hydrogen three times, and then hydrogen was refilled. The mixture was stirred at room temperature for 4 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain the crude product. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 90:10) to obtain 5-bromo-2-ethyl-3-methoxypyrazine (1904) (10 g, purity 90%, yield 59%) as a yellow oil. LCMS(ESI) C7H9BrN2O [M+H] + m / z Calculated value: 216.99, Measured value: 217.05.

[0338] Preparation of 3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopenta-2-en-1-one (1905) To a 1,4-dioxane / water = 10:1 (250 mL) solution of 5-bromo-2-ethyl-3-methoxypyrazine (1904) (10 g, 46.1 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-en-1-one (1303) (14.3 g, 69.1 mmol), K2CO3 (19 g, 138.3 mmol), and RuPhos Pd G3 ((2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 3.86 g, 4.6 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 4 hours. The mixture was filtered and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (PE / Â=100:0 to 50:50) to obtain 3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopenta-2-en-1-one (1905) (10 g, purity 90%, yield 89%) as a yellow solid. LCMS(ESI) C 12 H 14 N2O2[M+H] + m / z Calculated value: 219.11, Measured value: 219.15.

[0339] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1906) To a solution of 3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopenta-2-en-1-one (1905) (1000 mg, 4.6 mmol) in EtOH (150 mL), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (1306) (2.1 g, 9.2 mmol) was added, followed by the addition of 2 drops of acetic acid at room temperature. After 1 hour, NaBH(OAc)3 (1950 g, 9.2 mmol) and NaBH3CN (290 mg, 4.6 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain 5-(4-(3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1906) (1000 mg, purity 90%, yield 43%) as a yellow solid. LCMS(ESI) C 23 H 29 FN6O2[M+H] + m / z Calculated value: 441.23, Measured value: 443.20.

[0340] Preparation of 5-(4-(3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1907) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopenta-2-en-1-yl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1906) (1000 mg, 2.3 mmol) in MeOH (100 mL), Pd(OH)2 / C (300 mg) was added. The mixture was degassed and refilled with hydrogen, a process repeated three times, and then refilled with hydrogen. The resulting mixture was stirred at 50°C for 15 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (DCM / MeOH = 100:0 to 95:5) to obtain 5-(4-(3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1907) (1000 mg, purity 90%, yield 86%) as a yellow solid. LCMS(ESI) C 23 H 31 FN6O2[M+H] + m / z Calculated value: 443.25, Measured value: 443.15.

[0341] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (75cis-a / 75cis-b / 75trans-a / 75trans-b) 5-(4-(3-(5-ethyl-6-methoxypyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (1907) (1000 mg, 2.3 mmol) and 33 wt.% HBr aqueous solution (30 mL) were mixed at room temperature. The mixture was stirred at 70°C for 0.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH = 100:0 to 95:5) to obtain 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (75cis-a / 75cis-b / 75trans-a / 75trans-b) as a diastereomer mixture in the form of a white solid (200 mg, purity 90%, yield 17%).

[0342] Chiral separation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (75cis-a / 75cis-b / 75trans-a / 75trans-b) A mixture of 75 diastereomers was separated by SFC (column: (R,R)-Whelk-O1 250mmL × 20mm ID, 5μm; mobile phase: CO2 / MeOH[0.1%NH3]=60 / 40), concentrated under reduced pressure, and obtained the following fractions: 75trans-rac (80mg, purity 99%, white solid), a racemic mixture of 75trans-a and 75trans-b, as the first fraction; 75cis-a (48.5mg, purity 95.07%, ee%:100, white solid), as the second fraction; and 75cis-b (43.4mg, purity 96.63%, ee%:100, white solid), as the third fraction. 75cis-a LCMS(ESI) C 22 H 29 FN6O2[M+H] +m / z Calculated value: 429.23, Measured value: 429.45. 1 H NMR(400MHz,DMSO-d6,ppm) δ:12.60-12.36(m,1H),8.44-8.36(m,1H),7.89-7.82(m,1H),7.61-7 .52(m,1H),7.21-7.07(m,1H),3.30-3.14(m,4H),3.05-2.93(m,1H),2 .77(d,J=4.8Hz,3H),2.73-2.69(m,1H),2.68-2.57(m,6H),2.15-1.99(m,2H),1.88-1.70(m,3H),1.69-1.57(m,1H),1.11(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments. 75cis-b LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z Calculated value: 429.23, Measured value: 429.35. 1 H NMR(400MHz,DMSO-d6,ppm) δ:12.57-12.34(m,1H),8.45-8.34(m,1H),7.90-7.80(m,1H),7.63-7 .51(m,1H),7.21-7.05(m,1H),3.30-3.14(m,4H),3.05-2.93(m,1H),2 .77(d,J=4.8Hz,3H),2.74-2.69(m,1H),2.68-2.55(m,6H),2.16-1.98(m,2H),1.88-1.69(m,3H),1.69-1.58(m,1H),1.11(t,J=7.6Hz,3H). The stereochemistry of cis was assigned based on NOE experiments.

[0343] Chiral separation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazine-2-yl)cyclopentyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (racemic mixture of 75trans-a and 75trans-b) A racemic mixture of 75trans-a and 75trans-b was separated by SFC (column: DAIEL AS-H 250mmL × 20mm ID, 5μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 80 / 20), concentrated under reduced pressure, and obtained 75trans-a as the first fraction (23.9 mg, purity 99.84%, ee%: 100, white solid) and 75trans-b as the second fraction (26.3 mg, purity 99.74%, ee%: 95, white solid). 75trans-a LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z Calculated value: 429.23, Measured value: 429.35. 1 1H NMR (400MHz, DMSO-d6, ppm) δ:12.10-11.88(m,1H),8.44-8.35(m,1H),7.88-7.81(m,1H),7.61-7.49( m,1H),7.22-7.05(m,1H),3.20-3.11(m,4H),3.03-2.92(m,1H),2.91-2.81 (m,1H),2.76(d,J=4.8Hz,3H),2.64-2.55(m,6H),2.04-1.92(m,3H),1.85 -1.75(m,1H),1.72-1.60(m,1H),1.57-1.45(m,1H),1.11(t,J=7.6Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments. 75trans-b LCMS(ESI) C 22 H 29 FN6O2[M+H] + m / z Calculated value: 429.23, Measured value: 429.35. 11H NMR (400MHz, DMSO-d6, ppm) δ:12.09-11.89(m,1H),8.43-8.36(m,1H),7.88-7.81(m,1H),7.61-7.52( m,1H),7.22-7.07(m,1H),3.20-3.10(m,4H),3.03-2.92(m,1H),2.90-2.81 (m,1H),2.76(d,J=4.8Hz,3H),2.66-2.55(m,6H),2.04-1.91(m,3H),1.86 -1.75(m,1H),1.73-1.59(m,1H),1.58-1.46(m,1H),1.11(t,J=7.6Hz,3H). The stereochemistry of the trans group was assigned based on NOE experiments.

[0344] Example 11: Synthesis of 82 [ka]

[0345] Preparation of 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)bicyclo[2.1.1]hexane-1-carboxylic acid (2003) To a solution of 3-oxobicyclo[2.1.1]hexane-1-carboxylic acid (2001) (1.2 g, 8.60 mmol) in MeOH (20 mL), benzylpiperazine-1-carboxylate (2002) (2.0 g, 9.03 mmol), NaBH(OAc)3 (3.7 g, 17.20 mmol), and NaBH3CN (540 mg, 8.60 mmol) were added sequentially. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was quenched with water (20 mL), the pH of the mixture was adjusted to pH=3 with 2N aqueous HCl solution, and the mixture was extracted with ELISA (50 mL x 5). The combined organic layers were concentrated under reduced pressure to obtain 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)bicyclo[2.1.1]hexane-1-carboxylic acid (2003) (1.7 g, purity 90%, yield 51%) as a white solid. LCMS(ESI) C 19 H 24 N2O4[M+H] + m / z Calculated value: 345.17, Measured value: 345.05.

[0346] Preparation of benzyl 4-(4-carbamoylbicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2004) To a 30 mL solution of 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)bicyclo[2.1.1]hexane-1-carboxylic acid (2003) (1.7 g, 4.90 mmol) in DCM, NH4Cl (520 mg, 9.80 mmol), DIPEA (2.5 g, 19.60 mmol), and HATU (3.7 g, 9.80 mmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O and extracted with DCM (50 mL x 2). The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 97:3) to obtain benzyl 4-(4-carbamoylbicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2004) (1.2 g, purity 80%, yield 57%) as a white solid. LCMS(ESI) C 19 H 25 N3O3[M+H] + m / z Calculated value: 344.19, Measured value: 344.05.

[0347] Preparation of benzyl 4-(4-carbamimidylbicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2005) In a 15 mL solution of benzyl 4-(4-carbamoylbicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2004) (1.2 g, 3.50 mmol) in DCM, Me3O + BF4 - (1.0 g, 7.00 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved in NH3-MeOH (15 mL, 7 M). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain benzyl 4-(4-carbamimidylbicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2005) (1.2 g, purity 50%, yield 51%) as brown oil. LCMS(ESI) C 19 H26 N4O2[M+H] + m / z Calculated value: 343.21, Measured value: 343.15.

[0348] Preparation of benzyl 4-(4-(6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2007) To a solution of benzyl 4-(4-carbamimidylbicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2005) (1.2 g, 3.50 mmol) in DMF (15 mL), methyl 3-methoxyacrylate (2006) (810 mg, 7.00 mmol) and K2CO3 (1.45 g, 10.50 mmol) were added. The reaction mixture was stirred at 120 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water, and then extracted with ELISA (50 mL x 2). The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain benzyl 4-(4-(6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2007) (0.48 g, purity 90%, yield 31%) as a colorless oil. LCMS(ESI) C 22 H 26 N4O3[M+H] + m / z Calculated value: 395.20, Measured value: 395.15.

[0349] Preparation of benzyl 4-(4-(5-bromo-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2008) Benzyl 4-(4-(6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2007) (480 mg, 1.22 mmol) was dissolved in AcOH (5 mL) and Br2 (584 mg, 3.65 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with an aqueous solution of Na2S2O3 and then extracted with ELISA (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 97:3) to obtain benzyl 4-(4-(5-bromo-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2008) (330 mg, purity 80%, yield 45%) as a colorless oil. LCMS(ESI) C 22 H 25 BrN4O3[M+H] + m / z Calculated value: 473.11, Measured value: 472.82.

[0350] Preparation of benzyl 4-(4-(6-oxo-5-vinyl-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2010) To a 10 mL solution of benzyl 4-(4-(5-bromo-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2008) (330 mg, 0.70 mmol) in ACN (10 mL), tributyl(vinyl)tin (2009) (332 mg, 1.05 mmol) and Pd(AMPHOS)Cl2 (49 mg, 0.07 mmol) were sequentially added. The reaction mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain benzyl 4-(4-(6-oxo-5-vinyl-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2010) (210 mg, purity 80%, yield 57%) as a colorless oil. LCMS(ESI) C 24 H 28 N4O3[M+H] + m / z Calculated value: 421.22, Measured value: 421.08.

[0351] Preparation of 5-ethyl-2-(3-(piperazin-1-yl)bicyclo[2.1.1]hexane-1-yl)pyrimidine-4(3H)-one (2011) A solution of benzyl 4-(4-(6-oxo-5-vinyl-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazine-1-carboxylate (2010) (210 mg, 0.50 mmol) and PtO2 (57 mg, 0.25 mmol) in MeOH (5 mL) was stirred at room temperature for 16 hours under hydrogen balloon pressure. After filtering the mixture through a Celite pad, the filtrate was concentrated to obtain 5-ethyl-2-(3-(piperazine-1-yl)bicyclo[2.1.1]hexane-1-yl)pyrimidine-4(3H)-one (2011) (150 mg, purity 20%, yield 20%) as a colorless oil. LCMS(ESI) C 16 H 24 N4O [M+H] + m / z Calculated value: 289.20, Measured value: 289.25.

[0352] Preparation of methyl 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)picolinate (2013) To a solution of 5-ethyl-2-(3-(piperazin-1-yl)bicyclo[2.1.1]hexane-1-yl)pyrimidine-4(3H)-one (2011) (150 mg, 0.52 mmol) in ACN (5 mL), methyl 6-bromo-5-fluoropicolinate (2012) (122 mg, 0.52 mmol) and DIPEA (202 mg, 1.56 mmol) were added. The reaction mixture was stirred at 75 °C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain methyl 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)picolinate (2013) (20 mg, purity 80%, yield 6%) as a colorless oil. LCMS(ESI) C 23 H 28 BrN5O3[M+H] + m / z Calculated value: 502.14, Measured value: 502.05.

[0353] Preparation of 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)-N-methylpicolinamide (2014) A solution of methyl 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)picolinate (2013) (20 mg, 0.04 mmol) in MeNH2 (5 mL, 30 wt.% methanol solution) was stirred at 100°C for 2 hours in a steel pressure-resistant reaction vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)-N-methylpicolinamide (2014) (20 mg, purity 80%, yield 80%) as a colorless oil. LCMS(ESI) C 23 H 29 BrN6O2[M+H] + m / z Calculated value: 501.15, Measured value: 501.25.

[0354] Preparation of 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (82) 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)-N-methylpicolinamide (2014) (20 mg, 0.04 mmol) was dissolved in DMSO (2 mL), to which 18-crown-6 (21 mg, 0.08 mmol) and CsF (24 mg, 0.16 mmol) were sequentially added. The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water, and then extracted with ELISA (30 mL x 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: ACN-water (0.05% NH3); gradient: 20-60) to obtain a racemic mixture (2.7 mg, purity 97.60%, yield 15%) of 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (82) as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ:8.48-8.35(m,1H),7.90-7.80(m,1H),7.65-7.51(m,2H),3.21-3.12(m,4H),2.76(d,J=4.8Hz,3H), 2.60-2.56(m,4H),2.53-2.52(m,2H),2.28-2.20(m,2H),2.05-1.96(m,1H),1.95-1.89 (m,1H),1.83-1.72(m,2H),1.71-1.64(m,1H),1.43-1.31(m,1H),1.03(t,J=7.6Hz,3H). LCMS(ESI) C 23 H 29 FN6O2[M+H] + m / z Calculated value: 441.23, Measured value: 441.35.

[0355] Example 12: Assay Exemplary compounds of the present invention were prepared and tested to determine their effects as PARP1 and PARP2 inhibitors. Typical assays are described below.

[0356] Example 12A: PARP1 biochemical dissociation-enhanced lantanide fluorescence immunoassay (DELFIA assay) Optiplate HB 384-well plates were coated with anti-FLAG antibody. The anti-FLAG antibody was supplied as a 4 mg / ml solution, and coating was performed overnight at 4°C using pH 9.6 Na2CO3 / HCO3 coating buffer, ensuring that 0.3 g per well was ultimately immobilized. Next, the wells were washed three times for 5 minutes with coating wash buffer (PBS / 0.05% Tween (v / v)) and blocked overnight at 4°C with coating wash buffer containing 2% BSA (w / v). Before assay, each well was washed three times for 5 minutes with coating wash buffer. For the assay, 20 μL of 2.5 nM recombinant full-length N-terminal FLAG-tagged human PARP1 was added to each well of the 384-well plate and left at room temperature for 30 minutes. Then, 50 nL of DMSO solution of each compound was added using the pin tool technique. After incubation at room temperature for 30 minutes, 5 μL of assay buffer (20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), 0.02% Tween (v / v)) containing 10 μM biotin-NAD+ and 10 nM activated DNA (sequence below) was added. After allowing autoparylation of poly-ADP-ribosylation to proceed at room temperature for 2 hours, 5 μL of 12 mM NAD+ quench solution was added. After 30 minutes at room temperature, the assay solution was removed, the plate was washed 5 times for 3 minutes, and 100 μL of a 1:1000 dilution of DELFIA Eu-N1 streptavidin reagent was added. The plate was then incubated at room temperature for 30 minutes. The reaction mixture was removed, the plate was washed 5 times for 3 minutes, and 25 μL of DELFIA enhancement solution was added. After incubation at room temperature for 30 minutes, fluorescence was measured using Pherastar FS (Ex: 337 nm, Em: 620 nm, integration start: 60 μs, integration time: 400 μs).

[0357] Typically, the compound is tested in a 12-point concentration-response curve at 3-fold dilution intervals starting from 20 μM, and IC50 is measured. 50 The values ​​were determined. The data were analyzed using ActivityBase software, and the replicate values ​​for low control (no enzyme, 0.2% DMSO) and high control (0.2% DMSO) were averaged. The data obtained from the test compound were expressed as a percentage of 100% using the following formula: % value = 100 - (100 * ((high control - value) / (high control - low control)) The % data were fitted using a nonlinear regression equation (log inhibitor vs response - variable slope (4 parameters)), and IC 50 The value was calculated. IC of various test compounds 50 The values ​​are shown in Table 1.

[0358] Activated DNA sequence [ka]

[0359] Example 12B: PARP1 probe-substituted homogeneous time-resolved fluorescence assay (HTRF assay) 10 nM full-length N-terminal FLAG-tagged PARP1 was incubated with 2 nM anti-FLAG Tb-cryptate antibody and a PARP1 / 2 Cy5 fluorescent dye-labeled conjugated probe (10x probe Kd = 270 nM) in assay buffer (20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), 0.02% Tween (v / v)) at room temperature for 40 minutes. The Cy5-labeled conjugated probe is shown below and is also described in Papeo, G. et al. J. Biomol.Screen. 2014;19:1212-1219. Next, this reaction mixture (6 μL) was transferred to each well of a black non-binding surface 384-well plate, and DMSO solution (35 nL) of each compound was added using the pin tool technique. After incubation at room temperature for 1 hour, fluorescence was measured using an HTRF module with Pherastar FS (Ex: 337 nm, Em: 620 nm, em: 665 nm, integration start 60 μs, integration time 400 μs).

[0360] Typically, the compound is tested in a 12-point concentration-response curve at 3-fold dilution intervals starting from 58.5 μM, and IC50 is measured. 50 The values ​​were determined. Data were analyzed using ActivityBase software. The replicate values ​​for the low control (no enzyme, with probe and Tb-cryptate antibody, 0.6% DMSO) and high control (0.6% DMSO) were averaged, and the data obtained from the test compound were expressed as % activity relative to 100% using the following formula: % activity = 100 * (value - low control) / (high control - low control) The % activity data was fitted using a nonlinear regression equation, and IC 50 The value was calculated.

[0361] K d The values ​​were calculated using the Cheng-Prussoff formula: I C 50 =(1+([probe concentration] / [K m(probe) ]))*Kd Therefore, K d =IC 50 / (1+[[probe concentration] / [K m(probe) ]]) and 10 × K m Using the probe, this equation becomes K d =IC 50 It is equal to / 11.

[0362] Example 12C: PARP2 probe-substituted homogeneous time-resolved fluorescence assay (HTRF assay) This assay uses N-terminal FLAG-tagged PARP2 (amino acids 1-583) instead of PARP1, and uses a PARP1 / 2 binding probe with a 10x probe K d The assay was performed under the same conditions as for PARP1, except that it was performed at a concentration of 540 nM. Data analysis was performed using the same method as for PARP1.

[0363] Structure of the Cy5 probe [ka]

[0364] NanoBRET cell target occupation assay NanoBRET assays were used to demonstrate cell target engagement and selectivity for PARP1 and PARP2. These assays are based on bioluminescent resonance energy transfer (BRET) between a nano-luc tagged protein (e.g., PARP1 or PARP2) and a fluorescent group on a high-affinity NAD+ competitively binding probe. Such cell probe substitution assays can be used to measure inhibitor affinity and selectivity for PARP1 and 2.

[0365] Frozen HEK293 cells transiently transfected with either the PARP1-NanoLuc(R) fusion construct or the PARP2-NanoLuc(R) fusion construct (Promega) were thawed, and the suspension was dispensed into 384-well microplates at a cell density of 1750 cells per well. Next, NanoBRET was used for the PARP1 and PARP2 assays. TM TE PARP Tracer-01 was added to final concentrations of 11 nM and 2 nM, respectively. The compounds were added at 3-fold dilution intervals starting from 25 μM to create 12 points on the concentration-reaction curve, and the plate was incubated at 37°C for 2 hours. Next, NanoBRET was performed according to the manufacturer's instructions. TM After adding Nano-Glo(R) substrate and extracellular NanoLuc(R) inhibitor, the BRET ratio was measured using a NanoBRET module (LUM 610-LP 450-80) and a PHERAstar FS or FSX reader. d The values ​​were calculated using the Cheng-Prussoff formula: I C 50 =(1+([tracer concentration] / [K m(tracer) ]))*K d

[0366] Table 1 summarizes the efficacy, affinity, and selectivity data for various test compounds obtained using DELFIA and probe-substituted HTRF assays. Table 1 also summarizes the efficacy, affinity, and selectivity data for some test compounds obtained using the NanoBRET assay.

[0367] Table 1: Results of PARP1 / 2 assays for selected compounds (DELFIA and probe-substituted HTRF)

[0368] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0369] The suffixes X and Y indicate isomers that have different stereochemistry in ring A, but for which no stereochemistry has been assigned.

[0370] Table 2: Results of PARP1 / 2 assay for selected compounds (NanoBRET)

[0371] [Table 2-1] [Table 2-2]

[0372] Legend The results of the DELFIA, probe-substituted HTRF, and NanoBRET assays are categorized as follows: "-" is IC 50 or K d This indicates that the value is greater than 10M. "+" is IC 50 or K d This indicates that the value is greater than 1M and less than or equal to 10M. "++" is IC 50 or K d This indicates that the value is greater than 100 nM and less than or equal to 1 M. "+++" is IC 50 or K d This indicates that the value is greater than 10 nM and less than or equal to 100 nM. "++++" is IC 50 or K d This indicates that the value is 10 nM or less. Selectivity can be categorized as follows: The "-" indicates that the value is less than 10. The "+" sign indicates that the value is between 10 and 50 (inclusive). "++" indicates that the value is between 50 and 100. "+++" indicates that the value is 100 or greater. "NT" indicates that it has not been tested. The selectivity value represents the selectivity that preferentially inhibits PARP1 over PARP2. These are the K values ​​for inhibiting PARP1 and PARP2. d Based on the ratio of values, K d (PARP2) / K d It is calculated as (PARP1).

[0373] Other variations or uses of the technology described herein will be apparent to those skilled in the art who have access to this disclosure. The scope of this disclosure is not limited to the embodiments described herein, but is limited only by the appended claims.

Claims

1. A PARP1 inhibitor compound for use in pharmaceuticals, having the following structure: 【Chemistry 1】 (In the formula, R １ is selected from H and substituted or unsubstituted organic groups; R ２ It is either absent or selected from H and substituted or unsubstituted organic groups; R ３ It is either absent or selected from H and substituted or unsubstituted organic groups; R ４ is selected from H and substituted or unsubstituted organic groups; Z １ and Z ２ Each is independently selected from C and N; and, L is a group having the following structure: 【Chemistry 2】 (In the formula, X １ Each of these is selected independently from C and N; X ２ Each of these is independently selected from C, N, O, and S; Given that n + m is a number selected from 1, 2, 3, 4, 5, and 6, n is a number selected from 0, 1, 2, 3, 4, 5, and 6, and m is a number selected from 0, 1, 2, 3, 4, 5, and 6; Given that p + q is a number selected from 1, 2, 3, 4, 5, and 6, p is a number selected from 0, 1, 2, 3, 4, 5, and 6, and q is a number selected from 0, 1, 2, 3, 4, 5, and 6; Given that r+s is a number selected from 2, 3, 4, 5, and 6, r is a number selected from 0, 1, 2, 3, 4, 5, and 6, and s is a number selected from 0, 1, 2, 3, 4, 5, and 6; R ５Ａ 、 R ５Ｂ 、 and R ５Ｃ each is independently either non - existent or selected from H and substituted or unsubstituted organic groups; R ６ It is either absent or selected from H and substituted or unsubstituted organic groups; The lines forming rings A, B, and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; Each of Qa, Qb, and Qc is independently selected from a bond or group having a structure independently selected from the following: 【Transformation 3】 (In the formula, Given that t + u is a number selected from 0, 1, 2, 3, 4, 5, and 6, t is a number selected from 0, 1, 2, 3, 4, and 5, and u is a number independently selected from 0, 1, 2, 3, 4, and 5; R ７ and R ８ Each of these is independently selected from H and substituted or unsubstituted organic groups.

2. A PARP1 inhibitor compound for use in a pharmaceutical according to claim 1, wherein p+q is a number selected from 2, 3, 4, 5, and 6, and optionally m+n is a number selected from 2, 3, 4, 5, and 6.

3. X ２ Each of the is independently selected from C and N, a PARP1 inhibitor compound according to claim 1 or 2.

4. A PARP1 inhibitor compound according to any of the preceding claims, having a structure selected from the following: i) 【Chemistry 4】 (In the formula, R １ , R ２ , and R ４ Each of these is independently selected from H and substituted or unsubstituted organic groups. ii) 【Transformation 5】 (In the formula, R １ , R ３ , and R ４ Each of these is independently selected from H and substituted or unsubstituted organic groups. ); and, iii) 【Transformation 6】 (In the formula, R １ , R ２ , R ３ , and R ４ Each of these is independently selected from H and a substituted or unsubstituted organic group.

5. The PARP1 inhibitor compound according to claim 4 having the following structure: 【Transformation 7】 (In the formula, R １ , R ２ , R ３ , and R ４ Each of these is independently selected from H and a substituted or unsubstituted organic group.

6. The PARP1 inhibitor compound according to claim 4 having the following structure: 【Transformation 8】 (In the formula, R １ , R ３ , and R ４ Each of these is independently selected from H and a substituted or unsubstituted organic group.

7. R １ and R ２ However, each is independently selected from the following PARP1 inhibitor compounds according to any of the preceding claims: -H; -C １ ~C ６ Alkyl, aminoalkyl, alkoxy, or haloalkyl groups; -C ３ ~C ６ cycloalkyl groups; - Halogen group; and, 【Chemistry 9】 (In the formula, R ２２ H, C １ ~C ６ Selected from alkyl, cycloalkyl, alkoxy, or haloalkyl groups, and halogen groups; R ２３ Each of these is independently selected from H and a substituted or unsubstituted organic group; preferably, R ２３ Each of these is independently H, C １ ~C ６ Selected from alkyl, aminoalkyl, alkoxy, or haloalkyl groups, and halogen groups, preferably at least one R ２３ H is; however, R １ and R ２ (Provided that at least one of them is not H.)

8. R ２ It does not exist or is H, preferably R ２ A PARP1 inhibitor compound according to any of the prior claims, wherein is H.

9. R １ , R ２ , R ３ , and R ２２ At least one of them is -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ F, -CHF ２ , -CF ３ , -F, -Cl, -CH ２ CF ３ ien-CH ２ CH ２ F, -CH ２ CH ２ Selected from OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, or cyclopropylmethyl group, Optionally R １ , R ２ , and R ２２ At least one of them is -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ F, -CHF ２ , -CF ３ , -F, -Cl, -CH ２ CF ３ ien-CH ２ CH ２ F, -CH ２ CH ２ Selected from OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, or cyclopropylmethyl group, The PARP1 inhibitor compound according to claim 7.

10. below: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 A PARP1 inhibitor compound according to any of the preceding claims, having a structure selected from the above.

11. R １ and R ２ At least one of them 【Chemistry 11】 and R ２３ each is independently selected from H, F, C １ to C ３ alkyl groups, and C １ to C ３ fluoroalkyl groups, and is a PARP1 inhibitor compound according to any one of claims 7 to 10.

12. R １ is a PARP1 inhibitor compound according to any one of the preceding claims, selected from a halogen group (which may optionally be Cl), an alkyl group of C １ to C ４ , and a haloalkyl group of C １ to C ４ (which may optionally be a fluoroalkyl group of C １ to C ４ ).

13. R １ is, -CH ２ CH ３ , -CF ３ , 【Chemistry 12】 ien-CH ２ CH ２ F, -Cl, and -CH ２ CF ３ A PARP1 inhibitor compound according to claim 12, selected from the above.

14. R １ H, C １ ~C ３ alkyl group, C １ ~C ３ The alkoxy group of, and C １ ~C ３ A PARP1 inhibitor compound according to any of the preceding claims, selected from the haloalkyl groups.

15. R １ The PARP1 inhibitor compound according to claim 14, wherein is an ethyl group.

16. R ３ H, halogen, C １ ~C ３ alkyl group, C １ ~C ３ Haloalkyl groups, C １ ~C ３ The alcohol group of, and C １ ~C ３ Selected from aminoalkyl groups, optionally R ３ A PARP1 inhibitor compound according to any of the prior claims, wherein is H.

17. Z １ and Z ２ These are C, respectively; R ２ and R ３ These are H, halogen, and C, respectively, independently. １ ~C ３ alkyl group, C １ ~C ３ Selected from the haloalkyl groups, Optionally, R2 and R3 are independently H and C １ ~C ３ alkyl group, C １ ~C ３ Selected from the haloalkyl groups, The PARP1 inhibitor compound according to claim 16.

18. R ２ and R ３ The PARP1 inhibitor compound according to claim 17, wherein each of the elements is H.

19. R ４ H, C １ ~C ３ alkyl group, C １ ~C ３ Selected from the haloalkyl groups, preferably R ４ A PARP1 inhibitor compound according to any of the prior claims, wherein is H.

20. below: 【Chemistry 13】 A PARP1 inhibitor compound according to any of the preceding claims, having a structure selected from the above.

21. A PARP1 inhibitor compound according to any of the preceding claims, wherein ring A is a non-aromatic ring.

22. The PARP1 inhibitor compound according to claim 21, wherein L has the following structure: 【Chemistry 14】 (In the formula, ring A is a saturated or unsaturated aliphatic carbocyclic or heterocyclic ring.)

23. A PARP1 inhibitor compound according to any one of claims 1 to 21, wherein L has the following structure: 【Chemistry 15】 (In the formula, Ring A is a saturated or unsaturated aliphatic carbon ring or heterocycle; optionally, ring A is a cyclopentyl group and X of ring A １ Each atom has an R configuration, or the X of ring A. １ Each atom has an S configuration; furthermore, optionally, the X of ring A １ Each atom has an S configuration.

24. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring A is a saturated or unsaturated five-membered aliphatic carbocyclic or heterocyclic ring.

25. The PARP1 inhibitor compound according to any one of claims 1 to 23, wherein ring A is a saturated or unsaturated six-membered aliphatic carbocyclic or heterocyclic ring.

26. Qa is a bond or -CH ２ - and optionally Qa is a binding compound, the PARP1 inhibitor compound according to any of the preceding claims.

27. L has the following structure: 【Chemistry 16】 A PARP1 inhibitor compound according to any of the preceding claims, wherein the group is a group having the following characteristics.

28. L has the following structure: 【Chemistry 17】 A PARP1 inhibitor compound according to claim 27, wherein the group has the following characteristics.

29. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring B is a saturated heterocycle.

30. Ring A is as follows: [Chemistry 18] A PARP1 inhibitor compound selected from any of the preceding claims.

31. Qb is -CH ２ - The PARP1 inhibitor compound according to claim 30.

32. A PARP1 inhibitor compound according to any one of claims 1 to 29, wherein both n and m are at least 1.

33. i) Ring A is a substituted or unsubstituted 7-membered aliphatic carbocyclic or heterocyclic ring, optionally a cycloheptane, and further optionally a cycloheptane having a structure selected from the following: 【Chemistry 19】 (In the formula, R ５Ａ and R ５Ａ３ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R ５Ａ３ is most preferably H; or, ii) Ring A is a substituted or unsubstituted six-membered aliphatic carbocyclic or heterocyclic ring, optionally cyclohexane or tetrahydropyran, and further optionally having a structure selected from the following: 【Chemistry 20-1】 【Chemistry 20-2】 (In the formula, R ５Ａ and R ５Ａ３ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R ５Ａ３ is most preferably H; or, iii) Ring A is a substituted or unsubstituted five-membered aliphatic carbocyclic or heterocyclic ring, optionally cyclopentane, cyclopentene, or tetrahydrofuran, and further optionally having a structure selected from the following: 【Chemistry 21】 or 【Chemistry 22】 (In the formula, R ５Ａ and R ５Ａ３ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R ５Ａ３ is most preferably H; or, iv) Ring A is a five-membered aromatic ring, optionally pyrrole or pyrazole, and further optionally having a structure selected from the following: 【Chemistry 23】 (In the formula, R ５Ａ Each of these is independently selected from H and substituted or unsubstituted organic groups. ); or v) Ring A is a substituted or unsubstituted cyclobutane, which optionally has the following structure: 【Chemistry 24】 (In the formula, R ５Ａ and R ５Ａ３ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R ５Ａ３ H is the most preferred value. The PARP1 inhibitor compound according to claim 32.

34. Ring A is as follows: 【Chemistry 25】 A PARP1 inhibitor compound according to claim 33, having a structure selected from the above.

35. A PARP1 inhibitor compound according to any of the preceding claims, wherein ring A has the following structure: 【Chemistry 26】 (In the formula, n is 1, 2, or 3; m is 0, 1, or 2; X １ is C or N; X ２ Each of these is selected independently from C and O; R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ Each of these is independently either absent or selected from H and substituted or unsubstituted organic groups; however, X １ If R is N, ５Ａ１ It does not exist, and the corresponding X ２ If O, R ５Ａ２ (Assuming it does not exist.)

36. R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ Exactly two groups selected from the group combine to form C, which bridges ring A. １ ~C ３ It represents an alkyl group, or together with it, a phenyl group condensed on ring A; and, Other R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ Each of the groups is either nonexistent, H, or an oxo group, independently of the others. The PARP1 inhibitor compound according to claim 35.

37. R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ Each element is either H independently, or does not exist; Optionally R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ Each element is H. The PARP1 inhibitor compound according to claim 35.

38. Ring A has the following structure, the PARP1 inhibitor compound according to any one of claims 35 to 37: 【Chemistry 27】 (In the formula, m is either 1 or 2; n is either 1 or 2; R ５Ａ２ and R ５Ａ３ Each of these is independently either absent or selected from H and substituted or unsubstituted organic groups; preferably, ring A is an aliphatic ring and R ５Ａ３ H is, Here, (i) X １ C is R ５Ａ１ is selected from H and substituted or unsubstituted organic groups; or (ii) X １ is N, and R ５Ａ１ It does not exist.

39. R ５Ａ２ Each of these is either absent, H or an oxo group, or another R, independently of each other. ５Ａ２ , R ５Ａ１ , and R ５Ａ３ Together with one other group selected from -CH ２ - Forms a group; Optionally R ５Ａ２ Each of them is either nonexistent or H, The PARP1 inhibitor compound according to claim 38.

40. Ring A is as follows: 【Chemistry 28】 A PARP1 inhibitor compound according to claim 39, having a structure selected from the above.

41. Ring A is as follows: 【Chemistry 29】 The PARP1 inhibitor compound according to claim 40.

42. Ring A is as follows: 【Transformation 30】 A PARP1 inhibitor compound according to any one of claims 1 to 29, having a structure selected from the above.

43. Qb is a bond or -CH ２ - and optionally Qb is a binding compound, according to any of the preceding claims.

44. A PARP1 inhibitor compound according to any of the preceding claims, wherein both p and q are at least 1, optionally the sum of p and q is 3 or 4, and further optionally p is 2 and q is 2.

45. i) Ring B is a 7-membered saturated heterocycle and is optionally a homopiperazine having the following structure: 【Chemistry 31】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. ); or, ii) Ring B is a six-membered saturated heterocycle, optionally a piperazine, and optionally a piperazine having the following structure: 【Chemistry 32】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. ); or, iii) Ring B is a five-membered saturated heterocycle, optionally an imidazolidine, and optionally an imidazolidine having the following structure: 【Transformation 33】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. ); or, iv) Ring B is a four-membered saturated heterocycle and optionally has the following structure: 【Transformation 34】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. A PARP1 inhibitor compound according to any of the prior claims.

46. Ring B is as follows: 【Chemistry 35】 A PARP1 inhibitor compound according to claim 45, selected from the above.

47. Ring B is as follows: 【Transformation 36】 A PARP1 inhibitor compound according to claim 46, having the structure described above.

48. i) Ring B is azepane and optionally has the following structure: 【Chemistry 37】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. ); or, ii) Ring B is a piperidine and optionally has the following structure: 【Transformation 38】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. ); or, iii) Ring B is a pyrrolidine and optionally has the following structure: 【Chemistry 39】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of them is H. The PARP1 inhibitor compound according to claim 45.

49. Ring B is a PARP1 inhibitor compound according to any one of claims 1 to 44, having the following structure: 【Chemistry 40】 (In the formula, R ５Ｂ Each of these is independently selected from H and a substituted or unsubstituted organic group, where R is optionally included. ５Ｂ Each of these is H.

50. Qc is a bond or -CH ２ - and optionally Qc is a binding compound, as described in any of the preceding claims.

51. Ring B is a four-membered ring, Qc is -CH ２ -, -O-, and -NR ８ - Selected from, Optionally R ８ is H or C １ ~C ３ The alkyl group is A PARP1 inhibitor compound according to any one of claims 1 to 46.

52. The PARP1 inhibitor compound according to claim 51, wherein Qc is -O- or -NH-.

53. A PARP1 inhibitor compound according to any of the preceding claims, wherein both r and s are at least 1, and optionally the sum of r and s is 3 or 4.

54. R ５Ｃ Each of these is either absent or contains H, or a halo group, -CN, or C. １ ~C ３ The alkyl group and C １ ~C ３ It is an organic group selected from the haloalkyl groups, Optionally, R ５Ｃ Each of these is, independently, either absent, H, or an organic group selected from -Cl, -F, and -CN. A PARP1 inhibitor compound according to any of the prior claims.

55. Exactly one R ５Ｃ is an organic group, and other R ５Ｃ The PARP1 inhibitor compound according to claim 54, wherein each of the elements is either absent or H.

56. i) Ring C is a six-membered aliphatic ring, and optionally has the following structure: 【Chemistry 41】 (In the formula, R ５Ｃ and R ５Ｃ１ Each of these is independently selected from H and a substituted or unsubstituted organic group, where preferably R ５Ｃ１ is H, and more preferably R ５Ｃ１ and R ５Ｃ Each of these is H. ii) Ring C is a six-membered aromatic ring, optionally selected from the following: ii) Phenyl group, optionally having the following structure: 【Chemistry 42】 (In the formula, R ５Ｃ Each of these is independently selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ Each of them is H); iib) A pyridine group, optionally having a structure selected from the following: 【Chemistry 43】 (In the formula, R ５Ｃ Each of these is independently selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ Each of them is H); ii) Diazine group, optionally having a structure selected from the following: 【Chemistry 44】 (In the formula, R ５Ｃ Each of these is independently selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ Each of them is H); iii) Ring C is a five-membered aromatic ring, optionally selected from the following: iii) Imidazole group, optionally an imidazole group having a structure selected from the following: 【Chemistry 45】 (In the formula, R ５Ｃ Each of these is independently selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ Each of them is H); iiib) Thiophene group, optionally having a structure selected from the following: 【Chemistry 46】 (In the formula, R ５Ｃ Each of these is independently selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ Each of them is H); iii) Thiazole group, optionally having a structure selected from the following: 【Chemistry 47】 (In the formula, R ５Ｃ Each of these is independently selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ Each of them is H); iii) Triazole group, optionally a triazole group having the following structure: 【Chemistry 48】 (In the formula, R ５Ｃ is selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ (is H), A PARP1 inhibitor compound according to any one of claims 53 to 55.

57. Ring C is as follows: 【Chemistry 49-1】 【Chemistry 49-2】 A PARP1 inhibitor compound according to claim 56, having a structure selected from the above.

58. Ring C is a PARP1 inhibitor compound according to any of the preceding claims, having the following structure: [Transformation 50] (In the formula, X Ｃ Each of them is independently selected from C and N; X Ｃ If N, then the corresponding R ５ＣＯ or R ５ＣＭ The base does not exist; and, X Ｃ If C, then the corresponding R ５ＣＯ or R ５ＣＭ The group is H, or a halo group, -CN, C １ ~C ２ The alkyl group and C １ ~C ２ It is an organic group selected from the haloalkyl groups.

59. X Ｃ If C, then the corresponding R ５ＣＯ or R ５ＣＭ The PARP1 inhibitor compound according to claim 58, wherein the group is H, or an organic group selected from H, -Cl, -F, and -CN.

60. X is N ｃ The PARP1 inhibitor compound according to claim 58 or 59, wherein the compound has two or fewer atoms.

61. R ５ＣＯ Base and R ５ＣＭ A PARP1 inhibitor compound according to any one of claims 58 to 60, wherein exactly one group selected from the groups is an organic group.

62. Ring C has the following structure, the PARP1 inhibitor compound according to any one of claims 58 to 61: 【Chemistry 51】 (In the formula, R Ｃ２о is selected from H and halogen; and, i) X ２ＣＭ is C, and R ５Ｃ２ Is it H; or, ii) X ２ＣＭ is N, and R ５Ｃ２ It does not exist.

63. R Ｃ２о is a halogen, and optionally R Ｃ２о The PARP1 inhibitor compound according to claim 62, wherein is F.

64. Ring C is as follows: 【Chemistry 52】 A PARP1 inhibitor compound according to any of the preceding claims, having a structure selected from the above.

65. Ring C is as follows: 【Chemistry 53】 The PARP1 inhibitor compound according to claim 56.

66. R ６ H, -F, -Cl, -Br, -I, -CN, -CONR ５１ R ５１ , -NR ５１ COR ５２ , -SO ２ NR ５１ R ５１ , -NR ５１ SO ２ R ５２ , -O-CR ５２ R ５２ R ５２ , -CR ５２ R ５２ NR ５１ R ５１ , and a PARP1 inhibitor compound according to any of the preceding claims, selected from any of the following structures: 【Chemistry 54】 (In the formula, R ５１ and R ５２ Each of these is independently selected from H and a substituted or unsubstituted organic group, where optionally, R ５１ and R ５２ These are H, halogen, and C, respectively, independently. １ ~C ３ The alkyl group of, and C １ ~C ３ Selected from the haloalkyl groups.

67. R ６ The PARP1 inhibitor compound according to claim 66 has the following structure: 【Transformation 55】 (In the formula, R ５１ The following can be selected: -C １ ~C ６ Alkyl alkyl group, optionally C ３ ~C ６ Cycloalkyl groups, C １ ~C ３ an alkyl group, or C １ ~C ３ It may be a deuterated alkyl group; -C １ ~C ３ A haloalkyl group, optionally C １ ~C ３ It may be a fluoroalkyl group; and, - A saturated heterocyclic group with 4, 5, 6, or 7 members, or optionally a cyclic ether group with 4, 5, or 6 members.

68. R ６ The following: 【Transformation 56】 Alternatively, see below: 【Chemistry 57】 Or, R ６ The following: 【Chemistry 58】 A PARP1 inhibitor compound according to claim 67, selected from the above.

69. R ６ The PARP1 inhibitor compound according to claim 68, wherein is CONHMe.

70. R ６ The following: 【Chemistry 59】 The PARP1 inhibitor compound according to claim 68.

71. R ６ A PARP1 inhibitor compound according to any one of claims 1 to 65, having the following structure: 【Transformation 60】 (In the formula, X ６ Each of these is independently selected from C, N, and O; R ６１ It either does not exist or is H; R ６２ Each of these is either absent or contains H, a halo group (e.g., F), an oxo group, or C, independently of each other. １ ~C ３ alkyl group, C １ ~C ３ Haloalkyl group (optionally C １ ~C ３ (of fluoroalkyl groups), and -NHR ６３ (Here, R ６３ is H or C １ ~C ３ It is an alkyl group. (Selected from the following.)

72. R ６ The following: 【Chemistry 61】 A PARP1 inhibitor compound according to claim 71, selected from the above.

73. R ６ is either H, or -F, -Cl, -CN, -CONH ２ , -CONHMe, -CONHEt, -CONMe ２ , -CONHCMe, -CONHCH ２ -CH ２ OMe, -CONH-CH ２ -CH ２ F, -CONH-CH ２ -CF ３ , -CONH-CH ２ - CHF ２ , -OCHF ２ , -NHCOMe, -NHSO ２ Me, -SO ２ NHMe, -CONHSO ２ Me, and the following: 【Transformation 62】 A PARP1 inhibitor compound according to claim 66, selected from the above.

74. R ６ The PARP1 inhibitor compound according to claim 73, wherein is selected from -H, -F, -Cl, and -CN.

75. Ring C is as follows: 【Chemistry 63-1】 【Chemistry 63-2】 【Chemistry 63-3】 A PARP1 inhibitor compound according to any of the preceding claims, having a structure selected from the above.

76. R ６ Base, and one R ５Ｃ A PARP1 inhibitor compound according to any one of claims 1 to 57, wherein the groups combine to form a ring.

77. A PARP1 inhibitor compound according to any of the preceding claims, having the following structure: 【Chemistry 64】 (In the formula, Z １ and Z ２ These are independently selected from C and N, Z １ If R is N, ２ It does not exist; Z １ If C, then R ２ is H; Z ２ If R is N, ３ It does not exist; Z ２ If C, then R ３ is H; X Ｃ Each of them is independently selected from C and N; and, X Ｃ If N, then the corresponding R ５ＣＯ or R ５ＣＭ The basis does not exist; X Ｃ If C, then the corresponding R ５ＣＯ or R ５ＣＭ The group is either H, or a halo group, -CN, or C. １ or C ２ The alkyl group of, and C １ or C ２ It is an organic group selected from the haloalkyl groups; Two R's ５Ａ The base is combined -CH ２ - represents other R ５Ａ Each element is H.

78. Base L is as follows: 【Chemistry 65-1】 【Chemistry 65-2】 【Chemistry 65-3】 【Chemistry 65-4】 【Transformation 65-5】 【Transformation 65-6】 A PARP1 inhibitor compound selected from any one of claims 1 to 20.

79. Base L is as follows: 【Chemistry 66-1】 【Chemistry 66-2】 A PARP1 inhibitor compound according to claim 78, selected from the above.

80. below: 【Chemistry 67-1】 【Chemistry 67-2】 【Chemistry 67-3】 【Chemistry 67-4】 【Chemistry 67-5】 【Transformation 67-6】 【Transformation 67-7】 【Transformation 67-8】 【Chemistry 67-9】 【Chemistry 67-10】 【Chemistry 67-11】 【Chemistry 67-12】 【Chemistry 67-13】 【Chemistry 67-14】 【Chemistry 67-15】 【Chemistry 67-16】 【Chemistry 67-17】 【Chemistry 67-18】 【Chemistry 67-19】 【Chemistry 67-20】 A PARP1 inhibitor compound according to claim 1, having a structure selected from the above.

81. R １ , R ２ , R ３ , R ４ , R ５Ａ (For example, R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ ), R ５Ｂ , R ５Ｃ , R ６ , R ７ , R ５１ , R ５２ , and R ５３ If one or more of the organic groups are substituted or unsubstituted, then the substituted or unsubstituted organic groups are independently selected from the following: -deuterium; - Halogens (-F, -Cl, -Br, and -I, etc.); - Nitrile group; - Substitutable or unsubstituted linear or branched C １ ~C ６ Alkyl groups (methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group, etc.); - Substitutable or unsubstituted linear or branched C １ ~C ６ alkyl-aryl group (-CH ２ Ph, -CH ２ (2, 3 or 4) F-Ph, -CH ２ (2, 3 or 4) Cl-Ph, -CH ２ (2, 3 or 4) Br-Ph, -CH ２ (2, 3 or 4) I-Ph, -CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ CH ２ Ph, and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., pH); - Substitutable or unsubstituted linear or branched C １ ~C ６ Halogenated alkyl group (-CH ２ F, -CH ２ Cl, -CH ２ Br, -CH ２ I, -CHF ２ , -CF ３ , -CCl ３ , - CBr ３ , -CI ３ ien-CH ２ CH ２ F, -CH ２ CF ３ ien-CH ２ CCl ３ ien-CH ２ CBr ３ , and, -CH ２ CI ３ etc.); --NH ２ , or substituted or unsubstituted linear or branched primary, secondary or tertiary C １ ~C ６ amine group (-NMeH, -NMe ２ , -NEtH, -NEtMe, -NEt ２ , -NPrH, -NPrMe, -NPrEt, -NPr ２ , -NBuH, -NBuMe, -NBuEt, -CH ２ -NH ２ ien-CH ２ -NMeH, -CH ２ -NMe ２ ien-CH ２ -NETH, -CH ２ -NEtMe, -CH ２ -NET ２ ien-CH ２ -NPrH, -CH ２ -NPrMe, and -CH ２ (e.g., NPrEt); - Substituted or unsubstituted aminoaryl groups (-NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)Cl-Ph, -NH-(2,3 or 4)Br-Ph, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph, -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, -NH-(2,3 or 4)OMe-Ph, -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4)OPr-Ph, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F ２ -Ph, -NH-2, (3, 4, 5 or 6)Cl ２ -Ph, -NH-2, (3, 4, 5 or 6)Br ２ -Ph, -NH-2, (3, 4, 5 or 6)I ２ -Ph, -NH-2, (3, 4, 5 or 6)Me ２ -Ph, -NH-2, (3, 4, 5 or 6)Et ２ -Ph, -NH-2, (3, 4, 5 or 6)Pr ２ -Ph, and -NH-2, (3, 4, 5 or 6)Bu ２ (e.g., Ph); - Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); - Substituted or unsubstituted cyclic C ３ ~C ８ Alkyl compounds (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); --OH group; - Substitutable or unsubstituted linear or branched C １ ~C ６ The alcohol group (-CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )CH ２ OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ )CH ２ CH ２ OH, -CH(CH ３ )CH(CH ３ )OH, -CH(CH ２ CH ３ )CH ２ OH, -C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ CH ２ OH and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., OH); - Substituted or unsubstituted linear or branched C １ ~C ６ The carboxylic acid group (-COOH, -CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ CH ２ COOH and -CH ２ CH ２ CH ２ CH ２ CH ２ COOH, etc.; - Substituted or unsubstituted linear or branched carbonyl groups (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH ２ Ph, -(CO)CH ２ OH, -(CO)CH ２ OCH ３ ,-(CO)CH ２ NH ２ ,-(CO)CH ２ NHMe, -(CO)CH ２ NMe ２ -(CO)-cyclopropyl,-(CO)-1,3-epoxypropane-2-yl,-(CO)NH ２ , -(CO)NHMe, -(CO)NMe ２ , -(CO)NHEt, -(CO)NET ２ -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH ２ CH ２ OH, -(CO)NHCH ２ CH ２ OMe, -(CO)NHCH ２ CH ２ NH ２ , -(CO)NHCH ２ CH ２ NHMe and -(CO)NHCH ２ CH ２ NMe ２ etc.); - Substitutable or unsubstituted linear or branched C １ ~C ６ Carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH ２ COOMe, -CH ２ CH ２ COOMe, -CH ２ CH ２ CH ２ COOMe, and -CH ２ CH ２ CH ２ CH ２ COOME, etc.; - Substitutable or unsubstituted linear or branched C １ ~C ６ The amide group (-CO-NH ２ , -CO-NMeH, -CO-NMe ２ , -CO-NEtH, -CO-NEtMe, -CO-NEt ２ (e.g., -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); - Substitutable or unsubstituted linear or branched C １ ~C ７ The aminocarbonyl group (-NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, and -NMe-CO-Ph, etc.); - Substitutable or unsubstituted linear or branched C １ ~C ７ Alkoxy or aryloxy groups (-OMe, -OEt, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH ２ F, -OCHF ２ , -OCF ３ , -OCH ２ Cl, -OHCl ２ -OCCl ３ , -O-Ph, -O-CH ２ -Ph, -O-CH ２ -(2,3 or 4)-F-Ph, -O-CH ２ -(2,3 or 4)-Cl-Ph, -CH ２ OMe, -CH ２ OEt, -CH ２ OPr, -CH ２ OBu, -CH ２ CH ２ OMe, -CH ２ CH ２ CH ２ OMe, -CH ２ CH ２ CH ２ CH ２ OMe, and -CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., OMe); - Substituted or unsubstituted linear or branched aminoalkoxy groups (-OCH ２ NH ２ , -OCH ２ NHMe, -OCH ２ NMe ２ , -OCH ２ NHEt, -OCH ２ NET ２ , -OCH ２ CH ２ NH ２ , -OCH ２ CH ２ NHMe, -OCH ２ CH ２ NMe ２ , -OCH ２ CH ２ NHEt, and -OCH ２ CH ２ NET ２ etc.); - Substituted or unsubstituted sulfonyl group (-SO ２ Me, -SO ２ Et, -SO ２ Pr, -SO ２ iPr, -SO ２ Ph, -SO ２ -(2, 3 or 4)-F-Ph, -SO ２ -Cyclopropyl, -SO ２ CH ２ CH ２ OCH ３ , -SO ２ NH ２ , -SO ２ NHMe, -SO ２ NMe ２ , -SO ２ NHEt, -SO ２ NET ２ , -SO ２ -pyrrolidine-N-yl, -SO ２ -morpholine-N-yl, -SO ２ NHCH ２ OMe, and -SO ２ NHCH ２ CH ２ (e.g., OMe); - Substituted or unsubstituted aminosulfonyl group (-NHSO ２ Me, -NHSO ２ Et, -NHSO ２ Pr, - NHSO ２ iPr, -NHSO ２ Ph, -NHSO ２ -(2, 3 or 4)-F-Ph, -NHSO ２ -Cyclopropyl and -NHSO ２ CH ２ CH ２ OCH ３ etc.); - Substitutable or unsubstituted aromatic groups (Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F ２ -Ph-, 2, (3, 4, 5 or 6)-Cl ２ -Ph-, 2, (3, 4, 5 or 6)-Br ２ -Ph-, 2, (3, 4, 5 or 6)-I ２ -Ph-, 2, (3, 4, 5 or 6)-Me ２ -Ph-, 2, (3, 4, 5 or 6)-Et ２ -Ph-, 2, (3, 4, 5 or 6)-Pr ２ -Ph-, 2, (3, 4, 5 or 6)-Bu ２ -Ph-, 2, (3, 4, 5 or 6)-(CN) ２ -Ph-, 2, (3, 4, 5 or 6)- (NO ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(NH ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(MeO) ２ -Ph-, 2, (3, 4, 5 or 6)-(CF ３ ) ２ -Ph-, 3, (4 or 5)-F ２ -Ph-, 3, (4 or 5)-Cl ２ -Ph-, 3, (4 or 5)-Br ２ -Ph-, 3, (4 or 5)-I ２ -Ph-, 3, (4 or 5)-Me ２ -Ph-, 3, (4 or 5)-Et ２ -Ph-, 3, (4 or 5)-Pr ２ -Ph-, 3, (4 or 5)-Bu ２ -Ph-, 3, (4 or 5)-(CN) ２ -Ph-, 3, (4 or 5)- (NO ２ ) ２ -Ph-, 3, (4 or 5)-(NH ２ ) ２ -Ph-, 3, (4 or 5)-(MeO) ２ -Ph-, 3, (4 or 5)-(CF ３ ) ２ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO ２ )-Ph-, 3-(NO ２ )-Ph-, 4-(NO ２ )-Ph-, 2-(NH ２ )-Ph-, 3-(NH ２ )-Ph-, 4-(NH ２ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH ２ -CO)-Ph-, 3-(NH ２ -CO)-Ph-, 4-(NH ２ -CO)-Ph-, 2-CF ３ -Ph-, 3-CF ３ -Ph-, 4-CF ３ -Ph-, 2-CF ３ O-Ph-, 3-CF ３ O-Ph-, and 4-CF ３ O-Ph-, etc.); -Saturated or unsaturated substituted or unsubstituted heterocyclic groups, optionally aromatic heterocyclic groups or non-aromatic heterocyclic groups (pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1, 2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl, 2 -Azapiperidine-4-yl, 3-Azapiperidine-1-yl, 3-Azapiperidine-2-yl, 3-Azapiperidine-4-yl, 3-Azapiperidine-5-yl, Piperazine-1-yl, Piperazine-2-yl, Furan-2-yl, Furan-3-yl, Pyran-2-yl, Pyran-3-yl, Pyran-4-yl, 2-Azapyran-2-yl, 2-Azapyran-3-yl, 2-Azapyran-4-yl, 2-Azapyran-5-yl, 2-Azapyran-6-yl, 3-Azapyran-2-yl, 3-Azapyran-4-yl, 3-Azapyran-5-yl, 3- Azapiran-6-yl, 4-azapiran-2-yl, 4-azapiran-3-yl, 4-azapiran-4-yl, 4-azapiran-5-yl, 4-azapiran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl,3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-te Trahydropyran-4-yl, 3-azatetrahydropyran-5-yl, 3-azatetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophene-2-yl, thiophene-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2- Azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thian-2-yl, thian-3-yl, Thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl, and tetrazole-1-yl, tetrazole-2-yl, and tetrazole-5-yl, etc.); Here, A pair of R atoms bonded to different atoms ５Ａ The groups may together form a ring with the atoms constituting ring A, and / or A pair of R atoms bonded to different atoms ５Ｂ The groups may together form a ring with the atoms constituting ring B, and / or A pair of R atoms bonded to different atoms ５Ｃ The groups may together form a ring with the atoms constituting the ring C, and / or R bonded to different atoms ５Ｃ Base and R ６ The groups may come together to form a ring with the atoms that make up the ring C. A PARP1 inhibitor compound according to any of the prior claims.

82. R ５Ａ (For example, R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ ), R ５Ｂ , and R ５Ｃ Each of these is independent of the others, either nonexistent or selected from the following: -hydrogen; -deuterium; -Halogens (-F, -Cl, -Br, and -I, etc.; preferably F or Cl); - Nitrile group; - Substitutable or non-substitutable C １ ~C ６ alkyl group; - Substitutable or unsubstituted linear or branched C １ ~C ６ Halogenated alkyl group (preferably CF) ３ or CHF ２ ); - Cyclopropyl group; --OH group; - Substitutable or unsubstituted linear or branched C １ ~C ６ The alcohol group; - Substitutable or unsubstituted linear or branched C １ ~C ７ The aminocarbonyl group (-NH-CO-Me, etc.); --NH ２ base; - Substitutable or non-substitutable C １ ~C ６ The amino group; - Substitutable or non-substitutable C １ ~C ６ alkoxy group; Here, a pair of R atoms bonded to different atoms ５Ａ When the groups come together to form a ring with the atoms that make up ring A; and / or when a pair of R groups bonded to different atoms ５Ｂ When the groups come together to form a ring with the atoms that make up ring B; and / or when a pair of R groups bonded to different atoms ５Ｃ When the groups come together and form a ring with the atoms that make up the ring C, the pair of R ５Ａ group, R ５Ｂ Base, or R ５Ｃ Each of the elements is independently -CH ２ - or -CH ２ CH ２ A PARP1 inhibitor compound according to any of the preceding claims, comprising - or the pair of groups together comprising -CH=CH-CH=CH- or -NH-CO-NH-.

83. A PARP1 inhibitor compound according to any of the preceding claims, wherein at least one of Qa, Qb, and Qc is as follows: 【Transformation 68】 (In the formula, t+u is at least 1; and, R ７ This includes H, halogens (e.g., -F, -Cl, -Br, and -I, preferably -F), and substituted or unsubstituted C. １ ~C ６ Alkyl alkyl groups, substituted or unsubstituted linear or branched C １ ~C ６ Halogenated alkyl group (preferably CF) ３ ), -NH ２ C as a base, substituted, or unsubstituted group １ ~C ６ amino group, -OH group, or substituted or unsubstituted linear or branched C １ ~C ６ The alcohol group and substituted or unsubstituted C １ ~C ６ Selected from the alkoxy groups.

84. R ７ H, halogen (optionally F), substituted or unsubstituted C １ ~C ６ Alkyl groups, and substituted or unsubstituted linear or branched C １ ~C ６ A PARP1 inhibitor compound according to claim 83, selected from the halogenated alkyl groups.

85. A PARP1 inhibitor compound according to any of the preceding claims, wherein at least one of Qa, Qb, and Qc has the following structure: 【Transformation 69】 (In the formula, R ８ The following can be selected: -H; - Substitutable or unsubstituted linear or branched C １ ~C ６ Alkyl groups (methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group, etc.); - Substitutable or unsubstituted linear or branched C １ ~C ６ alkyl-aryl group (-CH ２ Ph, -CH ２ (2, 3 or 4) F-Ph, -CH ２ (2, 3 or 4) Cl-Ph, -CH ２ (2, 3 or 4) Br-Ph, -CH ２ (2, 3 or 4) I-Ph, -CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ CH ２ Ph, and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., pH); - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (-CH ２ F, -CF ３ ien-CH ２ CH ２ F, and -CH ２ CF ３ etc.); - Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidine-3-yl, piperidine-3-yl, piperidine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); - Substitutable or non-substitutable C ３ ~C ８ Cyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); - Substitutable or unsubstituted linear or branched C ２ ~C ６ The alcohol group (-CH ２ CH ２ OH, -CH(CH ３ )CH ２ OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ )CH ２ CH ２ OH, -CH(CH ３ )CH(CH ３ )OH, -CH(CH ２ CH ３ )CH ２ OH, -C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ CH ２ OH and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., OH); - Substitutable or unsubstituted linear or branched C ２ ~C ６ The carboxylic acid group (-CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ CH ２ COOH and -CH ２ CH ２ CH ２ CH ２ CH ２ COOH, etc.; - Substituted or unsubstituted linear or branched carbonyl groups (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH ２ Ph, -(CO)CH ２ OH, -(CO)CH ２ OCH ３ ,-(CO)CH ２ NH ２ ,-(CO)CH ２ NHMe, -(CO)CH ２ NMe ２ -(CO)-cyclopropyl,-(CO)-1,3-epoxypropane-2-yl,-(CO)NH ２ , -(CO)NHMe, -(CO)NMe ２ , -(CO)NHEt, -(CO)NET ２ -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH ２ CH ２ OH, -(CO)NHCH ２ CH ２ OMe, -(CO)NHCH ２ CH ２ NH ２ , -(CO)NHCH ２ CH ２ NHMe and -(CO)NHCH ２ CH ２ NMe ２ etc.); - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH ２ COOMe, -CH ２ CH ２ COOMe, -CH ２ CH ２ CH ２ COOMe, and -CH ２ CH ２ CH ２ CH ２ COOME, etc.; - Substituted or unsubstituted linear or branched C1-C6 amide groups (-CO-NH ２ , -CO-NMeH, -CO-NMe ２ , -CO-NEtH, -CO-NEtMe, -CO-NEt ２ (e.g., -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); - a substituted or unsubstituted sulfonyl group (-SO ２ Me, -SO ２ Et, -SO ２ Pr, -SO ２ iPr, -SO ２ Ph, -SO ２ -(2, 3 or 4)-F-Ph, -SO ２ -cyclopropyl, -SO ２ CH ２ CH ２ OCH ３ , -SO ２ NH ２ , -SO ２ NHMe, -SO ２ NMe ２ , -SO ２ NHEt, -SO ２ NEt ２ , -SO ２ -pyrrolidin-N-yl, -SO ２ -morpholin-N-yl, -SO ２ NHCH ２ OMe, and, -SO ２ NHCH ２ CH ２ OMe etc.); - Substitutable or unsubstituted aromatic groups (Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F ２ -Ph-, 2, (3, 4, 5 or 6)-Cl ２ -Ph-, 2, (3, 4, 5 or 6)-Br ２ -Ph-, 2, (3, 4, 5 or 6)-I ２ -Ph-, 2, (3, 4, 5 or 6)-Me ２ -Ph-, 2, (3, 4, 5 or 6)-Et ２ -Ph-, 2, (3, 4, 5 or 6)-Pr ２ -Ph-, 2, (3, 4, 5 or 6)-Bu ２ -Ph-, 2, (3, 4, 5 or 6)-(CN) ２ -Ph-, 2, (3, 4, 5 or 6)- (NO ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(NH ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(MeO) ２ -Ph-, 2, (3, 4, 5 or 6)-(CF ３ ) ２ -Ph-, 3, (4 or 5)-F ２ -Ph-, 3, (4 or 5)-Cl ２ -Ph-, 3, (4 or 5)-Br ２ -Ph-, 3, (4 or 5)-I ２ -Ph-, 3, (4 or 5)-Me ２ -Ph-, 3, (4 or 5)-Et ２ -Ph-, 3, (4 or 5)-Pr ２ -Ph-, 3, (4 or 5)-Bu ２ -Ph-, 3, (4 or 5)-(CN) ２ -Ph-, 3, (4 or 5)- (NO ２ ) ２ -Ph-, 3, (4 or 5)-(NH ２ ) ２ -Ph-, 3, (4 or 5)-(MeO) ２ -Ph-, 3, (4 or 5)-(CF ３ )( ２ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO ２ )-Ph-, 3-(NO ２ )-Ph-, 4-(NO ２ )-Ph-, 2-(NH ２ )-Ph-, 3-(NH ２ )-Ph-, 4-(NH ２ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH ２ -CO)-Ph-, 3-(NH ２ -CO)-Ph-, 4-(NH ２ -CO)-Ph-, 2-CF ３ -Ph-, 3-CF ３ -Ph-, 4-CF ３ -Ph-, 2-CF ３ O-Ph-, 3-CF ３ O-Ph-, and 4-CF ３ O-Ph-, etc.); and, - Substituted or unsubstituted heterocyclic groups (pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyridazine-4-yl, pyridazine-2-yl, pyrimidine-4-yl, pyridazine-4-yl, pyridazine-2-yl, pyrimidine-4-yl, pyridazine-4-yl) Limidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, fran-2-yl, fran-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran -5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-4-yl, 2-azapyran-tetrahydrofuran-5-yl, 3-azapyran-tetrahydrofuran-2-yl, 3-azapyran-tetrahydrofuran-4- Il, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl,Morpholin-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathio Pyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thioran-2-yl, thioran-3-yl, thian-2-yl, thian-3-yl, thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl, and tetrazole-5-yl, etc.

86. R ８ H, substituted or unsubstituted linear or branched C １ ~C ６ Alkyl groups, and substituted or unsubstituted linear or branched C １ ~C ６ A PARP1 inhibitor compound according to claim 85, selected from the halogenated alkyl groups.

87. The aforementioned compound, - Isolated enantiomer, or - A mixture of two or more enantiomers, or - A mixture of two or more diastereomers and / or epimers, - Racemic mixture, or - Tautomers of the above compound A PARP1 inhibitor compound according to any of the prior claims, comprising:

88. A PARP1 inhibitor compound according to any of the prior claims, exhibiting greater selectivity for PARP1 than for PARP2.

89. A compound according to any of the preceding claims, used for the treatment of cancer.

90. The aforementioned cancers were selected from the following: Cancers of the eyes, brain (glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma and astrocytoma, etc.), spinal cord, kidneys, mouth, lips, pharynx, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gallbladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal glands, lungs, bronchi, liver, skin, ureters, urethra, testicles, vagina, anus, laryngeal glands, ovaries, thyroid gland, esophagus, nasopharyngeal glands, pituitary gland, salivary gland, prostate, pancreas, and adrenal gland; endometrial cancer, oral cancer, malignant melanoma, neuroblastoma, gastric cancer, hemangioma, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN hamartoma syndrome (PHTS) Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome and Proteus-like syndrome, etc.), leukemia and lymphoma (acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prelymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary exudative lymphoma, AIDS-associated lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal cancer, and gastrointestinal cancer; Optionally, the cancer is a cancer of the brain or spinal cord. The PARP1 inhibitor compound according to claim 89.

91. The PARP1 inhibitor compound according to claim 89 or 90, wherein the cancer is deficient in DNA damage repair pathways such as homologous recombination-dependent DNA double-strand break DNA repair activity.

92. The PARP1 inhibitor compound according to any one of claims 89 to 91, wherein the cancer is deficient in the function of BRCA1 and / or BRCA2.

93. A PARP1 inhibitor compound according to any one of claims 89 to 92, which is administered in combination with further agents for treating cancer, Optionally, the further agents for treating cancer are PARP1 inhibitor compounds selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors.

94. The further agent for treating cancer is an immunotherapy agent selected from the following PARP1 inhibitor compound according to claim 93: Antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T-cell therapy); small molecule immunomodulators; and tumor microenvironment modifiers.

95. A pharmaceutical composition comprising a PARP1 inhibitor compound according to any one of claims 1 to 88.

96. The pharmaceutical composition according to claim 95, further comprising a pharmaceutically acceptable additive and / or excipient, and / or the compound in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

97. Equipped with further drugs to treat cancer, Optionally, the further agents for treating cancer are selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors. The pharmaceutical composition according to claim 95 or 96.

98. The pharmaceutical composition according to claim 97, wherein the further agent for treating cancer comprises an immunotherapy agent selected from the following: Antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T-cell therapy); small molecule immunomodulators; and tumor microenvironment modifiers.

99. A pharmaceutical composition according to any one of claims 95 to 98, used for treating cancer.

100. It is a medical kit for treating cancer, a) A PARP1 inhibitor compound according to any one of claims 1 to 88, and b) Further drugs to treat cancer, Equipped with; The aforementioned compounds and further agents are suitable for administration simultaneously, sequentially, or separately; Optionally, the further agents for treating cancer include microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapies, immunotherapeutic agents (antitumor vaccines; oncolytic viruses; anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti- A pharmaceutical kit comprising: immunostimulatory antibodies such as CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T-cell therapy); small molecule immunomodulators, and tumor microenvironment modifiers, etc.); apoptosis inducers; radioligand therapy; angiogenesis inhibitors; and cell cycle signaling inhibitors.

101. A method for treating a disease and / or condition and / or disorder, comprising administering to a patient a PARP1 inhibitor compound, composition, or kit described in any of the preceding claims.

102. The method according to claim 101, wherein the patient is an animal, preferably a mammal, optionally a human, dog, horse, or cat, preferably a human.

103. below: 【Chemistry 70-1】 【Chemistry 70-2】 【Chemistry 70-3】 【Chemistry 70-4】 【Transformation 70-5】 【Transformation 70-6】 【Transformation 70-7】 【Transformation 70-8】 【Chemistry 70-9】 【Transformation 70-10】 【Chemistry 70-11】 【Chemistry 70-12】 【Chemistry 70-13】 【Chemistry 70-14】 【Chemistry 70-15】 【Chemistry 70-16】 【Chemistry 70-17】 【Chemistry 70-18】 【Chemistry 70-19】 【Transformation 70-20】 A compound selected from the following.

104. The aforementioned compound, - Isolated enantiomer, or - A mixture of two or more enantiomers, or - A mixture of two or more diastereomers and / or epimers, - Racemic mixture, or - Tautomers of the above compound The compound according to claim 103, comprising:

105. A method for synthesizing a PARP1 inhibitor compound according to any one of claims 1 to 88, (i) A first reactant comprising a ring E having a portion of an L group, (ii) A second reactant comprising the remainder of the L group A method comprising carrying out a reaction between two points, thereby forming the PARP1 inhibitor compound.

106. The first reactant comprises ring E and ring A, The second reactant comprises a Qb precursor having a reactive group, The method according to claim 105, comprising attaching ring A to the Qb precursor.

107. The method according to claim 106, wherein the reactive group of the Qb precursor comprises a carbonyl group, an alkyl halogen, or an alkyl sulfonate.

108. The method according to any one of claims 105 to 107, wherein the reaction comprises alkylation, reductive amination, or amidation to form an L group.

109. The first reactant comprises ring E, ring A, Qa, and ring B, The method according to claim 108, wherein the second reactant comprises a derivative of ring C having a leaving group, such as a halide or a sulfonic acid ester.

110. The method according to claim 106 or 107, wherein the reaction comprises a nucleophilic substitution reaction, for example, an aromatic nucleophilic substitution reaction, in order to form an L group.

111. A method for synthesizing a PARP1 inhibitor compound in which L is a group having the following structure, 【Chemistry 71】 The first reactant described above has the following structure: 【Chemistry 72】 (In the formula, R ９ is a protecting group, and optionally C １ ~C ６ It is an alkyl group, preferably a methyl group. The second reactant has the following structure: 【Transformation 73】 Performing the aforementioned reaction involves: (i) Using a reducing agent in the presence of an acid, the first reactant and the second reactant are coupled to obtain an intermediate product having the following structure: 【Chemistry 74】 (ii) The process then comprises deprotecting the ring E' to form the PARP1 inhibitor compound, The method according to any one of claims 105 to 110.

112. The method according to claim 111, wherein rings A, B', and B are all saturated rings.

113. X of rings B and B' １ The method according to claim 112, wherein is N.

114. The method according to any one of claims 111 to 113, further comprising separating structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

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