Pharmaceutical compounds

Abstract

We provide PARP1 inhibitors for use in pharmaceuticals, pharmaceutical compositions, and pharmaceutical kits for treating cancer. [Solution] PARP1 inhibitors such as 5-{4-[3-(5-ethyl-4-oxo-3H-pyrimidine-2-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide and 5-{4-[3-(5-ethyl-6-oxo-1H-pyridine-2-yl)piperidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide are provided.

Description

[Technical Field]

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

[0002] The poly(ADP-ribose) polymerase (PARP) family consists of 17 PARP proteins that catalyze the transfer of ADP-ribose to target proteins, a post-translational process called polyADP-ribosylation (PARylation). Modification of target proteins by polyADP-ribosylation causes significant functional changes, and 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). 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) in DNA (Non-Patent Literature 2). PARP1 is activated by DNA damage breaks, and subsequent polyADP-ribosylation of the target protein leads to the recruitment of additional factors that initiate DNA damage repair. The auto-poly-ADP ribosylation of PARP triggers the dissociation of bound PARP from DNA, allowing other DNA repair proteins to access and complete the repair of the damage. This highlights the crucial role PARP plays in enabling cancer cells to repair DNA damage caused by exogenous agents such as radiation therapy and chemotherapy. Therefore, 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) in DNA 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 alternative, error-prone repair pathways, leading to genomic instability and cancer cell death.

[0003] By inhibiting PARP, inactivated PARP can be trapped at DNA damage sites. When a replication fork reaches the site of the trapped PARP, it stops during the S phase, then disintegrates, resulting in genotoxic DNA double-strand breaks. This PARP1-DNA trapping is thought to potentially lead to the selective death of cancer cells with HRD (Non-Patent Literature 3).

[0004] 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 with platinum sensitivity as a surrogate for HRD.

[0005] In recent years, it has been shown that genomic instability, in the form of unrepaired DNA double-strand breaks or micronuclear collapse, can trigger activation of the innate immune system via cyclic GMP-AMP synthase (cGAS), a cytoplasmic DNA sensor, leading to the production of cyclic guanosine-phosphate-adenosine-phosphate (cGAMP) and the dimerization of interferon gene stimulator (STING). Subsequently, STING moves from the endoplasmic reticulum to the Golgi apparatus, where it recruits and activates tank-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory transcription factor 3 (IRF3), which induces the production of type I interferons and supports the induction of an adaptive immune response (Non-Patent Literature 6).

[0006] For example, activation of the STING pathway and antitumor immune response induced by PARP inhibitors have been demonstrated in multiple tumor models, providing a basis for using a combination of PARP inhibitors and immunotherapy to improve therapeutic efficacy (Non-Patent Literature 7). For instance, the PARP inhibitor olaparib has recently been shown to induce synthetic lethal effects in combination with synthetic cyclic dinucleotide STING agonists in DNA damage repair-deficient cancer cells and BRCA-deficient breast cancer models (Non-Patent Literature 8).

[0007] Overall, in various cell and animal models, the regulation of nucleic acid recognition pathways through multiple mechanisms has been shown to enhance antitumor effects, and the use of PARP inhibitors has shown potential for enhancing the effects of immunotherapy and overcoming resistance to immune checkpoint inhibitors. Numerous clinical trials combining PARP inhibitors with immunotherapy are underway (reviewed in Non-Patent Document 9).

[0008] In recent years, it has been shown that PARP1 binds to the Epstein-Barr virus (EBV) genome, and that PARP1 inhibitors alter EBV chromatin structure and latent gene expression (Non-Patent Literature 10). Therefore, PARP1 inhibitors may play a role in EBV-related cancers such as Burkitt lymphoma, nasopharyngeal cancer, and gastrointestinal cancers. Interestingly, EBV has also been shown to be a causative factor in multiple sclerosis (MS), thereby significantly increasing the risk of subsequent MS after EBV infection (Non-Patent Literature 11).

[0009] First-generation PARP inhibitors generally exhibit non-selective activity against PARP1 and PARP2. Clinical use of these molecules is associated with hematological toxicities such as anemia, neutropenia, and thrombocytopenia, and dose-limiting cytopenia restricts their use in combination with cytotoxic chemotherapy and other targeted agents (Non-Patent Literature 12). Evidence from preclinical mouse studies strongly suggests that PARP2 inhibition is a major factor in these hematological toxicities and that PARP2 is particularly involved in mouse erythrocyte production (Non-Patent Literature 13). Furthermore, PARP2 function has been shown to be non-essential for antitumor activity in HRD mouse cancer models (Non-Patent Literature 14). In summary, these data suggest an unmet medical need for the development of inhibitors that offer improved selectivity for PARP1 compared to PARP2 and other PARPs, and therefore provide expanded therapeutic utility (1) as monotherapy and (2) in combination with other anticancer agents.

[0010] 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]

[0011] [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.

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

[0012] Taking the above into consideration, one object of the present invention is to provide a PARP1 inhibitor, in particular a PARP1 inhibitor for use in pharmaceuticals. Another object is to provide a pharmaceutical composition comprising such an inhibitor, and to provide compounds and pharmaceutical compositions for treating cancer. Another object is to provide a method for synthesizing the compounds. [Means for solving the problem]

[0013] Therefore, the present invention provides a PARP1 inhibitor compound for use in pharmaceuticals, comprising the following structure:

[0014] [ka] (In the formula, R 1 This is selected from H and substituted or unsubstituted organic groups; R 2 It may or may not be present, and is independently selected from H and substituted or unsubstituted organic groups; R 1 and R 2 They may come together to form a ring; R 3 This is independently selected from H and substituted or unsubstituted organic groups; R 6 It may or may not be present, and is independently selected from H and substituted or unsubstituted organic groups; Z 1 and Z 2 is selected independently of C and N; and, L comprises a group having the following structure: [ka] (wherein n is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; m is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; m + n is a number selected from 2, 3, 4, 5 and 6; Preferably, both n and m are at least 1; r is a number independently selected from 0, 1, 2, 3, 4 and 5; s is a number independently selected from 0, 1, 2, 3, 4 and 5; r + s is a number selected from 1, 2, 3, 4 and 5; Preferably, both r and s are at least 1; each X 1 may be the same or different and is independently selected from C, N, O and S; each X 3 may be the same or different and is independently selected from C, N, O and S; Preferably, at least one X 3 is independently N; each X 6 may be the same or different and is independently selected from C and N; each R 41 may be the same or different, may or may not be present, and is selected from H and a substituted or unsubstituted organic group; each R 43 may be the same or different, may or may not be present, and is selected from H and a substituted or unsubstituted organic group; R 44 may or may not be present and is selected from H and a substituted or unsubstituted organic group; The dotted line indicates that ring A may have a single bond or a combination of both a single bond and a double bond, and may be aliphatic or aromatic; and, independently, ring C may have a single bond or a combination of both a single bond and a double bond, and may be aliphatic or aromatic; R 5is selected from H and substituted or unsubstituted organic groups; preferably, it is a substituted or unsubstituted organic group; Each Q 1 These may be identical or different, may be present or absent, and comprise a base that is independently selected from the following structures: [ka] (In the formula, t is a number independently selected from 0, 1, 2, 3, 4, and 5; u is a number independently selected from 0, 1, 2, 3, 4, and 5; t+u is a number selected from 0, 1, 2, 3, 4, 5, and 6 (preferably a number selected from 0, 1, 2, and 3); Each R 45 These may be the same or different, and are independently selected from H and substituted or unsubstituted organic groups; R 46 (These are selected from H and substituted or unsubstituted organic groups); Q 2 It may or may not be present, and is a group having the following structure: [ka] (In the formula, p is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; q is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; p+q is a number selected from 2, 3, 4, 5, and 6; each X 2 They may be the same or different, and are selected independently from C, N, O, and S; X 5 It is selected independently of C and N; Each R 42 These may be the same or different, may be present or absent, and are selected from H and substituted or unsubstituted organic groups; The dotted line indicates that ring B may have single bonds or a combination of single and double bonds, and may be aliphatic or aromatic. Q 3 It may or may not exist, and comprises a base that is independently selected from the following structures: [ka] (In the formula, v is a number independently selected from 0, 1, 2, 3, 4, and 5; w is a number independently selected from 0, 1, 2, 3, 4, and 5; v+w is a number selected from 0, 1, 2, 3, 4, 5, and 6 (preferably a number selected from 0, 1, and 2).

[0015] In the context of the present invention, Z 1 , Z 2 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Atoms maintain their normal valence, and the number of substituents bonded to them depends on their properties and the number of other bonds they have. Maintaining valence means, in organic compounds, that atoms have their normal (typically most common) valence (i.e., 2 for oxygen and divalent sulfur, 3 for nitrogen, and 4 for carbon). A nitrogen atom may, in some cases, have four bonds, in which case the nitrogen atom is typically positively charged so that the compound may have a counterion. Such compounds are also considered part of the present invention, and in such cases, it will be clear that, due to the positive charge, the nitrogen atom still maintains its normal valence of 3. To avoid doubt, if the number of R groups can vary depending on the selection of X groups, it can vary as follows:

[0016] Z 1 If N, R 6 It does not exist. Z 2 If N, R 2 It does not exist. Each R41 They may be the same or different, but each X 1 The following condition is met: X 1 If is O or divalent S, then R 41 It does not exist; X 1 If N is double-bonded to an adjacent atom, then R 41 It does not exist; X 1 If it is N and not double-bonded to an adjacent atom, then R 41 There is one; X 1 If C is double-bonded to an adjacent atom, then R 41 There is one; X 1 If C is not double-bonded to an adjacent atom, then R 41 There are two of them. Each R 43 They may be the same or different, but each X 3 The following condition is met: X 3 If is O or divalent S, then R 43 It does not exist; X 3 If N is double-bonded to an adjacent atom, then R 43 It does not exist; X 3 If it is N and is not double-bonded to an adjacent atom, then R 43 There is one; X 3 If C is double-bonded to an adjacent atom, then R 43 There is one; X 3 If C is not double-bonded to an adjacent atom, then R 43 There are two of them. Each X 6 Regarding: X 6 If it is N or C and is double-bonded to an adjacent atom, then R 43 It does not exist; X 6 If C is not double-bonded to an adjacent atom, then R 43 There is one such thing. It is connected to X. 3 Regarding: X 3 If is O or divalent S, R 44 It does not exist; X 3 If is O or divalent S, then R 44 It does not exist; X 3is N and is double-bonded to an adjacent atom, R 44 does not exist; X 3 is N and is not double-bonded to an adjacent atom, R 44 exists once; X 3 is C and is double-bonded to an adjacent atom, R 44 exists once; X 3 is C and this C is bonded to R 43 and is not double-bonded to an adjacent atom, R 44 exists once. Each R 42 may be the same or different, provided that for each X 2 the following conditions are satisfied: X 2 is O or divalent S, R 42 does not exist; X 2 is N and is double-bonded to an adjacent atom, R 42 does not exist; X 2 is N and is not double-bonded to an adjacent atom, R 42 exists once; X 2 is C and is double-bonded to an adjacent atom, R 42 exists once; X 2 is C and is not double-bonded to an adjacent atom, R 42 exists twice. X 5 For X 5 is N or is C and is double-bonded to an adjacent atom, R 42 does not exist; X 5 is C and is not double-bonded to an adjacent atom, R 42 exists once. Each R 11 may be the same or different, provided that for each X 4 the following conditions are satisfied: X 4 is O or divalent S, R 11 does not exist; X 4 is N and is double-bonded to an adjacent atom, R 11 does not exist; X 4 is N and is not double-bonded to an adjacent atom, R 11 exists once; X4 If C is double-bonded to an adjacent atom, then R 11 There is one; X 4 If C is not double-bonded to an adjacent atom, then R 11 There are two of them. Each R is connected to N. 14 They may be the same or different, but if N is double-bonded to an adjacent atom, then R 14 It does not exist.

[0017] In these compounds, and elsewhere in this disclosure, in some embodiments, any R group may form a ring with any other R group on an adjacent and / or proximal atom, but in most embodiments, this is undesirable unless explicitly stated. Thus, in some embodiments, the following substituents may together form a ring: R 5 is R 44 and;R 11 is another R 11 and;R 13 is another R 13 and;R 41 is another R 41 and;R 42 is another R 42 and;R 43 is another R 43 and;R 45 is another R 45 In the context of the present invention, adjacent and / or proximal atoms mean another atom directly bonded to an atom (adjacent), two atoms with only one atom between them (proximal), or two atoms that are sterically close enough to form a ring (proximal). It is preferable that R groups bonded to the same atom do not form a ring together, but this embodiment is not excluded.

[0018] In this context, the present invention includes compounds in which one R group on an atom, or two R groups on the same atom, form a group double-bonded to that atom. Thus, one R group, or two R groups bonded to the same atom, may together form a =O group or a =C(R')² group (where each R' group is identical or different and is H or an organic group, preferably H or a linear or branched C1-C6 alkyl group). This is more typical when multiple R groups are bonded to a single C atom so as to form a C=O group or a C=C(R')² group. Thus, in some cases, the C ring atom in the ring is X, and / or R 11 , R 41 , R 42 , R 43 , R 44 , and R 45 Like one or more of the above, it may also have an O group.

[0019] In this context, the structural part within the parentheses (whether regular parentheses or square brackets) may be repeated the number of times indicated by the number next to the parentheses. For example, (C(R)) 0,1,2 or [C(R)] 0,1,2 In this case, the CR group may not be present, may be present once (i.e., -C(R)-), or may be present twice (i.e., -C(R)-C(R)-).

[0020] In the context of the present invention, 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, in an appropriate assay, IC 50 If the concentration is <10 μM, the compound is considered to be a PARP1 inhibitor. A suitable assay involves adding 2 nM PARP1 and 2 μM biotin-NAD to an assay buffer consisting of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v).+ The assay may be carried out using an assay solution containing [the compound]. Poly-ADP ribosylation (PARylation) may be performed at room temperature for 2 hours, and may also be detected using a readout from a dissociation-enhanced lantanide fluorescence immunoassay (DELFIA). Particularly suitable assays are described in the following examples. The compound is used in the PARP1 inhibitor assay, IC 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.

[0021] A compound is considered a selective PARP1 inhibitor if its presence can replace or reduce the ability of a high-affinity Cy5 fluorescent dye-labeled chemical probe to bind to PARP1, while simultaneously replacing the ability of the same chemical probe to bind to PARP2 by at least a tenfold decrease in activity. Typically, the compound exhibits an IC50% resistance to PARP1 in this assay. 50 A compound is considered a selective PARP1 inhibitor if it exhibits a concentration of <10 μM and at least 10-fold selectivity compared to PARP2. A suitable assay for this purpose may be performed at room temperature for 1 hour using 10 nM PARP1 or PARP2, a 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.

[0022] The compound also showed IC12 for PARP1 in the NanoBRET assay, which demonstrates engagement with cellular targets. 50A selective PARP1 inhibitor is considered to have a concentration of <10 μM and at least 10 times higher selectivity than for PARP2. These assays involve nano-luc labeled proteins (e.g., PARP1 or PARP2) and high-affinity NAD. + The assay is based on bioluminescence resonance energy transfer (BRET) between the fluorescent group on the 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. The selectivity for PARP1 over PARP2 is preferably at least 50-fold, and more preferably at least 100-fold.

[0023] In all embodiments of the present invention (both the embodiments described above and those described below), the substituents (each of the R groups) are not particularly limited as long as they do not hinder the expression of the PARP1 inhibitory function. In all embodiments referred to in connection with the present invention, both the embodiments described above and those described below, the substituents are selected from H and organic groups. Therefore, in both the above and below descriptions, the terms “substituent” and “organic group” are not particularly limited and may be any functional group or any atom, in particular any functional group or atom common in organic chemistry. Therefore, “substituent” and “organic group” may have any of the following meanings.

[0024] 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).

[0025] 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.

[0026] 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 straight-chain or branched-chain group, it may have one or more primary, secondary, and / or tertiary alkyl groups.

[0027] 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, tetrazol, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, ox Zole, isoxazole, 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-azathio Pyran, Chian, Indole, Indazole, Benzimidazole, 4-Azaindole, 5-Azaindole, 6-Azaindole, 7-Azaindole, Isoindole, 4-Azaisoindole, 5-Azaisoindole, 6-Azaisoindole, 7-Azaisoindole, Indoridine, 1-Azaindridin, 2-Azaindridin, 3-Azaindridin, 5-Azaindridin, 6-Azaindridin, 7-Azaindridin, 8-Azaindridin, 9-Azaindridin, Purine, Carbazole The compounds may include carboline, 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 to any point on the group, or to a heteroatom or a carbon atom.In some examples, specific binding sites are preferred, such as 1-yl, 2-yl, etc., and these are explicitly specified where appropriate. All tautomer ring forms are included in these definitions. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole, and 3H-pyrrole.

[0028] 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.

[0029] 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.

[0030] Furthermore, any substituent may comprise two or more combinations of substituents and / or functional groups as defined above.

[0031] Rings A, B (if present), and C of the compounds of the present invention may form bicyclic or tricyclic ring structures (which may include further fused rings if substituents on any of the rings form rings themselves). Each of rings A, B, C, and D is not particularly limited, as long as they do not interfere with the expression of PARP1 inhibitory function. Rings A, B, C, and D may independently consist of aromatic rings, non-aromatic rings, aliphatic rings, and / or heterocycles. These rings may be fully saturated, partially saturated, or completely unsaturated.Therefore, each ring independently comprises 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, tetrazol, pyrrolidine, oxetane, furan, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, Oxazole, isoxazole, 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 Thiopyran, thian, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaiisoindole, 5-azaiisoindole, 6-azaiisoindole, 7-azaiisoindole, indoridine, 1-azaindoridine, 2-azaindoridine, 3-azaindoridine, 5-azaindoridine, 6-azaindoridine, 7-azaindoridine, 8-azaindoridine, 9-azaindoridine, purine, carbazo The compounds may include ru, carboline, 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 rings may generally be substituted at any point of the group, and may be substituted on heteroatoms or carbon atoms.All tautomer rings are included in these definitions. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole, and 3H-pyrrole.

[0032] In a typical embodiment, the present invention is Q 3 The following compounds are provided, in which the group is either absent or independently selected from the following structures: [ka] (In the formula, Each R 45 They may be the same or different, and are independently selected from H and substituted or unsubstituted organic groups; R 46 (Selected from H and substituted or unsubstituted organic groups). Q 3 It is preferable that it is either absent or a group such as a -CH2- group, as shown below: [ka]

[0033] In a typical embodiment, the present invention is Q 2 There exists, and each Q 1 However, the following compounds are provided, which either do not exist independently or are groups independently selected from the following structures: [ka] (In the formula, Each R 45 They may be the same or different, and are independently selected from H and substituted or unsubstituted organic groups; R 46 (These are selected from H and substituted or unsubstituted organic groups). In particular, Q 2 If Q exists, 1 It is preferable that it is either absent or a group such as a -CH2- group, as shown below: [ka]

[0034] Q attached to ring A 1 The group is preferably a group shown below, such as a -CH2- group: [Chemical formula]

[0035] In some embodiments, the present invention provides a compound as defined above, wherein the L group comprises a group having the following structure: [Chemical formula] (wherein, Q 1 is absent or is a group as defined above; Q 3 is absent or is a group as defined above; n, m, p, q, r, s, X 1 X 2 X 3 X 5 X 6 R 41 R 42 R 43 R 44 R 5 and rings A, B and C are as defined above. X 5 is preferably N without the substituent R 42 ).

[0036] In some embodiments, the L group comprises a group having the following structure: [Chemical formula] (wherein, n, m, p, q, r, s, X 1 X 2 X 3 X 5 R 41 R 42 R 43 R 44 R 5 Q1 Q 3 Furthermore, rings A, B, and C are as defined above. 5 is a substituent R 42 It is preferable that N is free of [unclear].

[0037] In some embodiments, the L group comprises a group having the following structure: [ka] (In the formula, n, m, p, q, r, s, X 1 , X 3 , X 5 , R 41 , R 42 , R 43 , R 44 , R 5 Q 1 Q 3 Furthermore, rings A, B, and C are as defined above. 5 is a substituent R 42 It is preferable that N is free of [unclear].

[0038] In some embodiments, the L group comprises a group having the following structure: [ka] (In the formula, n, m, p, q, r, s, X 3 , X 5 , R 41 , R 42 , R 43 , R 44 , R 5 Furthermore, rings A, B, and C are as defined above. 5 is a substituent R 42 It is preferable that N is free of [unclear].

[0039] In some embodiments, the L group comprises a group having the following structure: [ka] (In the formula, n, m, p, q, r, s, X 3 , X 5 , R 41 , R 42 , R 43 , R 44 , R 5 Furthermore, ring C is as defined above. X 5 is a substituent R 42 It is preferable that N is free of [unclear].

[0040] In some embodiments, the L group comprises a group having the following structure: [ka] (In the formula, n, m, p, q, r, s, X 1 , X 2 , X 3 , X 5 , X 6 , R 41 , R 42 , R 43 , R 44 , R 5 Furthermore, ring C is as defined above. X 5 is a substituent R 42 It is preferable that N is free of [unclear].

[0041] In some embodiments, the L group comprises a group selected from the following structures: [ka] [ka] (In the formula, n, m, p, q, X 3 , R 41 , R 42 , R 43 , R 44 , and R 5 This is as defined above.

[0042] In these structures for the L group, m is preferably selected from 1 or 2, n is preferably selected from 2 or 3, p is preferably selected from 1, 2 or 3 (more preferably 2 or 3), and q is preferably selected from 1 or 2.

[0043] In some embodiments, the L group comprises a group having any of the following structures:

Chemical formula

Chemical formula

[0044] Typically, R 41 , R 42 , R 43 , R 44 , and R 45 are each independently selected from a group selected from H and the following groups: - deuterium; - halogen (-F, -Cl, -Br, and -I, etc.); - nitrile group; - substituted or unsubstituted linear or branched C1 - C6 alkyl group (such as 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 group (-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, -CF3, -CCl3, -CBr3, -CI3, -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, or substituted or unsubstituted linear or branched C1-C6 alcohol group (-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-);-Saturated or unsaturated, substituted or unsubstituted heterocyclic groups including aromatic heterocyclic groups and / 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-A Zapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, fran-2-yl, fran-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-a Zapiran-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-te Trahydropyran-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, 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, if there are two R groups bonded to the same atom, they may together form a group that double bonds to the atom (for example, a carbonyl group (=O) or an alkene group (=C(R')2) (where each R' group is either the same or different and is H or an organic group, preferably H or a linear or branched C1-C6 alkyl group)).

[0045] In some configurations, a pair of R atoms bonded to different atoms 41 The groups may come together to form a ring with the atoms of ring A, and / or a pair of R groups bonded to different atoms. 42 The groups may come together to form a ring with the atoms of ring B, and here, optionally, the pair of R 41 base and / or the pair of R 42 Each of the bases is independent, (X 7 ) 1又は2 It is equipped with, here, each X 7 X may be the same or different, and is selected independently from C, N, O and S; where each X 7 (i)X 7 If C, then it is independently substituted with H, or an organic group selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, halogens such as fluorine, or hydroxyl groups; (ii) X 7 If N is present, it is independently substituted with H, or an organic group selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, or C1-C6 amide groups.

[0046] In some configurations, R 5 and R 44 The elements come together, and they are bonded to the ring C's X 6 and X 3 They may form a ring with the atoms, and optionally, here, the R 5 and R 44 The base is, together, (X 8 ) 3、4又は5 Equipped with, here, each X 8X may be the same or different, and is selected independently from C, N, O and S; where each X 8 (i)X 8 If C, then it is independently substituted with H, or an organic group selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, halogens such as fluorine, or hydroxyl groups; (ii) X 8 If N is present, it is independently substituted with H, or an organic group selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, or C1-C6 amide groups.

[0047] R 41 , R 42 , R 43 and R 44 Each of these is preferably independently selected from H, deuterium, halogen (e.g., -F, -Cl, -Br, and -I, preferably F or Cl), nitrile group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (preferably CF3 or CHF2), cyclopropyl group, -OH group or substituted or unsubstituted linear or branched C1-C6 alcohol group, substituted or unsubstituted linear or branched C1-C7 aminocarbonyl group (e.g., -NH-CO-Me), -NH2 group or substituted or unsubstituted C1-C6 amino group, and substituted or unsubstituted C1-C6 alkoxy group; where a pair of R bonded to different atoms 41 When the groups come together to form a ring with the atoms of ring A, and / or when a pair of R groups bonded to different atoms 42 When the groups come together to form a ring with the atoms of ring B, the pair of R 41 Base, and / or the pair of R 42 Each group independently comprises -CH2- or -CH2CH2-; and, R 5 and R 44 When the groups come together to form a ring with the atoms of the ring C, R 5 and R 44 Together, they comprise -CH=CH-CH=CH- or -NH-CO-NH-.

[0048] R 45 It is preferable that the group 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.

[0049] Typically, R 46 The group is selected from H and the following groups: - Substituted or unsubstituted linear or branched C1-C6 alkyl groups (such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and hexyl); - 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, -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)-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-, etc.); and,- Substituted or unsubstituted saturated or unsaturated heterocyclic groups, including aromatic heterocyclic groups and / or non-aromatic 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, py Ridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-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, oxetane-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-4- Il, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-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, Morpholin-2-yl, Morpholin-3-yl, Thiofen-2-yl, Thiofen-3-yl, Isothiazole-3-yl, Isothiazole-4-yl, Isothiazole-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 (e.g., -yl, 4-azathiopyran-2-yl, 4-azathiopyran-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).

[0050] R 46 It is preferable that the element is selected from H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group.

[0051] The ring A of the L group preferably comprises one of the following structures: [ka] (In the formula, R 41 (This is defined as described herein.)

[0052] More preferably, the ring A of the L group has the following structure: [ka]

[0053] More preferably, the ring A of the L group comprises one of the following structures: [ka]

[0054] Particularly preferably, the ring A of the L group has the following structure: [ka]

[0055] In one configuration, the Q of the L group 2 It exists and also has one of the following structures: [ka] (In the formula, R 42 (This is defined as described herein.)

[0056] More preferably, the Q of the L group 2 It has one of the following structures: [ka]

[0057] Alternatively, the Q of the L group 2 The base does not exist, Q 1 There is only one base. In this configuration, the aforementioned Q 1 The group typically has rings A and C separated by three or four atoms in the linear direction, and may have one of the following structures: [ka] (In the formula, R 45 and R 46 (This is defined as described herein.)

[0058] In this configuration, the aforementioned Q 1 The base preferably comprises one of the following structures: [ka]

[0059] Preferably, the L-group ring C has one of the following structures: [ka] [ka] (In the formula, R 5 , R 43 , R 44 , and R 46 (This is defined as described herein.)

[0060] More preferably, the L-group ring C comprises one of the following structures: [ka] (In the formula, R 5 , and R 43 (This is defined as described herein.)

[0061] In some configurations, R 5 These are substituted or unsubstituted organic groups.

[0062] Preferably, R 5 It is not MeO, but more preferably H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 , -NR 51 COR 52 -SO2NR 51 R 51 , -NR 51 SO2R 53 , -O-CR 52 R 52 R 52 ,-CR 52 R 52NR 51 R 51 , and selected from one of the following structures: [ka] (In the formula, R 51 , R 52 , and R 53 Each of these may be the same or different, and can be independently selected from H and substituted or unsubstituted organic groups. More preferably, R 5 -CONR 51 R 51 (That is the case.)

[0063] More preferably, R 5 -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 one of the following: [ka]

[0064] Particularly preferred R 5 The group is -CONHMe, and in particular the ring C of the L group, [ka] , more: [ka] If R is provided, 5 The base is preferably -CONHMe.

[0065] In some embodiments, the L group of the compound according to the present invention comprises a group having any of the following structures: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0066] In some embodiments, compounds having any of the following structures are provided: [ka] (In the formula, The dotted line indicates that ring D may have single bonds or a combination of single and double bonds, and may be aliphatic or aromatic; each X 4 They may be the same or different, and are selected independently from C, N, O, and S; Each R 11 These may be the same or different, and are independently selected from H and substituted or unsubstituted organic groups; Z 1 , R 3 , R 6 and L are as defined in this disclosure. In some embodiments, one X of ring D 4 is N. At least one X 4It is preferable that it is C.

[0067] Preferably, the compound comprises one of the following structures: [ka] (In the formula, rings D, X 4 , R 11 , R 3 , R 6 , and L is as defined in this disclosure.

[0068] More preferably, the compound comprises one of the following structures: [ka] [ka] [ka] [ka] (In the formula, R 14 R is selected from H, C1-C3 alkyl groups, or C1-C3 fluoroalkyl groups; R 11 , ring D, R 3 , R 6 , and L are as defined in this disclosure.

[0069] More preferably, the compound comprises one of the following structures: [ka] [ka] [ka] [ka] [ka] (In the formula, R 3 , R 11 , R 14 , R 6 , and L are as defined in this disclosure.

[0070] Each R 11 This includes H, halogen, nitrile group, linear or branched C1-C3 alkyl group, linear or branched C1-C3 halogenated alkyl group (preferably fluoroalkyl group), -OH group, linear or branched C1-C3 alcohol group, halogenated (preferably fluorinated) linear or branched C1-C3 alcohol group, -NH2, linear or branched primary, secondary or tertiary C1-C3 amine group, halogenated (preferably fluorinated) linear or branched primary, secondary or tertiary C1-C3 amine group, linear or branched C1-C3 alkoxy group, linear or branched C1-C3 halogenated alkoxy group (preferably fluoroalkoxy group), and / or a pair of R groups bonded to the same atom that form =O. 11 The groups may be independently selected; or a pair of R groups bonded independently and / or to different atoms. 11 When the groups come together to form a ring with the atoms of ring D, the pair of R 11 The base is comprised of -CH2CH2CH2-.

[0071] Each R 11 This refers to a pair of R atoms bonded to the same atom that form H, Cl, F, CHF2, CF3, CH3, OH, CH3O, and NH2 and / or =O. 11 Preferably, the group is independently selected; a pair of R atoms bonded to different atoms independently. 11 When the groups come together to form a ring with the atoms of ring D, the pair of R 11 The group preferably comprises -CH2CH2CH2-.

[0072] In some embodiments, compounds having any of the following structures are provided: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (wherein L is as defined herein.)

[0073] In some embodiments, compounds having any of the following structures are provided: [ka] (In the formula, Each R 12 H, and a substituted or unsubstituted organic group, preferably a lower (C1-C6) alkyl group, alkoxy group or haloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group or heterocyclic group, and a halogen group, are independently selected from these; Here, at least one R 12 It is not H; Each R 13 These may be the same or different, and are independently selected from H and substituted or unsubstituted organic groups; R 3 , R 6 And L are as defined in this disclosure.

[0074] at least one R 12 It is preferable that the group be selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, -Cl, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, or cyclopropylmethyl group.

[0075] R 13 Preferably, it is selected from H, F, C1-C3 alkyl groups, or C1-C3 fluoroalkyl groups.

[0076] R 3 It is preferably H.

[0077] R 6 Preferably, the group is selected from H, a halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alcohol group, or a C1-C3 aminoalkyl group.

[0078] In some embodiments, compounds having any of the following structures are provided: [ka] [ka] (wherein L is as defined herein.)

[0079] In some embodiments, the present invention provides PARP1 inhibitor compounds having a chemical formula selected from the following: [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0080] The structures of the compounds of the present invention have been described in detail above. To avoid any doubt, any compound used in the present invention may comprise the following compounds or compositions, depending on their structure: Each structure -Isolated enantiomer, or - A mixture of 2 or more enantiomers, or - A mixture of 2 or more diastereomers and / or epimers, - Racemic mixture, or Tautomers of -1 or more.

[0081] Of the compounds numbered above, compounds 1, 2, 5, 8, 12, 15, 17-22, 25, 27-30, 36, 40, 41, 45, 47, 48, 54, 59, 63, 75, 168, 173, 179, 192, 193, 227, 228, 238, 259, 260, 284, 295, 299, 300, 302-305, 310-312, 330, 361, 368, 369, 373, 375, 376, 379-381, 383, 384, 387-389, 394, and 411 are achiral. The remaining compounds, as a racemic mixture and / or separated enantiomers, represent one or more enantiomer structures that may have PARP1 inhibitory activity. In the following examples, a compound with the suffix "a" (e.g., "10a") represents the enantiomer that elutes as the first fraction when a racemic mixture of two enantiomers is applied to a Daicel CHIRALPAL chiral chromatography column. In the following examples, a compound with the suffix "b" (e.g., "10a") represents the enantiomer that elutes as the second fraction when a racemic mixture of two enantiomers is applied to a Daicel CHIRALPAL chiral chromatography column. In the following examples, a compound without a suffix represents an achiral compound or a racemic mixture of enantiomers. In the following examples, a compound with the suffix "rac" represents a racemic mixture of enantiomers.

[0082] The compounds described herein may be provided for pharmaceutical use. In the context of the present invention, pharmaceutical uses are not particularly limited, insofar 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. Typically, this includes disease conditions and / or disorders selected from cancer, insofar as the cancer can be treated, prevented or improved with PARP1 inhibitors. Therefore, cancer is a solid or humoral tumor, including 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, PTEN hamartoma syndrome ( It may be a cancer selected from among PHTS (Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), 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, Hodgkin lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, and cutaneous T-cell lymphoma). In addition, the compounds described herein may be used for cancers associated with EBV, such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer.

[0083] The compounds described herein may be used to treat cancers lacking DNA damage response repair pathways, particularly cancers lacking homologous recombination-dependent DNA double break (DSB) repair activity. Components of homologous recombination-dependent DNA double break (DSB) repair pathways 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.

[0084] In some embodiments, cancer cells may have a phenotype lacking BRCA1 and / or BRCA2; that is, cancer cells may lack BRCA1 and / or BRCA2 expression due to mutations, polymorphisms, or epigenetic silencing of the nucleic acids encoding BRCA1 and / or BRCA2, or due to 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 BRCA1 and / or BRCA2 genes 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).

[0085] In some embodiments, as defined above, the compounds described in this disclosure are selective PARP1 inhibitors. Selective inhibition of PARP1 against PARP2 reduces PARP2-related side effects, including one or more hematological toxicities such as anemia, neutropenia, and thrombocytopenia. This enables the treatment of cancer patients with reduced hematological side effects. It also enables the administration of PARP1 inhibitors to patients at higher doses or in combination with chemotherapeutic agents.

[0086] The present invention also provides pharmaceutical compositions comprising the compounds defined above. The pharmaceutical compositions are not particularly limited, but typically further comprise pharmaceutically acceptable additives and / or excipients. In the pharmaceutical compositions, the compounds defined above may be present in the forms described above, or alternatively, in forms suitable for improving bioavailability, solubility and / or activity, and / or in forms suitable for improving formulation. Thus, the compounds may be in the form of pharmaceutically acceptable salts, hydrates, acids, esters, or other suitable alternative forms. Typically, the compositions are for treating the diseases, conditions, or disorders defined above. In some embodiments, the compounds may be present in the composition as pharmaceutically acceptable salts or other alternative forms of the compound to improve the pharmaceutical formulation.

[0087] In some embodiments, the pharmaceutical composition is a composition for treating cancer and further comprises a further agent for treating cancer. The further agent for treating cancer is not particularly limited as long as it provides some utility for cancer treatment. However, typically, the further agent for treating cancer is selected from ionizing radiation, as well as chemotherapeutic agents such as microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, 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 and cell cycle signaling inhibitors. Immunotherapy agents may consist of, but are not limited to, 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, tumor microenvironment modifiers, and anti-angiogenic agents.

[0088] In yet another embodiment, the present invention provides a pharmaceutical kit for treating cancer. This pharmaceutical kit includes: (a) Compounds as defined above; and, (b) Further agents for treating cancer Preferably, further agents for treating cancer include ionizing radiation and chemotherapeutic agents such as microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senescent cell deconjugates, hormones and hormone analogs, hormone depletion therapies, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, apoptosis inducers and cell cycle signaling inhibitors, wherein the compounds and further agents are suitable for simultaneous, sequential, or separate administration.

[0089] The present invention further provides a method for treating a disease and / or condition and / or disorder. The method comprises administering the compound, composition, or kit defined above to a patient (or subject). The method is typically a method for treating any disease condition or disorder described in this disclosure. In a typical embodiment, the method is a method for treating cancer. Preferably, the method comprises administering the compound or composition defined above and further agents for treating the cancer defined above to a patient (or subject). The compound or composition and further agents may be administered simultaneously, sequentially, or separately, depending on the agents involved, the patient, and the type of cancer to which the indication is.

[0090] Typically, in all embodiments of the present invention, both above and below, the patient (or subject) is an animal, typically a mammal including dogs, horses, and cats, and more typically a human.

[0091] The present invention further provides a method for synthesizing the compounds defined above, the method comprising a reaction between (i) a first reactant comprising a ring E having a portion of substituent L and (ii) a second reactant comprising the remainder of substituent L, in order to form a PARP1 inhibitor compound.

[0092] Typically, in one synthesis method, the first reactant comprises rings E and A, and the second reactant comprises a precursor of Q1 or Q2 having a reactive group, the method comprising bonding the N atom of ring A to the precursor of Q1 or Q2. In the method, the reactive group of the precursor of Q1 or Q2 may comprise a carbonyl group, an alkyl halide, or an alkyl sulfonate. Typically, the reaction may involve alkylation, reductive amination, or amide formation to form the L group.

[0093] Typically, in one other synthesis method, the first reactant comprises ring E, ring A, and at least one of Q1 and Q2, and the second reactant comprises a derivative of ring C having a leaving group, such as a halide or sulfonate. In this method, the reaction comprises a nucleophilic substitution reaction, such as an aromatic nucleophilic substitution reaction, to form the L group.

[0094] Those skilled in the art may select reaction conditions in these methods by reference to known synthesis techniques, depending on the appropriate starting materials. In some embodiments, the methods include one or more further steps. Exemplary synthesis methods are shown in the examples of this disclosure.

[0095] Typically, the formulas described above (and all formulas in this disclosure) are shown in the form of nonstereoisomers. To avoid doubt, throughout this disclosure, a single formula is intended to represent all possible stereoisomers of a particular structure, including all possible isolated enantiomers corresponding to that formula, all possible mixtures of enantiomers corresponding to that formula, all possible diastereomers corresponding to that formula, all possible epimers corresponding to that formula, and all possible racemic mixtures corresponding to that formula. Furthermore, the formulas described above (and all formulas in this disclosure) are intended to represent all tautomers equivalent to the corresponding formula.

[0096] As used herein and in the claims, the term “equipped with” means “including or consisting of.” The term indicates that an entity includes at least the feature following it, but does not exclude other features not expressly mentioned. The term may also indicate an entity consisting solely of the feature following it.

[0097] Detailed description of the invention The present invention will be described in more detail below with reference to the following specific embodiments, for illustrative purposes only.

[0098] example Exemplary Synthesis of the Compounds of the Present Invention The compounds of the present invention can be synthesized using readily available starting materials and known reactions. Examples of the synthesis of three compounds are shown below.

[0099] Example 1: Synthesis of Compound 42

[0100] Synthesis of INT-4 [ka]

[0101] Preparation of 2,4-dichloro-5-ethylpyrimidine (2) 5-ethyl-1,3-dihydropyrimidine-2,4-dione (1) (10.00 g, 0.07 mol) was dissolved in POCl3 (55.00 g, 0.36 mol) and DIEA (23.00 g, 0.18 mol) was added at 0°C. The mixture was then stirred at 120°C for 2 hours. The hot reaction mixture was poured into ice water, and the aqueous layer was extracted with ethyl acetate (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 PE / EA = 100:0 to 92:9) to obtain 2,4-dichloro-5-ethylpyrimidine (2) (4.80 g, yield 38%) as a white solid. LCMS(ESI)C6H6Cl2N2[M+H] + m / z Calculated value: 176.99, Measured value: 177.00.

[0102] Preparation of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (INT-4) [ka] To a solution of (4-methoxyphenyl)methanol (3) (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. Next, 2,4-dichloro-5-ethylpyrimidine (2) (4.80 g, 27.27 mmol) was added to this mixture at 0°C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting DCM / MeOH = 100:0 to 93:7) to obtain 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (INT-4) (4.00 g, yield 53%) as a white solid. LCMS(ESI)C14H15ClN2O2[M+H] + m / z Calculated value: 279.08, Measured value: 279.15.

[0103] Synthesis of compound 42 [ka]

[0104] Preparation of tert-butyl 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) To a 1,4-dioxane / H2O=4:1 (15 mL) solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (1) (500 mg, 1.69 mmol), 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (INT-4) (377.72 mg, 1.76 mmol) and Na2CO3 (189.11 mg, 3.01 mmol) were added, followed by the addition of Pd(dppf)Cl2 (247.89 mg, 0.34 mmol) at room temperature. The reaction mixture was refluxed at 100°C under a nitrogen atmosphere and stirred for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting petroleum ether / ethyl acetate = 100:0 to 85:15) to obtain tert-butyl 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) (250 mg, yield 31%) as a colorless oil. LCMS(ESI)C23H29N3O4[M+H] + m / z Calculated value: 412.22, Measured value: 412.28.

[0105] Preparation of tert-butyl 3-(5-ethyl-4-hydroxypyrimidine-2-yl)pyrrolidine-1-carboxylate (3) 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) (250 mg, 0.61 mmol) was dissolved in MeOH (15 mL) and Pd / C (97 mg, 0.91 mmol) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 50°C for 2 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain tert-butyl 3-(5-ethyl-4-hydroxypyrimidine-2-yl)pyrrolidine-1-carboxylate (3) (150 mg, yield 80%) as a colorless oil. LCMS(ESI)C15H23N3O3[M+H] + m / z Calculated value: 294.17, Measured value: 294.19.

[0106] Preparation of 5-ethyl-2-(pyrrolidine-3-yl)-3H-pyrimidine-4-one (4) To a solution of 3-(5-ethyl-4-hydroxypyrimidine-2-yl)pyrrolidine-1-carboxylate (3) (150 mg, 0.51 mmol), HCl (4 M, 10 mL) dissolved in dioxane was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 5-ethyl-2-(pyrrolidine-3-yl)-3H-pyrimidine-4-one (4) (100 mg, yield 94%) as a white solid. LCMS(ESI)C10H15N3O[M+H] + m / z Calculated value: 194.12, Measured value: 194.19.

[0107] Preparation of tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidine-2-yl)pyrrolidine-1-yl]piperidine-1-carboxylate (6) To a solution of 5-ethyl-2-(pyrrolidine-3-yl)-3H-pyrimidine-4-one (4) (100 mg, 0.52 mmol) in MeOH (15 mL), tert-butyl 4-oxopiperidine-1-carboxylate (5) (124.48 mg, 0.61 mmol) and NaBH3CN (145 mg, 3.11 mmol) were added. The reaction mixture was refluxed at 50°C under a nitrogen atmosphere and stirred for 18 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 tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidine-2-yl)pyrrolidine-1-yl]piperidine-1-carboxylate (6) (120 mg, yield 55%) as a white solid. LCMS(ESI)C20H32N4O3[M+H] + m / z Calculated value: 377.25, Measured value: 377.30.

[0108] Preparation of 5-ethyl-2-[1-(piperidine-4-yl)pyrrolidine-3-yl]-3H-pyrimidine-4-one (7) tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidine-2-yl)pyrrolidine-1-yl]piperidine-1-carboxylate (6) (120 mg, 0.32 mmol) was added to HCl (4 M, 10 mL) dissolved in dioxane at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to obtain 5-ethyl-2-[1-(piperidine-4-yl)pyrrolidine-3-yl]-3H-pyrimidine-4-one (7) (90 mg, yield 92%) as a white solid. LCMS(ESI)C15H24N4O[M+H] + m / z Calculated value: 277.20, Measured value: 277.24.

[0109] Preparation of 5-{4-[3-(5-ethyl-4-oxo-3H-pyrimidine-2-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compound 42) To a solution of 5-ethyl-2-[1-(piperidine-4-yl)pyrrolidine-3-yl]-3H-pyrimidine-4-one (7) (90 mg, 0.33 mmol) in DMF (10 mL), 5-fluoro-N-methylpyridine-2-carboxamide (8) (104 mg, 0.68 mmol) and Cs2CO3 (884 mg, 2.71 mmol) were added. The reaction mixture was irradiated in a microwave reactor at 150 °C for 3 hours. 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-oxo-3H-pyrimidine-2-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compound 42) (20 mg, purity 95%, yield 20%) as a white solid. 1H NMR (400MHz, DMSO) δ 12.16(s,1H), 8.42-8.38(m,1H), 8.28(d,J=2.4Hz,1H), 7.83(d,J=8.8Hz,1H), 7.73(s,1H), 7.42-7.39(dd,J=8.8,2.8Hz,1H), 3.87(d,J=12. 8Hz,2H), 3.29-3.25(m,2H), 3.17-3.13(m,1H), 2.94-2.74(m,8H), 2.3 4(q,J=7.2Hz,2H), 2.18-1.94(m,4H), 1.56-1.47(m,2H), 1.08(t,J=7.6 Hz, 3H). LCMS(ESI)C22H30N6O2[M+H] + m / z Calculated value: 411.24, Measured value: 411.33.

[0110] Example 2: Synthesis of Compound 53

[0111] Synthesis of intermediate INT [ka]

[0112] Preparation of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (3) To a solution of 5-fluoro-N-methylpyridine-2-carboxamide (1) (1.00 g, 6.50 mmol) in DMF (15 mL), 1,4-dioxa-8-azaspiro[4.5]decane (2) (1.40 g, 9.75 mmol) was added, followed by the addition of Cs2CO3 (2.12 g, 6.50 mmol) at room temperature. The reaction mixture was stirred at 150 °C for 5 hours using a microwave. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting DCM / MeOH = 100:0 to 97:3) to obtain 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (3) (1.50 g, yield 76%) as a white solid. LCMS(ESI)C14H19N3O3[M+H] + m / z Calculated value: 278.14, Measured value: 278.14.

[0113] Preparation of N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) To a solution of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (3) (1.50 g, 5.40 mmol) in H2O (10 mL), HCl (4 M, 20 mL) dissolved in 1,4-dioxane was added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to pH > 7 using NaHCO3 solution, extracted with ELISA (50 mL x 3), and the resulting organic phase was dried over Na2SO4 and concentrated to obtain N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (1.50 g, yield 76%) as a yellow solid. LCMS(ESI)C12H15N3O2[M+H] + m / z Calculated value: 234.12, Measured value: 234.18.

[0114] Preparation of compound 53 [ka]

[0115] Preparation of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3) To a 1,4-dioxane / H2O=4:1 (45 mL) solution of 6-bromo-2-methoxypyridine-3-amine (1) (2.00 g, 9.90 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (2) (3.98 g, 12.87 mmol) was added. Then, Pd(dppf)Cl2 (0.72 g, 0.99 mmol) and Na2CO3 (3.12 g, 99.00 mmol) were added at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / EA = 100:0 to 85:15) to obtain tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3) (3.00 g, yield 89%) as a white solid. LCMS(ESI)C16H23N3O3[M+H] + m / z Calculated value: 306.17, Measured value: 306.19.

[0116] Preparation of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)piperidine-1-carboxylate (4) To a solution of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3) (2.80 g, 9.20 mmol) in MeOH (50 mL), Pd / C (0.78 g, 7.36 mmol) was added at room temperature. The reaction mixture was stirred at 50°C for 2 hours under a hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the solution was concentrated under reduced pressure to obtain tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)piperidine-1-carboxylate (4) (2.80 g, yield 89%) as a white solid. LCMS(ESI)C16H25N3O3[M+H] + m / z Calculated value: 308.19, Measured value: 308.19.

[0117] Preparation of tert-butyl 3-(5-bromo-6-methoxypyridine-2-yl)piperidine-1-carboxylate (5) To a solution of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)piperidine-1-carboxylate (4) (2.80 g, 9.10 mmol) in ACN (50 mL), tert-butyl nitrite (2.82 g, 27.30 mmol) was added and the mixture was stirred for 15 minutes. Then, CuBr (5.22 g, 36.40 mmol) was added at room temperature. 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 purified by flash chromatography (eluting PE / EA = 100:0 to 85:15) to obtain tert-butyl 3-(5-bromo-6-methoxypyridine-2-yl)piperidine-1-carboxylate (5) (1.10 g, yield 30%) as a white solid. LCMS(ESI)C16H23BrN2O3[M+H] + m / z Calculated value: 371.09, Measured value: 371.15.

[0118] Preparation of tert-butyl 3-(5-ethyl-6-methoxypyridine-2-yl)piperidine-1-carboxylate (6) To a solution of tert-butyl 3-(5-bromo-6-methoxypyridine-2-yl)piperidine-1-carboxylate (5) (1.10 g, 2.96 mmol) in 1,4-dioxane (65 mL), Pd(dppf)Cl2 (219 mg, 0.30 mmol) was added. Next, Et2Zn (1 M, 11.84 mL, 11.84 mmol) was added at room temperature. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE / EA = 100:0 to 85:15) to obtain tert-butyl 3-(5-ethyl-6-methoxypyridine-2-yl)piperidine-1-carboxylate (6) (700 mg, yield 67%) as a white solid. LCMS(ESI)C18H28N2O3[M+H] + m / z Calculated value: 321.21, Measured value: 321.30.

[0119] Preparation of 3-ethyl-6-(piperidine-3-yl)-1H-pyridine-2-one (7) tert-butyl 3-(5-ethyl-6-methoxypyridine-2-yl)piperidine-1-carboxylate (6) (200 mg, 0.62 mmol) was dissolved in an aqueous HBr solution (48%, 6 mL). The reaction mixture was stirred at 100°C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain 3-ethyl-6-(piperidine-3-yl)-1H-pyridine-2-one (7) (80 mg, yield 56%) as a yellow solid. LCMS(ESI)C12H18N2O[M+H] + m / z Calculated value: 207.14, Measured value: 206.95.

[0120] Preparation of 5-{4-[3-(5-ethyl-6-oxo-1H-pyridine-2-yl)piperidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (8) To a solution of 3-ethyl-6-(piperidine-3-yl)-1H-pyridine-2-one (7) (80 mg, 0.38 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT) (89 mg, 0.38 mmol) was added. Then, two drops of acetic acid and NaBH3CN (24 mg, 0.38 mmol) were added at room temperature. 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-6-oxo-1H-pyridine-2-yl)piperidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (8) (48 mg, yield 31%) as a white solid. LCMS(ESI)C24H33N5O2[M+H] + m / z Calculated value: 424.26, Measured value: 424.37.

[0121] Preparation of 5-{4-[3-(5-ethyl-6-oxo-1H-pyridine-2-yl)piperidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compounds 53a and 53b) [ka] 5-{4-[3-(5-ethyl-6-oxo-1H-pyridine-2-yl)piperidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (8) was isolated by SFC (column: Daicel CHIRALPAK AD-H 250mm×20mm ID, 5μmm; mobile phase: CO2 / MeOH[0.1%(NH4)] 3 The compounds were separated at 75 / 25 and concentrated under reduced pressure to obtain compound 53a (7.16 mg, purity 95%, ee%: 100, white solid) as the first fraction and compound 53b (6.57 mg, purity 99%, ee%: 100, white solid) as the second fraction. Compound 53a 1 H NMR (400MHz, DMSO) δ 11.48(s,1H), 8.39(q,J=4.8Hz,1H), 8.26(d,J=2.8Hz,1H), 7.81(d,J=8.8Hz,1 H), 7.40(dd,J=8.8,2.8Hz,1H),7.17(d,J=6.8Hz,1H),5.98(d,J=7.2Hz,1H),3. 97(d,J=12.4Hz,2H), 2.91-2.77(m,7H), 2.67-2.54(m,2H), 2.36-2.28(m,4H), 1.83-1.81(m,3H), 1.68-1.65(m,1H), 1.59-1.40(m,4H),1.05(t,J=7.6Hz,3H). Compound 53b 1 H NMR (400MHz, DMSO) δ 11.48(s,1H), 8.39(q,J=4.4Hz,1H), 8.26(d,J=2.8Hz,1H), 7.81(d,J=8.8Hz,1 H), 7.40(dd,J=9.2,3.2Hz,1H),7.17(d,J=7.2Hz,1H),5.98(d,J=6.8Hz,1H),3. 97(d,J=12.4Hz,2H), 2.91-2.77(m,7H), 2.66-2.54(m,2H), 2.36-2.25(m,4H), 1.83-1.80(m,3H), 1.67-1.64(m,1H), 1.59-1.36(m,4H),1.05(t,J=7.6Hz,3H).

[0122] Example 3: Synthesis of Compound 2 [ka]

[0123] Preparation of 5-hydroxy-N-methylpicolinamide (2) To a solution of 5-hydroxypicolinic acid (1) (4.00 g, 28.72 mmol) in DMF (15 mL), HATU (12.55 g, 33.01 mmol) and DIEA (9.28 g, 71.80 mmol) were added. Next, methanamine (2 M, 15 mL, 30.00 mmol) was added at room temperature. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 93:7) to obtain 5-hydroxy-N-methylpicolinamide (2) (2.00 g, yield 46%) as a white solid. LCMS(ESI)C7H8N2O2[M+H] + m / z Calculated value: 153.06, Measured value: 153.10.

[0124] Preparation of 5-(3-hydroxypropoxy)-N-methylpicolinamide (3) To a solution of 5-hydroxy-N-methylpicolinamide (2) (1.00 g, 6.61 mmol) in DMF (10 mL), 3-bromopropan-1-ol (2.75 g, 19.58 mmol) and Cs2CO3 (3.23 g, 9.93 mmol) were added at room temperature. The mixture was then stirred at room temperature for 18 hours. The reaction solution was filtered to obtain 5-(3-hydroxypropoxy)-N-methylpicolinamide (3) (1.00 g, yield 65%) as oil. LCMS(ESI)C10H14N2O3[M+H] + m / z Calculated value: 211.10, Measured value: 211.05.

[0125] Preparation of 5-(3-bromopropoxy)-N-methylpicolinamide (INT-4-1) To a 15 mL solution of 5-(3-hydroxypropoxy)-N-methylpicolinamide (3) (250.00 mg, 1.19 mmol) in DCM, CBr4 (788.74 mg, 2.38 mmol) was added. Then, PPh3 (623.83 mg, 2.38 mmol) was added at room temperature. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting DCM / MeOH = 100:0 to 95:5) to obtain 5-(3-bromopropoxy)-N-methylpicolinamide (INT-4-1) (300 mg, yield 69%) as a white solid. LCMS(ESI)C10H13BrN2O2[M+H] + m / z Calculated value: 273.02, Measured value: 274.85.

[0126] Preparation of N-methyl-5-(3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)propoxy)picolinamide (compound 2) [ka] To a solution of 5-(3-bromopropoxy)-N-methylpicolinamide (INT-4-1) (150.00 mg, 0.55 mmol) in ACN (10 mL), 2-(piperidine-4-yl)-3H-quinazolin-4-one (INT-5) (151.10 mg, 0.66 mmol) was added. Next, DIEA (212.94 mg, 1.65 mmol) was added at room temperature. The mixture was then stirred at 67 °C for 18 hours. 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 N-methyl-5-(3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)propoxy)picolinamide (compound 2) (100 mg, yield 78%) as a white solid. 1H NMR(400MHz,DMSO) δ 12.15(s,1H), 8.57-8.54(m,1H), 8.29(d,J=2.8Hz,1H), 8.08 (d,J=8.0Hz,1H), 7.98(d,J=8.8Hz,1H), 7.78(t,J=7.6Hz,1H), 7.60(d,J=8.0Hz,1H), 7.54(dd,J=8.8,2.8Hz,1H), 7.47(t,J=7.6Hz,1H), 4.18(t,J=5.6Hz,2H), 3.10-2.8 6(m,2H), 2.79(d,J=4.8Hz,3H), 2.65-2.53(m,1H), 2.49-2.41(m,2H), 1.94(s,8H). LCMS(ESI)C23H27N5O3[M+H] + m / z Calculated value: 422.21, Measured value: 422.30.

[0127] Example 4: Synthesis of Compound 6 [ka] [ka]

[0128] Preparation of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) 2-aminobenzamide (1) (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (2) (10.11 g, 44.10 mmol) were dissolved in pyridine (50 mL) and EDCI (8.45 g, 44.10 mmol) was added. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were washed with 1 M HCl and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, yield 79%) as a white solid. LCMS(ESI)C18H25N3O4[MH] - m / z Calculated value: 346.18, Measured value: 346.20.

[0129] Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) To a diglym (80 mL) solution of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, 34.50 mmol), KOH (2.13 g, 37.95 mmol) was added, heated to 140 °C, stirred for 2 hours, cooled to 0 °C, ice water (100 mL) was added, and the pH was adjusted to < 7 using 1 M HCl solution to form a precipitate. The solution was filtered, the filtered cake was washed with ice water (50 mL x 3), dried, and tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) (11.00 g, yield 97%) was obtained as a white solid. LCMS(ESI)C18H23N3O3[M+H] + m / z Calculated value: 330.17, Measured value: 330.20.

[0130] Preparation of 2-(piperidine-3-yl)quinazoline-4(3H)-one (INT-5-1) To a solution of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) (3.30 g, 10.00 mmol) in DCM (10 mL), TFA (10 mL) was added and the mixture was stirred at room temperature for 1 hour. This mixture was concentrated under reduced pressure to obtain the crude, to which ice water (20 mL) was added, and the pH was adjusted to >7 with aqueous ammonia to produce a precipitate. The mixture was filtered, the filter cake was washed with ice water (50 mL x 3), and then dried to obtain 2-(piperidine-3-yl)quinazolin-4(3H)-one (INT-5-1) (1.50 g, yield 66%) as a white solid. LCMS(ESI)C13H15N3O[M+H] + m / z Calculated value: 230.12, Measured value: 230.00.

[0131] Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (7) To a solution of 2-(piperidine-3-yl)quinazoline-4(3H)-one (INT-5-1) (460 mg, 2.01 mmol) in MeOH (15 mL), tert-butyl 4-oxopiperidine-1-carboxylate (6) (8.45 g, 44.10 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (189.11 mg, 3.01 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 18 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 93:7) to obtain tert-butyl 3-(4-oxo-3,4-dihydroquinazoline-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (7) (300 mg, yield 36%) as a white solid. 1 H NMR(400MHz,DMSO) δ 12.40 (s,1H), 8.11(d,J=7.2Hz,1H), 7.81(s,1H), 7.62(d,J=7.8Hz,1H),7.51(s,1H),4.10-3.99(m,2H),3.53-3.44(m,1H) ,3.16-3.04(m,1H),2.94-2.62(m,4H),1.99(d,J=2.4Hz,4H),1.91(d,J=2.4Hz,2H),1.82-1.53(m,4H),1.41(s,9H).

[0132] Preparation of 2-([1,4'-bipiperidine]-3-yl)quinazoline-4(3H)-one(8) tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (7) (300 mg, 0.65 mmol) was added to HCl (4 M, 10 mL) dissolved in dioxane, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-([1,4'-bipiperidine]-3-yl)quinazolin-4(3H)-one (8) (200 mg, yield 88%) as a white solid. LCMS(ESI)C18H24N4O[M+H] + m / z Calculated value: 313.20, Measured value: 313.15.

[0133] Preparation of N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidine]-1'-yl)picolinamide (9) To a solution of 2-([1,4'-bipiperidine]-3-yl)quinazoline-4(3H)-one (8) (200 mg, 0.64 mmol) in DMF (10 mL), Cs2CO3 (1042.94 mg, 3.20 mmol) and 5-fluoro-N-methylpicolinamide (148.02 mg, 0.96 mmol) were added. The mixture was stirred at 150°C for 6 hours using microwaves. 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 N-methyl-5-(3-(4-oxo-3,4-dihydroquinazoline-2-yl)-[1,4'-bipiperidine]-1'-yl)picolinamide (9) (100 mg, purity 95%, yield 33%) as a yellow solid. LCMS(ESI)C25H30N6O2[M+H] + m / z Calculated value: 447.24, Measured value: 447.20.

[0134] Chiral separation of N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidine]-1'-yl)picolinamide (compounds 6a and 6b) [ka] Compound 9 was separated by SFC (column: Daicel CHIRALPAK OJ-H 250mm × 20mm ID, 5μmm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 70 / 30), concentrated under reduced pressure, and the first fraction was obtained as compound 6a (40.6 mg, purity 100%, ee%: 100, white solid), and the second fraction as compound 6b (39.5 mg, purity 99%, ee%: 100, white solid). compound 6a 1H NMR (400MHz, DMSO) δ 12.25(s,1H), 8.40(q,J=4.8Hz,1H), 8.29(d,J=2.8Hz,1H), 8.10(dd,J=7.6,1.6Hz,1H), 7.85-7.7 8(m,2H), 7.63(d,J=8.0Hz,1H), 7.49(t,J=7.4Hz,1H), 7.42(dd,J=8.8,2.8Hz,1H), 3.99(d,J=12. 8Hz,2H), 3.08(d,J=8.8Hz,1H),2.87-2.81(m,4H), 2.80(d,J=4.8Hz,3H), 2.61-2.55(m,2H), 2.32 (t,J=9.8Hz,1H), 1.98-1.96(m,1H), 1.87(d,J=12.4Hz,2H), 1.78-1.75(m,1H), 1.69-1.55(m,4H). LCMS(ESI)C25H30N6O2[M+H] + m / z calculated value: 447.24, measured value: 447. Compound 6b 1 H NMR (400MHz, DMSO) δ 12.25(s,1H), 8.39(q,J=4.8Hz,1H), 8.29(d,J=2.8Hz,1H), 8.10(dd,J=7.6,1.6Hz,1H), 7.84-7. 78(m,2H), 7.63(d,J=8.0Hz,1H), 7.50-7.47(m,1H), 7.42(dd,J=8.8,2.8Hz,1H), 3.99(d,J=12.8H z,2H),3.08(d,J=8.8Hz,1H),2.87-2.81(m,4H),2.80(d,J=4.8Hz,3H),2.61-2.55(m,2H),2.31( t,J=9.6Hz,1H), 1.98-1.96(m,1H), 1.87(d,J=12.4Hz,2H), 1.78-1.75(m,1H), 1.63-1.55(m,4H). LCMS(ESI)C25H30N6O2[M+H] + m / z calculated value: 447.24, measured value: 447.

[0135] Example 5: Synthesis of Compound 8

[0136] Synthesis of INT-5 [ka]

[0137] Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) 2-aminobenzamide (1) (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2) (10.11 g, 44.10 mmol) were dissolved in pyridine (50 mL), to which EDCI (8.45 g, 44.10 mmol) was added. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, yield 79%) as a white solid. LCMS(ESI)C18H25N3O4[M+Na] + m / z Calculated value: 370.42, Measured value: 370.15.

[0138] Preparation of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) To a diglym (80 mL) solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, 34.50 mmol), KOH (2.13 g, 37.95 mmol) was added, heated to 140 °C, stirred for 2 hours, cooled to 0 °C, ice water (100 mL) was added, and then the pH was adjusted to < 7 with 1 M HCl solution to form a precipitate. The solution was filtered, the filtered cake was washed with ice water (50 mL x 3), and then dried to obtain tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) (11.00 g, yield 97%) as a white solid. LCMS(ESI)C18H23N3O3[M+H] + m / z Calculated value: 330.17, Measured value: 330.20.

[0139] Preparation of 2-(piperidine-4-yl)quinazoline-4(3H)-one (INT-5) To a solution of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) (3.30 g, 10.00 mmol) in DCM (10 mL), TFA (10 mL) was added and the mixture was stirred at room temperature for 1 hour. This mixture was concentrated under reduced pressure to obtain a crude, to which ice water (20 mL) was added and the pH was adjusted to >7 with aqueous ammonia to produce a precipitate. The mixture was filtered, the filter cake was washed with ice water (50 mL x 3), and then dried to obtain 2-(piperidine-4-yl)quinazolin-4(3H)-one (INT-5) (1.50 g, yield 66%) as a white solid. LCMS(ESI)C13H15N3O[M+H] + m / z Calculated value: 230.12, Measured value: 230.20.

[0140] Synthesis of compound 8 [ka]

[0141] Preparation of tert-butyl 4-formylpiperidine-1-carboxylate (2) To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1) (837.00 mg, 3.85 mmol) in MeOH (50 mL), 2-(piperidine-4-yl)quinazoline-4(3H)-one (INT-5) (300 mg, 1.31 mmol) was added. Then, two drops of acetic acid and NaBH3CN (400.00 mg, 6.37 mmol) were added at room temperature. The reaction mixture was stirred at 65 °C for 18 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 tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-carboxylate (2) (500.00 mg, yield 90%) as a white solid. LCMS(ESI)C24H34N4O3[M+H] + m / z Calculated value: 427.26, Measured value: 427.30.

[0142] Preparation of tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-carboxylate (3) To a solution of tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-carboxylate (2) (500.00 mg, 1.17 mmol) in MeOH (5 mL), 4 M HCl-dioxane (10 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-(1-(piperidine-4-ylmethyl)piperidine-4-yl)quinazolin-4(3H)-one (3) (350.00 mg, yield 87%) as a white solid. LCMS(ESI)C19H26N4O[M+H] + m / z Calculated value: 327.21, Measured value: 327.15.

[0143] Preparation of N-methyl-5-(4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-yl)picolinamide (compound 8) 2-(1-(piperidine-4-ylmethyl)piperidine-4-yl)quinazoline-4(3H)-one (3) (300.00 mg, 0.92 mmol) was dissolved in DMF (5 mL) and 5-fluoro-N-methylpicolinamide (4) (354.14 mg, 2.30 mmol) was added. Then Cs2CO3 (2994.20 mg, 9.19 mmol) was added at room temperature. The reaction mixture was irradiated in a microwave reactor at 150 °C for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18 150×21.2mm, mobile phase: ACN-H2O (0.1% FA), gradient: 15-25) to obtain N-methyl-5-(4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-yl)picolinamide (compound 8) (100 mg, purity 98%, yield 24%) as a white solid. LCMS(ESI)C26H32N6O2[M+H] + m / z Calculated value: 461.26, Measured value: 461.20. 11H NMR (400MHz, DMSO) δ 12.13(s,1H), 8.37(d,J=4.8Hz,1H), 8.26(d,J=2.8Hz,1H), 8.08(d,J=7.6Hz,1H), 7.82-7.76(m,2H), 7.60(d,J=8.0Hz,1H), 7.50-7.35(m,2H) , 3.91(d,J=12.4Hz,2H), 2.95(d,J=10.8Hz,2H), 2.89-2.75(m,5H), 2.6 2-2.53(m,1H), 2.18(d,J=6.4Hz,2H), 1.98-1.73(m,9H), 1.23-1.17(m, 2H).

[0144] Example 6: Synthesis of Compound 10

[0145] Synthesis of compound 10 [ka]

[0146] Preparation of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate (3) 2-aminobenzamide (1) (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2) (9.49 g, 44.10 mmol) were dissolved in pyridine (50 mL), to which EDCI (8.45 g, 44.10 mmol) was added. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate (3) (12.00 g, yield 77%) as a white solid. LCMS(ESI)C17H23N3O4[M+Na] + m / z Calculated value: 356.17, Measured value: 356.00.

[0147] Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) To a diglym (80 mL) solution of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate (3) (12.00 g, 36.04 mmol), KOH (2.42 g, 43.25 mmol) was added, heated to 140°C, stirred for 0.5 hours, cooled to 0°C, ice water (100 mL) was added, and the pH was adjusted to <7 with 1 M HCl solution to form a precipitate. The solution was filtered, the filter cake was washed with ice water (50 mL x 3), and dried to obtain tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) (10.00 g, yield 83%) as a white solid. LCMS(ESI)C17H21N3O3[M+H] + m / z Calculated value: 316.16, Measured value: 316.05.

[0148] Preparation of 2-(pyrrolidine-3-yl)quinazoline-4(3H)-one (INT-5-2) To a solution of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) (10.00 g, 31.75 mmol) in DCM (20 mL), TFA (20 mL) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain crude, ice water (20 mL) was added, and the pH was adjusted to >7 with aqueous ammonia to form a precipitate. The mixture was filtered, the filter cake was washed with ice water (50 mL x 3), and dried to obtain 2-(pyrrolidine-3-yl)quinazolin-4(3H)-one (INT-5-2) (8.00 g, yield 80%) as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ 8.14-8.07(m,1H), 7.87-7.76(m,1H), 7.64(d,J=8.0Hz,1H), 7.57-7.44(m,1H), 3.76-3.61(m,1H), 3.61-3.49(m, 2H), 3.43-3.33(m,1H), 3.29(dt,J=11.4,5.6Hz,1H), 2.37(td,J=14.0,7.1Hz,1H), 2.21(td,J=13.5,7.2Hz,1H). LCMS(ESI)C12H13N3O[MH] -m / z Calculated value: 216.11, Measured value: 215.95.

[0149] Preparation of tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-carboxylate (7) To a solution of 2-(pyrrolidine-3-yl)quinazoline-4(3H)-one (INT-5-2) (600.00 mg, 2.79 mmol) in MeOH (30 mL), tert-butyl 4-oxopiperidine-1-carboxylate (6) (1.67 g, 8.36 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (1.05 g, 16.72 mmol) at room temperature. The reaction mixture was stirred at 50°C for 18 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 93:7) to obtain tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-carboxylate (7) (400 mg, yield 34%) as a white solid. LCMS(ESI)C22H30N4O3[M+H] + m / z Calculated value: 399.23, Measured value: 399.30.

[0150] Preparation of 2-(1-(piperidine-4-yl)pyrrolidine-3-yl)quinazoline-4(3H)-one(8) tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-carboxylate (7) (400 mg, 0.81 mmol) was added to a 4 M, 10 mL solution of hydrochloric acid dioxane, stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to obtain 2-(1-(piperidine-4-yl)pyrrolidine-3-yl)quinazolin-4(3H)-one (8) (200.00 mg, yield 79%) as a white solid. LCMS(ESI)C17H22N4O[M+H] + m / z Calculated value: 299.18, Measured value: 299.25.

[0151] Preparation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (9) To a solution of 2-(1-(piperidine-4-yl)pyrrolidine-3-yl)quinazoline-4(3H)-one (8) (200.00 mg, 0.67 mmol) in DMF (10 mL), Cs2CO3 (2.18 g, 6.70 mmol) and 5-fluoro-N-methylpicolinamide (9) (432.44 mg, 2.01 mmol) were added. The mixture was stirred using a microwave at 150°C for 6 hours. 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 N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (9) (100 mg, purity 95%, yield 33%) as a yellow solid. LCMS(ESI)C24H28N6O2[M+H] + m / z Calculated value: 433.23, Measured value: 433.25.

[0152] Chiral separation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (9) Compound 9 was separated by SFC (column: Daicel CHIRALPAK OJ-H 250mm×20mm ID, 5μmm; mobile phase: CO2 / MeOH [0.1%(NH3)] = 70 / 30), concentrated under reduced pressure, and the first fraction was obtained as compound 10a (16.4 mg, purity 100%, ee%: 100, off-white solid), and the second fraction as compound 10b (12.3 mg, purity 100%, ee%: 100, off-white solid). compound 10a 1H NMR (400MHz, DMSO-d6,ppm) δ 12.16(s,1H), 8.40-8.37(m,1H), 8.27(d,J= 2.8Hz,1H), 8.07(dd,J=7.6,1.6Hz,1H), 7.82-7.75(m,2H), 7.61(d,J= 8.0Hz,1H), 7.48-7.44(m,1H), 7.40(dd,J=8.8,2.8Hz,1H), 3.82(d,J=12.8Hz,2H) , 3.07(t,J=8.6Hz,2H), 2.95(t,J=10.8Hz,2H), 2.86-2.79(m,2H), 2.78-2.77(m,3 H), 2.69-2.63(m,1H), 2.33-2.32(m,1H), 2.20-2.13(m,2H), 1.96-1.93(m,2H), 1.58-1.47(m,2H). LCMS(ESI)C24H28N6O2[M+H] + m / z calculated value: 433.23, measured value: 433.20. Compound 10b 1 H NMR (400MHz, DMSO-d6, ppm) δ 8.39-8.38(m,1H), 8.28(d,J=3.2Hz,1H), 8.08(dd,J=7.6,1.6Hz,1H), 7.83-7.76(m,2 H), 7.61(d,J=8.0Hz,1H), 7.47(t,J=7.6Hz,1H), 7.40(dd,J=8.8,2.8Hz,1H), 3.83(d,J=12.8Hz,2H), 3.09(d,J=8.4Hz,2H), 2.95(t,J=12.4Hz ,2H), 2.88-2.79(m,2H), 2.79(d,J=4.8Hz,3H), 2.68-2.66(m,1H), 2.39 -2.31(m,1H), 2.21-2.14(m,2H), 1.97-1.94(m,2H), 1.59-1.47(m,2H). LCMS(ESI)C24H28N6O2[M+H] + m / z calculated value: 433.23, measured value: 433.20.

[0153] Example 7: Synthesis of Compound 14

[0154] Preparation of INT5-3 [ka]

[0155] Preparation of tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate (3) 2-aminobenzamide (1) (2.80 g, 20.60 mmol) and 2-(1-(tert-butoxycarbonyl)piperidine-3-yl)acetic acid (2) (5.00 g, 20.60 mmol) were dissolved in pyridine (50 mL) and EDCI (3.95 g, 20.60 mmol) was added. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate (3) (7.00 g, yield 94%) as a white solid. LCMS(ESI)C19H27N3O4[M+H] + m / z Calculated value: 362.20, Measured value: 362.25.

[0156] Preparation of tert-butyl 3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-carboxylate (4) To a diglym (80 mL) solution of tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate (3) (7.60 g, 21.00 mmol), KOH (1.18 g, 21.00 mmol) was added, heated to 140 °C, stirred for 2 hours, cooled to 0 °C, ice water (100 mL) was added, and the pH was adjusted to < 7 with 1 M HCl solution to form a precipitate. The solution was filtered, the filtered cake was washed with ice water (50 mL x 3), and then dried to obtain tert-butyl 3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-carboxylate (4) (6.80 g, yield 94%) as a white solid. LCMS(ESI)C19H25N3O3[M+H] + m / z Calculated value: 344.19, Measured value: 344.15.

[0157] Preparation of 2-(piperidine-3-ylmethyl)quinazoline-4(3H)-one (INT-5-3) To a solution of tert-butyl 3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-carboxylate (4) (2.00 g, 5.80 mmol) in DCM (10 mL), TFA (10 mL) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain crude, 20 mL of ice water was added, and the pH was adjusted to >7 with aqueous ammonia to form a precipitate. The mixture was filtered, the filter cake was washed with ice water (50 mL x 3), and dried to obtain 2-(piperidine-3-ylmethyl)quinazolin-4(3H)-one (INT-5-3) (1.20 g, yield 85%) as a white solid. LCMS(ESI)C14H17N3O[M+H] + m / z Calculated value: 244.14, Measured value: 244.20.

[0158] Synthesis of compound 14 [ka]

[0159] Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (2) 5-hydroxy-N-methylpicolinamide (1) (500.00 mg, 3.29 mmol) and Cs2CO3 (3.22 g, 9.87 mmol) were dissolved in DMF (15 mL), to which 1-bromo-2-chloroethane (2) (943.64 mg, 6.58 mmol) was added. The mixture was then stirred at 50°C for 3 hours. The reaction mixture was quenched with water, the aqueous layer was extracted with  (50 mL x 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE /  = 100:0 to 80:20) to obtain tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (2) (500.00 mg, yield 71%) as a colorless oil. LCMS(ESI)C9H11ClN2O2[M+H] + m / z Calculated value: 215.05, Measured value: 215.00.

[0160] Preparation of N-methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-yl)ethoxy)picolinamide (3) To a solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (2) (500.00 mg, 2.33 mmol) and Cs2CO3 (2.28 g, 6.99 mmol) in DMF (15 mL), 2-(piperidine-3-ylmethyl)quinazoline-4(3H)-one (INT5-3) (566.91 mg, 2.33 mmol) and KI (1.16 g, 6.99 mmol) were added. The mixture was then stirred at 80°C for 3 hours. The reaction mixture was quenched with water, the aqueous layer was extracted with ELISA (50 mL x 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 92:8) to obtain N-methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-yl)ethoxy)picolinamide (3) (200.00 mg, yield 20%) as a yellow solid. LCMS(ESI)C23H27N5O3[M+H] + m / z Calculated value: 422.21, Measured value: 422.10.

[0161] Chiral separation of N-methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-yl)ethoxy)picolinamide (compound 14) [ka] Compound 3 was separated by SFC (column: Daicel CHIRALPAK OJ-H 250mm×20mm ID, 5μmm; mobile phase: CO2 / MeOH[0.1%(FA)]=70 / 30), concentrated under reduced pressure, and the first fraction was obtained as compound 14a (31.6mg, purity 100%, ee%:100, white solid), and the second fraction as compound 14b (28.1mg, purity 99%, ee%:100, white solid). compound 14a 1H NMR (400MHz, DMSO-d6, ppm) δ 12.15(s,1H), 8.53(q,J=9.6,4.8Hz,1H), 8.23(d,J=2.8Hz,1H), 8.07(dd,J=8.0,1.2Hz,1H), 7.92(d,J=8.8Hz,1H), 7.79-7.73(m,1H), 7.56(d,J=8.0Hz,1H), 7.49-7.42(m,2H), 4.18(t,J= 5.6Hz,2H), 2.90-2.81(m,2H), 2.79(d,J=4.8Hz,3H), 2.73-2.65(m,2H), 2.55-2.51(m,2H), 2 .17-2.00(m,2H), 1.93-1.85(m,1H), 1.70-1.59(m,2H), 1.51-1.38(m,1H), 1.02-0.99(m,1H). LCMS(ESI)C23H27N5O3[M+H] + m / z calculated value: 422.21, measured value: 422.25. Compound 14b 1 H NMR (400MHz, DMSO-d6, ppm) δ 12.15 (s, 1H), 8.53 (q, J=9.6, 4.8Hz, 1 H), 8.23(d,J=2.8Hz,1H), 8.07(dd,J=8.0,1.2Hz,1H), 7.92(d,J=8.8Hz,1H), 7.79-7.73(m,1H), 7.56(d,J=8.0Hz,1H) ,7.49-7.42(m,2H),4.18(t,J=5.6Hz,2H),2.90-2.81(m,2H),2.79(d,J=4.8Hz,3H),2.73-2.65(m,2H),2.55-2.51(m,2 H)、2.17-2.00(m,2 H), 1.93-1.85(m,1H), 1.70-1.59(m,2H), 1.51-1.38(m,1H), 1.02-0.99(m,1H). LCMS(ESI)C23H27N5O3[M+H] + m / z calculated value: 422.21, measured value: 422.25.

[0162] Example 8: Synthesis of Compound 17

[0163] Synthesis of Compound 17 [ka]

[0164] Preparation of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (3) To a solution of ethyl 1H-pyrazole-4-carboxylate (1) (2.00 g, 14.30 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2) (4.99 g, 17.87 mmol) in DMF (60 mL), Cs2CO3 (10.02 g, 30.74 mmol) was added. The mixture was then stirred at 120 °C for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with SiO2 (200 mL x 3). The combined organic layers were washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (3) (2.00 g, yield 41%) as a white solid. LCMS(ESI)C16H25N3O4[M+H] + m / z Calculated value: 324.18, Measured value: 324.20.

[0165] Preparation of 1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-carboxylic acid (4) To a 40 mL MeOH / H2O = 1:1 solution of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (3) (1.50 g, 4.80 mmol), LiOH (460.00 mg, 19.20 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure at 40°C to obtain a residue. Water was added to the residue, and the mixture was acidified with 1 M aqueous HCl at 0°C to adjust the pH to 4-5. The aqueous layer was extracted with ELISA (200 mL x 3). The combined organic layers were washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 95:5) to obtain 1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-carboxylic acid (4) (1.00 g, yield 67%) as a white solid. LCMS(ESI)C14H21N3O4[M-56+H] + m / z Calculated value: 240.15, Measured value: 240.20. 1 H NMR(400MHz,DMSO-d6,ppm) δ 12.29(s,1 H), 8.30(s,1H), 7.81(s,1H), 4.52-4.30(m,1H), 4.03(d,J=11.2Hz,2H), 2.8 8(s,2H), 1.99(d,J=12.4Hz,2H), 1.78(dt,J=12.4,8.0Hz,2H), 1.41(s,9H).

[0166] Preparation of tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (6) 2-aminobenzamide (5) (299.66 mg, 2.20 mmol) and 1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazole-4-carboxylic acid (4) (650.00 mg, 2.20 mmol) were dissolved in pyridine (25 mL), to which EDCI (421.91 mg, 2.20 mmol) was added. The mixture was then stirred at room temperature for 12 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (6) (720.00 mg, yield 71%) as a white solid. LCMS(ESI)C21H27N5O4[M+H] + m / z Calculated value: 414.21, Measured value: 414.25.

[0167] Preparation of tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (7) To a diglym (15 mL) solution of tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (6) (700.00 mg, 1.69 mmol), KOH (113.99 mg, 2.03 mmol) was added, heated to 140°C, stirred for 2 hours, then cooled to 0°C, ice water (10 mL) was added, and the pH was adjusted to < 7 with 1 M HCl solution to form a precipitate. The solution was filtered, the filtered cake was washed with ice water (50 mL x 3), and then dried to obtain tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (7) (600 mg, yield 67%) as a white solid. LCMS(ESI)C21H25N5O3[M+H] + m / z Calculated value: 396.20, Measured value: 396.25.

[0168] Preparation of 2-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)quinazoline-4(3H)-one(8) To a room temperature solution of tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (7) (350.00 mg, 0.88 mmol), HCl-dioxane (4 M, 40 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product of 2-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)quinazolin-4(3H)-one (8) (200 mg, yield 73%) as a white solid. LCMS(ESI)C16H17N5O[M+H] + m / z Calculated value: 296.14, Measured value: 296.25.

[0169] Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-yl)piperidine-1-yl)picolinamide (compound 17) To a solution of 2-(1-(piperidine-4-yl)-1H-pyrazole-4-yl)quinazoline-4(3H)-one(8) (200.00 mg, 0.68 mmol) in DMF (10 mL), Cs2CO3 (2.21 g, 6.77 mmol) and 5-fluoro-N-methylpicolinamide (INT-9-1) (260.96 mg, 1.69 mmol) were added. The mixture was stirred using a microwave at 150°C for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting DCM / MeOH = 100:0 to 92:8) to obtain the crude, which was then purified by preparative HPLC (Gemini 5um C18 150×21.2mm, mobile phase: ACN-H2O (0.1% FA), gradient: 25~75) to obtain N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-yl)piperidine-1-yl)picolinamide (compound 17) (30 mg, purity 98%, yield 9%) as a white solid. 1H NMR(400MHz,DMSO-d6,ppm) δ 12.30(s,1H), 8.67(s,1H), 8.43-8.40(m,1H), 8.35(d,J=2.8Hz,1H), 8.26(s,1H) ), 8.09(d,J=8.0Hz,1H), 7.85(d,J=8.8Hz,1H), 7.80-7.76(m,1H), 7.61(d,J=8.0 Hz,1H), 7.50-7.42(m,2H), 4.56-4.53(m,1H), 4.08(d,J=12.8Hz,2H), 3.10(t,J =11.6,10.8Hz,2H), 2.79(d,J=4.8Hz,3H),2.19-2.17(m,2H), 2.06-1.98(m,2H). LCMS(ESI)C23H23N7O2[M+H] + m / z Calculated value: 430.19, Measured value: 430.25.

[0170] Example 9: Synthesis of Compound 40

[0171] Synthesis of compound 40 [ka]

[0172] Preparation of 8-chloroquinazoline-2,4(1H,3H)-dione(2) To a solution of 2-amino-3-chlorobenzoic acid (1) (10.00 g, 58.30 mmol) in HOAC (100 mL), KOCN (14.19 g, 174.90 mmol) was slowly added at room temperature. The mixture was heated to 100 °C, stirred for 15 hours, cooled to 0 °C, and ice water (30 mL) was added. The precipitate was collected by filtration, washed with a mixture of petroleum ether:siRNA = 5:1 (100 mL), and filtered to obtain 8-chloroquinazoline-2,4(1H,3H)-dione (2) (5.00 g, yield 40%) as a white solid, which was used directly in the next step without further purification. LCMS(ESI)C8H5ClN2O2[M+H] + m / z Calculated value: 197.00, Measured value: 196.95.

[0173] Preparation of 2,4,8-trichloroquinazoline (3) To a solution of 8-chloroquinazoline-2,4(1H,3H)-dione(2) (5.00 g, 25.40 mmol) in POCl3 (45 mL), DMF (3 mL) was slowly added at room temperature. The mixture was heated at 100 °C for 12 hours. The resulting mixture was diluted with ice water (200 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, eluted at 100:0 to 50:50) to obtain 2,4,8-trichloroquinazoline(3) (2.00 g, yield 32%) as a white solid. LCMS(ESI)C8H3Cl3N2[M+H] + m / z Calculated value: 232.94, Measured value: 232.90.

[0174] Preparation of 2,8-dichloroquinazoline-4(3H)-one(4) NaOH (690 mg, 17.20 mmol) was added to a THF / H2O = 1:1 (200 mL) solution of 2,4,8-trichloroquinazoline (3) (2.00 g, 8.60 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure at 40 °C to obtain the residue. Water was added to this residue, and the solution was acidified at 0 °C with 1 M aqueous HCl to adjust the pH to 4-5. The mixture was extracted with ELISA (200 mL x 3). The combined organic phases were washed with saline solution (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluent: DCM / MeOH = 100:0 to 95:5) to obtain 2,8-dichloroquinazoline-4(3H)-one (4) (1.60 g, yield 82%) as a white solid. LCMS(ESI)C8H4Cl2N2O[M+H] + m / z Calculated value: 214.97, Measured value: 214.95.

[0175] Preparation of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5) 2,8-Dichloroquinazoline-4(3H)-one(4) (400 mg, 1.86 mmol) was sequentially added dropwise to a dioxane / H2O = 10:1 (40 mL) solution, followed by tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (690 mg, 2.23 mmol), Pd(dppf)Cl2 (50 mg, 0.07 mmol), and Na2CO3 (591 mg, 5.58 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 18 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saline solution (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude. This crude was purified by flash column chromatography (PE / siRNA = 100:0 to 20:80) to obtain tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5) (550 mg, yield 77%) as a yellow solid. LCMS(ESI)C18H20ClN3O3[M+H] + m / z Calculated value: 362.12, Measured value: 362.10.

[0176] Preparation of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (6) PtO2 (110 mg) was added to a solution of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5) (550 mg, 1.52 mmol) in siRNA (200 mL). The mixture was evacuated and the cycle of filling with hydrogen was repeated three times, after which hydrogen was refilled. The resulting mixture was stirred at room temperature for 1 hour. Next, the mixture was filtered through Celite and concentrated under vacuum to obtain crude, which was purified by flash column chromatography (PE / siRNA = 100:0 to 50:50) to obtain tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (6) (400 mg, yield 65%) as a yellow solid. LCMS(ESI)C18H22ClN3O3[M+H] + m / z Calculated value: 364.13, Measured value: 364.10.

[0177] Preparation of 8-chloro-2-(piperidine-4-yl)quinazoline-4(3H)-one(7) To a solution of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (6) (400 mg, 1.21 mmol) in DCM (5 mL), TFA (2 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain crude, and ice water (2 mL) was added. The pH was adjusted to >7 with aqueous ammonia to form a precipitate, which was then filtered. The filtered cake was washed with ice water (5 mL x 3) and then dried to obtain 8-chloro-2-(piperidine-4-yl)quinazolin-4(3H)-one (7) (300 mg, yield 89%) as a white solid. LCMS(ESI)C13H14ClN3O[M+H] + m / z Calculated value: 264.08, Measured value: 264.10.

[0178] Preparation of tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-carboxylate (8) To a solution of 8-chloro-2-(piperidine-4-yl)quinazoline-4(3H)-one (7) (300 mg, 1.14 mmol) in MeOH (60 mL), tert-butyl 4-oxopiperidine-1-carboxylate (727 mg, 3.41 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (428 mg, 6.82 mmol) at room temperature. The reaction mixture was stirred at 50°C for 18 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 90:10) to obtain tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-carboxylate (8) (300 mg, yield 51%) as a white solid. LCMS(ESI)C24H33ClN4O3[M+H] + m / z Calculated value: 361.17, Measured value: 361.05.

[0179] Preparation of 8-chloro-2-(1-(piperidine-4-ylmethyl)piperidine-4-yl)quinazoline-4(3H)-one(9) tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-carboxylate (8) (300 mg, 0.65 mmol) was added to HCl (4 M, 30 mL) dissolved in dioxane, stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to obtain 8-chloro-2-(1-(piperidine-4-ylmethyl)piperidine-4-yl)quinazolin-4(3H)-one (9) (200 mg, yield 81%) as a white solid. LCMS(ESI)C19H25ClN4O[M+H] + m / z Calculated value: 361.17, Measured value: 361.05.

[0180] Preparation of 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-yl)-N-methylpicolinamide (compound 40) To a solution of 8-chloro-2-(1-(piperidine-4-ylmethyl)piperidine-4-yl)quinazoline-4(3H)-one (9) (150 mg, 0.42 mmol) in DMF (10 mL), Cs2CO3 (1.35 g, 4.16 mmol) and 5-fluoro-N-methylpicolinamide (INT-9-1) (160 mg, 1.03 mmol) were added. The mixture was stirred using a microwave at 150 °C for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain the crude product of 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-yl)-N-methylpicolinamide (compound 40) as a yellow solid. This crude product was purified by preparative HPLC (Gemini 5um C18 150×21.2mm, mobile phase: ACN-H2O (0.1% FA), gradient: 20-80) to obtain 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-yl)methyl)piperidine-1-yl)-N-methylpicolinamide (compound 40) (24.2 mg, purity 96%, yield 11%) as a white solid. 1H NMR (400MHz, DMSO-d6, ppm) δ 12.39(s,1H), 8.40-8.37(m,1H), 8.26(d,J=2.8Hz,1H), 8.04(dd,J=7.6,1.2Hz,1H), 7.94(dd,J=7.8,1.2Hz,1H), 7.8 1(d,J=8.8Hz,1H), 7.46-7.36(m,2H), 3.91(d,J=12.8Hz,2H), 2.97-2.94(m,2H), 2.86-2.81(m,2H), 2.77(d,J=4.8Hz, 3H), 2.65-2.53(m,1H),2.18(d,J=6.8Hz,2H),1.97-1.80(m,9H),1.23-1.17(m,2H). LCMS(ESI)C26H31ClN6O2[M+H) + m / z calculated value: 495.22, measured value: 495.15.

[0181] Example 10: Synthesis of Compound 52

[0182] Synthesis of Compound 52

change

[0183] Preparation of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3) To a 1,4-dioxane / H2O=5:1 (60 mL) solution of 2,8-dichloroquinazoline-4(3H)-one (1) (500 mg, 2.35 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) (900 mg, 3.00 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol), and Na2CO3 (740 mg, 6.98 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 18 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 91:9) to obtain tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3) (400 mg, yield 40%) as a white solid. LCMS(ESI)C17H18ClN3O3[M+H] + m / z Calculated value: 348.10, Measured value: 348.17.

[0184] Preparation of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) To a solution of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3) (400 mg, 1.15 mmol) in siRNA (50 mL), PtO2 (80 mg, 0.35 mmol) was added under an H2 atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain the crude product of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) (200 mg, yield 50%) as a white solid. LCMS(ESI)C17H20ClN3O3[M+H] + m / z Calculated value: 350.12, Measured value: 350.18.

[0185] Preparation of 8-chloro-2-(pyrroridine-3-yl)quinazoline-4(3H)-one(5) tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) (200 mg, 0.57 mmol) was added to HCl (4 M, 5 mL) dissolved in dioxane, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 8-chloro-2-(pyrrolidine-3-yl)quinazolin-4(3H)-one (5) (130 mg, yield 82%) as a white solid. LCMS(ESI)C12H12ClN3O[M+H] + m / z Calculated value: 250.07, Measured value: 250.12.

[0186] Preparation of 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (7) To a solution of 8-chloro-2-(pyrroridine-3-yl)quinazoline-4(3H)-one (5) (80 mg, 0.32 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (6) (50 mg, 0.21 mmol) was added, followed by the addition of 3 drops of acetic acid and NaBH3CN (15 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at 50°C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH = 100:0 to 92:8) to obtain 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (7) (40 mg, yield 40%) as a white solid. LCMS(ESI)C24H27ClN6O2[M+H] + m / z Calculated value: 467.19, Measured value: 467.28.

[0187] Preparation of 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compound 52a and compound 52b) 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (7) was separated by SFC (column: DAIEL AS-H 4.6 mm ID * 250 mm L 5 μm, mobile phase: CO2 / IPA [0.1% NH3 (7 M, MeOH solution)] = 60 / 40), concentrated under reduced pressure, and the first fraction was obtained as compound 52a (14.4 mg, purity 97%, ee%: 100, white solid), and the second fraction as compound 52b (15.4 mg, purity 99%, ee%: 100, white solid). Compound 52a 1 H NMR(400MHz,DMSO) δ 8.42(d,J=4.8Hz,1H), 8.27(d,J=2.8Hz,1H), 8.05(d,J=8.0Hz,1H), 7.94(d,J=8.0Hz, 1H), 7.82(d,J=8.8Hz,1H), 7.48-7.38(m,2H), 3.83(d,J=12.8Hz,2H), 3.40-3.32(m,1H ), 3.06(t,J=9.2Hz,1H), 2.95(dd,J=22.0,12.0Hz,3H), 2.80-2.68(m,5H), 2.38(t,J= 10.4Hz,1H), 2.24-2.15(m,2H), 1.96(d,J=11.2Hz,2H), 1.53(dd,J=22.8,10.8Hz,2H). LCMS(ESI)C24H27ClN6O2[M+H] + m / z Calculated value: 467.19, Measured value: 467.28. Compound 52b 1H NMR(400MHz,DMSO) δ 8.49(d,J=4.8Hz,1H), 8.34(d,J=2.4Hz,1H), 8.11(d,J=7.6Hz,1H), 8.01(d,J=7.6Hz ,1H), 7.89(d,J=8.8Hz,1H), 7.55-7.45(m,2H), 3.90(d,J=12.4Hz,2H), 3.45-3.39(m, 1H), 3.13(t,J=8.8Hz,1H), 3.01(dd,J=22.8,11.6Hz,3H), 2.87-2.77(m,5H), 2.43(d, J=10.0Hz,1H), 2.26(d,J=6.4Hz,2H), 2.02(d,J=11.2Hz,2H), 1.59(d,J=12.0Hz,2H). LCMS(ESI)C24H27ClN6O2[M+H] + m / z Calculated value: 467.19, Measured value: 467.28.

[0188] Example 11: Synthesis of Compound 54

[0189] Synthesis of Compound 54 [ka]

[0190] Preparation of tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate (3) 2.82 g, 14.70 mmol was added to a pyridine (50 mL) solution of 2-aminobenzamide (1) (2.00 g, 14.70 mmol) and {1-[(tert-butoxy)carbonyl]piperidine-4-yl}acetic acid (2) (3.58 g, 14.70 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with RINKAN (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate (3) (5.76 g, yield 92%) as a yellow oil. LCMS(ESI)C19H27N3O4[M+H] +m / z Calculated value: 362.20, Measured value: 262.30.

[0191] Preparation of tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate (4) To a diglym (40 mL) solution of tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate (3) (5.76 g, 15.90 mmol), KOH (1.16 g, 20.67 mmol) was added, heated to 140 °C, stirred for 2 hours, cooled to 0 °C, ice water (50 mL) was added, and the pH was adjusted to < 7 with 1 M HCl solution to form a precipitate. The solution was filtered, the filter cake was washed with ice water (50 mL x 3), and dried to obtain the product tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate (4) (4.20 g, yield 73%) as a white solid. LCMS(ESI)C19H25N3O3[M+H] + m / z Calculated value: 344.19, Measured value: 344.25.

[0192] Preparation of 2-(piperidine-4-ylmethyl)-3H-quinazoline-4-one (5) To a solution of tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate (4) (4.20 g, 10.00 mmol) in DCM (13 mL), TFA (13 mL) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude, 20 mL of ice water was added, and the pH was adjusted to >7 with aqueous ammonia to form a precipitate. The solution was filtered, the filter cake was washed with ice water (50 mL x 3), and dried to obtain 2-(piperidine-4-ylmethyl)-3H-quinazolin-4-one (5) (2.32 g, yield 90%) as a white solid. LCMS(ESI)C14H17N3O[M+H] + m / z Calculated value: 244.14, Measured value: 244.25.

[0193] Preparation of tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-yl}piperidine-1-carboxylate (6) To a solution of 2-(piperidine-4-ylmethyl)-3H-quinazolin-4-one (5) (500 mg, 2.06 mmol) in MeOH (50 mL), tert-butyl 4-oxopiperidine-1-carboxylate (532 mg, 2.67 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (504 mg, 8.01 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting DCM / MeOH = 100:0 to 91:9) to obtain tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-yl}piperidine-1-carboxylate (6) (244 mg, yield 25%) as a white solid. LCMS(ESI)C24H34N4O3[M+H] + m / z Calculated value: 427.26, Measured value: 427.40.

[0194] Preparation of tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate (7) tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-yl}piperidine-1-carboxylate (6) (244 mg, 0.57 mmol) was added to HCl (4 M, 8 mL) dissolved in dioxane, stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to obtain 2-{[1-(piperidine-4-yl)piperidine-4-yl]methyl}-3H-quinazolin-4-one (7) (187 mg, yield 90%) as a white solid. LCMS(ESI)C19H26N4O[M+H] + m / z Calculated value: 327.21, Measured value: 327.44.

[0195] Preparation of N-methyl-5-(4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-yl}piperidine-1-yl)pyridine-2-carboxamide (compound 54) To a solution of 2-{[1-(piperidine-4-yl)piperidine-4-yl]methyl}-3H-quinazolin-4-one (7) (200 mg, 0.61 mmol) in DMF (16 mL), Cs2CO3 (1.20 g, 3.68 mmol) and 5-fluoro-N-methylpyridine-2-carboxamide (5) (208 mg, 1.35 mmol) were added. The mixture was stirred using a microwave at 150°C for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 91:9) to obtain N-methyl-5-(4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-yl}piperidine-1-yl)pyridine-2-carboxamide (compound 54) (20.11 mg, purity 99%, yield 7%) as a white solid. 1 H NMR(400MHz,DMSO) δ 12.16(s,1H), 8.37(d,J=4.8Hz,1H), 8.25(d,J=2.8Hz,1H), 8.07(d,J=8.0Hz,1H), 7 .83-7.74(m,2H), 7.59(d,J=8.0Hz,1H), 7.45(t,J=7.6Hz,1H), 7.37(dd,J=8.8,2.8 Hz,1H), 3.93(d,J=12.4Hz,2H), 2.90-2.74(m,8H), 2.14(t,J=10.8Hz,2H), 1.81(d, J=11.6Hz,3H), 1.64(d,J=10.8Hz,2H), 1.49(d,J=8.8Hz,2H), 1.23(d,J=9.2Hz,3H). LCMS(ESI)C24H28N6O2[M+H] + m / z Calculated value: 461.26, Measured value: 461.40.

[0196] Example 12: Synthesis of compounds 136rac, 136a, and 136b

[0197] Synthesis of compounds 136rac, 136a, and 136b [ka]

[0198] Preparation of N,N-diethyl-2-fluoro-6-methylbenzamide (3) To a 50 mL solution of 2-fluoro-6-methylbenzoic acid (1) (1.00 g, 6.50 mmol) and diethylamine (2) (0.57 g, 7.80 mmol) in DCM, tri(o-tolyl)phosphine (50% in Â) (3.10 g, 9.75 mmol) and DIEA (4.20 g, 32.50 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / Â = 100:0 to 90:10) to obtain N,N-diethyl-2-fluoro-6-methylbenzamide (3) (0.90 g, yield 63%) as a white solid. LCMS(ESI)C12H16FNO[M+H] + m / z Calculated value: 210.12, Measured value: 210.09.

[0199] Preparation of 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid (5) In a dry, three-necked, round-bottom flask equipped with an additional funnel, 30 ml of anhydrous THF was added at -78°C under an inert atmosphere. 0.9 ml of LDA solution (2.5 M in THF) was added dropwise. Throughout this addition process, the internal temperature was maintained below -70°C. At -78°C, after 0.5 hours, a solution of N,N-diethyl-2-fluoro-6-methylbenzamide (3) (300 mg, 1.43 mmol) in anhydrous THF (10 mL) was added dropwise, and the mixture was stirred for 1 hour. Then, tert-butyl 3-cyanopyrrolidine-1-carboxylate (4) (366 mg, 1.86 mmol) was added at -78°C. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / EtOAC = 100:0 to 80:20) to obtain 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid (5) (160 mg, yield 32%) as a white solid. LCMS(ESI)C18H21FN2O3[M+H] + m / z Calculated value: 333.15, Measured value: 333.25.

[0200] Preparation of 8-fluoro-3-(pyrrolidine-3-yl)-2H-isoquinoline-1-one (6) 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid (5) (160 mg, 0.48 mmol) was added to HCl-dioxane (4 M, 10 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 8-fluoro-3-(pyrrolidine-3-yl)-2H-isoquinoline-1-one (6) (120 mg, 97% yield) as a white solid. LCMS(ESI)C13H13FN2O[M+H] + m / z Calculated value: 233.10, Measured value: 233.12.

[0201] Preparation of 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compound 136rac) To a solution of 8-fluoro-3-(pyrroridine-3-yl)-2H-isoquinoline-1-one (6) (120 mg, 0.52 mmol) in MeOH (15 mL), N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT) (100 mg, 0.55 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (30 mg, 0.46 mmol) at room temperature. The reaction mixture was stirred at 50°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-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compound 136rac) (65 mg, yield 25%, purity 99%) as a yellow solid. compound 136rac 1H NMR(400MHz,DMSO) δ 11.10(s,1H), 8.41-8.38(m,1H), 8.28(d,J=2.8Hz,1H), 7.83(d,J=8.8Hz,1H), 7.62- 7.58(m,1H), 7.45-7.36(m,2H), 7.10(dd,J=11.6,8.0Hz,1H), 6.46(d,J=1.6Hz,1H), 3 .84-3.80(m,2H), 3.23-3.16(m,1H), 3.00-2.92(m,3H), 2.84-2.65(m,6H), 2.38-2.3 3(m,1H), 2.24-2.18(m,1H), 1.97-1.97(m,2H), 1.84-1.76(m,1H), 1.60-1.49(m,2H). LCMS(ESI)C25H28FN5O2[M+H] + m / z Calculated value: 450.22, Measured value: 450.30.

[0202] Preparation of 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compounds 136a and 136b) [ka] 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (compound 136rac) was separated by SFC (column: Daicel CHIRALPAK OJ-H 250mm×20mm ID, 5μmm; mobile phase: CO2 / MeOH[0.1%(NH3)]=70 / 30), concentrated under reduced pressure, and the first fraction was obtained as compound 136a (12.8mg, purity 99%, ee%:100, white solid), and the second fraction as compound 136b (13.8mg, purity 99%, ee%:97, white solid). Compound 136a 1H NMR (400MHz, DMSO) δ 11.10(s,1H), 8.41(q,J=4.4Hz,1H), 8.28(d,J=2.8Hz,1H), 7.83(d,J=8.8Hz,1H), 7.62-7 .58(m,1H), 7.42-7.36(m,2H), 7.10(dd,J=12.0,8.0Hz,1H), 6.46(s,1H), 3.84-3.80(m,2 H), 3.22-3.15(m,1H), 3.00-2.90(m,3H), 2.81-2.63(m,6H), 2.36-2.31(m,1 H), 2.23-2.18(m,1H), 1.97-1.93(m,2H), 1.87-1.79(m,1H), 1.56-1.52(m,2 H). LCMS(ESI)C25H28FN5O2[M+H] + m / z calculated value: 450.22, measured value: 450.20. Compound 136b 1 H NMR (400MHz, DMSO) δ 11.10(s,1H), 8.40(q,J=4.8Hz,1H), 8.28 (d,J=2.8Hz,1H), 7.82(d,J=8.8Hz,1H), 7.61-7.58(m,1H), 7.42-7.36(m,2 H), 7.10(dd,J=11.6,8.0Hz,1H), 6.46(s,1H), 3.84-3.80(m,2H), 3.22-3.15(m,1H), 3.00-2.90(m,3H), 2.8 1-2.63(m,6H), 2.36-2.31(m,1H), 2.25-2.18(m,1H), 1.97-1.94(m,2H), 1.87-1.79(m,1H), 1.56-1.52(m,2 H). LCMS(ESI)C25H28FN5O2[M+H] + m / z calculated value: 450.22, measured value: 450.25.

[0203] Example 13: Synthesis of compounds 151rac, 151a, and 151b

[0204] Synthesis of compounds 151rac, 151a, and 151b

change

[0205] Preparation of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)-2,5-dihydropyrrole-1-carboxylate (3) To a 1,4-dioxane / H2O=4:1 (20 mL) solution of 6-bromo-2-methoxypyridine-3-amine (1) (1.38 g, 6.80 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (2) (2.01 g, 6.80 mmol) was added, followed by the addition of Pd(dppf)Cl2 (0.50 g, 0.68 mmol) and Na2CO3 (2.23 g, 21.08 mmol) at room temperature. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / EA = 100:0 to 85:15) to obtain tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)-2,5-dihydropyrrole-1-carboxylate (3) (1.50 g, yield 72%) as a white solid. LCMS(ESI)C15H21N3O3[M+H] + m / z Calculated value: 292.16, Measured value: 292.19.

[0206] Preparation of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (4) To a solution of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)-2,5-dihydropyrrole-1-carboxylate (3) (1.50 g, 5.10 mmol) in MeOH (20 mL), Pd / C (0.54 g, 5.10 mmol) was added at room temperature. The reaction mixture was stirred at 50°C for 2 hours under a hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the solution was concentrated under reduced pressure to obtain the product of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (4) (1.20 g, yield 76%) as a white solid. LCMS(ESI)C15H23N3O3[M+H] + m / z Calculated value: 294.17, Measured value: 294.18.

[0207] Preparation of tert-butyl 3-(5-bromo-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (5) To a solution of tert-butyl 3-(5-amino-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (4) (1.40 g, 4.80 mmol) in ACN (20 mL), tert-butyl nitrite (1.14 g, 11.04 mmol) was added. Then, CuBr (1.38 g, 9.60 mmol) was added at room temperature. 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 purified by flash chromatography (eluting at PE / EA = 100:0 to 85:15) to obtain tert-butyl 3-(5-bromo-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (5) (0.65 g, yield 35%) as a white solid. LCMS(ESI)C15H21BrN2O3[M+H] + m / z Calculated value: 357.07, Measured value: 357.11.

[0208] Preparation of tert-butyl 3-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (6) To a solution of tert-butyl 3-(5-bromo-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (5) (300 mg, 0.84 mmol) in 1,4-dioxane (15 mL), Pd(dppf)Cl2 (61 mg, 0.08 mmol) was added. Then, Et2Zn (5 mL, 0.14 mmol) was added at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80 °C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / EA = 100:0 to 85:15) to obtain tert-butyl 3-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (6) (120 mg, yield 44%) as a white solid. LCMS(ESI)C17H26N2O3[M+H] + m / z Calculated value: 307.19, Measured value: 307.25.

[0209] Preparation of 3-ethyl-6-(pyrrolidine-3-yl)-1H-pyridine-2-one (7) tert-butyl 3-(5-ethyl-6-methoxypyridine-2-yl)pyrrolidine-1-carboxylate (6) (120 mg, 0.39 mmol) was added to hydrogen bromide solution (48%, 15 mL). The reaction mixture was stirred at 100 °C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain 3-ethyl-6-(pyrrolidine-3-yl)-1H-pyridine-2-one (7) (70 mg, yield 88%) as a white solid. LCMS(ESI)C11H16N2O[M+H] + m / z Calculated value: 193.13, Measured value: 193.14.

[0210] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-6-fluoro-N-methylpicolinamide (151rac) To a solution of 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (100 mg, 0.40 mmol) in MeOH (40 mL), 3-ethyl-6-(pyrrolidine-3-yl)-1H-pyridine-2-one (7) (115 mg, 0.60 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (38 mg, 0.61 mmol) at room temperature. 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 chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-6-fluoro-N-methylpicolinamide (151rac) (40 mg, purity 95%, yield 22.34%) as a white solid. LCMS(ESI)C23H30FN5O2[M+H] + m / z Calculated value: 428.24, Measured value: 428.10.

[0211] Chiral separation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridine-2-yl)pyrrolidine-1-yl)piperidine-1-yl)-6-fluoro-N-methylpicolinamide (compound 151a and compound 151b) [ka] Compound 151をSFC(カラム: Daicel CHIRALPAK AD-H SFC 250mm×20mm ID, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 80 / 20), separation under reduced pressure, concentration under reduced pressure, first fractionation of compound 151a (15.8 mg, purity 92%, ee%: 100, white solid), the second fraction of compound 151b (15.9 mg, purity 95%, ee%: 100, white solid) was obtained. Compound 151a 1 ¹H NMR (400MHz, DMSO-d6, ppm) δ:11.28(s,1H), 8.44-8.37(m,1H), 7.83(dd,J=8.0,1.2Hz,1H), 7.61-7.52( m,1H), 7.17(d,J=7.2Hz,1H), 6.03(d,J=6.4Hz,1H), 3.56-3.43(m,2H), 3.17- 3.09(m,1H), 2.90-2.74(m,7H), 2.68-2.60(m,2H), 2.35-2.17(m,4H), 1.96(d ,J=12.0Hz,2H), 1.79-1.70(m,1H), 1.63-1.52(m,2H), 1.06(t,J=7.2Hz,3H). LCMS(ESI)C23H30FN5O2[M+H) + m / z calculated value: 428.24, measured value: 428.10. Compound 151b 1 ¹H NMR (400MHz, DMSO-d6, ppm) δ:11.28(s,1H), 8.45-8.35(m,1H), 7.83(dd,J=8.0,1.2Hz,1H), 7.64-7.51 (m,1H), 7.17(d,J=6.8Hz,1H), 6.03(d,J=6.8Hz,1H), 3.58-3.41(m,2H),3.1 7-3.09(m,1H), 2.93-2.74(m,7H), 2.68-2.60(m,2H), 2.35-2.16(m,4H), 2.0 1-1.92(m,2H), 1.79-1.70(m,1H), 1.64-1.52(m,2H), 1.06(t,J=7.2Hz,3H). LCMS(ESI)C23H30FN5O2[M+H) +m / z Calculated value: 428.24, Measured value: 428.20.

[0212] Synthesis of INT-2 [ka]

[0213] Preparation of 6-chloro-5-fluoro-N-methylpicolinamide (2) To a solution of 6-chloro-5-fluoropicolinic acid (1) (2.00 g, 11.40 mmol) in DMF (50 mL), methanamine (420 mg, 13.68 mmol), DIEA (4.42 g, 34.20 mmol), and HATU (6.50 g, 17.10 mmol) were sequentially added at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with ethyl acetate (200 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / ethyl acetate = 100:0 to 70:30) to obtain 6-chloro-5-fluoro-N-methylpicolinamide (2) (2.00 g, yield 88%) as a white solid. LCMS(ESI)C7H6ClFN2O[M+H] + m / z Calculated value: 189.02, Measured value: 188.90.

[0214] Preparation of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (4) To a solution of 6-chloro-5-fluoro-N-methylpicolinamide (2) (2.00 g, 10.60 mmol) in DMF (20 mL), Cs2CO3 (6.91 g, 21.20 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (3) (3.04 g, 21.20 mmol) were added. The mixture was stirred at 120 °C for 4 hours using a sealed test tube. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / EtOAC = 100:0 to 50:50) to obtain 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (4) (1.60 g, yield 42%) as a white solid. LCMS(ESI)C14H18ClN3O3[M+H] + m / z Calculated value: 312.10, Measured value: 311.95.

[0215] Preparation of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (5) 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (4) (300 mg, 0.96 mmol) was dissolved in DMF (20 mL) and CsF (293 mg, 1.93 mmol) was added. The mixture was stirred at 150 °C for 20 hours using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting from PE / EtOAC = 100:0 to 30:70) to obtain 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (5) (200 mg, yield 69%) as a yellow solid. LCMS(ESI)C14H18FN3O3[M+H] + m / z Calculated value: 296.13, Measured value: 295.95.

[0216] Preparation of 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) 6-Fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (5) (200 mg, 0.68 mmol) was dissolved in H2O (3 mL), to which formic acid (2 mL) was added and the mixture was stirred at 50°C for 1 hour. The pH of the aqueous solution was adjusted to 7 or higher using NaHCO3 solution. The mixture was diluted with water (50 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with saline solution (100 mL x 2), dried over Na2SO4, and concentrated to obtain the crude product of 6-Fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (100 mg, yield 47%) as a yellow solid. LCMS(ESI)C14H14FN3O2[M+H] + m / z Calculated value: 252.11, Measured value: 251.90.

[0217] Example 14: Synthesis of compounds 154rac, 154a, and 154b

[0218] Synthesis of compounds 154rac, 154a, and 154b [ka]

[0219] Preparation of 3-chloro-7-fluoro-1-methoxyisoquinoline (2) To a solution of 1,3-dichloro-7-fluoroisoquinoline (1) (500 mg, 2.32 mmol) in MeOH (50 mL), MeONa (150 mg, 2.78 mmol) was added at room temperature. The mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE / EtOAC = 100:0 to 98:2) to obtain 3-chloro-7-fluoro-1-methoxyisoquinoline (2) (160 mg, yield 33%) as a white solid. LCMS(ESI)C10H7ClFNO[M+H] + m / z Calculated value: 212.02, Measured value: 211.90.

[0220] Preparation of tert-butyl 3-(7-fluoro-1-methoxyisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4) To a 20 mL solution of 3-chloro-7-fluoro-1-methoxyisoquinoline (2) (160 mg, 0.76 mmol) in dioxane:H2O=5:1, tert-butyl 3-(4,4,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3) (270 mg, 0.92 mmol), Pd(dppf)Cl2 (50 mg, 0.07 mmol), and K2CO3 (250 mg, 1.81 mmol) were added at room temperature. The reaction mixture was stirred at 90°C for 3 hours under an N2 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 95:5) to obtain tert-butyl 3-(7-fluoro-1-methoxyisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4) (160 mg, yield 61%) as a white solid. LCMS(ESI)C19H21FN2O3[M+H] +m / z Calculated value: 345.15, Measured value: 345.11.

[0221] Preparation of tert-butyl 3-(7-fluoro-1-methoxyisoquinoline-3-yl)pyrrolidine-1-carboxylate (5) To a solution of tert-butyl 3-(7-fluoro-1-methoxyisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4) (160 g, 0.46 mmol) in MeOH (20 mL), Pd / C (35 mg, 0.29 mmol) was added under an H2 atmosphere. The reaction mixture was stirred at room temperature for 5 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain tert-butyl 3-(7-fluoro-1-methoxyisoquinoline-3-yl)pyrrolidine-1-carboxylate (5) (140 mg, yield 88%) as a white solid. LCMS(ESI)C19H23FN2O3[M+H] + m / z Calculated value: 347.17, Measured value: 347.18.

[0222] Preparation of 7-fluoro-3-(pyrrolidine-3-yl)isoquinoline-1(2H)-one(6) tert-butyl 3-(7-fluoro-1-methoxyisoquinoline-3-yl)pyrrolidine-1-carboxylate (5) (140 mg, 0.40 mmol) was added to hydrogen bromide solution (48%, 3 mL). The mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 7-fluoro-3-(pyrrolidine-3-yl)isoquinoline-1(2H)-one (6) (90 mg, yield 97%) as a white solid. LCMS(ESI)C13H13FN2O[M+H] + m / z Calculated value: 233.10, Measured value: 232.95.

[0223] Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compound 154rac) To a solution of 7-fluoro-3-(pyrrolidine-3-yl)isoquinoline-1(2H)-one (6) (90 mg, 0.39 mmol) in MeOH (15 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (100 mg, 0.43 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (25 mg, 0.40 mmol) at room temperature. The reaction mixture was stirred at 50°C for 4 hours. After cooling to room temperature, the residue was purified by preparative HPLC (column: Gemini 5um C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 10-25) to obtain 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compound 154rac) (35 mg, purity 99%, yield 20%) as a white solid. compound 154rac 1 H NMR(400MHz,DMSO) δ 11.35(s,1H), 8.39(q,J=4.8Hz,1H), 8.30(d,J=2.8Hz,1H), 7.87-7.76(m,2H),7.70(dd,J=8.8,5.2Hz,1H), 7.59(td,J=8.8,2.8Hz,1H), 7.43(dd,J=8.8, 2.8Hz,1H), 6.57(s,1H), 4.02-3.85(m,2H), 3.31-2.71(m,11H), 2.40-2.25(m,1H), 2.13-1.88(m,3H), 1.68-1.52(m,2H). LCMS(ESI)C25H28FN5O2[M+H] + m / z Calculated value: 450.22, Measured value: 450.23.

[0224] Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compounds 154a and 154b) [ka] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compound 154rac) was separated by SFC (column: Daicel CHIRALPAK OJ-H 4.6mm ID*250mmL 5μmm; mobile phase: CO2 / MeOH [0.1% NH3 (solution of 7M in MeOH)] = 75 / 25), concentrated under reduced pressure, and the first fraction was obtained as compound 154a (10 mg, purity 99%, ee%: 100, white solid), and the second fraction as compound 154b (10 mg, purity 97%, ee%: 100, white solid). Compound 154a 1 H NMR(400MHz,DMSO) δ 11.25(s,1H), 8.39(d,J=4.8Hz,1H), 8.28(d,J=2.8Hz,1H), 7.82(d,J=8.4Hz,1H), 7.77(dd,J=9.2,2 .8Hz,1H), 7.68(dd,J=8.8,5.6Hz,1H), 7.56(td,J=8.8,2.8Hz,1H), 7.40(dd,J=8.8,2.8Hz,1H), 6.5 1(s,1H), 3.87-3.77(m,2H), 3.25-3.17(m,1H), 3.03-2.91(m,3H), 2.85-2.75(m,4H), 2.74-2.66(m, 2H), 2.35-2.32(m,1H), 2.28-2.17(m,1H), 2.01-1.90(m,2H), 1.88-1.78(m,1H), 1.60-1.47(m,2H). LCMS(ESI)C25H28FN5O2[M+H] + m / z Calculated value: 450.22, Measured value: 450.20. Compound 154b 1H NMR (400MHz, DMSO) δ 11.25(s,1H), 8.39(d,J=4.8Hz,1H), 8.28(d,J=2.8Hz,1H), 7.82(d,J=8.8H z,1H), 7.77(dd,J=9.2,2.8Hz,1H), 7.68(dd,J=8.8,5.2Hz,1H), 7.56(td,J =8.8,2.8Hz,1H), 7.40(dd,J=8.8,2.8Hz,1H), 6.51(s,1H), 3.88-3.78(m,2H), 3.26-3.16(m,1H), 3.03-2.91(m,3H), 2.83-2. 78(m,4H), 2.74-2.66(m,2H), 2.35-2.31(m,1H), 2.28-2.17(m,1H), 2.00-1.92(m,2H), 1.89-1.79(m,1H), 1.61-1.47(m,2H). LCMS(ESI)C25H28FN5O2[M+H] + m / z calculated value: 450.22, measured value: 450.20.

[0225] Example 15: Synthesis of compounds 162rac, 162a, and 162b

[0226] Synthesis of compounds 162rac, 162a, and 162b

change

change

change

[0227] Preparation of 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2) 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1) (5 g, 26.50 mmol) was dissolved in ACN / DMF = 1:1 (100 mL) and NIS (8.9 g, 39.75 mmol) was added. The resulting mixture was stirred at 90 °C for 3 hours. The residue was purified by flash chromatography (eluting PE / ELISA = 100:0 to 72:28) to obtain 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2) (2.9 g, yield 35%) as a white solid. LCMS(ESI)C5HCl2IN4[M+H] + m / z Calculated value: 314.86, Measured value: 314.85.

[0228] Preparation of 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (3) To a solution of 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2) (2.9 g, 9.24 mmol) in THF (40 mL), NaH (290 mg, 11.96 mmol) was added at 0°C, and the mixture was stirred for 10 minutes. Then, SEMCl (2.3 g, 13.80 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (3) (3.6 g, yield 88%) as a white solid. LCMS(ESI)C11H15Cl2IN4OSi[M+H] + m / z Calculated value: 444.94, Measured value: 444.85.

[0229] Preparation of 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (4) 4,6-Dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (3) (1.5 g, 3.39 mmol) was dissolved in MeOH (45 mL), to which MeONa (183 mg, 3.39 mmol) was added. The mixture was stirred at room temperature for 1 hour. The residue was purified by flash chromatography (eluting at PE / Âx = 100:0 to 95:5) to obtain 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (4) (282 mg, yield 19%) as a white solid. LCMS(ESI)C12H18ClIN4O2Si[M+H] + m / z Calculated value: 440.99, Measured value: 441.01.

[0230] Preparation of 6-chloro-4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (6) To a solution of 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (4) (282 mg, 0.64 mmol) and 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (5) (491 mg, 2.56 mmol) in DMF (15 mL), CuCl2 (131 mg, 0.98 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 2 hours. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 96:4) to obtain 6-chloro-4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (6) (220 mg, yield 90%) as a white solid. LCMS(ESI)C13H18ClF3N4O2Si[M+H] + m / z Calculated value: 383.08, Measured value: 383.08.

[0231] Preparation of tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) Na2CO3 (165 mg, 1.56 mmol) was added under a nitrogen atmosphere to a 1,4-dioxane / H2O = 10:1 (11 mL) solution of tert-butyl 3-(4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (6) (200 mg, 0.52 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (154 mg, 0.52 mmol) and Pd(dppf)Cl2 (23 mg, 0.031 mmol). The reaction mixture was stirred at 100°C for 2 hours. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 93:7) to obtain tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (280 mg, yield 94%) as an orange oil. LCMS(ESI)C27H32F3N5O4Si[M+H] + m / z Calculated value: 516.22, Measured value: 516.23.

[0232] Preparation of tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)pyrrolidine-1-carboxylate (9) To a solution of tert-butyl 3-(4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrazolo[2,3-d]pyrimidine-2-yl)pyrrolidine-1-carboxylate (8) (280 mg, 0.54 mmol) in MeOH (15 mL), Pd / C (114 mg, 1.08 mmol) was added under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)pyrrolidine-1-carboxylate (9) (158 mg, yield 56%) as a white solid. LCMS(ESI)C22H34F3N5O4Si[M+H] + m / z Calculated value: 518.23, Measured value: 518.25.

[0233] Preparation of 6-(pyrrolidine-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (10) tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)pyrrolidine-1-carboxylate (9) (158 mg, 0.31 mmol) was added to hydrogen bromide solution (5 mL). The reaction mixture was stirred at 100 °C for 2 hours. The mixture was then concentrated under vacuum to obtain 6-(pyrrolidine-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (10) (80 mg, yield 96%) as a white solid. LCMS(ESI)C10H10F3N5O[M+H] + m / z Calculated value: 274.08, Measured value: 274.00.

[0234] Preparation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrro[3,4-d]pyrimidine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (162rac) Two drops of HOAC were added to a 10 mL solution of 6-(pyrroridine-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (10) (80 mg, 0.29 mmol), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (90 mg, 0.29 mmol), and sodium triacetoxyborohydride (92 mg, 0.44 mmol) in MeOH, and the solution was stirred at 50°C for 0.5 hours. Then, NaBH3CN (22 mg, 0.35 mmol) was added. The mixture was stirred at 50°C for 18 hours. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrro[3,4-d]pyrimidine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (162rac) (69 mg, yield 48%) as a white solid. LCMS(ESI)C22H25F3N8O2[M+H] + m / z Calculated value: 491.21, Measured value: 491.25.

[0235] Chiral separation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrro[3,4-d]pyrimidine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (162a and 162b) Compound 162rac was separated by SFC (column: Daicel OJ-H 4.6mm ID*250mmL 5μm; mobile phase: CO2 / MeOH [0.1% NH3 (7M solution in MeOH)] = 70 / 30), concentrated under reduced pressure, and the first fraction was obtained as 162a (39 mg, purity 93%, ee%: 100, white solid), and the second fraction as compound 162b (31 mg, purity 99%, ee%: 100, white solid). Compound 162a 1H NMR (400MHz, DMSO) δ 14.37(s,1H), 12.27(s,1H), 8.39(q,J=4.4Hz,1H), 8.27(d,J=2.8Hz,1H), 7.82(d, J=8.8Hz,1H), 7.40(dd,J=8.4,2.8Hz,1H), 3.83(d,J=12.8Hz,2H), 3.38-3.35(m,1 H), 3.06(t,J=8.4Hz,1H), 2.98-2.88(m,2H), 2.83-2.73(m,5H), 2.68-2.61(m,1H) ,2.39-2.29(m,1H), 2.21-2.09(m,2H), 1.93(d,J=11.6Hz,2H), 1.55-1.43(m,2H). LCMS(ESI)C22H25F3N8O2[M+H] + m / z calculated value: 491.21, measured value: 491.26. Compound 162b 1 H NMR(400MHz,) δ 14.41(s,1H), 12.41(s,1H), 8.39(q,J=4.8Hz,1H), 8.28(d,J=2.0Hz,1H), 7.82(d,J=8.8Hz,1H), 7.41(dd,J=8.8,2.0Hz,1H), 3 .86(s,1H), 3.30-3.27(m,1H), 3.16-3.03(m,1H), 2.96-2.58(m,8H), 2.34-2.10(m,3H), 2.03-1.88(m,2H), 1.63-1.44(m,2H). LCMS(ESI)C22H25F3N8O2[M+H] + m / z calculated value: 491.21, measured value: 491.25.

[0236] Example 16: Synthesis of compounds 184rac, 184a, and 184b

[0237] Synthesis of compounds 184rac, 184a, and 184b

change

[0238] Preparation of 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (184rac) To a solution of 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT-1) (92 mg, 0.40 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (2) (intermediate (6) in the synthesis of compound 136) (100 mg, 0.40 mmol) was added. Then, two drops of acetic acid and NaBH3CN (25 mg, 0.26 mmol) were added at room temperature. The reaction mixture was stirred at 50°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 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (184rac) (60 mg, yield 27%) as a colorless oil. LCMS(ESI)C25H27F2N5O2[M+H] + m / z Calculated value: 468.21, Measured value: 468.26.

[0239] Preparation of 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (184a and 184b) 6-Fluoro-5-{4-[3-(8-Fluoro-1-oxo-2H-isoquinoline-3-yl)pyrrolidine-1-yl]piperidine-1-yl}-N-methylpyridine-2-carboxamide (184rac) was separated by SFC (column: Daicel CHIRALPAK OJ-H 250mm×20mm ID5μmm; mobile phase: CO2 / MeOH[0.1%NH3]=80 / 20), concentrated under reduced pressure, and the first fraction was obtained as 184a (24.5mg, purity 98%, ee%:100, white solid), and the second fraction as compound 184b (24.4mg, purity 99%, ee%:97, white solid). Compound 184a 1H NMR (400MHz, DMSO) δ 11.10(s,1H), 8.41(q,J=5.2Hz,1H), 7.85(d,J=7.2Hz,1H), 7.64-7.56(m,2H), 7.39(d,J=7.6Hz,1H), 7.10(dd,J=12.0 ,8.0Hz,1H), 6.47(s,1H), 3.52-3.51(m,2H), 3.22-3.16(m,1H), 2.91-2.73(m,8H), 2.67-2.63(m,1H), 2.30-2.22(m,2 H), 2.00-1.97(m,2H), 1.86-1.79(m,1H), 1.68-1.53​​(m,2H). LCMS(ESI)C25H27F2N5O2[M+H) + m / z calculated value: 468.21, measured value: 468.22. Compound 184b 1 H NMR (400MHz, DMSO) δ 11.10(s,1H), 8.41(q,J=4.8Hz,1H), 7.85(dd,J=8.0,1.2Hz,1H), 7.64-7.5 6(m,2H), 7.39(d,J=7.6Hz,1H), 7.11(dd,J=11.6,8.0Hz,1H), 6.46(s,1H), 3 .53-3.49(m,2H), 3.21-2.87(m,1H), 2.93-2.71(m,8H), 2.68-2.63(m,1H), 2.28-2.19(m,2H), 2.00-1.97(m,2H), 1.88-1.79(m,1H), 1.64-1.54(m,2H). LCMS(ESI)C25H27F2N5O2[M+H) + m / z calculated value: 468.21, measured value: 468.18.

[0240] Example 17: Synthesis of Compound 192

[0241] Synthesis of compound 192

change

[0242] Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) 2-aminobenzamide (1) (360 mg, 2.64 mmol) and 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (2) (500 mg, 2.20 mmol) were dissolved in pyridine (30 mL), to which EDCI (422 mg, 2.20 mmol) was added. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with siRNA (200 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (600 mg, 90% yield) as a white solid. LCMS(ESI)C18H23N3O4[M+Na] + m / z Calculated value: 368.17, Measured value: 368.05.

[0243] Preparation of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) To a solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate(3) (600 mg, 1.74 mmol) in DME (60 mL), KOH (195 mg, 3.47 mmol) was added, the mixture was heated to 60 °C, stirred for 2 hours, cooled to 25 °C, and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate(4) (400 mg, yield 63%) as a white solid. LCMS(ESI)C18H21N3O3[M+H] + m / z Calculated value: 328.16, Measured value: 328.05.

[0244] Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)quinazoline-4(3H)-one(5) tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (400 mg, 0.56 mmol) was added to a 4 M, 10 mL solution of dioxane in HCl. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-(2-azabicyclo[2.1.1]hexane-4-yl)quinazolin-4(3H)-one (5) (320 mg, 93% yield) as a white solid. LCMS(ESI)C13H13N3O[M+H] + m / z Calculated value: 228.11, Measured value: 228.02.

[0245] Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (compound 192) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)quinazoline-4(3H)-one (5) (80 mg, 0.35 mmol) in MeOH (40 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT, 98 mg, 0.42 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH(OAC)3 (149 mg, 0.70 mmol) at room temperature. The reaction mixture was stirred at 50°C for 1 hour. Then, NaBH3CN (11.06 mg, 0.176 mmol) was added. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using a C18 column (mobile phase: ACN-H2O (0.1% FA), gradient: 10-95) to obtain N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (compound 192) (25.6 mg, purity 99%, yield 16%) as a white solid. compound 192 1H NMR(400MHz,DMSO-d6,ppm) δ:12.17(s,1H), 8.43-8.36(m,1H), 8.29(d,J=2.8Hz,1H), 8.17(s,1H), 8.10(dd,J=8.0, 1.2Hz,1H), 7.86-7.76(m,2H), 7.62(d,J=7.8Hz,1H), 7.52-7.47(m,1H), 7.42(dd,J=8.8 ,2.9Hz,1H), 3.93-3.86(m,2H), 3.76(s,1H), 3.12(s,2H), 2.97-2.90(m,2H), 2.78(d,J= 4.8Hz,3H), 2.69-2.62(m,1H), 2.19-2.14(m,2H), 2.02-1.90(m,4H), 1.54-1.44(m,2H). LCMS(ESI)C25H28N6O2[M+H] + m / z calculated value: 445.23, measured value: 445.15.

[0246] Example 18: Synthesis of compounds 194a and 194b

[0247] Synthesis of compounds 194a and 194b

change

change

change

[0248] Preparation of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2) 6-chloro-1H-pyrazolo[4,3-c]pyridine (1) (10.00 g, 0.06 mol) was dissolved in DMF (200 mL) and NIS (8.44 g, 0.08 mol) was added. The mixture was stirred at 60°C for 3 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE / ELISA = 100:0 to 60:40) to obtain 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2) (10.5 g, yield 64%) as a yellow solid. LCMS(ESI)C6H3ClIN3[M+H] + m / z Calculated value: 279.91, Measured value: 280.00.

[0249] Preparation of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(3) 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine(2) (10.50 g, 0.04 mol) and NaH (2.70 g, 0.11 mol) were suspended in DMF (200 mL) and stirred at 0°C for 30 minutes, then SEMCl (12.30 g, 0.08 mol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / ELISA = 100:0 to 70:30) to obtain 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(3) (9.90 g, yield 61%) as a yellow solid. LCMS(ESI)C12H17ClIN3OSi[M+H] + m / z Calculated value: 409.99, Measured value: 410.05.

[0250] Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (5) To a solution of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (3) (9.90 g, 0.02 mol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4) (23.04 g, 0.12 mol) in DMF (80 mL), CuI (9.15 g, 0.04 mmol) and HMPA (21.35 g, 0.12 mmol) were added at room temperature. The mixture was stirred at 110 °C for 2 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / Â=100:0 to 80:20) to obtain 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (5) (3.30 g, yield 38%) as a yellow solid. LCMS(ESI)C13H17ClF3N3OSi[M+H] + m / z Calculated value: 352.08, Measured value: 352.20.

[0251] Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (6) 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(5) (3.30 g, 0.01 mmol) was dissolved in HOAc solution (20 mL) and H2O2 (20 mL) was added. The reaction mixture was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (30 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE / ELISA = 100:0 to 55:45) to obtain 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide(6) (1.60 g, yield 48%) as a yellow oil. LCMS(ESI)C13H17ClF3N3O2Si[M+H] + m / z Calculated value: 368.07, Measured value: 367.97.

[0252] Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (7) To a solution of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (6) (800 mg, 2.16 mmol), H2O (15 mL) and MsCl (1.00 g, 8.62 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE / ELISA = 100:0 to 85:15) to obtain 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (7) (400 mg, yield 48%) as a yellow oil. LCMS(ESI)C13H17ClF3N3O2Si[M+H] + m / z Calculated value: 368.07, Measured value: 368.01.

[0253] Preparation of 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (8) 6-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (7) (400 mg, 1.07 mmol) and Cs2CO3 (1.25 g, 3.85 mmol) were dissolved in DMF (15 mL), to which PMBCl (0.84 g, 5.35 mmol) was added at room temperature. The reaction mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the combined organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / Â=100:0 to 85:15) to obtain 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (8) (200 mg, yield 32%) as a yellow oil. LCMS(ESI)C21H25ClF3N3O3Si[M+H] +m / z Calculated value: 488.13, Measured value: 488.15.

[0254] Preparation of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) To a 15 mL solution of 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (8) (200 mg, 0.48 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (9) (150 mg, 0.50 mmol) in a dioxane:H2O=5:1 ratio, Pd(dppf)Cl2 (50 mg, 0.07 mmol) and Na2CO3 (70 mg, 0.06 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (eluting at PE / siRNA = 100:0 to 80:20) to obtain tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) (140 mg, yield 60%) as a yellow oil. LCMS(ESI)C30H39F3N4O5Si[M+H] + m / z Calculated value: 621.26, Measured value: 621.30.

[0255] Preparation of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-yl)pyrrolidine-1-carboxylate (11) To a solution of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) (140 mg, 0.30 mmol) in MeOH (15 mL), Pd / c (60 mg, 0.57 mmol) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-yl)pyrrolidine-1-carboxylate (11) (120 mg, yield 80%) as a colorless oil. LCMS(ESI)C30H41F3N4O5Si[M+H] + m / z Calculated value: 623.28, Measured value: 623.30.

[0256] Preparation of 6-(pyrroridine-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (12) Two drops of TfOH were added to a solution of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazole[4,3-c]pyridine-6-yl)pyrrolidine-1-carboxylate (11) (120 mg, 0.19 mmol) in TFA (5 mL). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 6-(pyrrolidine-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazole[4,3-c]pyridine-4-one (12) (50 mg, yield 90%) as a yellow oil. LCMS(ESI)C11H11F3N4O[M+H] + m / z Calculated value: 273.09, Measured value: 273.15.

[0257] Preparation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[4,3-c]pyridine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (racemic mixture of 194a and 194b) To a solution of 6-(pyrrolidine-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one (12) (50 mg, 0.18 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT) (43 mg, 0.18 mmol) was added. Then, two drops of acetic acid and NaBH3CN (12 mg, 0.18 mmol) were added at room temperature. The reaction mixture was stirred at 50°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 N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (racemic mixture of compounds 194a and 194b) (30 mg, yield 32%) as a white solid. LCMS(ESI)C23H26F3N7O2[M+H] + m / z Calculated value: 490.21, Measured value: 490.17.

[0258] Chiral separation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[4,3-c]pyridine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (compounds 194a and 194b) A racemic mixture (194rac) of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[4,3-c]pyridine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide was separated by SFC (column: Daicel CHIRALPAK OJ-H 250mm×20mm ID5μmm; mobile phase: CO2 / MeOH[0.1%NH3]=70 / 30), concentrated under reduced pressure, and the first fraction was obtained as compound 194a (9.9mg, purity 98%, ee%:100, white solid), and the second fraction as compound 194b (9.4mg, purity 100%, ee%:98, white solid). Compound 194a 1H NMR (400MHz, DMSO) δ 13.82(s,1H), 11.10(s,1H), 8.39(q,J=4.4Hz,1H), 8.28(d,J=2.8Hz,1H), 7.83(d,J=8.8H z,1H), 7.41(dd,J=8.8,2.8Hz,1H), 6.39(s,1H), 3.84-3.81(m,2H), 3.29-3.25(m,1H), 2. 98(t,J=11.2Hz,2H), 2.89-2.85(m,1H), 2.81-2.78(m,5H), 2.60-2.56(m,1H), 2.39-2.30 (m,1H), 2.30-2.17(m,1H), 1.97(d,J=12.0Hz,2H), 1.83-1.77(m,1H), 1.56-1.51(m,2H). LCMS(ESI)C23H26F3N7O2[M+H) + m / z calculated value: 490.21, measured value: 490.20. Compound 194b 1 H NMR (400MHz, DMSO) δ 13.82(s,1H), 11.10(s,1H), 8.39(q,J=4.4Hz,1H), 8.28(d,J=2.8Hz,1H), 7.83 (d,J=8.8Hz,1H), 7.41(dd,J=8.8,2.8Hz,1H), 6.39(s,1H), 3.84-3.81(m,2H), 3.29-3.25(m,1H), 2.98(t,J=11.2Hz,2H), 2.89-2.85(m,1H), 2.81-2.78(m,5H ), 2.60-2.56(m,1H), 2.39-2.30(m,1H), 2.30-2.17(m,1H), 1.97(d,J=12.0Hz,2 H), 1.83-1.77(m,1H), 1.56-1.51(m,2H). LCMS(ESI)C23H26F3N7O2[M+H) + m / z calculated value: 490.21, measured value: 490.16.

[0259] Example 19: Synthesis of compounds 208a and 208b

[0260] Synthesis of compounds 208a and 208b

change

[0261] Preparation of 2-chloropyrido[2,3-d]pyrimidine-4(3H)-one(2) To a solution of 2,4-dichloropyrido[2,3-d]pyrimidine (1) (1.5 g, 0.0075 mol) in EtOH (30 mL), NaOH (0.66 g, 0.017 mol) and H2O (16.5 mL) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, and the pH was adjusted to 4-5 using 1 M HCl. The solution was filtered, the filter cake was collected, and dried under vacuum to obtain 2-chloropyrido[2,3-d]pyrimidine-4(3H)-one (2) (1.1 g, purity 90%, yield 73%) as a yellow solid. LCMS(ESI)C7H4ClN3O[M+H] + m / z Calculated value: 182.00, Measured value: 181.90.

[0262] Preparation of 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(3) 2-chloropyrido[2,3-d]pyrimidine-4(3H)-one (2) (1.1 g, 0.0061 mol) was dissolved in THF / H2O = 4:1 (50 mL), and PtO2 (0.14 g) was added to the solution. The mixture was then stirred at room temperature under a hydrogen atmosphere for 18 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one (3) (1.1 g, purity 95%, yield 91%) as a yellow solid. LCMS(ESI)C7H8ClN3O[M+H] + m / z Calculated value: 186.04, Measured value: 185.95.

[0263] Preparation of 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(4) To a DMSO (150 mL) solution of 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one (3) (0.9 g, 4.85 mmol), Cs2CO3 (4.7 g, 14.5 mmol) and PMBCl (1.52 g, 9.7 mmol) were added at room temperature. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was quenched with water and extracted with ELISA (100 mL x 3). The combined organic phases were washed three times with saline solution and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 50:50) to obtain 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(4) (1.23 g, purity 90%, yield 74%) as a white solid. LCMS(ESI)C15H16ClN3O2[M+H] + m / z Calculated value: 306.09, Measured value: 305.80.

[0264] Preparation of 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(5) To a solution of 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(4) (1.2 g, 0.004 mol) in DMF (50 mL), MeI (3.05 g, 0.02 mol) and NaH (60% in mineral oil, 0.32 g, 0.008 mol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with ELISA (100 mL x 3). The combined organic layers were washed three times with saline solution and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 50:50) to obtain 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(5) (450 mg, purity 90%, yield 33%) as a yellow oil. LCMS(ESI)C16H18ClN3O2[M+H] + m / z Calculated value: 320.11, Measured value: 320.00.

[0265] Preparation of tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) To a 30 mL solution of 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one (5) (450 mg, 1.41 mmol) in a dioxane / H2O ratio of 5:1, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (6) (500 mg, 1.69 mmol), Pd(dppf)Cl2·DCM (115 mg, 0.14 mmol), and K2CO3 (587 mg, 4.22 mmol) were added at room temperature. The reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was quenched with water and extracted with ELISA (50 mL x 3). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 50:50) to obtain tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (550 mg, purity 90%, yield 77%) as a white solid. LCMS(ESI)C25H32N4O4[M+H] + m / z Calculated value: 453.24, Measured value: 453.20.

[0266] Preparation of tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)pyrrolidine-1-carboxylate (8) To a solution of tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (550 mg, 1.2 mmol) in MeOH (15 mL), Pd / C (55 mg) was added at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered, and the filter cake was washed with MeOH (5 mL x 2). The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)pyrrolidine-1-carboxylate (8) (400 mg, purity 90%, yield 88%) as a yellow oil. LCMS(ESI)C17H26N4O3[M+H] + m / z Calculated value: 335.20, Measured value: 335.30

[0267] Preparation of 8-methyl-2-(pyrrolidine-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one hydrochloride (9) A solution of tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)pyrrolidine-1-carboxylate (8) (200 mg, 0.60 mmol) in HCl-dioxane (4 M, 10 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The formed precipitate was washed with DCM (5 mL x 3), collected, and dried under reduced pressure to obtain 8-methyl-2-(pyrrolidine-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one hydrochloride (9) (110 mg, purity 90%, yield 70%) as a white solid. LCMS(ESI)C12H18N4O[M+H] + m / z Calculated value: 235.15, Measured value: 235.00.

[0268] Preparation of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (208a and 208b) To a solution of 8-methyl-2-(pyrroridine-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one hydrochloride (9) (110 mg, 0.46 mmol) in MeOH (1 mL), TEA (1 mL) was added at room temperature and the mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure until dry. The residue was dissolved in MeOH (15 mL) and AcOH (0.01 mL) at room temperature, and N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (131 mg, 0.56 mmol) and NaBH3CN (88 mg, 1.40 mmol) were added. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain a racemic mixture (208rac) (120 mg, purity 99%, yield 55%) of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide as a white solid. LCMS(ESI)C24H33N7O2[M+H] + m / z Calculated value: 452.27, Measured value: 452.20.

[0269] Chiral separation of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (208rac) A racemic mixture of compounds 208a and 208b was separated by SFC (column: Daicel CHIRALPAK IH SFC, 250mm × 20mm ID, 5μmm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 70 / 30), concentrated under reduced pressure, and the first fraction was obtained as compound 208a (52.3 mg, purity 99%, ee%: 100, white solid), and the second fraction as compound 208b (54.2 mg, purity 100%, ee%: 98, white solid). Compound 208a 1H NMR(400MHz,DMSO-d6,ppm) δ:11.37(s, 1H), 8.43-8.34(m,1H), 8.26(d,J=2.8Hz,1H), 7.81(d,J=8.8Hz,1H), 7.39(dd,J=8.8, 3.2Hz,1H), 3.82-3.77(m,2H), 3.23-3.20(m,2H), 3.13-3.09(m,1H), 3.03(s,3H), 2.9 9-2.92(m,3H), 2.78(d,J=4.8Hz,3H), 2.68-2.66(m,1H), 2.59-2.57(m,1H), 2.35-2.2 6(m,4H), 2.07-2.00(m,2H), 1.94-1.88(m,2H), 1.78-1.72(m,2H), 1.53-1.44(m,2H). LCMS(ESI)C24H33N7O2[M+H] + m / z calculated value: 452.27, measured value: 452.30. Compound 208b 1 H NMR(400MHz,DMSO-d6,ppm) δ:11.35(s,1H), 8.41-8.33(m,1H), 8.26(d,J=2.8Hz,1H), 7.81(d,J=8.8Hz,1H), 7.39(d d,J=8.8,2.8Hz,1H), 3.85-3.75(m,2H), 3.24-3.19(m,2H), 3.14-3.07(m,1H), 3.03(s,3H ), 3.00-2.88(m,3H), 2.77(d,J=4.8Hz,3H), 2.67-2.62(m,1H), 2.61-2.56(m,1H), 2.35- 2.21(m,4H), 2.09-1.99(m,2H), 1.96-1.87(m,2H), 1.79-1.70(m,2H), 1.55-1.43(m,2H). LCMS(ESI)C24H33N7O2[M+H] + m / z calculated value: 452.27, measured value: 452.30.

[0270] Example 20: Synthesis of compound INT-3

[0271] Synthesis of compound INT-3

[0272] Preparation of tert-butyl 3-(4-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-carboxylate (INT-3) [ka] To a solution of tert-butyl 3-(1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-carboxylate (1) (500 mg, 1.59 mmol) in DMAC (20 mL), Selectfluor (563 mg, 1.59 mmol) was added at room temperature. The mixture was stirred at 150 °C for 10 minutes. After cooling to room temperature, the reaction mixture was added to cold water and extracted with  (100 mL x 3). The combined organic phase was washed with saline solution, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE /  = 100:0 to 50:50) to obtain tert-butyl 3-(4-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-carboxylate (INT-3) (100 mg, purity 60%, yield 11%) as a yellow oil. LCMS(ESI)C18H21FN2O3[M+H] + m / z Calculated value: 333.15, Measured value: 332.90.

[0273] Example 21: Synthesis of Compound 259

[0274] Synthesis of compound 259 [ka]

[0275] Preparation of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) 2-amino-5-fluorobenzamide (1) (30 mg, 2.21 mmol) and 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (2) (520 mg, 2.20 mmol) were dissolved in pyridine (20 mL), to which EDCI (423 mg, 2.21 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ELISA (150 mL x 3). The combined organic phases were washed with 1 M HCl solution and saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, yield 56%) as a white solid. LCMS(ESI)C18H22FN3O4[M+Na] + m / z Calculated value: 386.16, Measured value: 385.95.

[0276] Preparation of tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) To a solution of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, 1.38 mmol) in DME (60 mL), KOH (154 mg, 2.75 mmol) was added. This solution was stirred at 60 °C for 2 hours, cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (400 mg, yield 76%) as a white solid. LCMS(ESI)C18H20FN3O3[M+H] + m / z Calculated value: 346.15, Measured value: 345.85

[0277] Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazoline-4(3H)-one(5) To a solution of tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (400 mg, 1.16 mmol) in DCM (10 mL), a solution of dioxane in HCl (4 mL, 20 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazolin-4(3H)-one (5) (200 mg, yield 63%) as a white solid. LCMS(ESI)C15H17N3O[M+H] + m / z Calculated value: 246.10, Measured value: 245.95.

[0278] Preparation of 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)-N-methylpicolinamide (compound 259) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazoline-4(3H)-one (5) (60 mg, 0.24 mmol) in MeOH (20 mL), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (61 mg, 0.24 mmol) was added. Then, two drops of acetic acid and NaBH3CN (8 mg, 0.13 mmol) were added at room temperature. The reaction mixture was stirred at 50 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using a C18 column (mobile phase: ACN-H2O (0.1% FA), gradient: 10-95) to obtain 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)-N-methylpicolinamide (259) (45.5 mg, purity 99%, yield 15%) as a white solid. 1H NMR(400MHz,DMSO-d6,ppm) δ:12.29(s,1H), 8.40(q,1H), 7.84(dd,J=8.0,1.2Hz,1H), 7.77(dd,J=8.4,2.8 Hz,1H), 7.72-7.65(m,2H), 7.62-7.56(m,1H), 3.70(s,1H), 3.59-3.53(m,2H), 3 .05(s,2H), 2.86(t,J=11.2Hz,2H), 2.77(d,J=4.8Hz,3H), 2.57-2.52(m,1H), 2 .15-2.09(m,2H), 1.99(d,J=10.8Hz,2H), 1.92-1.86(m,2H), 1.58-1.47(m,2H). LCMS(ESI)C25H26F2N6O2[M+H] + m / z Calculated value: 481.21, Measured value: 481.05.

[0279] Example 22: Synthesis of Compound 299

[0280] Synthesis of compound 299 [ka]

[0281] Preparation of tert-butyl ((1-(6-(methylcarbamoyl)pyridine-3-yl)piperidine-4-yl)methyl)carbamate (2) 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (1) (500 mg, 2.19 mmol) was dissolved in DCM (20 mL) and NH4Cl (234 mg, 4.38 mmol), DIPEA (1415 mg, 10.95 mmol), and HATU (1249 mg, 3.28 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with DCM (50 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH / DCM, eluted at 3%~5%) to obtain tert-butyl 4-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (2) (400 mg, purity 90%, yield 72%) as a white solid. LCMS(ESI)C11H18N2O3[M-56+H] + m / z Calculated value: 171.13, Measured value: 171.10.

[0282] Preparation of tert-butyl 4-carbamimidyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) tert-butyl 4-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate(2) (400 mg, 1.76 mmol) is added to Me3O + BF 4- (312 mg, 2.1 mmol) was added to a suspension in DCM (10 mL). The mixture was stirred under an argon atmosphere at room temperature for 2 hours. The solvent was removed to obtain the imidate salt of the crude. This crude was dissolved in NH3 / MeOH (7 M, 10 mL) and stirred at room temperature for 16 hours. Boc2O (1152 mg, 5.28 mmol) was then added. The mixture was stirred at room temperature for 10 minutes and concentrated to obtain crude tert-butyl 4-carbamimidyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, purity 50%, yield 62%) as a white solid. LCMS(ESI)C11H19N3O2[M+H] + m / z Calculated value: 226.15, Measured value: 226.05.

[0283] Preparation of tert-butyl 4-(6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) To a solution of tert-butyl 4-carbamimidyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, 2.21 mmol) in DMF (20 mL), K2CO3 (916 mg, 6.63 mmol) and methyl (E)-3-methoxyacrylate (4) (770 mg, 6.63 mmol) were added simultaneously. The reaction mixture was heated at 120 °C for 2 hours with stirring. The reaction mixture was concentrated and purified by silica gel column chromatography (siRNA / PE, eluting at 50% to 100%) to obtain tert-butyl 4-(6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (200 mg, purity 90%, yield 29%) as a white solid. LCMS(ESI)C14H19N3O3[M+H] + m / z Calculated value: 278.15, Measured value: 277.95.

[0284] Preparation of tert-butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) To a solution of tert-butyl 4-(6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (215 mg, 0.77 mmol) in AcOH (5 mL), NIS (260 mg, 1.16 mmol) was added all at once. The reaction mixture was heated at 50°C for 2 hours with stirring. The reaction mixture was concentrated and purified by silica gel column chromatography (siRNA / PE, elution at 50%~70%) to obtain tert-butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) (180 mg, purity 90%, yield 51%) as a white solid. LCMS(ESI)C14H18IN3O3[M+H] + m / z Calculated value: 404.04, Measured value: 403.85.

[0285] Preparation of tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8) A solution of tert-butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) (180 mg, 0.44 mmol), tributyl(vinyl) stannan (7) (282 mg, 0.89 mmol), and Pd(AMPHOS)Cl2 (32 mg, 0.04 mmol) in ACN (10 mL) was purged with N2 for 2 minutes, and then stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (ethylacetate / PE, eluting at 50%-70%) to obtain tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8) (120 mg, purity 90%, yield 79%) as a white solid. LCMS(ESI)C16H21N3O3[M+H] +m / z Calculated value: 304.16, Measured value: 304.20

[0286] Preparation of tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9) To a solution of tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8) (120 mg, 0.40 mmol) in MeOH (5 mL), 10% Pd / C (12 mg) was added. The mixture was subjected to three cycles of evacuating and nitrogen filling, followed by hydrogen filling. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain crude tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9) (120 mg, purity 90%, yield 89%) as a white solid. This was used directly in the next step without further purification. LCMS(ESI)C16H23N3O3[M+H] + m / z Calculated value: 306.18, Measured value: 306.00.

[0287] Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-ethylpyrimidine-4(3H)-one(10) To a solution of tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9) (120 mg, 0.39 mmol) in DCM (4 mL), TFA (1 mL) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting mixture was quenched with Et3N and concentrated under reduced pressure to obtain 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-ethylpyrimidine-4(3H)-one (10) (120 mg, purity 50%, yield 74%). LCMS(ESI)C11H15N3O[M+H] + m / z Calculated value: 206.12, Measured value: 206.00.

[0288] Preparation of 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)-N-methylpicolinamide (299) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-ethylpyrimidine-4(3H)-one (10) (40 mg, 0.19 mmol) in MeOH (5 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (68 mg, 0.29 mmol) was added. Then, at room temperature, 2 drops of acetic acid and NaBH(OAc)3 (82 mg, 0.39 mmol) were added. After 1 hour, NaBH3CN (12 mg, 0.19 mmol) was added. The reaction mixture was stirred at 50°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 μm C18 150 × 21.2 mm, eluted with 10% to 40% ACN / H2O containing 0.1% NH3·H2O) and preparative TLC (MeOH / DCM, 1 / 20) to obtain 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)-N-methylpicolinamide (299) (3.2 mg, purity 99%, yield 3%) as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ:12.30(s,1H), 8.39(q,J=4.8Hz,1H), 8.27(d,J=2.8Hz,1H), 7.81(d,J=8.8Hz,1H) , 7.72(s,1H), 7.40(dd,J=8.8,2.8Hz,1H), 3.94-3.81(m,2H), 3.64(s,1H), 3.00-2.8 5(m,4H), 2.78(d,J=4.8Hz,3H), 2.57-2.52(m,1H), 2.40-2.27(m,2H), 2.07-2.01(m, 2H), 1.96-1.91(m,2H), 1.87-1.72(m,2H), 1.50-1.36(m,2H), 1.07(t,J=7.6Hz,3H). LCMS(ESI)C23H30N6O2[M+H] + m / z Calculated value: 423.25, Measured value: 423.15.

[0289] Example 23: Synthesis of compounds 309a and 309b

[0290] Synthesis of compounds 309a and 309b [ka]

[0291] Preparation of 2-chloro-6-methoxypyridine-4-amine (2) To a solution of 2,6-dichloropyridine-4-amine (1) (1.0 g, 6.1 mmol) in dioxane (15 mL), MeONa (3.3 g, 61.0 mmol) and TBAI (230 mg, 0.6 mmol) were added at room temperature. The reaction mixture was stirred in a sealed tube at 150 °C for 15 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / Â=100:0 to 95:5) to obtain 2-chloro-6-methoxypyridine-4-amine (2) (880 mg, purity 90%, yield 81%) as a white solid. LCMS(ESI)C6H7ClN2O[M+H] + m / z Calculated value: 159.02, Measured value: 158.93.

[0292] Preparation of 3-bromo-6-chloro-2-methoxypyridine-4-amine (3) To a solution of 2-chloro-6-methoxypyridine-4-amine (2) (880 mg, 5.5 mmol) in DMF (40 mL), NBS (1.2 g, 6.7 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the aqueous layer was extracted with Âx (100 mL x 3). The combined organic layers were washed with saline solution (100 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / Âx = 100:0 to 70:30) to obtain 3-bromo-6-chloro-2-methoxypyridine-4-amine (3) (950 mg, purity 90%, yield 64%) as a white solid. LCMS(ESI)C6H6BrClN2O[M+H] + m / z Calculated value: 236.94, Measured value: 236.87.

[0293] Preparation of tert-butyl(3-bromo-6-chloro-2-methoxypyridine-4-yl)carbamate (4) To a 30 mL solution of DCM containing 3-bromo-6-chloro-2-methoxypyridine-4-amine (3) (950 mg, 4.0 mmol), Boc2O (1.31 g, 6.0 mmol), Et3N (810 mg, 8.0 mmol), and DMAP (244 mg, 2.0 mmol) were sequentially added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / Â=100:0 to 80:20) to obtain a mixture of tert-butyl (3-bromo-6-chloro-2-methoxypyridine-4-yl)carbamate (4) and tert-butyl (3-bromo-6-chloro-2-methoxypyridine-4-yl)(tert-butoxycarbonyl)carbamate (4a) (750 mg, purity 90%, yield 49%) as a white solid. LCMS(ESI)C11H14BrClN2O3[M+H] + m / z Calculated value: 336.99, Measured value: 336.92.

[0294] Preparation of ethyl(E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)acrylate(6) To a solution of a mixture of tert-butyl(3-bromo-6-chloro-2-methoxypyridine-4-yl)carbamate (4) and tert-butyl(3-bromo-6-chloro-2-methoxypyridine-4-yl)(tert-butoxycarbonyl)carbamate (4a) (750 mg, 2.2 mmol) in dioxane / H2O (25 mL, 10:1), ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (5) (751 mg, 3.3 mmol), Pd(dppf)Cl2·DCM (181 mg, 0.22 mmol), and K3PO4·H2O (1.5 g, 6.6 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 100°C for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / siRNA = 100:0 to 70:30) to obtain a mixture of ethyl(E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)acrylate (6) and ethyl(E)-3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)acrylate (6a) (410 mg, purity 90%, yield 46%) as a white solid. LCMS(ESI)C16H21ClN2O5[M+H] + m / z Calculated value: 357.11, Measured value: 357.00.

[0295] Preparation of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)propanoate (7) A 10 mL solution of ethyl (E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)acrylate (6), ethyl (E)-3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)acrylate (6a) (410 mg, 0.9 mmol), and PtO2 (50 mg) in ethyl (E) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The resulting solution was filtered through diatomaceous earth, and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure to obtain a mixture of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)propanoate (7) and ethyl 3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)propanoate (7a) (210 mg, purity 90%, yield 45%) as a colorless oil. LCMS(ESI)C16H23ClN2O5[M+H] + m / z Calculated value: 359.13, Measured value: 359.08.

[0296] Preparation of 7-chloro-5-methoxy-3,4-dihydro-1,6-naphthyrizine-2(1H)-one (8) A mixture of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)propanoate (7) and ethyl 3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridine-3-yl)propanoate (7a) (210 mg, 0.6 mmol) was dissolved in HCl-dioxane (10 mL, 4 M) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 7-chloro-5-methoxy-3,4-dihydro-1,6-naphthyridine-2(1H)-one (8) (110 mg, purity 90%, yield 79%) as a white solid. LCMS(ESI)C9H9ClN2O2[M+H] + m / z Calculated value: 213.04, Measured value: 212.92.

[0297] Preparation of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) To a solution of 7-chloro-5-methoxy-3,4-dihydro-1,6-naphthyridine-2(1H)-one (8) (110 mg, 0.5 mmol) in dioxane / H2O (10 mL, 10:1), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (9) (184 mg, 0.6 mmol), Pd(dppf)Cl2 (42 mg, 0.06 mmol), and K3PO4·H2O (357 mg, 1.6 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / siRNA = 100:0 to 20:80) to obtain tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyrizin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) (150 mg, purity 90%, yield 75%) as a white solid. LCMS(ESI)C18H23N3O4[M+H] + m / z Calculated value: 346.17, Measured value: 346.05.

[0298] Preparation of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyrizin-7-yl)pyrrolidine-1-carboxylate (11) A solution of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) (150 mg, 0.4 mmol) and Pd / C (20 mg) in MeOH (10 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting solution was filtered through diatomaceous earth, and the filter cake was washed with DCM (20 mL x 3). The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-7-yl)pyrroridine-1-carboxylate (11) (140 mg, purity 90%, yield 83%) as a colorless oil. LCMS(ESI)C18H25N3O4[M+H] + m / z Calculated value: 348.18, Measured value: 347.95.

[0299] Preparation of 7-(pyrroridine-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (12) A solution of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthiridine-7-yl)pyrrolidine-1-carboxylate (11) (120 mg, 0.34 mmol) in HBr (48% in H2O, 5 mL) was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and Et3N (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure to obtain 7-(pyrrolidine-3-yl)-4,6-dihydro-1,6-naphthiridine-2,5(1H,3H)-dione (12) (65 mg, purity 90%, yield 72%) as a brown solid. LCMS(ESI)C12H15N3O2[M+H] + m / z Calculated value: 234.12, Measured value: 234.06.

[0300] Preparation of 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (racemic mixture of compounds 309a and 309b) To a 10 mL solution of 7-(pyrroridine-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (12) (65 mg, 0.3 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (78 mg, 0.3 mmol), AcOH (2 drops), and NaBH3CN (35 mg, 0.6 mmol) were added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was quenched with water (2 mL), and the reaction solution 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-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide, a racemic mixture of compounds 309a and 309b (35 mg, purity 98%, yield 27%), as a white solid.

[0301] Chiral separation of 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (racemic mixture of compounds 309a and 309b) A racemic mixture of compounds 309a and 309b was separated by SFC (column: Daicel CHIRALPAK IH SFC, 20mm ID × 250mm, 5μmm; mobile phase: CO2 / MeOH [0.1% (NH3) (7M solution in MeOH)] = 60 / 40), concentrated under reduced pressure, and obtained compound 309a (4.8 mg, purity 95%, ee%: 100, white solid) from the first fraction and compound 309b (8.7 mg, purity 95%, ee%: 98, white solid) from the second fraction. Compound 309a 1 H NMR(400MHz,DMSO-d6,ppm) δ:11.08(s,1H), 10.04(s,1H), 8.43-8.34(m,1H), 8.27(d,J=2.8Hz,1H), 7.81(d,J=8.8Hz,1H), 7.48-7.36(m,1H), 5.83 (s,1H), 3.89-3.76(m,2H), 3.14-3.07(m,1H), 3.01-2.91(m,2H), 2.84-2.72(m,5H), 2.60-2.56(m,3H), 2.43-2.41(m,3 H), 2.24-2.10(m,2H), 1.96-1.88(m,2H), 1.72-1.62(m,1H), 1.55-1.46(m,2H). LCMS(ESI)C24H30N6O3[M+H] + m / z Calculated value: 451.24, Measured value: 451.40. Compound 309b 1H NMR(400MHz,DMSO-d6,ppm) δ:11.07(s,1H), 10.04(s,1H), 8.46-8.32(m,1H), 8.27(d,J=2.8Hz,1H), 7.81(d,J=8. 8Hz,1H), 7.40(dd,J=8.8,2.8Hz,1H), 5.83(s,1H), 3.87-3.76(m,2H), 3.14-3.04(m,1H ), 3.02-2.91(m,2H), 2.84-2.75(m,5H), 2.58-2.54(m,3H), 2.44-2.37(m,3H), 2.30-2. 24(m,1H), 2.23-2.12(m,1H), 1.97-1.90(m,2H), 1.75-1.63(m,1H), 1.59-1.44(m,2H). LCMS(ESI)C24H30N6O3[M+H] + m / z calculated value: 451.24, measured value: 451.20.

[0302] Example 24: Synthesis of compound 324rac

[0303] Synthesis of compound 324rac

change

[0304] Preparation of 2-(2-ethoxy-2-oxoethyl)-5-fluoropyridine-3-carboxylic acid (3) To a solution of ethyl 3-oxobutanoate (2) (4.57 g, 0.0351 mol) in DME (250 mL), t-BuOK (5.25 g, 0.0468 mol) was added. The mixture was stirred at room temperature for 1 hour. Cu(OAc)2 (1.70 g, 0.00936 mol) and 2-chloro-5-fluoropyridine-3-carboxylic acid (1) (4.1 g, 0.0234 mol) were added, and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 24 hours. The mixture was diluted with water, acidified to pH=2 with 1 M HCl, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (DCM / MeOH = 100:0 to 90:10) to obtain 2-(2-ethoxy-2-oxoethyl)-5-fluoropyridine-3-carboxylic acid (3) (2.4 g, purity 90%, yield 40%) as a white solid. LCMS(ESI)C10H10FNO4[M+H] + m / z Calculated value: 228.06, Measured value: 228.00.

[0305] Preparation of 3-fluoro-6,8-dihydro-1,6-naphthyridine-5,7-dione (4) To a solution of 2-(2-ethoxy-2-oxoethyl)-5-fluoropyridine-3-carboxylic acid (3) (2400 mg, 10.56 mmol) and TEA (2137 mg, 21.12 mmol) in THF (40 mL), ethyl carbono chloride (2281 mg, 21.12 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at this temperature for 1 hour, then NH3·H2O (28%, 1285 mg) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was collected in Biotage Isolera One(C) 18 The solution was purified by column chromatography (elution with 5%-90% MeCN / H2O containing 0.1% FA) to obtain 3-fluoro-6,8-dihydro-1,6-naphthiridine-5,7-dione (4) (505 mg, purity 90%, yield 23%) as a white solid. LCMS(ESI)C8H5FN2O2[M+H] +m / z Calculated value: 181.03, Measured value: 180.90.

[0306] Preparation of 5,7-dichloro-3-fluoro-1,6-naphthyridine (5) A solution of 3-fluoro-6,8-dihydro-1,6-naphthirizine-5,7-dione (4) (300 mg, 1.66 mmol) in PhPOCl2 (3 mL) was stirred at 110°C for 12 hours under a nitrogen atmosphere. The mixture was cooled, the pH was adjusted to 9-10 with aqueous KOH (5% wt), and diluted with ethyl acetate. The mixture was washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / Â5 = 100:0 to 50:50) to obtain 5,7-dichloro-3-fluoro-1,6-naphthirizine (5) (125 mg, purity 90%, yield 31%) as a white solid. LCMS(ESI)C8H3C2FN2[M+H] + m / z Calculated value: 216.97, Measured value: 216.90.

[0307] Preparation of 7-chloro-3-fluoro-5-methoxy-1,6-naphthyridine (6) To a solution of 5,7-dichloro-3-fluoro-1,6-naphthirizine (5) (195 mg, 0.8985 mmol) in MeOH (20 mL), MeONa (48 mg, 0.8985 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was separated with  (20 mL x 3) and saline solution. The combined organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE /  = 100:0 to 95:5) to obtain 7-chloro-3-fluoro-5-methoxy-1,6-naphthirizine (6) (135 mg, purity 90%, yield 63%) as a white solid. LCMS(ESI)C9H6ClFN2O[M+H] + m / z Calculated value: 213.02, Measured value: 212.90.

[0308] Preparation of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) A mixture of 7-chloro-3-fluoro-5-methoxy-1,6-naphthyridine (6) (100 mg, 0.470 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (167 mg, 0.564 mmol), Pd(dppf)Cl2 (38 mg, 0.047 mmol), and Na2CO3 (306 mg, 0.941 mmol) in dioxane-H2O (3:1, 2 mL) was degassed with N2 and heated at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated and purified by flash silica chromatography to obtain tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (100 mg, purity 90%, yield 24%) as a colorless oil. LCMS(ESI)C18H20FN3O3[M+H] + m / z Calculated value: 346.15, Measured value: 346.15.

[0309] Preparation of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridine-7-yl)pyrrolidine-1-carboxylate (9) A mixture of 3-(3-fluoro-5-methoxy-1,6-naphthiridine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (100 mg, 0.289 mmol) and Pd / C (31 mg) was added to MeOH (2 mL), degassed with H2, and stirred at room temperature under an H2 atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthiridine-7-yl)pyrrolidine-1-carboxylate (9) (100 mg, purity 60%, yield 59%) as a yellow oil. LCMS(ESI)C18H22FN3O3[M+H] + m / z Calculated value: 348.16, Measured value: 348.05.

[0310] Preparation of 3-fluoro-7-(pyrrolidine-3-yl)-1,6-naphthyridine-5(6H)-one hydrobromide (10) A solution of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthiridine-7-yl)pyrrolidine-1-carboxylate (9) (100 mg, 0.287 mmol) in hydrobromide (48%, 10 mL) was heated at 100°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 3-fluoro-7-(pyrrolidine-3-yl)-1,6-naphthiridine-5(6H)-one hydrobromide (10) (80 mg, purity 90%, yield 79%) as a white solid. LCMS(ESI)C12H12FN3O[M+H] + m / z Calculated value: 234.10, Measured value: 233.95.

[0311] Preparation of 6-fluoro-5-(4-(3-(3-fluoro-5-oxo-5,6-dihydro-1,6-naphthyridine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compound 324rac) To a solution of 3-fluoro-7-(pyrroridine-3-yl)-6H-1,6-naphthyrizin-5-one hydrobromide (10) (40 mg, 0.127 mmol) in MeOH (10 mL), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT-2) (32 mg, 0.127 mmol) was added, followed by the addition of 2 drops of acetic acid and NaBH3CN (40 mg, 0.636 mmol) at room temperature. The reaction mixture was stirred at 50°C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 324 rac (13.2 mg, purity 95%, yield 21%) of a racemic mixture of 6-fluoro-5-(4-(3-(3-fluoro-5-oxo-5,6-dihydro-1,6-naphthyridine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide as a white solid. 1H NMR(400MHz,DMSO-d6,ppm) δ 11.56(s,1H), 8.92(d,J=2.8Hz,1H), 8.42-8.35(m,1H), 8.23-8.17(m,1H), 8.16(s,1H), 7 .84(d,J=8.0Hz,1H), 7.62-7.54(m,1H), 6.61(s,1H), 3.54-3.49(m,2H), 3.31-3.27(m,1H) , 2.97-2.84(m,4H), 2.83-2.79(m,1H), 2.77(d,J=4.8Hz,3H), 2.70-2.64(m,1H), 2.38-2.3 1(m,1H), 2.30-2.23(m,1H), 1.99(d,J=12.4Hz,2H), 1.92-1.81(m,1H), 1.67-1.55(m,2H). LCMS(ESI)C24H26F2N6O2[M+H] + m / z Calculated value: 469.21, Measured value: 469.10

[0312] Example 25: Synthesis of compounds 337a and 337b

[0313] Synthesis of compounds 337a and 337b [ka]

[0314] Preparation of 5,6,7,8-tetrahydroisoquinoline-1(2H)-one(2) 2H-isoquinoline-1-one (8 g, 0.05 mol) and PtO2 (0.9 g, 0.003 mol) were added to TFA (80 mL) and stirred at 100°C for 12 hours under an H2 (1 MPa) atmosphere. The precipitate was collected by filtration and extracted with ethyl acetate (400 mL x 3). The combined organic phase was washed with saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE / ethyl acetate = 100:0 to 80:20) to obtain 5,6,7,8-tetrahydroisoquinoline-1(2H)-one (2) (7.00 g, yield 77%) as a black oil. LCMS(ESI)C9H11NO[M+H] + m / z Calculated value: 150.08, Measured value: 150.00.

[0315] Preparation of 1-chloro-5,6,7,8-tetrahydroisoquinoline (3) A solution of sodium salt of 5,6,7,8-tetrahydro-2H-isoquinoline-1-one(2) (7 g, 0.047 mmol) in POCl3 (100 mL) was stirred at 110°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, transferred to ice water, neutralized with NH3·H2O while cooling, and then extracted with siRNA (300 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / siRNA = 100:0 to 80:20) to obtain 1-chloro-5,6,7,8-tetrahydroisoquinoline(3) (5 g, purity 90%, yield 57%) as a colorless oil. LCMS(ESI)C9H10ClN[M+H] + m / z Calculated value: 168.05, Measured value: 168.00.

[0316] Preparation of 1-chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide (4) 1-Chloro-5,6,7,8-tetrahydroisoquinoline(3) (5g, 0.029mol) was added to AcOH / H2O2 (100mL). The reaction mixture was stirred at 70°C for 2 hours. The precipitate was collected by filtration and extracted with EtPAc (200mL x 3). The combined organic phase was washed with saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: DCM / MeOH = 100:0 to 90:10) to obtain 1-chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide(4) (2.00g, yield 73%) as a yellow oil. LCMS(ESI)C9H10ClNO[M+H] + m / z Calculated value: 184.05, Measured value: 184.00.

[0317] Preparation of 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline (5) 1-Chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide (4) (2.00 g, 0.019 mmol) was slowly added to POCl3 (50 mL) at room temperature. The mixture was heated to 110°C and stirred for 3 hours. The resulting mixture was diluted with ice water (200 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic phases were washed with saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE / ethyl acetate = 100:0 to 70:30) to obtain 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline (5) (370 mg, yield 15%) as a yellow oil. LCMS(ESI)C9H9Cl2N[M+H] + m / z Calculated value: 202.01, Measured value: 201.95.

[0318] Preparation of 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline (6) To a solution of 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline (5) (350 mg, 1.73 mmol) in MeOH (15 mL), MeONa (280 mg, 5.20 mmol) was added, and the mixture was heated at 60°C for 3 hours with stirring. The precipitate was collected by filtration and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE / Â5 = 100:0 to 90:10) to obtain 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline (6) (250 mg, yield 66%) as a white solid. LCMS(ESI)C10H12ClNO[M+H] + m / z Calculated value: 198.06, Measured value: 197.95.

[0319] Preparation of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) To a 60 mL solution of 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline (6) (240 mg, 1.21 mmol) in a dioxane / H2O ratio of 10:1, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (394 mg, 1.33 mmol), Pd(dppf)Cl2 (88 mg, 0.12 mmol), and Na2CO3 (503 mg, 3.64 mmol) were sequentially added at room temperature. The reaction mixture was stirred at 90°C for 3 hours under an N2 atmosphere. The mixture was diluted with water (50 mL) and extracted with Â(100 mL × 3). The combined organic layers were washed with saline solution (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. This was purified by flash column chromatography (PE / Â5 = 100:0 to 85:15) to obtain tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (140 mg, yield 31%) as a yellow solid. LCMS(ESI)C19H26N2O3[M+H] + m / z Calculated value: 331.19, Measured value: 331.15.

[0320] Preparation of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)pyrrolidine-1-carboxylate (9) To a solution of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (130 mg, 0.39 mmol) in MeOH (50 mL), Pd / C (30 mg) was added. The mixture was evacuated and refilled with hydrogen, and this cycle was repeated three times, after which hydrogen was refilled. The resulting mixture was stirred at room temperature 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 column chromatography (PE / Â=100:0 to 50:50) to obtain tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)pyrrolidine-1-carboxylate (9) (130 mg, yield 89%) as a yellow solid. LCMS(ESI)C19H28N2O3[M+H] + m / z Calculated value: 333.21, Measured value: 333.10.

[0321] Preparation of 3-(pyrrolidine-3-yl)-5,6,7,8-tetrahydroisoquinoline-1(2H)-one(10) tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)pyrrolidine-1-carboxylate (9) (115 mg, 0.71 mmol) was added to HBr water (10 mL). The mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the product 3-(pyrrolidine-3-yl)-5,6,7,8-tetrahydroisoquinoline-1(2H)-one (10) (80 mg, yield 95%) as a white solid. LCMS(ESI)C13H18N2O[M+H] + m / z Calculated value: 219.14, Measured value: 219.05.

[0322] Preparation of 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (racemic mixture of compounds 337a and 337b) To a solution of 3-(pyrroridine-3-yl)-5,6,7,8-tetrahydroisoquinoline-1(2H)-one(10) (60 mg, 0.27 mmol), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide(INT-2) (69 mg, 0.27 mmol), and AcOH (2 drops) in MeOH (5 mL), sodium triacetoxyborohydride (146 mg, 0.69 mmol) was added and the mixture was stirred at 50°C for 1 hour. Then, NaBH3CN (21 mg, 0.33 mmol) was added and the mixture was stirred 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 90:10) to obtain 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide, a racemic mixture of compounds 337a and 337b (22 mg, yield 18%), as a white solid. LCMS(ESI)C25H32FN5O2[M+H] + m / z Calculated value: 454.25, Measured value: 454.15.

[0323] Chiral separation of 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (racemic mixture of compound 337a and compound 337b) A racemic mixture of compounds 337a and 337b was separated by SFC (column: DAISEL OD-H 4.6mm ID*250mmL 5μm; mobile phase: CO2 / MeOH [0.1% (NH3) (7M solution in MeOH)] = 70 / 30) and concentrated under reduced pressure to obtain compound 337a (7 mg, purity 95%, ee%: 100, white solid) from the first fraction and compound 337b (5 mg, purity 92%, ee%: 100, white solid) from the second fraction. Compound 337a 1H NMR (400MHz, DMSO) δ 11.03(s,1H), 8.40(d,J=4.8Hz,1H), 7.83(d,J=7.8Hz,1H), 7.57(dd,J=10.6,8.4Hz,1 H), 5.83(s,1H), 3.55-3.44(m,2H), 3.14-3.04(m,1H), 2.86(t,J=11.6Hz,3H), 2.75(t, J=6.4Hz,4H), 2.63(dd,J=14.8,8.0Hz,2H), 2.44(s,2H), 2.27(s,3H), 2.21-2.10(m,1H ), 1.95(d,J=13.2Hz,2H), 1.73(dd,J=12.8,8.4Hz,1H), 1.58(dd,J=22.4,12.0Hz,6H). LCMS(ESI)C25H32FN5O2[M+H) + m / z calculated value: 454.25, measured value: 454.20. Compound 337b 1 H NMR (400MHz, DMSO) δ 11.03(s,1H), 8.40(d,J=4.4Hz,1H), 7.83(d,J=8.0Hz,1H), 7.70-7.45(m,1H) , 5.83(s,1H), 3.49(d,J=11.2Hz,2H), 3.08(d,J=6.4Hz,1H), 2.85(t,J=11.2H z,3H), 2.76(d,J=4.4Hz,4H), 2.69-2.57(m,2H), 2.44(s,2H), 2.27(s,3H), 2. 20-2.10(m,1H), 1.95(d,J=12.4Hz,2H), 1.80-1.68(m,1H), 1.68-1.51(m,6H). LCMS(ESI)C25H32FN5O2[M+H) + m / z calculated value: 454.25, measured value: 454.15.

[0324] Example 26: Synthesis of compounds 343a and 343b

[0325] Synthesis of compounds 343a and 343b

change

[0326] Preparation of 4-chloro-5-fluoronicotinic acid (2) N-BuLi (2.4 M in hexane, 10 mL, 23.9 mmol) was added to THF (100 mL) and cooled to -78°C. i-PrNH2 (2.54 g, 25.0 mmol) was slowly added to this solution, followed by 4-chloro-3-fluoropyridine (1) (3 g, 22.8 mmol). After stirring at -78°C for 2 hours, crushed dry ice was added all at once. The reaction mixture was stirred until it warmed to room temperature. The reaction was quenched by adding aqueous ammonium chloride solution, acidified to pH=2 with concentrated hydrochloric acid, and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with saline solution (10 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain 4-chloro-5-fluoronicotinic acid (2) (2.2 g, purity 70%, yield 36%) as a yellow solid. LCMS(ESI)C6H3ClFNO2[M+H] + m / z Calculated value: 175.99, Measured value: 175.80.

[0327] Preparation of methyl 4-chloro-5-fluoronicotinic acid (3) To a solution of 4-chloro-5-fluoronicotinic acid (2) (2.2 g, 11.6 mmol) in ACN (100 mL), DBU (5.29 g, 34.8 mmol) and CH3I (8.2 g, 58.0 mmol) were added dropwise at 0°C. The mixture was stirred at room temperature for 5 hours. The resulting mixture was diluted with water (300 mL) and extracted with Depositphotos (100 mL x 3). The combined organic phases were washed with saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography ( Depositphotos / PE, eluted at 20% to 50%) to obtain methyl 4-chloro-5-fluoronicotinic acid (3) (1.5 g, purity 90%, yield 63%) as a white solid. LCMS(ESI)C7H5ClFNO2[M+H] + m / z Calculated value: 190.00, Measured value: 189.95.

[0328] Preparation of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)ethynyl)-5-fluoronicotinic acid (5) A mixture of methyl 4-chloro-5-fluoronicotinic acid (3) (150 mg, 0.79 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (4) (233 mg, 1.19 mmol), PdCl2(PPh3)2 (55 mg, 0.079 mmol), and DIPEA (511 mg, 3.96 mmol) in ACN (15 mL) was heated at 85°C for 5 hours under an N2 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 phases were washed with water and saline solution, dried over sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography (Â / PE, 20% to 40%) to obtain methyl 4-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)ethynyl)-5-fluoronicotinic acid (5) (150 mg, purity 90%, yield 48%) as a yellow solid. LCMS(ESI)C18H21FN2O4[M+H] + m / z Calculated value: 349.15, Measured value: 348.95.

[0329] Preparation of 4-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)ethynyl)-5-fluoronicotinic acid (6) To a solution of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)ethynyl)-5-fluoronicotinic acid (5) (150 mg, 0.43 mmol) in THF / H2O (3 / 1, 10 mL), LiOH (31 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 2 hours. Next, the organic solvent was removed under reduced pressure. The aqueous solution was adjusted to pH 3-4 with 1 M HCl and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 4-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)ethynyl)-5-fluoronicotinic acid (6) (120 mg, purity 90%, yield 75%) as a yellow oil. LCMS(ESI)C17H19FN2O4[M+H] + m / z Calculated value: 335.14, Measured value: 335.00.

[0330] Preparation of tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridine-3-yl)pyrrolidine-1-carboxylate (7) To a solution of 4-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)ethynyl)-5-fluoronicotinic acid (6) (120 mg, 0.36 mmol) in DCM (10 mL), TfOH (161 mg, 1.07 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with DIPEA (231 mg, 1.79 mmol), and then Boc2O (156 mg, 0.716 mmol) was added. After stirring at room temperature for 1 hour, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (siRNA / PE, eluting at 20% to 40%) to obtain tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridine-3-yl)pyrrolidine-1-carboxylate (7) (70 mg, purity 90%, yield 52%) as a white solid. LCMS(ESI)C17H19FN2O4[M-tBu+H] + m / z Calculated value: 279.14, Measured value: 278.85.

[0331] Preparation of tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridine-3-yl)pyrrolidine-1-carboxylate (8) A solution of tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyrrolidine-3-yl)pyrrolidine-1-carboxylate (7) (70 mg, 0.21 mmol) in NH3·MeOH (7M, 5 mL) was stirred in a sealed test tube at 90°C for 1 hour. The reaction product was then concentrated under reduced pressure to obtain tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridine-3-yl)pyrrolidine-1-carboxylate (8) (70 mg, purity 90%, yield 90%) as a yellow solid. LCMS(ESI)C17H20FN3O3[M+H] + m / z Calculated value: 334.15, Measured value: 333.95.

[0332] Preparation of 5-fluoro-3-(pyrrolidine-3-yl)-2,7-naphthyrizine-1(2H)-one(9) A mixture of tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridine-3-yl)pyrrolidine-1-carboxylate (8) (70 mg, 0.44 mmol) in a HCl dioxane solution (4 M, 5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and quenched with Et3N. The resulting solution was concentrated under vacuum to obtain 5-fluoro-3-(pyrrolidine-3-yl)-2,7-naphthyridine-1(2H)-one (9) (50 mg, purity 90%, yield 92%) as a yellow oil. LCMS(ESI)C12H12FN3O[M+H] + m / z Calculated value: 234.10, Measured value: 234.05.

[0333] Preparation of 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (racemic mixture of compounds 343a and 343b) To a solution of 5-fluoro-3-(pyrroridine-3-yl)-2,7-naphthyridine-1(2H)-one (9) (70 mg, 0.30 mmol) in MeOH (10 mL), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (113 mg, 0.45 mmol) was added. Then, at room temperature, 2 drops of acetic acid, NaBH3CN (19 mg, 0.30 mmol), and NaBH(OAc)3 (191 mg, 0.90 mmol) were added. The reaction mixture was stirred at 50°C for 1 hour. 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 90:10) to obtain 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide, a racemic mixture of compounds 343a and 343b (50 mg, purity 95%, yield 33%), as a white solid.

[0334] Chiral separation of 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (racemic mixture of compound 343a and compound 343b) Compound 343a and び343bのラセミmixtureをSFC(カラム:DAICEL CHIRALPAK IH 20mm ID×250mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 70 / 30), separation, concentration under reduced pressure, and first fractionation of compound 343a (19.7m g, purity 99%, ee%: 100, white solid), the second fraction of compound 343b (24.7 mg, purity 98%, ee%: 90, white solid) was obtained. Compound 343a 1 ¹H NMR (400MHz, DMSO-d6, ppm) δ:11.74(s,1H), 9.09(s,1H), 8.68(d,J=2.0Hz,1H), 8.40(d,J=4.8Hz,1H), 7. 87-7.80(m,1H), 7.58(dd,J=10.6,8.2Hz,1H), 6.54(s,1H), 3.58-3.47(m,2H), 3.29-3.16(m,1H), 2.91-2.83(m,5H), 2.77(d,J=4.8Hz,3H), 2.72-2.58(m,1H ), 2.47-2.23(m,2H), 2.10-1.96(m,2H), 1.95-1.81(m,1H), 1.77-1.50(m,2H). LCMS(ESI)C24H26F2N6O2[M+H] + m / z calculated value: 469.21, measured value: 469.07. Compound 343b 1 ¹H NMR (400MHz, DMSO-d6, ppm) δ:11.77(s,1H), 9.09(s,1H), 8.68(d,J=2.0Hz,1H), 8.45-8.31(m,1H), 7.89 -7.76(m,1H), 7.58(dd,J=10.6,8.2Hz,1H), 6.55(s,1H), 3.54-3.46(m,2H), 3 .29-3.23(m,1H), 2.94-2.82(m,5H), 2.77(d,J=4.8Hz,3H), 2.69-2.58(m,1H) , 2.36-2.25(m,2H), 2.02-1.94(m,2H), 1.91-1.78(m,1H), 1.67-1.56(m,2H). LCMS(ESI)C24H26F2N6O2[M+H] + m / z Calculated value: 469.21, Measured value: 469.10.

[0335] Example 27: Synthesis of Compound 361

[0336] Synthesis of compound 361 [ka]

[0337] Preparation of tert-butyl 4-((2-(ethoxycarbonyl)cyclohexa-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) To a solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (1) (110 mg, 0.48 mmol) in pyridine (10 mL), ethyl 2-aminocyclohexa-1-ene-1-carboxylate (2) (160 mg, 0.95 mmol) was added at room temperature, followed by the addition of 10 drops of POCl3. The reaction mixture was stirred at room temperature for 3 hours. After cooling to room temperature, the reaction mixture was poured into water, and the aqueous layer was extracted three times with organic solvent (50 mL). The combined organic layers were washed with saline solution (50 mL), dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / Â=100:0 to 85:15) to obtain tert-butyl 4-((2-(ethoxycarbonyl)cyclohexa-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (100 mg, yield 55%) as a white solid. LCMS(ESI)C20H30N2O5[M-56+H] + m / z Calculated value: 323.22, Measured value: 323.05.

[0338] Preparation of 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)cyclohexa-1-ene-1-carboxylic acid (4) To a 10 mL MeOH:H2O = 1:1 solution of tert-butyl 4-((2-(ethoxycarbonyl)cyclohexa-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (100 mg, 0.26 mmol), LiOH (30 mg, 1.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)cyclohexa-1-en-1-carboxylic acid (4) (80 mg, yield 88%) as a white solid. LCMS(ESI)C18H26N2O5[M-56+H] + m / z Calculated value: 295.18, Measured value: 295.05

[0339] Preparation of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) To a solution of 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)cyclohexa-1-ene-1-carboxylic acid (4) (80 mg, 0.23 mmol) in ACN (10 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate / TCFH (150 mg, 0.54 mmol) and N-methylimidazole / NMI (50 mg, 0.61 mmol) were added at room temperature. After 10 minutes, an excess amount of NH3-MeOH (7 M, 5 mL) was added at 50°C. The mixture was stirred at 50°C for 18 hours. The residue was concentrated under reduced pressure and purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 96:4) to obtain tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (60 mg, yield 79%) as a white solid. LCMS(ESI)C18H25N3O3[M+H] + m / z Calculated value: 332.19, Measured value: 332.10.

[0340] Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5,6,7,8-tetrahydroquinazoline-4(3H)-one(6) tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (60 mg, 0.18 mmol) was added to a 4 M, 3 mL solution of dioxane in HCl, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6) (40 mg, yield 96%) as a white solid. LCMS(ESI)C13H17N3O[M+H] + m / z Calculated value: 232.14, Measured value: 232.05.

[0341] Preparation of N-methyl-5-(4-(4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (compound 361) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5,6,7,8-tetrahydroquinazoline-4(3H)-one (6) (40 mg, 0.17 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT) (40 mg, 0.17 mmol) and 3 drops of HOAc were added, followed by the addition of NaBH3CN (10 mg, 0.16 mmol). The reaction mixture was stirred at 50°C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 10-25) to obtain N-methyl-5-(4-(4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (361) (30 mg, purity 97%, yield 38%) as a white solid. compound 361 1H NMR(400MHz,DMSO) δ 12.11(s,1H), 8.38(q,J=4.8Hz,1H), 8.28(d,J=2.8Hz,1H), 7.82(d,J=8.8Hz,1H), 7.40(dd ,J=8.8,2.8Hz,1H), 3.87(d,J=12.8Hz,2H), 3.69(s,1H), 2.98(s,2H), 2.91(t,J=11.2Hz,2 H), 2.78(d,J=4.8Hz,3H), 2.61-2.54(m,1H), 2.48-2.44(m,2H), 2.31(t,J=6.0Hz,2H), 2.0 9-2.02(m,2H), 1.99-1.92(m,2H), 1.84-1.78(m,2H), 1.72-1.59(m,4H), 1.51-1.41(m,2H). LCMS(ESI)C25H32N6O2[M+H] + m / z Calculated value: 449.26, Measured value: 449.20.

[0342] Example 28: Synthesis of Compound 375

[0343] Synthesis of Compound 375 [ka]

[0344] Preparation of tert-butyl 4-((3-carbamoylpyridine-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) To a 15 mL solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (2) (500 mg, 2.19 mmol), 2-aminonicotinamide (1) (330 mg, 2.41 mmol), T3P (50% wt  solution, 4.18 g, 6.57 mmol), and DIPEA (850 mg, 6.57 mmol) were sequentially added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain tert-butyl 4-((3-carbamoylpyridine-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate(3) (330 mg, purity 90%, yield 39%) as a white solid. LCMS(ESI)C17H22N4O4[M+H] + m / z Calculated value: 347.16, Measured value: 346.85.

[0345] Preparation of tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) To a solution of tert-butyl 4-((3-carbamoylpyridine-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (330 mg, 0.95 mmol) in DME (20 mL), KOH (160 mg, 2.85 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 6 hours. The reaction solution was filtered to remove the KOH. The filtrate was diluted with water and extracted with  (10 mL × 3). The aqueous phase was purified using a silica gel C18 column (eluted with 10% to 50% MeCN / H2O containing 0.1% formic acid) to obtain tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (220 mg, purity 80%, yield 56%) as a white solid. LCMS(ESI)C17H20N4O3[M+H] + m / z Calculated value: 329.15, Measured value: 329.00.

[0346] Preparation of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) To a THF / H2O=4:1 (20 mL) solution of tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (200 mg, 0.607 mmol), PtO2 (41 mg) was added. The mixture was then stirred at room temperature under a hydrogen atmosphere for 18 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (200 mg, purity 90%, yield 88%) as a yellow solid. LCMS(ESI)C17H24N4O3[M+H] +m / z Calculated value: 333.18, Measured value: 333.25.

[0347] Preparation of tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) To a 10 mL solution of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (200 mg, 0.6 mmol) in DMSO (10 mL), Cs2CO3 (586 mg, 1.8 mmol) and PMBCl (188 mg, 1.2 mmol) were added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. The reaction solution was quenched with water and extracted with RINKAN (30 mL x 3). The combined organic phases were washed three times with saline solution and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 50:50) to obtain tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) (150 mg, purity 90%, yield 49%) as a white solid. LCMS(ESI)C25H32N4O4[M+H] + m / z Calculated value: 453.24, Measured value: 453.05.

[0348] Preparation of tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (7) To a solution of methyl tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) (50 mg, 0.11 mmol) in DMF (10 mL), NaH (7 mg, 0.17 mmol, 60% wt) and MeI (24 mg, 0.17 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with water and extracted with ELISA (50 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 70:30) to obtain tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (7) (30 mg, purity 90%, yield 52%) as a white solid. LCMS(ESI)C26H34N4O4[M+H] + m / z Calculated value: 467.26, Measured value: 467.30.

[0349] Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(8) To a solution of tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (7) (30 mg, 0.064 mmol) in TFA (5 mL), TfOH (0.2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction solution was adjusted to pH 8 at 0 °C using a saturated aqueous solution of NaHCO3. This basicized solution was extracted using DCM (10 mL x 3). The combined organic layers were washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure to obtain 2-(2-azabicyclo[2.1.1]hexane-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(8) (25 mg, purity 60%, yield 94%) as a yellow oil. LCMS(ESI)C13H18N4O[M+H]+ m / z Calculated value: 247.15, Measured value: 247.25.

[0350] Preparation of 6-fluoro-N-methyl-5-(4-(4-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (compound 375) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4(3H)-one(8) (25 mg, 0.10 mmol) in MeOH (15 mL) and AcOH (0.01 mL), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide(INT-2) (31 mg, 0.12 mmol) and NaBH3CN (10 mg, 0.15 mmol) were added at room temperature. The reaction mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 90:10) and preparative HPLC (Gemini 5um C18 150×21.2mm, mobile phase: ACN-H2O (0.05%NH3), gradient: 25-95) to obtain 6-fluoro-N-methyl-5-(4-(4-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (375) (5.0 mg, purity 97%, yield 10%) as a white solid. 1 1H NMR (400MHz, DMSO-d6, ppm) δ:11.32(s,1H), 8.43-8.35(m,1H), 7.83(d,J=8.0Hz,1H), 7.63-7.53(m,1 H), 3.61(s,1H), 3.57-3.50(m,2H), 3.25-3.18(m,2H), 3.03(s,3H), 2.91( s,2H), 2.84(t,J=11.2Hz,2H), 2.76(d,J=4.8Hz,3H), 2.47-2.42(m,1H), 2 .37-2.31(m,2H), 2.03-1.90(m,4H),1.80-1.71(m,4H), 1.55-1.42(m,2H). LCMS(ESI)C25H32FN7O2[M+H] + m / z Calculated value: 482.26, Measured value: 482.15.

[0351] Example 29: Synthesis of compound 393rac

[0352] Synthesis of compound 393rac [ka]

[0353] Preparation of 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinoline-1(2H)(3) Tributyl(vinyl) stannan (2) (1995 mg, 6.294 mmol) was added to a solution of 3-chloro-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one (1) (2000 mg, 6.294 mmol) and Pd(AMPHOS)Cl2 (445 mg, 0.6294 mmol) in ACN (30 mL). The mixture was heated in a sealed test tube at 100 °C for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Â / PE, elution at 0-15%) to obtain 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinoline-1(2H)-one (3) (1500 mg, purity 90%, yield 69%) as a white solid. LCMS(ESI)C19H16FNO2[M+H] + m / z Calculated value: 310.12, Measured value: 309.90.

[0354] Preparation of 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4) To a solution of 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinoline-1(2H)-one (3) (1500 mg, 4.85 mmol) in MeOH / H2O (3:1, 80 mL), NaIO4 (4150 mg, 19.40 mmol) and K2OsO4·2H2O (178 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with siRNA (200 mL x 3). The combined organic layers were washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (siRNA / PE, eluting at 0-25%) to obtain 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4) (430 mg, purity 90%, yield 25%) as a yellow solid. LCMS(ESI)C18H14FNO3[M+H] + m / z Calculated value: 312.10, Measured value: 311.90.

[0355] Preparation of 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one (5) 8-Fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4) (430 mg, 1.38 mmol), PPh3 (724 mg, 2.76 mmol), and LiI (369 mg, 2.76 mmol) were dissolved in DMF / dioxane (8%, 10 mL) and TMSCF3 (491 mg, 3.45 mmol). The mixture was heated in a sealed test tube at 130 °C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Â1 / PE, eluting at 0-15%) to obtain 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one (5) (200 mg, purity 60%, yield 25%) as a white solid. LCMS(ESI)C19H14F3NO3[M+H] + m / z Calculated value: 346.10, Measured value: 346.00.

[0356] Preparation of 3-(1-benzyl-4,4-difluoropyrrolidine-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one(7) To a solution of 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one (5) (260 mg, 0.75 mmol) and LiF (39 mg, 1.51 mmol) in ACN (50 mL), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methaneamine (6) (357 mg, 1.51 mmol) was added. The mixture was stirred at 60 °C for 16 hours. The resulting mixture was diluted with water and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Â1 / PE, eluting at 0-15%) to obtain 3-(1-benzyl-4,4-difluoropyrrolidine-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one(7) (25 mg, purity 90%, yield 6%) as a white solid. LCMS(ESI)C28H25F3N2O2[M+H] + m / z Calculated value: 479.19, Measured value: 479.20.

[0357] Preparation of 3-(4,4-difluoropyrrolidine-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one(7) To a solution of 3-(1-benzyl-4,4-difluoropyrrolidine-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one(7) (130 mg, 0.271 mmol) in MeOH (5 mL), one drop of concentrated hydrochloric acid, 10% Pd / C (20 mg), and 10% Pd(OH)2 / C (20 mg) were added. The mixture was evacuated and refilled with hydrogen three times, and then filled with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then filtered through Celite and concentrated under vacuum to obtain crude 3-(4,4-difluoropyrrolidine-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one(8) (100 mg, purity 50%, yield 47%) as a white solid. This was used directly in the next step without further purification. LCMS(ESI)C21H19F3N2O2[M+H] + m / z Calculated value: 389.14, Measured value: 389.00.

[0358] Preparation of 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10) To a solution of 3-(4,4-difluoropyrrolidine-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one(8) (100 mg, 0.257 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide(INT) (90 mg, 0.386 mmol) was added. At room temperature, two drops of acetic acid and NaBH3CN (24 mg, 0.386 mmol) were added. The reaction mixture was stirred at 50°C for 1 hour. 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 90:10) to obtain 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10) (80 mg, purity 50%, yield 25%) as a white solid. LCMS(ESI)C33H34F3N5O3[M+H] + m / z Calculated value: 606.26, Measured value: 606.20.

[0359] Preparation of 5-(4-(3,3-difluoro-4-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (compound 393rac) To a solution of 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10) (80 mg, 0.13 mmol) in TFA (5 mL), TfOH (1 mL) was added dropwise at room temperature. The reaction mixture was stirred at 100 °C for 5 minutes. The pH of the resulting mixture was adjusted to around 8.0 by gradually adding a saturated solution of NaHCO3, and then extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um C18 150×21.2mm, eluted with 35%-40% ACN / H2O containing 0.1% FA) to obtain 5-(4-(3,3-difluoro-4-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (393rac) (6.2 mg, purity 93%, yield 9%) as a brown solid. 1 1H NMR (400MHz, CD3OD_SPE, ppm) δ:8.31(d,J=2.8Hz,1H), 7.95(d,J=8.8Hz,1H), 7.72-7.65(m,1H), 7.57-7 .47(m,1H), 7.43(d,J=8.0Hz,1H), 7.17(dd,J=11.8,8.2Hz,1H), 6.76-6.6 8(m,1H), 4.10-3.94(m,2H), 3.85-3.50(m,5H), 3.28-3.25(m,1H), 3.07(t ,J=12.4Hz,2H), 2.96-2.90(m,3H), 2.24-2.09(m,2H), 1.84-1.66(m,2H). LCMS(ESI)C25H26F3N5O2[M+H] + m / z Calculated value: 486.21, Measured value: 486.40.

[0360] 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.

[0361] 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 Na2CO3 / HCO3 coating buffer at pH 9.6, so 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, using the pin tool technique, 50 nL of DMSO solution of each compound was added. After incubation at room temperature for 30 minutes, 10 μM biotin-NAD was added. + 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 nM activated DNA (sequence below) was added. Autoparylation was allowed to proceed at room temperature for 2 hours, followed by 12 mM NAD + 5 μL of quenching solution was added. After 30 minutes at room temperature, the assay solution was removed, the plate was washed five 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 five 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).

[0362] Typically, the compound is tested using a 12-point concentration-response curve with 3-fold dilution intervals starting from 20 μM, and IC50 is measured. 50The 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.

[0363] Activated DNA sequence [ka]

[0364] 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).

[0365] 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. The 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. K d The values ​​were calculated using the Cheng-Prussoff formula: I C 50 =(1+([probe concentration] / [K m(probe) ]))*K d 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.

[0366] 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.

[0367] Structure of the Cy5 probe [ka]

[0368] NanoBRET cell target occupation assay NanoBRET assays were used to demonstrate cell target engagement and selectivity for PARP1 and PARP2. These assays target high affinity NAD to nano-luc tagged proteins (e.g., PARP1 or PARP2). + This assay is based on bioluminescent resonance energy transfer (BRET) between the fluorescent group on a competitively bound probe and the cell probe. Such cell probe substitution assays can be used to measure inhibitor affinity and selectivity for PARP1 and PARP2.

[0369] 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 achieve 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 used 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

[0370] Table 1 summarizes the efficacy, affinity, and selectivity data for various test compounds obtained using DELFIA and probe-substituted HTRF assays. Table 2 summarizes the efficacy, affinity, and selectivity data for some test compounds obtained using NanoBRET assays.

[0371] Table 1 Results of PARP1 / 2 assays for selected compounds (DELFIA and probe-substituted HTRF) [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] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

[0372] Table 2 Results of PARP1 / 2 assay for selected compounds (NanoBRET) [Table 2-1] [Table 2-2]

[0373] Legend: The results of the DELFIA, probe-substituted HTRF, and NanoBRET assays are categorized as follows: "-" indicates that the IC50 or Kd value is greater than 10M. The "+" indicates that the IC50 or Kd value is greater than 1M and less than or equal to 10M. "++" indicates that the IC50 or Kd value is greater than 100 nM and less than or equal to 1 M. "+++" indicates that the IC50 or Kd value is greater than 10 nM and less than or equal to 100 nM. "++++" indicates that the IC50 is 10nM 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. The selectivity value represents the selectivity that prioritizes PARP1 over PARP2. These values ​​are calculated as Kd(PARP2) / Kd(PARP1), based on the ratio of Kd values ​​for inhibiting PARP1 and PARP2.

Claims

1. PARP1 inhibitors for pharmaceutical use, containing compounds having one of the following structures: 【Chemistry 1】 (In the formula, Each R １２ is independently selected from H and substituted or unsubstituted organic groups; where at least one R １２ It is not H; Each R １３ is independently selected from H and substituted or unsubstituted organic groups; R ６ is H or a substituted or unsubstituted organic group; and, L has the following structure: 【Chemistry 2】 (In the formula, n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; m+n is 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, 5, or 6; p+q is 2, 3, 4, 5, or 6; r is 0, 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, 4, or 5; r+s is 1, 2, 3, 4, or 5; each X １ It is independently selected from C, N, O, and S; each X ２ It is independently selected from C, N, O, and S; each X ３ It is independently selected from C, N, O, and S; X ５ is selected from C and N; Each X ６ is independently selected from C and N; Q １ and Q ３ These are, independently, non-existent or below: 【Transformation 3】 (In the formula, t is 0, 1, 2, 3, 4 or 5; u is 0, 1, 2, 3, 4 or 5; t + u is 0, 1, 2, 3, 4, 5 or 6; where Q １ and Q ３ When both conditions are met, the values ​​of t and u are chosen independently; Each R ４５ is independently selected from H and substituted or unsubstituted organic groups; R ４６ (is selected from H and substituted or unsubstituted organic groups;) The dotted lines indicate that rings A, B, and C, independently, each possess a single bond or a combination of both single and double bonds, and are either aliphatic or aromatic; Each R ４１ , R ４２ , R ４３ and R ４４ Each of these is independently selected from non-existent or H and substituted or unsubstituted organic groups; and, R ５ This is a substituted or unsubstituted organic group.

2. at least one R １２ C １ ~C ６ Alkyl, alkoxy, or haloalkyl groups, substituted or unsubstituted C ３ ~C ６ A PARP1 inhibitor according to claim 1, selected from a cycloalkyl or heterocyclic group and a halogen group.

3. at least one R １２ However, -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 A PARP1 inhibitor according to claim 1, selected from OH, methoxy group, methoxymethyl group, methoxyethyl group, isopropyl group, cyclopropyl group, and cyclopropylmethyl group.

4. Each R １３ However, H, F, C １ ~C ３ The alkyl group and C １ ~C ３ A PARP1 inhibitor according to claim 1, independently selected from the fluoroalkyl groups.

5. R ６ However, H, halogen, C １ ~C ３ alkyl group, C １ ~C ３ Haloalkyl groups, C １ ~C ３ The alcohol group and C １ ~C ３ A PARP1 inhibitor according to claim 1, selected from aminoalkyl groups.

6. Each R ４１ , R ４２ , R ４３ and R ４４ However, each of the following PARP1 inhibitors according to claim 1 is independently selected: H, deuterium, halogen, nitrile group, substituted or unsubstituted C １ ~C ６ Alkyl alkyl groups, substituted or unsubstituted linear or branched C １ ~C ６ Halide alkyl groups, cyclopropyl groups, -OH groups, substituted or unsubstituted linear or branched C1-C6 alcohol groups, substituted or unsubstituted linear or branched C １ ~C ７ The aminocarbonyl group, -NH ２ C as a base, substituted, or unsubstituted component １ ~C ６ The amino group, and substituted or unsubstituted C １ ~C ６ alkoxy group; A pair of R atoms bonded to different atoms ４１ The groups together form a ring with the atoms of ring A, and / or a pair of R groups bonded to different atoms. ４２ The groups come together to form a ring with the atoms of ring B; here, the pair of R ４１ Base, and / or the pair of R ４２ Each element is independent of the other, -CH ２ - or -CH ２ CH ２ - to be equipped; or, R ５ and R ４４ The groups come together to form a ring with the atoms of the ring C, R ５ and R ４４ Together, they comprise -CH=CH-CH=CH- or -NH-CO-NH-.

7. At least Q １ and Q ３ The PARP1 inhibitor according to claim 1, wherein one of the following is selected: 【Chemistry 4】 (In the formula, Each R ４５ is independently selected from H, halogen, C １ to C ６ alkyl groups, linear or branched C １ to C ６ haloalkyl groups, -NH ２ groups, C １ to C ６ amino groups, -OH groups, linear or branched C １ to C ６ alcohol groups, and substituted or unsubstituted C １ to C ６ alkoxy groups; R ４６ is selected from alkyl groups of H, C １ ~C ６ , and linear or branched C １ ~C ６ halogenated alkyl groups. ).

8. R ５ However, -F, -Cl, -Br, -I, -CN, -CONR ５１ R ５１ , -NR ５１ COR ５２ , -SO ２ NR ５１ R ５１ , -NR ５１ SO ２ R ５３ , -O-CR ５２ R ５２ R ５２ , -CR ５２ R ５２ NR ５１ R ５１ , and one of the following structures: 【Transformation 5】 (In the formula, Each R ５１ , R ５２ and R ５３ The PARP1 inhibitor according to claim 1, wherein H and a substituted or unsubstituted organic group are selected independently.

9. R ５ is - F, - Cl, - CN, - CONH ２ , - CONHMe, - CONHEt, - CONMe ２ , - CONHCOMe, - 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: 【Transformation 6】 A PARP1 inhibitor according to claim 1, selected from the above.

10. Q ３ However, it does not exist, or has the following structure: 【Transformation 7】 A PARP1 inhibitor according to claim 1, wherein the group is independently selected from the above.

11. The ring A of the L group is as follows: 【Transformation 8】 A PARP1 inhibitor according to claim 1, selected from the above.

12. The ring A of the L group is as follows: 【Chemistry 9】 A PARP1 inhibitor according to claim 11, selected from the above.

13. The ring C of the L group is as follows: 【Chemistry 10-1】 【Chemistry 10-2】 A PARP1 inhibitor according to claim 1, selected from the above.

14. The ring C of the L group is as follows: 【Chemistry 11】 A PARP1 inhibitor according to claim 13, selected from the above.

15. Q １ However, it does not exist, or the following: 【Chemistry 12】 A PARP1 inhibitor according to claim 1, selected from the above.

16. X ５ The PARP1 inhibitor according to claim 15, wherein is N.

17. The ring B of the L group is as follows: 【Chemistry 13】 A PARP1 inhibitor according to claim 16, selected from the above.

18. The ring B of the L group has the following structure: 【Chemistry 14】 A PARP1 inhibitor according to claim 17, comprising any of the following:

19. The L group has the following structure: 【Chemistry 15】 A PARP1 inhibitor according to claim 1, comprising:

20. each X ２ The PARP1 inhibitor according to claim 19, wherein C is C.

21. each X １ The PARP1 inhibitor according to claim 20, wherein C is C.

22. The PARP1 inhibitor according to claim 21, wherein the bonds constituting ring A and ring B are single bonds.

23. The L group has the following structure: 【Chemistry 16】 A PARP1 inhibitor according to claim 1, comprising:

24. The L group is: 【Chemistry 17-1】 【Chemistry 17-2】 A PARP1 inhibitor according to claim 23, comprising a structure selected from the above.

25. m is selected from 1 or 2; n is selected from 2 or 3; p is selected from 1, 2, or 3; The PARP1 inhibitor according to claim 1, wherein q is selected from 1 or 2.

26. The L group has the following structure: 【Chemistry 18-1】 【Chemistry 18-2】 A PARP1 inhibitor according to claim 25, comprising any of the following:

27. The L group has the following structure: 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 【Chemistry 19-7】 【Chemistry 19-8】 【Chemistry 19-9】 A PARP1 inhibitor according to claim 1, comprising any of the following:

28. The compound has the following structure: 【Chemistry 20】 A PARP1 inhibitor according to claim 1, comprising any of the following:

29. The aforementioned compound is as follows: 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】 【Chemistry 21-7】 【Chemistry 21-8】 【Chemistry 21-9】 【Chemistry 21-10】 【Chemistry 21-11】 【Chemistry 21-12】 [Chemistry 21-13] [Chemistry 21-14] A PARP1 inhibitor according to claim 1, comprising a chemical formula selected from the following.

30. A PARP1 inhibitor according to any one of claims 1 to 29, used for treating cancer.

31. A compound according to any one of claims 1 to 29, and Pharmaceutically acceptable additives and / or excipients A pharmaceutical composition comprising the following features.

32. It is a medical kit for treating cancer, (a) A compound according to any one of claims 1 to 29, and (b) Further agents for treating cancer A pharmaceutical kit comprising the compound and the further agent, suitable for simultaneous, sequential, or separate administration.

33. A compound selected from the compounds defined in claim 29.

Images