Pharmaceutical Compounds

Abstract

A compound having the chemical formula: [Formula 1] TIFF2025508714000307.tif92101 (in the formula, R 1 is selected from H and a substituted or unsubstituted organic group; R 2 is optionally present and is independently selected from H and a substituted or unsubstituted organic group; R 1 and R 2 may be taken together to form a ring; R 3 is independently selected from H and a substituted or unsubstituted organic group; R 6 is optionally present and is independently selected from H and a substituted or unsubstituted organic group; Z 1 and Z 2 is independently selected from C and N; and L comprises an organic group as defined herein.

Description

[Technical field]

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

[0002] The poly(ADP-ribose) polymerase (PARPs) family is composed of 17 PARP proteins that catalyze the transfer of ADP-ribose to target proteins, a post-translational process called poly ADP-ribosylation (PARylation). Modification of target proteins by poly ADP-ribosylation causes profound changes in function, and thus PARPs play important roles in many cellular processes, such as chromatin remodeling, transcription, replication, recombination, cell cycle progression, and DNA damage repair (Non-Patent Document 1). PARP1 and 2 are the most widely studied PARP enzymes, primarily due to their role in DNA damage repair, particularly in the base excision repair (BER) process of DNA single-strand breaks (SSBs) (Non-Patent Document 2). PARP1 is activated by DNA damage breaks, and the subsequent poly ADP-ribosylation of target proteins leads to the recruitment of additional factors that initiate the repair of DNA damage. AutopolyADP-ribosylation of PARP triggers the dissociation of bound PARP from DNA, allowing other DNA repair proteins access to complete the repair of the damage. This highlights the important role of PARP in enabling cancer cells to repair DNA damage caused by exogenous agents such as radiation therapy and chemotherapeutic agents. Therefore, inhibition of the PARP enzyme has been exploited as a strategy to selectively kill cancer cells with genetic defects in complementary DNA damage repair pathways (Non-Patent Document 3). This synthetic lethal approach has been successfully demonstrated in tumors with epigenetic modifications or deleterious mutations in BRCA1 and BRCA2, two functionally redundant tumor suppressor proteins involved in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) (Non-Patent Document 4). Such tumors with homologous recombination repair deficiency (HRD) depend on the function of PARP 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] Inhibition of PARP can trap inactivated PARP at DNA damage sites. When the replication fork reaches the site of trapped PARP, it stops in S phase and then collapses, resulting in genotoxic DNA double-strand breaks. It is believed that this trapping of PARP1-DNA may lead to selective death of cancer cells with HRD (Non-Patent Document 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 for the maintenance treatment of ovarian cancer, where platinum sensitivity is a surrogate for HRD.

[0005] Recently, it has been shown that genomic instability, in the form of unrepaired DNA double-strand breaks or micronuclei collapse, can trigger the activation of the innate immune system through the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS), leading to the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and the induction of dimerization of stimulator of interferon genes (STING). STING then translocates 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 adaptive immune responses (Non-Patent Document 6).

[0006] For example, activation of the STING pathway and antitumor immune responses induced by PARP inhibitors have been demonstrated in multiple tumor models, providing a rationale for the use of a combination of PARP inhibitors and immunotherapy to improve therapeutic efficacy (Non-Patent Document 7). For example, the PARP inhibitor olaparib has also 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 Document 8).

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

[0008] Recently, PARP1 has been shown to bind to the Epstein-Barr Virus (EBV) genome, and PARP1 inhibitors have been shown to alter EBV chromatin structure and expression of latent genes (Non-Patent Document 10). Thus, PARP1 inhibitors may play a role in EBV-associated cancers, such as Burkitt's lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer. Interestingly, EBV has also been shown to be a causative factor in multiple sclerosis (MS), whereby EBV infection significantly increases the risk of subsequent MS (Non-Patent Document 11).

[0009] First generation PARP inhibitors generally exhibit nonselective activity against PARP1 and 2. Clinical use of these molecules is accompanied by hematologic toxicities such as anemia, neutropenia, and thrombocytopenia, limiting their use in combination with cytotoxic chemotherapy and other targeted agents due to dose-limiting cytopenias (Non-Patent Document 12). Evidence from preclinical mouse studies strongly suggests that inhibition of PARP2 is a major contributor to these hematologic toxicities, implicating PARP2 specifically in erythropoiesis in mice (Non-Patent Document 13). Furthermore, PARP2 function has been shown to be dispensable for antitumor activity in HRD mouse cancer models (Non-Patent Document 14). Taken together, these data suggest an unmet medical need for the development of inhibitors with improved selectivity for PARP1 over PARP2 and other PARPs, thus providing expanded therapeutic utility (1) as single agents and (2) in combination with other anticancer drugs.

[0010] To date, two PARP1 selective inhibitors, AZD5305 and AZD9574, have entered clinical development. AZD5305 is a potent PARP1 inhibitor, a trapper, with 500-fold selectivity over PARP2, and is said to have less off-target activity against secondary pharmacological targets than first-generation PARP inhibitors (Non-Patent Document 15). Importantly, in rodent models, AZD5305 was observed to cause significantly less hematologic toxicity than first-generation PARP inhibitors, confirming the reported pathogenic role of PARP2 in hematologic toxicity (Non-Patent Document 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.

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[0012] In view of the above, one object of the present invention is to provide a PARP1 inhibitor, in particular a PARP1 inhibitor for use in medicine. It is a further object to provide a pharmaceutical composition comprising such an inhibitor, and to provide a compound and a pharmaceutical composition for treating cancer. It is also an object to provide a method for synthesizing said compound. [Means for solving the problem]

[0013] Accordingly, the present invention provides a PARP1 inhibitor compound for use in medicine, the compound having the structure:

[0014] [ka] (In the formula, R 1 is selected from H and a substituted or unsubstituted organic group; R 2 is optionally present and is independently selected from H and a substituted or unsubstituted organic group; R 1 and R 2 may be taken together to form a ring; R 3 is independently selected from H and a substituted or unsubstituted organic group; R 6 is optionally present and is independently selected from H and a substituted or unsubstituted organic group; Z 1 and Z 2 is independently selected from C and N; and L comprises a group having the structure: [ka] (In the formula, 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 are independently selected from C, N, O and S; each X 3 may be the same or different and are independently selected from C, N, O and S; Preferably, at least one X 3 are independently N; each X 6 may be the same or different and are independently selected from C and N; Each R 41 may be the same or different, may be present or absent and is selected from H and a substituted or unsubstituted organic group; Each R 43 may be the same or different, may be present or absent and is selected from H and a substituted or unsubstituted organic group; R 44 is optional and is selected from H and a substituted or unsubstituted organic group; The dotted lines indicate that ring A may have single bonds or a combination of both single and double bonds and may be aliphatic or aromatic; and, independently, ring C may have single bonds or a combination of both single and double bonds and may be aliphatic or aromatic; R 5is selected from H and substituted or unsubstituted organic groups; preferably, substituted or unsubstituted organic groups; Each Q 1 may be the same or different, may be present or absent, and comprise groups 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 may be the same or different and are independently selected from H and a substituted or unsubstituted organic group; R 46 is selected from H and substituted or unsubstituted organic groups; Q 2 is an optional group having the 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 may be the same or different and are independently selected from C, N, O and S; X 5 is independently selected from C and N; Each R 42 may be the same or different, may be present or absent and is selected from H and a substituted or unsubstituted organic group; The dotted line indicates that ring B may have single bonds or a combination of both single and double bonds and may be aliphatic or aromatic); Q 3 is optional and comprises a group 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 attached to them depends on their nature and the number of other bonds they have. Maintaining valence means that in organic compounds, the atoms have their normal (typically the most common) valence (i.e., 2 for oxygen and divalent sulfur, 3 for nitrogen, and 4 for carbon). Nitrogen atoms may in some cases have 4 bonds, in which case they are typically positively charged so that the compound may have a counter ion. Such compounds are also considered to be part of the present invention, and it will be clear that in such cases the nitrogen atom still maintains its normal valence of 3 due to the positive charge. For the avoidance of doubt, where the number of R groups may vary depending on the selection of X groups, it may vary as follows:

[0016] Z 1 If N, then R 6 does not exist. 2 If N, then R 2 does not exist. Each R41 may be the same or different, but each X 1 Provided that the following conditions are met: 1 is O or divalent S, R 41 does not exist;X 1 is N and double-bonded to the adjacent atom, R 41 does not exist;X 1 is N and is not double-bonded to adjacent atoms, R 41 There is one X 1 is C and is double-bonded to adjacent atoms, R 41 There is one X 1 is C and is not double-bonded to adjacent atoms, R 41 There are two R 43 may be the same or different, but each X 3 Provided that the following conditions are met: 3 is O or divalent S, R 43 does not exist;X 3 is N and double-bonded to the adjacent atom, R 43 does not exist;X 3 is N and is not double-bonded to an adjacent atom, R 43 There is one X 3 is C and is double-bonded to an adjacent atom, R 43 There is one X 3 is C and is not double-bonded to an adjacent atom, R 43 There are two X 6 About: 6 is N or C and is double-bonded to the adjacent atom, R 43 does not exist;X 6 is C and is not double-bonded to an adjacent atom, R 43 There is one X to which it is bound. 3 About: 3 When is O or divalent S, R 44 does not exist;X 3 is O or divalent S, R 44 does not exist;X 3is N and double-bonded to the adjacent atom, R 44 does not exist;X 3 is N and is not double-bonded to an adjacent atom, R 44 There is one X 3 is C and is double-bonded to an adjacent atom, R 44 There is one X 3 is C, and the C is R 43 is bonded to an adjacent atom and is not double-bonded to R 44 There is one R 42 may be the same or different, but each X 2 Provided that the following conditions are met: 2 is O or divalent S, R 42 does not exist;X 2 is N and double-bonded to the adjacent atom, R 42 does not exist;X 2 is N and is not double-bonded to an adjacent atom, R 42 There is one X 2 is C and is double-bonded to an adjacent atom, R 42 There is one X 2 is C and is not double-bonded to an adjacent atom, R 42 There are two X 5 About: 5 is N or C and is double-bonded to the adjacent atom, R 42 does not exist;X 5 is C and is not double-bonded to an adjacent atom, R 42 There is one R 11 may be the same or different, but each X 4 Provided that the following conditions are met: 4 is O or divalent S, R 11 does not exist;X 4 is N and double-bonded to the adjacent atom, R 11 does not exist;X 4 is N and is not double-bonded to an adjacent atom, R 11 There is one X4 is C and is double-bonded to an adjacent atom, R 11 There is one X 4 is C and is not double-bonded to an adjacent atom, R 11 There are two R 14 may be the same or different, but when N is double-bonded to an adjacent atom, R 14 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, although in most embodiments this is not preferred unless explicitly stated. Thus, in some embodiments, the following substituents may be taken together to 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 preferred that R groups bonded to the same atom do not join together to form a ring, although this embodiment is not excluded.

[0018] In this context, the invention includes compounds in which an R group on an atom or two R groups on the same atom form a group that is double-bonded to that atom. Thus, an R group or two R groups attached to the same atom together form a =O group or =C(R') 2groups (wherein each R′ group is the same or different and is H or an organic group, preferably H or a linear or branched C 1 ~C 6 The R groups may be taken together to form a C=O group or a C=C(R') 2 It is more typical when the ring is bonded to one C atom to form a group. Thus, in some cases, the C ring atom in the ring is bonded to X and / or R 11 , R 41 , R 42 , R 43 , R 44 , and R 45 As well as one or more of the following, may also comprise a =O group.

[0019] In this context, parts of a structure that are enclosed in parentheses (whether normal or square brackets) may be repeated the number of times given by the number next to the parentheses, e.g. (C(R)). 0,1,2 or [C(R)] 0,1,2 In the formula (I), the C-R group may be absent, present once (i.e., -C(R)-), or present twice (i.e., -C(R)-C(R)-).

[0020] In the context of the present invention, a compound is considered to be a PARP1 inhibitor if its presence is able to prevent or reduce the ability of immobilized PARP1 to undergo auto-polyADP-ribosylation (AutoPARylation) following incubation with biotinylated-NAD+, compared to the same process in its absence. Typically, the IC 50 If the concentration is <10 μM, the compound is considered to be a PARP1 inhibitor. A suitable assay consists of 2 nM PARP1 and 2 μM biotin-NAD in an assay buffer of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), 0.02% Tween (v / v). +Poly ADP ribosylation (PARylation) may be performed for 2 hours at room temperature and detected using a dissociation enhanced lanthanide fluorescent immunoassay (DELFIA) readout. A particularly suitable assay is described in the Examples below. Compounds may be detected in the PARP1 inhibitor assay with an IC 50 <1 μM is preferred, 50 <100 nM is more preferable, and IC 50 <10 nM is most preferred.

[0021] A compound is also considered to be a selective PARP1 inhibitor if its presence is capable of displacing or reducing the ability of a high affinity Cy5 fluorescent dye-labeled chemical probe to bind to PARP1 while displacing the ability of the same chemical probe to bind to PARP2 with at least 10-fold weaker activity. Typically, a compound has an IC 50 If the compound shows <10 μM and is at least 10-fold more selective than PARP2, the compound is considered to be a selective PARP1 inhibitor. Such a suitable assay may be performed at room temperature for 1 hour using 10 nM PARP1 or PARP2, Tb-cryptate antibody, and PARP1 / 2 binding probe in an assay buffer of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), 0.02% Tween (v / v). Displacement of probe binding may be detected using homogeneous time-resolved fluorescence. Particularly suitable assays are described in the examples below. The selectivity in favor of PARP1 over PARP2 is preferably at least 50-fold, more preferably at least 100-fold.

[0022] The compound also showed IC 306.111 against PARP1 in a NanoBRET assay indicating engagement of the cellular target. 50Selective PARP1 inhibitors are considered to be those with a selectivity of <10 μM and at least 10-fold more selective than PARP2. These assays involve the binding of Nano-luc labeled proteins (e.g., PARP1 or PARP2) to high affinity NADs. + It is based on bioluminescence resonance energy transfer (BRET) between fluorescent groups on competitive binding probes. Such cell probe displacement assays can be used to measure the affinity and selectivity of inhibitors for PARP1 and 2. Particularly suitable assays are described in the examples below. The selectivity in favor of PARP1 over PARP2 is preferably at least 50-fold, more preferably at least 100-fold.

[0023] In all embodiments of the present invention (both the corresponding embodiments described above and the embodiments described below in this disclosure), the substituents (respective R groups) are not particularly limited, as long as they do not prevent the expression of PARP1 inhibitory function. In all embodiments mentioned in connection with the present invention, both the embodiments described above and the embodiments described below, the substituents are selected from H and organic groups. Thus, both above and below, 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. Thus, "substituent" and "organic group" may have any of the following meanings:

[0024] An organic group can include any one or more atoms from any of Groups IIIA, IVA, VA, VIA, or VIIA of the periodic table, such as B, Si, N, P, O, or S atoms (e.g., OH, OR, NH 2 , N.H.R., N.R. 2 , S.H., S.R., and S.O. 2 R, SO 3 H, P.O. 4 H 2 ) or a halogen atom (e.g., F, Cl, Br or I), where R is a linear or branched lower hydrocarbon (1 to 6 C atoms) or a linear or branched higher hydrocarbon (7 or more C atoms, e.g., 7 to 40 C atoms).

[0025] The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight chain, branched chain, or cyclic group. 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 comprises an unsaturated group, the hydrocarbon may comprise one or more alkene functionalities and / or one or more alkyne functionalities. If the hydrocarbon comprises a straight or branched chain group, the hydrocarbon may comprise one or more primary, secondary, and / or tertiary alkyl groups.

[0027] When the hydrocarbon comprises a cyclic group, the hydrocarbon may comprise an aromatic ring, a non-aromatic ring, an aliphatic ring, a heterocyclic ring, and / or fused ring derivatives of these groups. The ring may be fully saturated, partially saturated, or fully unsaturated.Thus, the cyclic group may be any of benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxa azole, isoxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolane, 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, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2-azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8-azaindolizine, 9-azaindolizine, purine, carbazole , 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, phenoxanthiin, and / or thianthrene, as well as positional isomers of the above groups. These groups may generally be attached at any point in the group, and may be attached to a heteroatom or a carbon atom.In some instances, certain attachment positions are preferred, such as 1-yl, 2-yl, etc., and these are explicitly identified where appropriate. All tautomeric 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 the hydrocarbon group is not particularly limited, but the hydrocarbon group preferably comprises 1 to 40 C atoms. Thus, the hydrocarbon group may be a lower hydrocarbon (1 to 6 C atoms) or a higher hydrocarbon (7 or more C atoms, for example, 7 to 40 C atoms). The lower hydrocarbon group may be a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, or a positional isomer of these groups, for example, an isopropyl group, an isobutyl group, a tert-butyl group, etc. The number of atoms in the ring of the cyclic group is not particularly limited, but the ring of the cyclic group preferably comprises 3 to 10 atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 atoms.

[0029] The above-mentioned heteroatom-containing groups may contain 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), as well as other groups defined above. Thus, the substituents may contain one or more of the common functional groups in organic chemistry, such as hydroxyl, carboxylic acid, ester, ether, aldehyde, ketone, amine, amide, imine, thiol, thioether, sulfate, sulfonic acid, sulfonyl and phosphate groups. The substituents may also contain derivatives of these groups, such as carboxylic acid anhydrides and carboxylic acid halides.

[0030] Additionally, any substituent may bear a combination of two or more of the above-defined substituents and / or functional groups.

[0031] The rings A, B (if present), and C of the compound of the present invention may form a bicyclic or tricyclic ring structure (which may have additional condensed rings when the substituents on any ring form a ring by themselves). Each of the rings A, B, C, and D is not particularly limited as long as they do not prevent the expression of PARP1 inhibitory function. The rings A, B, C, and D may be independently composed of an aromatic ring, a non-aromatic ring, an aliphatic ring, and / or a heterocyclic ring. These rings may be fully saturated, partially saturated, or fully unsaturated.Thus, each ring may independently be selected from the group consisting of benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, oxetane, furan, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, Oxazole, isoxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolane, 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-aza Thiopyran, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2-azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8-azaindolizine, 9-azaindolizine, purine, carbazo The ring may comprise aryl, 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 thianthrene, as well as positional isomers of the above groups. These rings may generally be substituted at any point in the group and may be substituted on a heteroatom or carbon atom.All tautomeric ring forms are included within these definitions, for example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole and 3H-pyrrole.

[0032] In an exemplary embodiment, the present invention provides a method for the preparation of a 3 is absent or is a group independently selected from the following structures: [ka] (In the formula, Each R 45 may be the same or different and are independently selected from H and substituted or unsubstituted organic groups; R 46 is selected from H and substituted or unsubstituted organic groups. 3 is absent or, for example, -CH 2 -group, such as the groups shown below: [ka]

[0033] In an exemplary embodiment, the present invention provides a method for the preparation of a 2 exists and each Q 1 is independently absent or a group independently selected from the following structures: [ka] (In the formula, Each R 45 may be the same or different and are independently selected from H and substituted or unsubstituted organic groups; R 46 is selected from H and substituted or unsubstituted organic groups. In particular, Q 2 If there is, Q 1 is absent or, for example, -CH 2 -group, such as the groups shown below: [ka]

[0034] Q attached to ring A 1 The group is, for example, -CH 2 -group, such as the groups shown below: [ka]

[0035] In some embodiments, the present invention provides a compound as defined above, wherein the L group comprises a group having the structure: [ka] (In the formula, Q 1 is absent or a group as defined above; Q 3 is absent or 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. 5 is a substituent R 42 It is preferable that the N is free of .

[0036] In some embodiments, the L group comprises a group having the structure: [ka] (In the formula, n, m, p, q, r, s, X 1 , X 2 , X 3 , X 5 , R 41 , R 42 , R43 , R 44 , R 5 , Q 1 , Q 3 and rings A, B and C are as defined above. 5 is a substituent R 42 It is preferable that the N is free of .

[0037] In some embodiments, the L group comprises a group having the 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 and rings A, B and C are as defined above. 5 is a substituent R 42 It is preferable that the N is free of .

[0038] In some embodiments, the L group comprises a group having the 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 and rings A, B and C are as defined above. 5 is a substituent R 42 It is preferable that the N is free of .

[0039] In some embodiments, the L group comprises a group having the 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 and ring C is as defined above. X 5 is a substituent R 42 It is preferable that the N is free of .

[0040] In some embodiments, the L group comprises a group having the 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 and ring C is as defined above. X 5 is a substituent R 42 It is preferable that the N is free of .

[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 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: [ka] [ka] (In the formula, R 41 , R 42 , R 43 , R 44 , and R 5 is as defined above.

[0044] Typically, R 41 , R 42 ,R 43 , R 44 and R 45 are each independently selected from H and a group selected from the following groups: -deuterium; - halogens (such as -F, -Cl, -Br, and -I); - nitrile groups; -Substituted or unsubstituted linear or branched C 1 ~C 6 alkyl groups (such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and hexyl); -Substituted or unsubstituted linear or branched C 1 ~C 6 Alkyl-aryl groups (-CH 2 Ph, -CH 2 (2, 3 or 4)F-Ph, -CH 2 (2, 3 or 4)Cl-Ph, -CH 2 (2, 3 or 4)Br-Ph, -CH2 (2, 3 or 4)I-Ph, -CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 CH 2 CH 2 Ph and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Ph, etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 Alkyl halide (-CH 2 F, -CH 2 Cl, -CH 2 Br, -CH 2 I, -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CH 2 CF 3 , -CH 2 CCl 3 , -CH 2 CBr 3 , and -CH 2 CI 3 etc.); --NH 2 or substituted or unsubstituted linear or branched primary, secondary or tertiary C 1 ~C 6 Amine groups (-NMeH, -NMe 2 , -NEtH, -NEtMe, -NEt 2 , -NPrH, -NPrMe, -NPrEt, -NPr 2 , -NBuH, -NBuMe, -NBuEt, -CH 2 -NH 2 , -CH 2 -NMeH, -CH 2 -NMe 2, -CH 2 -NEtH, -CH 2 -NEtMe, -CH 2 -NEt 2 , -CH 2 -NPrH, -CH 2 -NPrMe and -CH 2 -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)F 2 -Ph, -NH-2,(3, 4, 5 or 6)Cl 2 -Ph, -NH-2, (3, 4, 5 or 6)Br 2 -Ph, -NH-2, (3, 4, 5 or 6)I 2 -Ph, -NH-2,(3, 4, 5 or 6)Me 2 -Ph, -NH-2,(3, 4, 5 or 6)Et 2 -Ph, -NH-2,(3, 4, 5 or 6)Pr 2 -Ph and -NH-2,(3, 4, 5 or 6)Bu 2 -Ph, etc.) - substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); -Substituted or unsubstituted cyclic C 3 ~C 8alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); --OH group or substituted or unsubstituted linear or branched C 1 ~C 6 Alcohol group (-CH 2 OH, -CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 CH 2 OH, -CH(CH 3 )CH(CH 3 )OH, -CH(CH 2 CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 CH 2 OH and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH, etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 Carboxylic acid groups (-COOH, -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 CH 2COOH and -CH 2 CH 2 CH 2 CH 2 CH 2 COOH, etc.); - a substituted or unsubstituted straight or branched chain carbonyl group (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH 2 Ph, -(CO)CH 2 OH, -(CO)CH 2 OCH 3 , -(CO)CH 2 NH 2 , -(CO)CH 2 NHMe, -(CO)CH 2 NMe 2 , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl, -(CO)NH 2 , -(CO)NHMe, -(CO)NMe 2 , -(CO)NHEt, -(CO)NEt 2 , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH 2 CH 2 OH, -(CO)NHCH 2 CH 2 OMe, -(CO)NHCH 2 CH 2 NH 2 , -(CO)NHCH 2 CH 2 NHMe and -(CO)NHCH 2 CH 2 NMe 2 etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 Carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH 2 COOMe, -CH 2 CH 2COOMe, -CH 2 CH 2 CH 2 COOMe and -CH 2 CH 2 CH 2 CH 2 COOMe etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 The amide group (-CO-NH 2 , -CO-NMeH, -CO-NMe 2 , -CO-NEtH, -CO-NEtMe, -CO-NEt 2 , -CO-NPrH, -CO-NPrMe, and -CO-NPrEt, etc.); -Substituted or unsubstituted linear or branched C 1 ~C 7 aminocarbonyl groups (such as -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); -Substituted or unsubstituted linear or branched C 1 ~C 7 Alkoxy or aryloxy groups (-OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -O-Ph, -O-CH 2 -Ph, -O-CH 2 -(2, 3 or 4)-F-Ph, -O-CH 2 -(2, 3 or 4)-Cl-Ph, -CH 2 OMe, -CH 2 OEt, -CH 2 OPr, -CH 2 OBu, -CH 2 CH2 OMe, -CH 2 CH 2 CH 2 OMe, -CH 2 CH 2 CH 2 CH 2 OMe and -CH 2 CH 2 CH 2 CH 2 CH 2 OMe, etc.); - Substituted or unsubstituted linear or branched aminoalkoxy group (-OCH 2 NH 2 , -OCH 2 NHMe, -OCH 2 NMe 2 , -OCH 2 NHEt, -OCH 2 NEt 2 , -OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NHMe, -OCH 2 CH 2 NMe 2 , -OCH 2 CH 2 NHEt and -OCH 2 CH 2 NEt 2 etc.); -Substituted or unsubstituted sulfonyl group (-SO 2 Me, -SO 2 Et, -SO 2 Pr, -SO 2 iPr, -SO 2 Ph, -SO 2 -(2, 3 or 4)-F-Ph, -SO 2 -Cyclopropyl, -SO 2 CH 2 CH 2 OCH 3 , -SO 2 NH 2 , -SO 2 NHMe, -SO 2 NMe 2 , -SO 2 NHEt, -SO 2 NEt2 , -SO 2 -Pyrrolidin-N-yl, -SO 2 -morpholin-N-yl, -SO 2 NHCH 2 OMe and -SO 2 NHCH 2 CH 2 OMe, etc.); -Substituted or unsubstituted aminosulfonyl group (-NHSO 2 Me, -NHSO 2 Et, -NHSO 2 Pr, -NHSO 2 iPr, -NHSO 2 Ph, -NHSO 2 -(2, 3 or 4)-F-Ph, -NHSO 2 -Cyclopropyl and -NHSO 2 CH 2 CH 2 OCH 3 etc.); - 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)-F 2 -Ph-, 2,(3,4,5 or 6)-Cl 2 -Ph-, 2,(3,4,5 or 6)-Br 2 -Ph-, 2,(3,4,5 or 6)-I 2 -Ph-, 2,(3,4,5 or 6)-Me 2 -Ph-, 2,(3,4,5 or 6)-Et 2 -Ph-, 2,(3,4,5 or 6)-Pr 2 -Ph-, 2,(3,4,5 or 6)-Bu 2 -Ph-, 2,(3,4,5 or 6)-(CN) 2 -Ph-, 2,(3,4,5 or 6)-(NO 2 ) 2 -Ph-, 2,(3,4,5 or 6)-(NH 2 ) 2 -Ph-, 2,(3,4,5 or 6)-(MeO) 2-Ph-, 2,(3,4,5 or 6)-(CF 3 ) 2 -Ph-, 3,(4 or 5)-F 2 -Ph-, 3,(4 or 5)-Cl 2 -Ph-, 3,(4 or 5)-Br 2 -Ph-, 3,(4 or 5)-I 2 -Ph-, 3,(4 or 5)-Me 2 -Ph-, 3,(4 or 5)-Et 2 -Ph-, 3,(4 or 5)-Pr 2 -Ph-, 3,(4 or 5)-Bu 2 -Ph-, 3,(4 or 5)-(CN) 2 -Ph-, 3,(4 or 5)-(NO 2 ) 2 -Ph-, 3,(4 or 5)-(NH 2 ) 2 -Ph-, 3,(4 or 5)-(MeO) 2 -Ph-, 3,(4 or 5)-(CF 3 ) 2 -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph -, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO 2 )-Ph-, 3-(NO 2 )-Ph-, 4-(NO 2 )-Ph-, 2-(NH 2 )-Ph-, 3-(NH 2 )-Ph-, 4-(NH 2 )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH 2 -CO)-Ph-, 3-(NH 2 -CO)-Ph-, 4-(NH 2 -CO)-Ph-, 2-CF 3 -Ph-, 3-CF 3 -Ph-, 4-CF 3 -Ph-, 2-CF 3 O-Ph-, 3-CF 3 O-Ph- and 4-CF3 O-Ph- etc.); - saturated or unsaturated, substituted or unsubstituted heterocyclic groups, including aromatic and / or non-aromatic heterocyclic groups (pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-6-yl, 1,2,4-triazol-7-yl, 1,2,4-triazol-8-yl, 1,2,4-triazol-9-yl, 1,2,4-triazol-10-yl, 1,2,4-triazol-11-yl, 1,2,4-triazol-12-yl, 1,2,4-triazol-13-yl, 1,2,4-triazol-14-yl, 1,2,4-triazol-15-yl, 1,2,4-triazol-16-yl, 1,2,4-triazol-17-yl, 1,2,4-triazol-18-yl, 1,2,4-triazol-19-yl, 1,2,4-triazol-20-yl, 1,2,4-triazol-21-yl, 1,2,4-triazol-22-yl, 1 -triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-1-yl, 2-azapiperidin-3-yl, 2-azapiperidin-4-yl, Azapiperidin-4-yl, 3-azapiperidin-1-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-1-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran- zapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl,3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-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, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, and tetrazol-1-yl, tetrazol-2-yl, and tetrazol-5-yl, etc.; where, when there are two R groups attached to the same atom, they may together form a group that is double-bonded to said atom (e.g., a carbonyl group (=O) or an alkene group (=C(R') 2 ) (wherein each R′ group is the same or different and is H or an organic group, preferably H or a linear or branched C 1 ~C 6 ) etc.).

[0045] In some configurations, a pair of Rs attached to different atoms 41 The groups may be taken together to form a ring with the atoms of ring A and / or a pair of R 42 The groups may be taken together to form a ring with the atoms of ring B, where optionally, the pair of R 41 group and / or the pair of R 42 Each of the groups is independently 7 ) 1又は2 where each X 7 may be the same or different and are independently selected from C, N, O, and S; 7 is independently unsubstituted, or 7 If is C, then H or C 1 ~C 6 Alkyl groups of C 1 ~C 6 (ii) X is independently substituted with an organic group selected from a halogenated alkyl group, a halogen such as fluorine, or a hydroxyl group; 7 is N, H or C 1 ~C 6 Alkyl groups of C 1 ~C 6 or C 1 ~C 6 and the amide groups are independently substituted with organic groups selected from the group consisting of

[0046] In some configurations, R 5 and R 44 The groups taken together form the X of the ring C to which they are attached. 6 and X 3Together with the atoms, optionally, a ring may be formed, where R 5 and R 44 The radicals, taken together, form (X 8 ) 3、4又は5 where each X 8 may be the same or different and are independently selected from C, N, O, and S; 8 is independently unsubstituted, or 8 If is C, then H or C 1 ~C 6 Alkyl groups of C 1 ~C 6 (ii) X is independently substituted with an organic group selected from a halogenated alkyl group, a halogen such as fluorine, or a hydroxyl group; 8 is N, H or C 1 ~C 6 Alkyl groups of C 1 ~C 6 or C 1 ~C 6 and the amide groups are independently substituted with organic groups selected from the group consisting of

[0047] R 41 , R 42 , R 43 and R 44 are each independently H, deuterium, a halogen (e.g., -F, -Cl, -Br, and -I, preferably F or Cl), a nitrile group, a substituted or unsubstituted C 1 ~C 6 Alkyl groups of substituted or unsubstituted straight or branched C 1 ~C 6 halogenated alkyl group (preferably CF 3 or CHF 2 ), a cyclopropyl group, an -OH group or a substituted or unsubstituted linear or branched C 1 ~C 6 Alcohol groups, substituted or unsubstituted, linear or branched, C 1 ~C 7 Aminocarbonyl groups (e.g., -NH-CO-Me, etc.), -NH 2 Group or substituted or unsubstituted C 1 ~C6 and substituted or unsubstituted C 1 ~C 6 wherein each pair of R 41 When the groups are taken together to form a ring with an atom of ring A, and / or when a pair of R 42 When the groups taken together form a ring with the atoms of ring B, the pair of R 41 group and / or the pair of R 42 Each group is independently -CH 2 -or-CH 2 CH 2 and, where R 5 and R 44 When the groups taken together form a ring with the ring C atoms, R 5 and R 44 taken together comprise -CH=CH-CH=CH- or -NH-CO-NH-.

[0048] R 45 is H, halogen (e.g., -F, -Cl, -Br, -I, etc., preferably -F), substituted or unsubstituted C 1 ~C 6 Alkyl groups of substituted or unsubstituted straight or branched C 1 ~C 6 halogenated alkyl group (preferably CF 3 ), -NH 2 Group or substituted or unsubstituted C 1 ~C 6 an amino group, an -OH group, or a substituted or unsubstituted linear or branched C 1 ~C 6 and substituted or unsubstituted C 1 ~C 6 It is preferred that the alkoxy group is selected from the following alkoxy groups:

[0049] Typically, R 46 is selected from H and a group selected from the following groups: -Substituted or unsubstituted linear or branched C 1 ~C 6alkyl groups (such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl and hexyl); -Substituted or unsubstituted linear or branched C 1 ~C 6 Alkyl-aryl groups (-CH 2 Ph, -CH 2 (2, 3 or 4)F-Ph, -CH 2 (2, 3 or 4)Cl-Ph, -CH 2 (2, 3 or 4)Br-Ph, -CH 2 (2, 3 or 4)I-Ph, -CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 CH 2 CH 2 Ph and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Ph, etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 Alkyl halide (-CH 2 F and -CH 2 CF 3 etc.); - substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); -Substituted or unsubstituted C 3 ~C 8 cyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); -Substituted or unsubstituted linear or branched C2 ~C 6 Alcohol group (-CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 CH 2 OH, -CH(CH 3 )CH(CH 3 )OH, -CH(CH 2 CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 CH 2 OH and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH, etc.); -Substituted or unsubstituted linear or branched C 2 ~C 6 Carboxylic acid group (-CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 CH 2 COOH and -CH 2 CH 2 CH 2 CH 2 CH 2 COOH, etc.); - a substituted or unsubstituted straight or branched chain carbonyl group (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH 2 Ph, -(CO)CH 2 OH, -(CO)CH 2 OCH 3 , -(CO)CH 2 NH 2 , -(CO)CH 2 NHMe, -(CO)CH 2 NMe 2 , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl, -(CO)NH 2 , -(CO)NHMe, -(CO)NMe 2 , -(CO)NHEt, -(CO)NEt 2 , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH 2 CH 2 OH, -(CO)NHCH 2 CH 2 OMe, -(CO)NHCH 2 CH 2 NH 2 , -(CO)NHCH 2 CH 2 NHMe and -(CO)NHCH 2 CH 2 NMe 2 etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 Carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH 2 COOMe, -CH 2 CH 2 COOMe, -CH 2 CH 2 CH 2 COOMe and -CH 2 CH 2 CH2 CH 2 COOMe etc.); -Substituted or unsubstituted linear or branched C 1 ~C 6 The amide group (-CO-NH 2 , -CO-NMeH, -CO-NMe 2 , -CO-NEtH, -CO-NEtMe, -CO-NEt 2 , -CO-NPrH, -CO-NPrMe, and -CO-NPrEt, etc.); -Substituted or unsubstituted sulfonyl group (-SO 2 Me, -SO 2 Et, -SO 2 Pr, -SO 2 iPr, -SO 2 Ph, -SO 2 -(2, 3 or 4)-F-Ph, -SO 2 -Cyclopropyl, -SO 2 CH 2 CH 2 OCH 3 , -SO 2 NH 2 , -SO 2 NHMe, -SO 2 NMe 2 , -SO 2 NHEt, -SO 2 NEt 2 , -SO 2 -Pyrrolidin-N-yl, -SO 2 -morpholin-N-yl, -SO 2 NHCH 2 OMe and -SO 2 NHCH 2 CH 2 OMe, 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)-F 2 -Ph-, 2,(3,4,5 or 6)-Cl 2 -Ph-, 2,(3,4,5 or 6)-Br 2-Ph-, 2,(3,4,5 or 6)-I 2 -Ph-, 2,(3,4,5 or 6)-Me 2 -Ph-, 2,(3,4,5 or 6)-Et 2 -Ph-, 2,(3,4,5 or 6)-Pr 2 -Ph-, 2,(3,4,5 or 6)-Bu 2 -Ph-, 2,(3,4,5 or 6)-(CN) 2 -Ph-, 2,(3,4,5 or 6)-(NO 2 ) 2 -Ph-, 2,(3,4,5 or 6)-(NH 2 ) 2 -Ph-, 2,(3,4,5 or 6)-(MeO) 2 -Ph-, 2,(3,4,5 or 6)-(CF 3 ) 2 -Ph-, 3,(4 or 5)-F 2 -Ph-, 3,(4 or 5)-Cl 2 -Ph-, 3,(4 or 5)-Br 2 -Ph-, 3,(4 or 5)-I 2 -Ph-, 3,(4 or 5)-Me 2 -Ph-, 3,(4 or 5)-Et 2 -Ph-, 3,(4 or 5)-Pr 2 -Ph-, 3,(4 or 5)-Bu 2 -Ph-, 3,(4 or 5)-(CN) 2 -Ph-, 3,(4 or 5)-(NO 2 ) 2 -Ph-, 3,(4 or 5)-(NH 2 ) 2 -Ph-, 3,(4 or 5)-(MeO) 2 -Ph-, 3,(4 or 5)-(CF 3 ) 2 -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph -, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO 2 )-Ph-, 3-(NO 2)-Ph-, 4-(NO 2 )-Ph-, 2-(NH 2 )-Ph-, 3-(NH 2 )-Ph-, 4-(NH 2 )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH 2 -CO)-Ph-, 3-(NH 2 -CO)-Ph-, 4-(NH 2 -CO)-Ph-, 2-CF 3 -Ph-, 3-CF 3 -Ph-, 4-CF 3 -Ph-, 2-CF 3 O-Ph-, 3-CF 3 O-Ph- and 4-CF 3 O-Ph- etc.); and, - substituted or unsubstituted, saturated or unsaturated, substituted or unsubstituted heterocyclic groups, including aromatic and / or non-aromatic heterocyclic groups (pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-6-yl, pyridin-6-yl, pyridin-5 ... ridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-3-yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-2-yl, furan-2-yl, furan-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, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl yl, 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, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6 -yl, 4-azathiopyran-2-yl, 4-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, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, and tetrazol-5-yl, etc.

[0050] R 46 is H, substituted or unsubstituted C 1 ~C 6 or a substituted or unsubstituted linear or branched C 1 ~C 6 Preferably, the halogenated alkyl group is selected from the group consisting of the halogenated alkyl groups listed above.

[0051] Ring A of the L group preferably has any of the following structures: [ka] (In the formula, R 41 are as defined in this disclosure.

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

[0053] Even more preferably, ring A of the L group has any of the following structures: [ka]

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

[0055] In one embodiment, Q of the L group 2 is present and has one of the following structures: [ka] (In the formula, R 42 are as defined in this disclosure.

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

[0057] Alternatively, the Q of the L group 2 There is no group, Q 1 In this configuration, there is only one Q group. 1 The group typically separates ring A and ring C in the linear direction by 3 or 4 atoms and may have any of the following structures: [ka] (In the formula, R 45 and R46 are as defined in this disclosure.

[0058] In this configuration, the Q 1 Preferably, the group has one of the following structures: [ka]

[0059] Preferably, ring C of the L group has any of the following structures: [ka] [ka] (In the formula, R 5 , R 43 , R 44 , and R 46 are as defined in this disclosure.

[0060] More preferably, ring C of the L group has any of the following structures: [ka] (In the formula, R 5 , and R 43 are as defined in this disclosure.

[0061] In some configurations, R 5 is a substituted or unsubstituted organic group.

[0062] Preferably, R 5 is not MeO, and is more preferably H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 , -NR 51 COR 52 , -SO 2 NR 51 R 51 , -NR 51 SO 2 R 53 , -O-CR52 R 52 R 52 , -CR 52 R 52 NR 51 R 51 and one of the following structures: [ka] (In the formula, R 51 , R 52 , and R 53 Each may be the same or different and is independently selected from H and substituted or unsubstituted organic groups. More preferably, R 5 -CONR 51 R 51 ).

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

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

[0065] In some embodiments, the L group of the compounds of the 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 contain single bonds or a combination of both single and double bonds and may be aliphatic or aromatic; each X 4may be the same or different and are independently selected from C, N, O and S; Each R 11 may be the same or different and are independently selected from H and a substituted or unsubstituted organic group; Z 1 , R 3 , R 6 and L are as defined herein. In some embodiments, one X of ring D is 4 is N. At least one X 4 is preferably C.

[0067] Preferably, the compound has any of the following structures: [ka] (In the formula, rings D, X 4 , R 11 , R 3 , R 6 , and L is as defined herein.

[0068] More preferably, the compound has any of the following structures: [ka] [ka] [ka] [ka] (In the formula, R 14 , H, C 1 ~C 3 or an alkyl group of C 1 ~C 3 R 11 , ring D, R 3 , R 6 , and L are as defined in this disclosure.

[0069] Even more preferably, the compound has any 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 is H, halogen, nitrile group, linear or branched C 1 ~C 3 Alkyl groups of linear or branched C 1 ~C 3 a halogenated alkyl group (preferably a fluoroalkyl group), an -OH group, a linear or branched C 1 ~C 3 Alcohol groups of the formula: 1 ~C 3 Alcohol group, -NH 2 , linear or branched primary, secondary or tertiary C 1 ~C 3 Amine groups, linear or branched C 1 ~C 3 Alkoxy groups, linear or branched C 1 ~C 3 and / or a pair of R 11 groups; and independently and / or a pair of R 11When the groups taken together form a ring with the atoms of ring D, the pair of R 11 The group is -CH 2 CH 2 CH 2 -Equipped with.

[0071] Each R 11 are H, Cl, F, and CHF 2 , C.F. 3 , C.H. 3 , OH, CH 3 O and NH 2 , and / or a pair of R bound to the same atom forming =O 11 groups; and preferably, a pair of R 11 When the groups taken together form a ring with the atoms of ring D, the pair of R 11 The group is -CH 2 CH 2 CH 2 It is preferable to have

[0072] In some embodiments, compounds having any of the following structures are provided: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] where L is as defined in this disclosure.

[0073] In some embodiments, compounds having any of the following structures are provided: [ka] (In the formula, Each R 12 represents H and a substituted or unsubstituted organic group, preferably a lower (C 1 ~C 6 ) an alkyl group, an alkoxy group or a haloalkyl group, a substituted or unsubstituted C 3 ~C 6 and a halogen group; Here, at least one R 12 is not H; Each R 13 may be the same or different and are independently selected from H and a substituted or unsubstituted organic group; R 3 , R 6 and L is as defined in this disclosure.

[0074] At least one R 12 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -Cl, -F, -Cl, -CH 2 CF 3 , -CH 2 CH 2 F, -CH 2 CH 2It is preferably selected from OH, a methoxy group, a methoxymethyl group, a methoxyethyl group, an isopropyl group, a cyclopropyl group or a cyclopropylmethyl group.

[0075] R 13 is preferably H, F, C 1 ~C 3 or an alkyl group of C 1 ~C 3 The fluoroalkyl groups are selected from the following:

[0076] R 3 is preferably H.

[0077] R 6 is preferably H, halogen, C 1 ~C 3 Alkyl groups of C 1 ~C 3 Haloalkyl groups of C 1 ~C 3 or C 1 ~C 3 The aminoalkyl groups are selected from the group consisting of:

[0078] In some embodiments, compounds having any of the following structures are provided: [ka] [ka] where L is as defined in this disclosure.

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

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[0080] The structures of the compounds of the present invention have been described in detail above. For the avoidance of doubt, any compounds used in the present invention may have the following compounds or compositions depending on their structures: Each structure the isolated enantiomer, or - a mixture of two or more enantiomers, or a mixture of two or more diastereomers and / or epimers, or a racemic mixture, or -1 or more tautomers.

[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 represent one or more enantiomeric structures that may possess PARP1 inhibitory activity, either as racemic mixtures and / or as separated enantiomers. In the examples below, compounds with an "a" suffix (e.g., "10a") represent the enantiomer that elutes as the first fraction when a racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAL chiral chromatography column. In the examples below, compounds with a "b" suffix (e.g., "10a") represent the enantiomer that elutes as the second fraction when a racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAL chiral chromatography column. In the examples below, compounds without a suffix represent achiral compounds or racemic mixtures of enantiomers. In the examples below, compounds with a "rac" suffix represent racemic mixtures of enantiomers.

[0082] The compounds described in the present disclosure may be provided for use in medicine.In the context of the present invention, the medicinal use is not particularly limited, as long as it is an application that is promoted by the PARP1 inhibitory effect of the compound.Therefore, the compounds of the present invention may be used for any disease, condition or disorder that can be prevented, improved or treated with a PARP1 inhibitor.Typically, this includes disease conditions and / or disorders selected from cancer, as long as the cancer can be treated, prevented or improved with a PARP1 inhibitor, without being particularly limited. Thus, cancer may be any solid or liquid tumor, including cancer of the eye, brain (such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma and astrocytoma), 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, bronchus, liver, skin, ureter, urethra, testis, vagina, anus, laryngeal gland, ovary, thyroid gland, esophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal gland; endometrial cancer, oral cancer, malignant melanoma, neuroblastoma, gastric cancer, hemangiomatosis, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN hamartoma syndrome ( The cancer may be selected from among PHTS (such as 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 prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, Hodgkin lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma). In addition, the compounds described in the present disclosure may be used in cancers where EBV is involved, such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer.

[0083] The compounds described in the present disclosure may be used to treat cancers with defective DNA damage response repair pathways, particularly cancers with defective homologous recombination-dependent DNA double-strand break (DSB) repair activity. Components of the homologous recombination-dependent DNA double-strand break (DSB) repair pathway and other DNA damage response pathways include, but are not limited to, the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, and BLM. Other components involved in homologous recombination (HR)-dependent DNA double-strand breaks (DSBs) include, for example, regulatory factors such as ESMY (Non-Patent Document 17). Cancers that are defective in the repair function of 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, the cancer cells may have a BRCA1 and / or BRCA2-deficient phenotype; i.e., the cancer cells may lack expression of BRCA1 and / or BRCA2 due to mutations, polymorphisms, or epigenetic silencing of nucleic acids encoding BRCA1 and / or BRCA2, or due to amplification, polymorphism, or mutation of genes encoding regulators (e.g., the ESMY gene encoding the BRCA2 regulator; Non-Patent Document 17). Amplification of the ESMY gene is 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. Wild-type alleles of BRCA1 and / or BRCA2 are frequently lost in tumors of heterozygous carriers (Non-Patent Document 18), and their detection is well known in the art as a means of patient selection (Non-Patent Document 19; Non-Patent Document 20).

[0085] In some embodiments, the compounds described in the present disclosure are selective PARP1 inhibitors, as defined above. The selective inhibition of PARP1 over PARP2 reduces the side effects associated with PARP2, including one or more hematological toxicities, such as anemia, neutropenia, thrombocytopenia, etc. This allows the treatment of cancer patients with reduced hematological side effects. This also allows the administration of PARP1 inhibitors to patients at higher doses, or in combination with chemotherapeutic agents.

[0086] The present invention also provides a pharmaceutical composition comprising the compound defined above. The pharmaceutical composition is not particularly limited, but typically further comprises pharma- ceutically acceptable additives and / or excipients. In the pharmaceutical composition, the compound defined above may be present in the form described above, or alternatively, in a form suitable for improving bioavailability, solubility and / or activity, and / or for improving formulation. Thus, the compound may be in a pharma- ceutical acceptable salt, hydrate, acid, ester, or other alternative suitable form. Typically, the composition is for treating a disease, condition, or disorder defined above. In some embodiments, the compound may be present in the composition as a pharma- ceutical acceptable salt, or other alternative form of the compound, to improve pharmaceutical formulation.

[0087] In some embodiments, the pharmaceutical composition is a composition for treating cancer, and further comprises an additional agent for treating cancer. The additional agent for treating cancer is not particularly limited, as long as it provides some usefulness in cancer treatment. Typically, however, the additional agent for treating cancer is selected from ionizing radiation and chemotherapeutic agents, such as microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody drug conjugates, immunotherapeutic agents, hormone ablation therapy, apoptosis inducers, and cell cycle signal transduction inhibitors. Immunotherapeutic agents may consist of, but are not limited to, anti-tumor vaccines; oncolytic viruses; immune stimulatory 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, comprising: (a) a compound as defined above; and (b) an additional agent for treating cancer and preferably the further agent for treating cancer is selected from ionizing radiation and chemotherapeutic agents such as, for example, microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogues, hormone ablation therapy, signal transduction 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 said compound and said further agent are suitable for simultaneous, sequential or separate administration.

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

[0090] Typically, in all embodiments of the 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 the synthesis of a compound as defined above, said method comprising reacting between (i) a first reactant comprising a ring E bearing a portion of a substituent L, and (ii) a second reactant comprising the remainder of the substituent L, to form a PARP1 inhibitor compound.

[0092] Typically, in one synthesis method, a first reactant comprises a ring E and a ring A, a second reactant comprises a precursor of Q1 or Q2 having a reactive group, and the method comprises attaching an 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 comprise alkylation, reductive amination, or amide formation to form the L group.

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

[0094] Those skilled in the art can select reaction conditions in these methods according to suitable starting materials and by referring to known synthesis techniques. In some embodiments, the method comprises one or more additional steps. Exemplary synthesis methods are shown in the examples of the present disclosure.

[0095] Typically, the above formula (and all formulas in this disclosure) are shown in non-stereoisomeric form. For the avoidance of 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 above formula (and all formulas in this disclosure) is intended to represent all tautomers equivalent to the corresponding formula.

[0096] The term "comprises" as used in this specification and in the claims means "including or consisting of." This term indicates the inclusion of at least the feature that follows the term and does not exclude the inclusion of other features not expressly mentioned. This term can also indicate an entity consisting only of the feature that follows the term.

[0097] Detailed Description of the Invention The invention will now be described in more detail, by way of example only, with reference to the following specific embodiments.

[0098] example Exemplary Syntheses of Compounds of the 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) of POCl 3 To the solution of (55.00 g, 0.36 mol) was added DIEA (23.00 g, 0.18 mol) at 0° C. Then, this mixture was stirred at 120° C. for 2 h. The hot reaction mixture was poured into ice water, and the aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layer was diluted with Na 2 SO 4 The mixture was dried at 40° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (eluted with PE / EA=100:0 to 92:9) to give 2,4-dichloro-5-ethylpyrimidine (2) (4.80 g, 38% yield) as a white solid. LCMS(ESI)C6H6Cl2N2[M+H]+ m / z calculated: 176.99, found: 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) was added tBuOLi (2.30 g, 28.75 mmol) over 15 min at 70° C. Then, 2,4-dichloro-5-ethylpyrimidine (2) (4.80 g, 27.27 mmol) was added to the mixture at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 93:7) to give 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (INT-4) (4.00 g, 53% yield) as a white solid. LCMS(ESI)C14H15ClN2O2[M+H] + m / z calculated: 279.08, found: 279.15.

[0103] Synthesis of compound 42 [ka]

[0104] Preparation of tert-butyl 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) 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) in 1,4-dioxane / H 2 In a 4:1 (15 mL) solution of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (INT-4) (377.72 mg, 1.76 mmol) and Na 2 CO 3 (189.11 mg, 3.01 mmol) was added, followed by Pd(dppf)Cl 2(247.89 mg, 0.34 mmol) was added at room temperature. The reaction mixture was refluxed at 100° C. under nitrogen atmosphere and stirred for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with petroleum ether / ethyl acetate=100:0 to 85:15) to give tert-butyl 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2) (250 mg, 31% yield) as a colorless oil. LCMS(ESI)C23H29N3O4[M+H] + m / z calculated: 412.22, found: 412.28.

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

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

[0107] Preparation of tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (6) A solution of 5-ethyl-2-(pyrrolidin-3-yl)-3H-pyrimidin-4-one (4) (100 mg, 0.52 mmol) in MeOH (15 mL) was treated with tert-butyl 4-oxopiperidine-1-carboxylate (5) (124.48 mg, 0.61 mmol) and NaBH 3 CN (145 mg, 3.11 mmol) was added. The reaction mixture was refluxed at 50° C. under nitrogen atmosphere and stirred for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 95:5) to give tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (6) (120 mg, 55% yield) as a white solid. LCMS(ESI)C20H32N4O3[M+H] + m / z calculated: 377.25, found: 377.30.

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

[0109] Preparation of 5-{4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (compound 42) A solution of 5-ethyl-2-[1-(piperidin-4-yl)pyrrolidin-3-yl]-3H-pyrimidin-4-one (7) (90 mg, 0.33 mmol) in DMF (10 mL) was treated with 5-fluoro-N-methylpyridine-2-carboxamide (8) (104 mg, 0.68 mmol) and Cs 2 CO 3 (884 mg, 2.71 mmol) was added. The reaction mixture was irradiated in a microwave reactor at 150° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 95:5) to give 5-{4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (compound 42) (20 mg, 95% purity, 20% yield) as a white solid. 1 H 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: 411.24, found: 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]decan-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, and the mixture was heated at room temperature for 1 h. 2 CO 3 (2.12 g, 6.50 mmol) was added. The reaction mixture was stirred at 150° C. for 5 h using microwave. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH=100:0 to 97:3) to give 5-{1,4-dioxa-8-azaspiro[4.5]decan-8-yl}-N-methylpyridine-2-carboxamide (3) (1.50 g, 76% yield) as a white solid. LCMS(ESI)C14H19N3O3[M+H] + m / z calculated: 278.14, found: 278.14.

[0113] Preparation of N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) 5-{1,4-dioxa-8-azaspiro[4.5]decan-8-yl}-N-methylpyridine-2-carboxamide (3) (1.50 g, 5.40 mmol) 2 To a solution of 20H2O (10 mL) at room temperature was added HCl (4 M, 20 mL) dissolved in 1,4-dioxane. The reaction mixture was stirred at 50 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted with NaHCO 3 The pH was adjusted to >7 using this solution, extracted with EtOAc (50 mL x 3), and the resulting organic phase was 2 SO 4 The mixture was dried at 40° C. and concentrated to give N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (1.50 g, 76% yield) as a yellow solid. LCMS(ESI)C12H15N3O2[M+H] + m / z calculated: 234.12, found: 234.18.

[0114] Preparation of compound 53 [ka]

[0115] Preparation of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3) 6-Bromo-2-methoxypyridin-3-amine (1) (2.00 g, 9.90 mmol) in 1,4-dioxane / H 2 To a 45 mL solution of 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)Cl 2 (0.72 g, 0.99 mmol) and Na 2 CO 3 (3.12 g, 99.00 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 3 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EA=100:0 to 85:15) to give tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3) (3.00 g, 89% yield) as a white solid. LCMS(ESI)C16H23N3O3[M+H] + m / z calculated: 306.17, found: 306.19.

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

[0117] Preparation of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)piperidine-1-carboxylate (5) To a solution of tert-butyl 3-(5-amino-6-methoxypyridin-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 stirred for 15 min, then CuBr (5.22 g, 36.40 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EA=100:0 to 85:15) to give tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)piperidine-1-carboxylate (5) (1.10 g, 30% yield) as a white solid. LCMS(ESI)C16H23BrN2O3[M+H] + m / z calculated: 371.09, found: 371.15.

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

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

[0120] Preparation of 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (8) To a solution of 3-ethyl-6-(piperidin-3-yl)-1H-pyridin-2-one (7) (80 mg, 0.38 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide (INT) (89 mg, 0.38 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (24 mg, 0.38 mml) was added at room temperature. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH = 100:0 to 95:5) to give 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (8) (48 mg, 31% yield) as a white solid. LCMS(ESI)C24H33N5O2[M+H] + m / z calculated: 424.26, found: 424.37.

[0121] Preparation of 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (Compound 53a and Compound 53b) [ka] 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (8) was separated by SFC (column: Daicel CHIRALPAK AD-H 250 mm × 20 mm ID, 5 μmm; mobile phase: CO 2 / MeOH[0.1%(NH 3 )]=75 / 25) and concentrated under reduced pressure to give 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) was added HATU (12.55 g, 33.01 mmol) and DIEA (9.28 g, 71.80 mmol). Methanamine (2 M, 15 mL, 30.00 mmol) was then added at room temperature. The mixture was then stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH = 100:0 to 93:7) to give 5-hydroxy-N-methylpicolinamide (2) (2.00 g, 46% yield) as a white solid. LCMS(ESI)C7H8N2O2[M+H] + m / z calculated: 153.06, found: 153.10.

[0124] Preparation of 5-(3-hydroxypropoxy)-N-methylpicolinamide (3) A solution of 5-hydroxy-N-methylpicolinamide (2) (1.00 g, 6.61 mmol) in DMF (10 mL) was added with 3-bromopropan-1-ol (2.75 g, 19.58 mmol) and Cs 2 CO 3 (3.23 g, 9.93 mmol) was 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, 65% yield) as an oil. LCMS(ESI)C10H14N2O3[M+H] + m / z calculated: 211.10, found: 211.05.

[0125] Preparation of 5-(3-bromopropoxy)-N-methylpicolinamide (INT-4-1) A solution of 5-(3-hydroxypropoxy)-N-methylpicolinamide (3) (250.00 mg, 1.19 mmol) in DCM (15 mL) was added to CBr4 (788.74 mg, 2.38 mmol) was then added. 3 (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 (eluted with DCM / MeOH=100:0 to 95:5) to give 5-(3-bromopropoxy)-N-methylpicolinamide (INT-4-1) (300 mg, 69% yield) as a white solid. LCMS(ESI)C10H13BrN2O2[M+H] + m / z calculated: 273.02, found: 274.85.

[0126] Preparation of N-methyl-5-(3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-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-(piperidin-4-yl)-3H-quinazolin-4-one (INT-5) (151.10 mg, 0.66 mmol) was added. Then, 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 (eluted with DCM / MeOH=100:0 to 92:8) to give N-methyl-5-(3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)propoxy)picolinamide (compound 2) (100 mg, 78% yield) 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: 422.21, found: 422.30.

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

[0128] Preparation of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) To a solution of 2-aminobenzamide (1) (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (2) (10.11 g, 44.10 mmol) in pyridine (50 mL) was added EDCI (8.45 g, 44.10 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl and brine, and then extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure to give tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, 79% yield) as a white solid. LCMS(ESI)C18H25N3O4[MH] -m / z calculated: 346.18, found: 346.20.

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

[0130] Preparation of 2-(piperidin-3-yl)quinazolin-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 stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was added with ice water (20 mL) and adjusted to pH>7 with aqueous ammonia to cause precipitation, filtered, and the filter cake was washed with ice water (50 mL×3), then dried to obtain 2-(piperidin-3-yl)quinazolin-4(3H)-one (INT-5-1) (1.50 g, 66% yield) as a white solid. LCMS(ESI)C13H15N3O[M+H] + m / z calculated: 230.12, found: 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-(piperidin-3-yl)quinazolin-4(3H)-one (INT-5-1) (460 mg, 2.01 mmol) in MeOH (15 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6) (8.45 g, 44.10 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (189.11 mg, 3.01 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 93:7) to give tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4′-bipiperidine]-1′-carboxylate (7) (300 mg, 36% yield) 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´-bipiperidin]-3-yl)quinazolin-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) in dioxane was added in HCl (4 M, 10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-([1,4'-bipiperidine]-3-yl)quinazolin-4(3H)-one (8) (200 mg, 88% yield) as a white solid. LCMS(ESI)C18H24N4O[M+H] + m / z calculated: 313.20, found: 313.15.

[0133] Preparation of N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4´-bipiperidin]-1´-yl)picolinamide (9) A solution of 2-([1,4´-bipiperidin]-3-yl)quinazolin-4(3H)-one (8) (200 mg, 0.64 mmol) in DMF (10 mL) was added with Cs 2 CO 3 (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 h using a microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 92:8) to give N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4′-bipiperidine]-1′-yl)picolinamide (9) (100 mg, 95% purity, 33% yield) as a yellow solid. LCMS(ESI)C25H30N6O2[M+H] + m / z calculated: 447.24, found: 447.20.

[0134] Chiral separation of N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidine]-1'-yl)picolinamide (Compound 6a and Compound 6b) [ka] Compound 9 was purified by SFC (column: Daicel CHIRALPAK OJ-H 250 mm × 20 mm ID, 5 μmm; mobile phase: CO 2 / MeOH[0.1%(NH 3 The mixture was separated using a solvent-free solvent system (mixture of 100% ethyl acetate and 100% ethyl acetate) and concentrated under reduced pressure to give compound 6a (40.6 mg, purity 100%, ee%: 100, white solid) as the first fraction, and compound 6b (39.5 mg, purity 99%, ee%: 100, white solid) as the second fraction. compound 6a 11H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 8.40 (q, J = 4.8 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.10 (dd, J = 7.6, 1.6 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 3.99 (d, J = 12.8 Hz, 2H), 3.08 (d, J = 8.8 Hz, 1H), 2.87 - 2.81 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.61 - 2.55 (m, 2H), 2.32 (t, J = 9.8 Hz, 1H), 1.98 - 1.96 (m, 1H), 1.87 (d, J = 12.4 Hz, 2H), 1.78 - 1.75 (m, 1H), 1.69 - 1.55 (m, 4H). LCMS (ESI) C25H30N6O2 [M + H] + Calculated m / z: 447.24, Measured: 447. Compound 6b 1 1H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 8.39 (q, J = 4.8 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.10 (dd, J = 7.6, 1.6 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 3.99 (d, J = 12.8 Hz, 2H), 3.08 (d, J = 8.8 Hz, 1H), 2.87 - 2.81 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.61 - 2.55 (m, 2H), 2.31 (t, J = 9.6 Hz, 1H), 1.98 - 1.96 (m, 1H), 1.87 (d, J = 12.4 Hz, 2H), 1.78 - 1.75 (m, 1H), 1.63 - 1.55 (m, 4H). LCMS (ESI) C25H30N6O2 [M + H] + Calculated m / z: 447.24, Measured: 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) To a solution of 2-aminobenzamide (1) (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2) (10.11 g, 44.10 mmol) in pyridine (50 mL) was added EDCI (8.45 g, 44.10 mmol). 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 EtOAc (50 mL x 3). The combined organic layer was washed with 1M HCl solution and brine, and then extracted with NaCl. 2 SO 4 The organic layer was dried at 40° C. for 24 hours and concentrated under reduced pressure to give tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, 79% yield) as a white solid. LCMS(ESI)C18H25N3O4[M+Na] + m / z calculated: 370.42, found: 370.15.

[0138] Preparation of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) To a solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3) (12.00 g, 34.50 mmol) in diglyme (80 mL), KOH (2.13 g, 37.95 mmol) was added, heated to 140° C., stirred for 2 h, cooled to 0° C., added ice water (100 mL), and then adjusted to pH<7 using 1 M HCl solution to cause precipitation, filtered, and the filter cake was washed with ice water (50 mL×3), then dried to give tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4) (11.00 g, 97% yield) as a white solid. LCMS(ESI)C18H23N3O3[M+H] + m / z calculated: 330.17, found: 330.20.

[0139] Preparation of 2-(piperidin-4-yl)quinazolin-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 stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was added with ice water (20 mL) and adjusted to pH>7 with aqueous ammonia to cause precipitation, filtered, and the filter cake was washed with ice water (50 mL×3), then dried to obtain 2-(piperidin-4-yl)quinazolin-4(3H)-one (INT-5) (1.50 g, 66% yield) as a white solid. LCMS(ESI)C13H15N3O[M+H] + m / z calculated: 230.12, found: 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) was added 2-(piperidin-4-yl)quinazolin-4(3H)-one (INT-5) (300 mg, 1.31 mmol). Then, 2 drops of acetic acid and NaBH 3 CN (400.00 mg, 6.37 mmol) was 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 (eluted with DCM / MeOH=100:0 to 92:8) to give tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (2) (500.00 mg, 90% yield) as a white solid. LCMS(ESI)C24H34N4O3[M+H]+ m / z calculated: 427.26, found: 427.30.

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

[0143] Preparation of N-methyl-5-(4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)picolinamide (compound 8) To a solution of 2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one (3) (300.00 mg, 0.92 mmol) in DMF (5 mL) was added 5-fluoro-N-methylpicolinamide (4) (354.14 mg, 2.30 mmol). 2 CO 3 (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 5 um C18 150×21.2 mm), mobile phase: ACN-H 2 0 (0.1% FA), gradient: 15-25) to give N-methyl-5-(4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)picolinamide (compound 8) (100 mg, purity 98%, yield 24%) as a white solid. LCMS(ESI)C26H32N6O2[M+H] + m / z calculated: 461.26, found: 461.20. 1 H 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) To a solution of 2-aminobenzamide (1) (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2) (9.49 g, 44.10 mmol) in pyridine (50 mL) was added EDCI (8.45 g, 44.10 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with 1 M HCl solution and brine, and then extracted with Na 2 SO 4 The extract was dried at 40° C. and concentrated under reduced pressure to give tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate (3) (12.00 g, 77% yield) as a white solid. LCMS(ESI)C17H23N3O4[M+Na] + m / z calculated: 356.17, found: 356.00.

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

[0148] Preparation of 2-(pyrrolidin-3-yl)quinazolin-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 h. The mixture was concentrated under reduced pressure to give a crude, ice water (20 mL) was added, and the pH was adjusted to >7 with aqueous ammonia to form a precipitate, which was filtered, and the filter cake was washed with ice water (50 mL x 3) and dried to give 2-(pyrrolidin-3-yl)quinazolin-4(3H)-one (INT-5-2) (8.00 g, 80% yield) 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: 216.11, found: 215.95.

[0149] Preparation of tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (7) To a solution of 2-(pyrrolidin-3-yl)quinazolin-4(3H)-one (INT-5-2) (600.00 mg, 2.79 mmol) in MeOH (30 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6) (1.67 g, 8.36 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (1.05 g, 16.72 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 93:7) to give tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (7) (400 mg, 34% yield) as a white solid. LCMS(ESI)C22H30N4O3[M+H] + m / z calculated: 399.23, found: 399.30.

[0150] Preparation of 2-(1-(piperidin-4-yl)pyrrolidin-3-yl)quinazolin-4(3H)-one (8) tert-Butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (7) (400 mg, 0.81 mmol) was added to a solution of hydrochloric acid in dioxane (4 M, 10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(1-(piperidin-4-yl)pyrrolidin-3-yl)quinazolin-4(3H)-one (8) (200.00 mg, 79% yield) as a white solid. LCMS(ESI)C17H22N4O[M+H] + m / z calculated: 299.18, found: 299.25.

[0151] Preparation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (9) A solution of 2-(1-(piperidin-4-yl)pyrrolidin-3-yl)quinazolin-4(3H)-one (8) (200.00 mg, 0.67 mmol) in DMF (10 mL) was added with Cs 2 CO 3 (2.18 g, 6.70 mmol) and 5-fluoro-N-methylpicolinamide (9) (432.44 mg, 2.01 mmol) were added. The mixture was stirred at 150° C. for 6 hours using a microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 92:8) to give N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (9) (100 mg, 95% purity, 33% yield) as a yellow solid. LCMS(ESI)C24H28N6O2[M+H] + m / z calculated: 433.23, found: 433.25.

[0152] Chiral separation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (9) Compound 9 was purified by SFC (column: Daicel CHIRALPAK OJ-H 250 mm × 20 mm ID, 5 μmm; mobile phase: CO 2 / MeOH[0.1%(NH 3 )]=70 / 30) and concentrated under reduced pressure to give the first fraction 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 1 H NMR (400MHz, DMSO-d 6, ppm) δ 12.16 (s, 1H), 8.40 - 8.37 (m, 1H), 8.27 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 7.6, 1.6 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 3.82 (d, J = 12.8 Hz, 2H), 3.07 (t, J = 8.6 Hz, 2H), 2.95 (t, J = 10.8 Hz, 2H), 2.86 - 2.79 (m, 2H), 2.78 - 2.77 (m, 3H), 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] + Calculated m / z: 433.23, Found: 433.20. Compound 10b 1 H NMR (400 MHz, DMSO - d 6 , ppm) δ 8.39 - 8.38 (m, 1H), 8.28 (d, J = 3.2 Hz, 1H), 8.08 (dd, J = 7.6, 1.6 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 3.83 (d, J = 12.8 Hz, 2H), 3.09 (d, J = 8.4 Hz, 2H), 2.95 (t, J = 12.4 Hz, 2H), 2.88 - 2.79 (m, 2H), 2.79 (d, J = 4.8 Hz, 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] + Calculated m / z: 433.23, Found: 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) To a solution of 2-aminobenzamide (1) (2.80 g, 20.60 mmol) and 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)acetic acid (2) (5.00 g, 20.60 mmol) in pyridine (50 mL) was added EDCI (3.95 g, 20.60 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with 1 M HCl solution and brine, and then extracted with Na 2 SO 4 The organic layer was dried over rt and concentrated under reduced pressure to give tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate (3) (7.00 g, 94% yield) as a white solid. LCMS(ESI)C19H27N3O4[M+H] + m / z calculated: 362.20, found: 362.25.

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

[0157] Preparation of 2-(piperidin-3-ylmethyl)quinazolin-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 h. The mixture was concentrated under reduced pressure to give a crude, ice water (20 mL) was added, and the pH was adjusted to >7 with aqueous ammonia to form a precipitate, which was filtered, and the filter cake was washed with ice water (50 mL x 3) and dried to give 2-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (INT-5-3) (1.20 g, 85% yield) as a white solid. LCMS(ESI)C14H17N3O[M+H] + m / z calculated: 244.14, found: 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 Cs 2 CO 3 To a solution of (3.22 g, 9.87 mmol) in DMF (15 mL) was added 1-bromo-2-chloroethane (2) (943.64 mg, 6.58 mmol). The mixture was then stirred at 50° C. for 3 h. The reaction mixture was quenched with water, the aqueous layer was extracted with EtOAc (50 mL×3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 80:20) to give tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (2) (500.00 mg, 71% yield) as a colorless oil. LCMS(ESI)C9H11ClN2O2[M+H] +m / z calculated: 215.05, found: 215.00.

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

[0161] Chiral separation of N-methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidin-1-yl)ethoxy)picolinamide (compound 14) [ka] Compound 3 was purified by SFC (column: Daicel CHIRALPAK OJ-H 250 mm × 20 mm ID, 5 μmm; mobile phase: CO 2 / MeOH [0.1% (FA)] = 70 / 30) and concentrated under reduced pressure to give compound 14a (31.6 mg, purity 100%, ee%: 100, white solid) as the first fraction, and compound 14b (28.1 mg, purity 99%, ee%: 100, white solid) as the second fraction. compound 14a 11H NMR (400 MHz, DMSO-d 6 , ppm) δ 12.15 (s, 1H), 8.53 (q, J = 9.6, 4.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 8.0, 1.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.49 - 7.42 (m, 2H), 4.18 (t, J = 5.6 Hz, 2H), 2.90 - 2.81 (m, 2H), 2.79 (d, J = 4.8 Hz, 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] + Calculated m / z: 422.21, Found: 422.25. Compound 14b 1 1H NMR (400 MHz, DMSO-d 6 , ppm) δ 12.15 (s, 1H), 8.53 (q, J = 9.6, 4.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 8.0, 1.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.49 - 7.42 (m, 2H), 4.18 (t, J = 5.6 Hz, 2H), 2.90 - 2.81 (m, 2H), 2.79 (d, J = 4.8 Hz, 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] + Calculated m / z: 422.21, Found: 422.25.

[0162] Example 8: Synthesis of compound 17

[0163] Synthesis of compound 17 [ka]

[0164] Preparation of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-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), Cs 2 CO 3 (10.02 g, 30.74 mmol) was added. The mixture was then stirred at 120° C. for 18 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine and added with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 95:5) to give tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3) (2.00 g, 41% yield) as a white solid. LCMS(ESI)C16H25N3O4[M+H] + m / z calculated: 324.18, found: 324.20.

[0165] Preparation of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid (4) tert-Butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3) (1.50 g, 4.80 mmol) in MeOH / H 2 LiOH (460.00 mg, 19.20 mmol) was added to the 1:1 O=1 (40 mL) solution. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure at 40° C. to obtain a residue. Water was added to the obtained residue, and the mixture was acidified with 1M HCl aqueous solution at 0° C. to adjust the pH to 4-5, and the aqueous layer was extracted with EtOAc (200 mL×3). The combined organic layer was washed with brine and then with Na 2 SO4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 95:5) to give 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid (4) (1.00 g, 67% yield) as a white solid. LCMS(ESI)C14H21N3O4[M-56+H] + m / z calculated: 240.15, found: 240.20. 1 H NMR (400MHz, DMSO-d 6 ,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-pyrazol-1-yl)piperidine-1-carboxylate (6) To a solution of 2-aminobenzamide (5) (299.66 mg, 2.20 mmol) and 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid (4) (650.00 mg, 2.20 mmol) in pyridine (25 mL) was added EDCI (421.91 mg, 2.20 mmol). 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 EtOAc (50 mL x 3). The combined organic layer was washed with 1M HCl solution and brine, and then extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure to give tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6) (720.00 mg, 71% yield) as a white solid. LCMS(ESI)C21H27N5O4[M+H] + m / z calculated: 414.21, found: 414.25.

[0167] Preparation of tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (7) To a solution of tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6) (700.00 mg, 1.69 mmol) in diglyme (15 mL), 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 using 1M HCl solution to form a precipitate, filtered, and the filter cake was washed with ice water (50 mL×3), and then dried to give tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (7) (600 mg, 67% yield) as a white solid. LCMS(ESI)C21H25N5O3[M+H] + m / z calculated: 396.20, found: 396.25.

[0168] Preparation of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one (8) To a room temperature solution of tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (7) (350.00 mg, 0.88 mmol) was added HCl-dioxane (4M, 40 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one (8) (200 mg, 73% yield) as a white solid. LCMS(ESI)C16H17NO[M+H] + m / z calculated: 296.14, found: 296.25.

[0169] Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)picolinamide (compound 17) A solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one (8) (200.00 mg, 0.68 mmol) in DMF (10 mL) was added with Cs 2 CO 3(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 at 150° C. for 6 hours using microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 92:8) to give a crude, which was purified by preparative HPLC (Gemini 5um C18 150×21.2 mm, mobile phase: ACN-H 2 HO (0.1% FA, gradient: 25–75) to give N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)picolinamide (compound 17) (30 mg, purity 98%, yield 9%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ,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: 430.19, found: 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) was added KOCN (14.19 g, 174.90 mmol) slowly at room temperature. The mixture was heated to 100° C. and stirred for 15 h, cooled to 0° C., and ice water (30 mL) was added. The precipitate was collected by filtration, washed with a mixture of petroleum ether:EtOAc = 5:1 (100 mL), and filtered to give 8-chloroquinazoline-2,4(1H,3H)-dione (2) (5.00 g, 40% yield) as a white solid, which was used directly in the next step without further purification. LCMS(ESI)C8H5ClN2O2[M+H] + m / z calculated: 197.00, found: 196.95.

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

[0174] Preparation of 2,8-dichloroquinazolin-4(3H)-one (4) 2,4,8-Trichloroquinazoline (3) (2.00 g, 8.60 mmol) in THF / H 2To the 1:1 HCl (200 mL) solution was added NaOH (690 mg, 17.20 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure at 40° C. to give a residue. Water was added to it and the mixture was acidified to pH 4-5 with 1M HCl aqueous solution at 0° C. The mixture was extracted with EtOAc (200 mL×3). The combined organic phase was washed with brine (100 mL×3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (eluent: DCM / MeOH=100:0 to 95:5) to give 2,8-dichloroquinazolin-4(3H)-one (4) (1.60 g, 82% yield) as a white solid. LCMS(ESI)C8H4Cl2N2O[M+H] + m / z calculated: 214.97, found: 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-Dichloroquinazolin-4(3H)-one (4) (400 mg, 1.86 mmol) was dissolved in dioxane / H 2 In a 10:1 (40 mL) solution of 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)Cl 2 (50mg, 0.07mmol) and Na 2 CO 3 (591 mg, 5.58 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 80° C. for 18 hours under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (100 mL×2) and extracted with Na 2 SO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give a crude which was purified by flash column chromatography (PE / EtOAc = 100:0 to 20:80) to give tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5) (550 mg, 77% yield) as a yellow solid. LCMS(ESI)C18H20ClN3O3[M+H] + m / z calculated: 362.12, found: 362.10.

[0176] Preparation of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (6) 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 EtOAc (200 mL), was added PtO 2 (110 mg) was added. The mixture was evacuated and filled with hydrogen three times, then filled with hydrogen. The resulting mixture was stirred at room temperature for 1 h. The mixture was then filtered through Celite and concentrated in vacuo to give a crude which was purified by flash column chromatography (PE / EtOAc = 100:0 to 50:50) to give tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (6) (400 mg, 65% yield) as a yellow solid. LCMS(ESI)C18H22ClN3O3[M+H] + m / z calculated: 364.13, found: 364.10.

[0177] Preparation of 8-chloro-2-(piperidin-4-yl)quinazolin-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 stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give a crude, ice water (2 mL) was added, and the pH was adjusted to >7 with aqueous ammonia to form a precipitate, which was filtered and the filter cake was washed with ice water (5 mL x 3), then dried to give 8-chloro-2-(piperidin-4-yl)quinazolin-4(3H)-one (7) (300 mg, 89% yield) as a white solid. LCMS(ESI)C13H14ClN3O[M+H] + m / z calculated: 264.08, found: 264.10.

[0178] Preparation of tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (8) To a solution of 8-chloro-2-(piperidin-4-yl)quinazolin-4(3H)-one (7) (300 mg, 1.14 mmol) in MeOH (60 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (727 mg, 3.41 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (428 mg, 6.82 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 90:10) to give tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (8) (300 mg, 51% yield) as a white solid. LCMS(ESI)C24H33ClN4O3[M+H] + m / z calculated: 361.17, found: 361.05.

[0179] Preparation of 8-chloro-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one (9) tert-Butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (8) (300 mg, 0.65 mmol) was added to HCl (4 M, 30 mL) in dioxane and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 8-chloro-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one (9) (200 mg, 81% yield) as a white solid. LCMS(ESI)C19H25ClNO[M+H] + m / z calculated: 361.17, found: 361.05.

[0180] Preparation of 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-methylpicolinamide (compound 40) A solution of 8-chloro-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one (9) (150 mg, 0.42 mmol) in DMF (10 mL) was added with Cs 2 CO 3 (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 at 150° C. for 6 hours using a microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH=100:0 to 90:10) to give the crude product of 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-methylpicolinamide (compound 40) as a yellow solid. The crude product was purified by preparative HPLC (Gemini 5um C18 150×21.2 mm, mobile phase: ACN-H 2 0 (0.1% FA, gradient: 20-80) to give 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-methylpicolinamide (compound 40) (24.2 mg, purity 96%, yield 11%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ,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: 495.22, found: 495.15.

[0181] Example 10: Synthesis of compound 52

[0182] Synthesis of compound 52 [ka]

[0183] Preparation of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3) 2,8-Dichloroquinazolin-4(3H)-one (1) (500 mg, 2.35 mmol) in 1,4-dioxane / H 2 In a 5:1 (60 mL) solution of 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)Cl 2 (170mg, 0.23mmol) and Na 2 CO 3 (740 mg, 6.98 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 91:9) to give tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3) (400 mg, 40% yield) as a white solid. LCMS(ESI)C17H18ClN3O3[M+H] + m / z calculated: 348.10, found: 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 EtOAc (50 mL), 2 PtO2 (80 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the crude product of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4) (200 mg, 50% yield) as a white solid. LCMS(ESI)C17H20ClN3O3[M+H] + m / z calculated: 350.12, found: 350.18.

[0185] Preparation of 8-chloro-2-(pyrrolidin-3-yl)quinazolin-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) in dioxane and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the product 8-chloro-2-(pyrrolidin-3-yl)quinazolin-4(3H)-one (5) (130 mg, 82% yield) as a white solid. LCMS(ESI)C12H12ClN3O[M+H] + m / z calculated: 250.07, found: 250.12.

[0186] Preparation of 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (7) To a solution of 8-chloro-2-(pyrrolidin-3-yl)quinazolin-4(3H)-one (5) (80 mg, 0.32 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (6) (50 mg, 0.21 mmol), followed by 3 drops of acetic acid and NaBH 3CN (15 mg, 0.24 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 4 h. 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 give 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (7) (40 mg, 40% yield) as a white solid. LCMS(ESI)C24H27ClN6O2[M+H] + m / z calculated: 467.19, found: 467.28.

[0187] Preparation of 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (Compound 52a and Compound 52b) 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (7) was purified by SFC (column: DAICEL AS-H 4.6 mm ID *250 mmL 5 μm, mobile phase: CO 2 / IPA [0.1%NH 3 (7M, MeOH solution)] = 60 / 40) and concentrated under reduced pressure to give the first fraction 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 11H NMR (400 MHz, DMSO) δ 8.42 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.48 - 7.38 (m, 2H), 3.83 (d, J = 12.8 Hz, 2H), 3.40 - 3.32 (m, 1H), 3.06 (t, J = 9.2 Hz, 1H), 2.95 (dd, J = 22.0, 12.0 Hz, 3H), 2.80 - 2.68 (m, 5H), 2.38 (t, J = 10.4 Hz, 1H), 2.24 - 2.15 (m, 2H), 1.96 (d, J = 11.2 Hz, 2H), 1.53 (dd, J = 22.8, 10.8 Hz, 2H). LCMS (ESI) C24H27ClN6O2 [M + H] + Calculated m / z: 467.19, Found: 467.28. Compound 52b 1 1H NMR (400 MHz, DMSO) δ 8.49 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.55 - 7.45 (m, 2H), 3.90 (d, J = 12.4 Hz, 2H), 3.45 - 3.39 (m, 1H), 3.13 (t, J = 8.8 Hz, 1H), 3.01 (dd, J = 22.8, 11.6 Hz, 3H), 2.87 - 2.77 (m, 5H), 2.43 (d, J = 10.0 Hz, 1H), 2.26 (d, J = 6.4 Hz, 2H), 2.02 (d, J = 11.2 Hz, 2H), 1.59 (d, J = 12.0 Hz, 2H). LCMS (ESI) C24H27ClN6O2 [M + H] + Calculated m / z: 467.19, Found: 467.28.

[0188] Example 11: Synthesis of compound 54

[0189] Synthesis of compound 54

Chem.

[0190] Preparation of tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate (3) To a solution of 2-aminobenzamide (1) (2.00 g, 14.70 mmol) and {1-[(tert-butoxy)carbonyl]piperidin-4-yl}acetic acid (2) (3.58 g, 14.70 mmol) in pyridine (50 mL) was added EDCI (2.82 g, 14.70 mmol). The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, and then extracted with Na 2 SO 4 The extract was dried at 40° C. for 1 hour and concentrated under reduced pressure to give tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate (3) (5.76 g, 92% yield) as a yellow oil. LCMS(ESI)C19H27N3O4[M+H] + m / z calculated: 362.20, found: 262.30.

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

[0192] Preparation of 2-(piperidin-4-ylmethyl)-3H-quinazolin-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 a crude product, ice water (20 mL) was added, and the pH was adjusted to > 7 using aqueous ammonia to form a precipitate, which was then filtered. The filter cake was washed with ice water (50 mL x 3) and dried to obtain 2-(piperidin-4-ylmethyl)-3H-quinazolin-4-one (5) (2.32 g, 90% yield) as a white solid. LCMS(ESI)C14H17N3O[M+H] + m / z calculated: 244.14, found: 244.25.

[0193] Preparation of tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidine-1-carboxylate (6) To a solution of 2-(piperidin-4-ylmethyl)-3H-quinazolin-4-one (5) (500 mg, 2.06 mmol) in MeOH (50 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (532 mg, 2.67 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (504 mg, 8.01 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 91:9) to give tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidine-1-carboxylate (6) (244 mg, 25% yield) as a white solid. LCMS(ESI)C24H34N4O3[M+H] + m / z calculated: 427.26, found: 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]piperidin-1-yl}piperidine-1-carboxylate (6) (244 mg, 0.57 mmol) was added to HCl (4 M, 8 mL) in dioxane and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-{[1-(piperidin-4-yl)piperidin-4-yl]methyl}-3H-quinazolin-4-one (7) (187 mg, 90% yield) as a white solid. LCMS(ESI)C19H26N4O[M+H] + m / z calculated: 327.21, found: 327.44.

[0195] Preparation of N-methyl-5-(4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidin-1-yl)pyridine-2-carboxamide (compound 54) A solution of 2-{[1-(piperidin-4-yl)piperidin-4-yl]methyl}-3H-quinazolin-4-one (7) (200 mg, 0.61 mmol) in DMF (16 mL) was added with Cs 2 CO 3 (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 at 150° C. for 5 h using a microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 91:9) to give N-methyl-5-(4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidin-1-yl)pyridine-2-carboxamide (compound 54) (20.11 mg, 99% purity, 7% yield) as a white solid. 1H 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: 461.26, found: 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 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 (50 mL) was added tri(o-tolyl)phosphine (50% in EtOAc) (3.10 g, 9.75 mmol) and DIEA (4.20 g, 32.50 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 90:10) to give N,N-diethyl-2-fluoro-6-methylbenzamide (3) (0.90 g, 63% yield) as a white solid. LCMS(ESI)C12H16FNO[M+H] + m / z calculated: 210.12, found: 210.09.

[0199] Preparation of 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid (5) A dry three-neck round bottom flask equipped with an addition funnel was charged with anhydrous THF (30 ml) at −78° C. under an inert atmosphere. A solution of LDA (2.5 M in THF, 0.9 ml) was added dropwise. The internal temperature was maintained below −70° C. throughout the addition process. After 0.5 h at −78° C., a solution of N,N-diethyl-2-fluoro-6-methylbenzamide (3) (300 mg, 1.43 mmol) in anhydrous THF (10 mL) was added dropwise, the mixture was stirred for 1 h, and 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 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAC=100:0 to 80:20) to give 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid (5) (160 mg, 32% yield) as a white solid. LCMS(ESI)C18H21FN2O3[M+H] + m / z calculated: 333.15, found: 333.25.

[0200] Preparation of 8-fluoro-3-(pyrrolidin-3-yl)-2H-isoquinolin-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 give 8-fluoro-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one (6) (120 mg, 97% yield) as a white solid. LCMS(ESI)C13H13FN2O[M+H] + m / z calculated: 233.10, found: 233.12.

[0201] Preparation of 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (compound 136rac) To a solution of 8-fluoro-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one (6) (120 mg, 0.52 mmol) in MeOH (15 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide (INT) (100 mg, 0.55 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (30 mg, 0.46 mmol) was 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 (eluted with DCM / MeOH=100:0 to 92:8) to give 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (compound 136rac) (65 mg, 25% yield, 99% purity) as a yellow solid. compound 136rac 1 H 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: 450.22, found: 450.30.

[0202] Preparation of 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (Compound 136a and Compound 136b) [ka] 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (compound 136rac) was purified by SFC (column: Daicel CHIRALPAK OJ-H 250 mm × 20 mm ID, 5 μmm; mobile phase: CO 2 / MeOH[0.1%(NH 3 )]=70 / 30) and concentrated under reduced pressure to obtain the first fraction as compound 136a (12.8 mg, purity 99%, ee%: 100, white solid) and the second fraction as compound 136b (13.8 mg, purity 99%, ee%: 97, white solid). Compound 136a 1 H 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: 450.22, found: 450.20. Compound 136b 1H 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: 450.22, found: 450.25.

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

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

[0205] Preparation of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-2,5-dihydropyrrole-1-carboxylate (3) 6-Bromo-2-methoxypyridin-3-amine (1) (1.38 g, 6.80 mmol) in 1,4-dioxane / H 2 To a 4:1 (20 mL) solution of 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 addition of Pd(dppf)Cl 2 (0.50 g, 0.68 mmol) and Na 2 CO 3(2.23 g, 21.08 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EA=100:0 to 85:15) to give tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-2,5-dihydropyrrole-1-carboxylate (3) (1.50 g, 72% yield) as a white solid. LCMS(ESI)C15H21N3O3[M+H] + m / z calculated: 292.16, found: 292.19.

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

[0207] Preparation of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (5) To a solution of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (4) (1.40 g, 4.80 mmol) in ACN (20 mL) was added tert-butyl nitrite (1.14 g, 11.04 mmol). Then CuBr (1.38 g, 9.60 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EA=100:0 to 85:15) to give tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (5) (0.65 g, 35% yield) as a white solid. LCMS(ESI)C15H21BrN2O3[M+H] + m / z calculated: 357.07, found: 357.11.

[0208] Preparation of tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (6) A solution of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (5) (300 mg, 0.84 mmol) in 1,4-dioxane (15 mL) was added to Pd(dppf)Cl 2 (61 mg, 0.08 mmol) was then added. 2 Zn (5 mL, 0.14 mml) was added at room temperature. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EA=100:0 to 85:15) to give tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (6) (120 mg, 44% yield) as a white solid. LCMS(ESI)C17H26N2O3[M+H] + m / z calculated: 307.19, found: 307.25.

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

[0210] Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-6-fluoro-N-methylpicolinamide (151rac) To a solution of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) (100 mg, 0.40 mmol) in MeOH (40 mL) was added 3-ethyl-6-(pyrrolidin-3-yl)-1H-pyridin-2-one (7) (115 mg, 0.60 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (38 mg, 0.61 mmol) was added 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 (eluted with DCM / MeOH=100:0 to 90:10) to give 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)piperidin-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: 428.24, found: 428.10.

[0211] Chiral separation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-6-fluoro-N-methylpicolinamide (Compound 151a and Compound 151b) [ka] Compound 151 was separated by SFC (column: Daicel CHIRALPAK AD-H SFC 250 mm×20 mm I.D., 5 μm; mobile phase: CO 2 / MeOH[0.1%(NH 3 )]=80 / 20), concentrated under reduced pressure, and the first fraction was obtained as compound 151a (15.8 mg, purity 92%, ee%: 100, white solid), and the second fraction was obtained as compound 151b (15.9 mg, purity 95%, ee%: 100, white solid). Compound 151a 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ: 11.28 (s, 1H), 8.44 - 8.37 (m, 1H), 7.83 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 - 7.52 (m, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.03 (d, J = 6.4 Hz, 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 = 12.0 Hz, 2H), 1.79 - 1.70 (m, 1H), 1.63 - 1.52 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). LCMS (ESI) C23H30FN5O2 [M + H] + m / z calculated value: 428.24, measured value: 428.10. Compound 151b 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ: 11.28 (s, 1H), 8.45 - 8.35 (m, 1H), 7.83 (dd, J = 8.0, 1.2 Hz, 1H), 7.64 - 7.51 (m, 1H), 7.17 (d, J = 6.8 Hz, 1H), 6.03 (d, J = 6.8 Hz, 1H), 3.58 - 3.41 (m, 2H), 3.17 - 3.09 (m, 1H), 2.93 - 2.74 (m, 7H), 2.68 - 2.60 (m, 2H), 2.35 - 2.16 (m, 4H), 2.01 - 1.92 (m, 2H), 1.79 - 1.70 (m, 1H), 1.64 - 1.52 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). LCMS(ESI)C23H30FN5O2[M+H] + m / z calculated: 428.24, found: 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) was added methanamine (420 mg, 13.68 mmol), DIEA (4.42 g, 34.20 mmol), and HATU (6.50 g, 17.10 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with PE / EtOAc=100:0 to 70:30) to give 6-chloro-5-fluoro-N-methylpicolinamide (2) (2.00 g, 88% yield) as a white solid. LCMS(ESI)C7H6ClFN2O[M+H] + m / z calculated: 189.02, found: 188.90.

[0214] Preparation of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide (4) A solution of 6-chloro-5-fluoro-N-methylpicolinamide (2) (2.00 g, 10.60 mmol) in DMF (20 mL) was added to the reaction mixture. 2 CO 3(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 h in a sealed flask. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAC=100:0 to 50:50) to give 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (4) (1.60 g, 42% yield) as a white solid. LCMS(ESI)C14H18ClN3O3[M+H] + m / z calculated: 312.10, found: 311.95.

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

[0216] Preparation of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) 6-Fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide (5) (200 mg, 0.68 mmol) 2 To a solution of 1H2O (3 mL), formic acid (2 mL) was added and stirred at 50 °C for 1 h. 3The pH of the aqueous solution was adjusted to 7 using a solution of 100 mL of ethyl acetate. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) (100 mg, 47% yield) as a yellow solid. LCMS(ESI)C14H14FN3O2[M+H] + m / z calculated: 252.11, found: 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) was added MeONa (150 mg, 2.78 mmol) at room temperature. The mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAC=100:0 to 98:2) to give 3-chloro-7-fluoro-1-methoxyisoquinoline (2) (160 mg, 33% yield) as a white solid. LCMS(ESI)C10H7ClFNO[M+H] + m / z calculated: 212.02, found: 211.90.

[0220] Preparation of tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4) A solution of 3-chloro-7-fluoro-1-methoxyisoquinoline (2) (160 mg, 0.76 mmol) in dioxane:HO = 5:1 (20 mL) was added with 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)Cl 2 (50 mg, 0.07 mmol), and K 2 CO 3 (250 mg, 1.81 mmol) was added at room temperature. The reaction mixture was diluted with N 2 The mixture was stirred at 90° C. under atmospheric pressure for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 95:5) to give tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4) (160 mg, 61% yield) as a white solid. LCMS(ESI)C19H21FN2O3[M+H] + m / z calculated: 345.15, found: 345.11.

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

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

[0223] Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (compound 154rac) To a solution of 7-fluoro-3-(pyrrolidin-3-yl)isoquinolin-1(2H)-one (6) (90 mg, 0.39 mmol) in MeOH (15 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (100 mg, 0.43 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (25 mg, 0.40 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the residue was purified by preparative HPLC (column: Gemini 5 um C18 150×21.2 mm, mobile phase: ACN-H 2 0 (0.1% FA), gradient: 10-25) to give 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (compound 154rac) (35 mg, 99% purity, 20% yield) as a white solid. compound 154rac 1H 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: 450.22, found: 450.23.

[0224] Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (compounds 154a and 154b) [ka] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (compound 154rac) was purified by SFC (column: Daicel CHIRALPAK OJ-H 4.6 mm ID*250 mmL 5 μmm; mobile phase: CO 2 / MeOH[0.1%NH 3 (7M solution in MeOH)]=75 / 25) and concentrated under reduced pressure to give the first fraction 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 11H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 9.2, 2.8 Hz, 1H), 7.68 (dd, J = 8.8, 5.6 Hz, 1H), 7.56 (td, J = 8.8, 2.8 Hz, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 6.51 (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] + Calculated m / z: 450.22, Found: 450.20. Compound 154b 1 1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 9.2, 2.8 Hz, 1H), 7.68 (dd, J = 8.8, 5.2 Hz, 1H), 7.56 (td, J = 8.8, 2.8 Hz, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 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] + Calculated m / z: 450.22, Found: 450.20.

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

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

[0227] Preparation of 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2) To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1) (5 g, 26.50 mmol) in ACN / DMF=1:1 (100 mL) was added NIS (8.9 g, 39.75 mmol). The resulting mixture was stirred at 90° C. for 3 h. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 72:28) to give 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2) (2.9 g, 35% yield) as a white solid. LCMS(ESI)C5HCl2IN4[M+H] + m / z calculated: 314.86, found: 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) was added NaH (290 mg, 11.96 mmol) at 0° C. and stirred for 10 min, then SEMCl (2.3 g, 13.80 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (3) (3.6 g, 88% yield) as a white solid. LCMS(ESI)C11H15Cl2IN4OSi[M+H] + m / z calculated: 444.94, found: 444.85.

[0229] Preparation of 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (4) To a solution of 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (3) (1.5 g, 3.39 mmol) in MeOH (45 mL) was added MeONa (183 mg, 3.39 mmol). The mixture was stirred at room temperature for 1 h. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 95:5) to give 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (4) (282 mg, 19% yield) as a white solid. LCMS(ESI)C12H18ClIN4O2Si[M+H] + m / z calculated: 440.99, found: 441.01.

[0230] Preparation of 6-chloro-4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (6) 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 methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (5) (491 mg, 2.56 mmol) in DMF (15 mL) was added under a nitrogen atmosphere with CuCl 2 (131 mg, 0.98 mmol) was added. The reaction mixture was stirred at 100° C. for 2 h. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 96:4) to give 6-chloro-4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (6) (220 mg, 90% yield) as a white solid. LCMS(ESI)C13H18ClF3N4O2Si[M+H] + m / z calculated: 383.08, found: 383.08.

[0231] Preparation of tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) tert-Butyl 3-(4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-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)Cl 2 (23mg, 0.031mmol) of 1,4-dioxane / H 2 In a 11 mL solution of NaCl, 2 CO 3 (165 mg, 1.56 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 2 h. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 93:7) to give tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (280 mg, 94% yield) as an orange oil. LCMS(ESI)C27H32F3N5O4Si[M+H] + m / z calculated: 516.22, found: 516.23.

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

[0233] Preparation of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (10) tert-Butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate (9) (158 mg, 0.31 mmol) was added to aqueous hydrogen bromide (5 mL). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was then concentrated in vacuo to give 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (10) (80 mg, 96% yield) as a white solid. LCMS(ESI)C10H10F3NO[M+H] + m / z calculated: 274.08, found: 274.00.

[0234] Preparation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (162rac) To a solution of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (10) (80 mg, 0.29 mmol), N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (90 mg, 0.29 mmol), and sodium triacetoxyborohydride (92 mg, 0.44 mmol) in MeOH (10 mL) was added 2 drops of HOAC and the solution was stirred at 50 °C for 0.5 h. Then, NaBH 3 CN (22 mg, 0.35 mmol) was added. The mixture was stirred at 50° C. for 18 h. The residue was purified by flash chromatography (eluting with DCM / MeOH=100:0 to 90:10) to give N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (162rac) (69 mg, 48% yield) as a white solid. LCMS(ESI)C22H25F3N8O2[M+H] + m / z calculated: 491.21, found: 491.25.

[0235] Chiral separation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (162a and 162b) Compound 162rac was purified by SFC (column: Daicel OJ-H 4.6 mm ID*250 mmL 5 μm; mobile phase: CO 2 / MeOH[0.1%NH 3 (7M solution in MeOH)]=70 / 30) and concentrated under reduced pressure to give the first fraction 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 11H NMR (400 MHz, DMSO) δ 14.37 (s, 1H), 12.27 (s, 1H), 8.39 (q, J = 4.4 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.4, 2.8 Hz, 1H), 3.83 (d, J = 12.8 Hz, 2H), 3.38 - 3.35 (m, 1H), 3.06 (t, J = 8.4 Hz, 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 = 11.6 Hz, 2H), 1.55 - 1.43 (m, 2H). LCMS (ESI) C22H25F3N8O2 [M + H] + Calculated m / z: 491.21, Found: 491.26. Compound 162b 1 1H NMR (400 MHz, ) δ 14.41 (s, 1H), 12.41 (s, 1H), 8.39 (q, J = 4.8 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.0 Hz, 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] + Calculated m / z: 491.21, Found: 491.25.

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

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

Chem.

[0238] Preparation of 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (184rac) To a solution of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide (INT-1) (92 mg, 0.40 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide (2) (intermediate (6) in the synthesis of compound 136) (100 mg, 0.40 mmol). Then, 2 drops of acetic acid and NaBH 3 CN (25 mg, 0.26 mmol) was 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 (eluted with DCM / MeOH=100:0 to 92:8) to give 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (184rac) (60 mg, 27% yield) as a colorless oil. LCMS(ESI)C25H27F2N5O2[M+H] + m / z calculated: 468.21, found: 468.26.

[0239] Preparation of 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (184a and 184b) 6-Fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (184rac) was purified by SFC (column: Daicel CHIRALPAK OJ-H 250 mm × 20 mm ID 5 μmm; mobile phase: CO 2 / MeOH[0.1%NH 3 ]=80 / 20) and concentrated under reduced pressure to give the first fraction as 184a (24.5 mg, purity 98%, ee%: 100, white solid), and the second fraction as compound 184b (24.4 mg, purity 99%, ee%: 97, white solid). Compound 184a 11H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.41 (q, J = 5.2 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 12.0, 8.0 Hz, 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, 2H), 2.00 - 1.97 (m, 2H), 1.86 - 1.79 (m, 1H), 1.68 - 1.53 (m, 2H). LCMS (ESI) C25H27F2N5O2 [M+H] + Calculated m / z: 468.21, Found: 468.22. Compound 184b 1 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.41 (q, J = 4.8 Hz, 1H), 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 11.6, 8.0 Hz, 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] + Calculated m / z: 468.21, Found: 468.18.

[0240] Example 17: Synthesis of Compound 192

[0241] Synthesis of compound 192

Chem.

[0242] Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) To a solution of 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) in pyridine (30 mL) was added EDCI (422 mg, 2.20 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, and the mixture was concentrated to dryness. 2 SO 4 The extract was dried at 40° C. for 1 hour and concentrated under reduced pressure to give 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: 368.17, found: 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) was added KOH (195 mg, 3.47 mmol), heated to 60° C., stirred for 2 h, cooled to 25° C., and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 90:10) to give tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (400 mg, 63% yield) as a white solid. LCMS(ESI)C18H21N3O3[M+H] + m / z calculated: 328.16, found: 328.05.

[0244] Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)quinazolin-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 solution of HCl in dioxane (4 M, 10 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 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: 228.11, found: 228.02.

[0245] Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (compound 192) To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)quinazolin-4(3H)-one (5) (80 mg, 0.35 mmol) in MeOH (40 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT, 98 mg, 0.42 mmol), followed by 2 drops of acetic acid and NaBH (OAC) 3 (149 mg, 0.70 mmol) was added at room temperature. The reaction mixture was stirred at 50 for 1 h. Then, NaBH 3 CN (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 by column chromatography (mobile phase: ACN-H 2 0 (0.1% FA, gradient: 10-95) to give N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (compound 192) (25.6 mg, 99% purity, 16% yield) as a white solid. compound 192 1 H NMR (400MHz, DMSO-d 6,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: 445.23, found: 445.15.

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

[0247] Synthesis of Compounds 194a and 194b [ka] [ka] [ka]

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

[0249] Preparation of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (3) A suspension of 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) in DMF (200 mL) was stirred at 0° C. for 30 min, and SEMCl (12.30 g, 0.08 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 70:30) to give 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (3) (9.90 g, 61% yield) as a yellow solid. LCMS(ESI)C12H17ClIN3OSi[M+H] + m / z calculated: 409.99, found: 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) was added CuI (9.15 g, 0.04 mmol) and HMPA (21.35 g, 0.12 mmol) at room temperature. The mixture was stirred at 110° C. for 2 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to give 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (5) (3.30 g, 38% yield) as a yellow solid. LCMS(ESI)C13H17ClF3N3OSi[M+H] + m / z calculated: 352.08, found: 352.20.

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

[0252] Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (7) 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) was added to H 2 0 (15 mL) and MsCl (1.00 g, 8.62 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 85:15) to give 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (7) (400 mg, 48% yield) as a yellow oil. LCMS(ESI)C13H17ClF3N3O2Si[M+H] + m / z calculated: 368.07, found: 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]pyridin-4-one (8) 6-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (7) (400 mg, 1.07 mmol) and Cs 2 CO 3 To a solution of (1.25 g, 3.85 mmol) in DMF (15 mL) was added PMBCl (0.84 g, 5.35 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 85:15) to give 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (8) (200 mg, 32% yield) as a yellow oil. LCMS(ESI)C21H25ClF3N3O3Si[M+H] + m / z calculated: 488.13, found: 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]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) 6-Chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-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 dioxane:H 2 In a 5:1 (15 mL) solution of Pd(dppf)Cl 2 (50mg, 0.07mmol) and Na 2 CO 3 (70 mg, 0.06 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (eluted with PE / EtOAc=100:0 to 80:20) to give tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) (140 mg, 60% yield) as a yellow oil. LCMS(ESI)C30H39F3N4O5Si[M+H] + m / z calculated: 621.26, found: 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]pyridin-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]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) (140 mg, 0.30 mmol) in MeOH (15 mL) was added Pd / c (60 mg, 0.57 mmol). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-1-carboxylate (11) (120 mg, 80% yield) as a colorless oil. LCMS(ESI)C30H41F3N4O5Si[M+H] + m / z calculated: 623.28, found: 623.30.

[0256] Preparation of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (12) 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]pyridin-6-yl)pyrrolidine-1-carboxylate (11) (120 mg, 0.19 mmol) in TFA (5 mL) was added 2 drops of TfOH. The reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (12) (50 mg, 90% yield) as a yellow oil. LCMS(ESI)C11H11F3N4O[M+H] + m / z calculated: 273.09, found: 273.15.

[0257] Preparation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of 194a and 194b) To a solution of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (12) (50 mg, 0.18 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide (INT) (43 mg, 0.18 mmol). Then, 2 drops of acetic acid and NaBH 3 CN (12 mg, 0.18 mmol) was 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 (eluted with DCM / MeOH=100:0 to 92:8) to give N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of compounds 194a and 194b) (30 mg, 32% yield) as a white solid. LCMS(ESI)C23H26F3N7O2[M+H] + m / z calculated: 490.21, found: 490.17.

[0258] Chiral separation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (compounds 194a and 194b) A racemic mixture of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (194rac) was purified by SFC (column: Daicel CHIRALPAK OJ-H 250 mm × 20 mm ID 5 μmm; mobile phase: CO 2 / MeOH[0.1%NH 3 ]=70 / 30) and concentrated under reduced pressure to obtain the first fraction as 194a (9.9 mg, purity 98%, ee%: 100, white solid), and the second fraction as compound 194b (9.4 mg, purity 100%, ee%: 98, white solid). Compound 194a 11H NMR (400 MHz, DMSO) δ 13.82 (s, 1H), 11.10 (s, 1H), 8.39 (q, J = 4.4 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1H), 6.39 (s, 1H), 3.84 - 3.81 (m, 2H), 3.29 - 3.25 (m, 1H), 2.98 (t, J = 11.2 Hz, 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 = 12.0 Hz, 2H), 1.83 - 1.77 (m, 1H), 1.56 - 1.51 (m, 2H). LCMS (ESI) C23H26F3N7O2 [M + H] + Calculated m / z: 490.21, Found: 490.20. Compound 194b 1 1H NMR (400 MHz, DMSO) δ 13.82 (s, 1H), 11.10 (s, 1H), 8.39 (q, J = 4.4 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1H), 6.39 (s, 1H), 3.84 - 3.81 (m, 2H), 3.29 - 3.25 (m, 1H), 2.98 (t, J = 11.2 Hz, 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 = 12.0 Hz, 2H), 1.83 - 1.77 (m, 1H), 1.56 - 1.51 (m, 2H). LCMS (ESI) C23H26F3N7O2 [M + H] + Calculated m / z: 490.21, Found: 490.16.

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

[0260] Synthesis of Compounds 208a and 208b

Chem.

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

[0262] Preparation of 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (3) 2-Chloropyrido[2,3-d]pyrimidin-4(3H)-one (2) (1.1 g, 0.0061 mol) in THF / H 2 In a solution of PtO 2 (0.14 g) was added. The mixture was then stirred under hydrogen atmosphere at room temperature for 18 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (3) (1.1 g, 95% purity, 91% yield) as a yellow solid. LCMS(ESI)C7H8ClN3O[M+H] + m / z calculated: 186.04, found: 185.95.

[0263] Preparation of 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (4) A solution of 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (3) (0.9 g, 4.85 mmol) in DMSO (150 mL) was added at room temperature to Cs 2 CO 3(4.7 g, 14.5 mmol) and PMBCl (1.52 g, 9.7 mmol) were added. The reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine three times and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 50:50) to give 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (4) (1.23 g, 90% purity, 74% yield) as a white solid. LCMS(ESI)C15H16ClN3O2[M+H] + m / z calculated: 306.09, found: 305.80.

[0264] Preparation of 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (5) To a solution of 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (4) (1.2 g, 0.004 mol) in DMF (50 mL) was added MeI (3.05 g, 0.02 mol) and NaH (60% in mineral oil, 0.32 g, 0.008 mol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine three times and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to give 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (5) (450 mg, purity 90%, yield 33%) as a yellow oil. LCMS(ESI)C16H18ClN3O2[M+H] + m / z calculated: 320.11, found: 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]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) 2-Chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (5) (450 mg, 1.41 mmol) in dioxane / H 2 In a 5:1 (30 mL) solution of 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)Cl 2 DCM (115 mg, 0.14 mmol) and K 2 CO 3 (587 mg, 4.22 mmol) was added. The reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL×3). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 50:50) to give tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (550 mg, 90% purity, 77% yield) as a white solid. LCMS(ESI)C25H32N4O4[M+H] + m / z calculated: 453.24, found: 453.20.

[0266] Preparation of tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-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]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7) (550 mg, 1.2 mmol) in MeOH (15 mL) was added Pd / C (55 mg) at room temperature. The reaction mixture was stirred at room temperature under 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 give tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate (8) (400 mg, 90% purity, 88% yield) as a yellow oil. LCMS(ESI)C17H26N4O3[M+H] + m / z calculated: 335.20, measured: 335.30

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

[0268] Preparation of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (208a and 208b) To a solution of 8-methyl-2-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one hydrochloride (9) (110 mg, 0.46 mmol) in MeOH (1 mL) was added TEA (1 mL) at room temperature and stirred for 5 min. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (15 mL) and AcOH (0.01 mL) at room temperature and diluted with N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (131 mg, 0.56 mmol) and NaBH 3 CN (88 mg, 1.40 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with DCM / MeOH=100:0 to 90:10) to give the racemic mixture of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (208rac) (120 mg, 99% purity, 55% yield) as a white solid. LCMS(ESI)C24H33N7O2[M+H] + m / z calculated: 452.27, found: 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]pyrimidin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (208rac) The racemic mixture of compounds 208a and 208b was subjected to SFC (column: Daicel CHIRALPAK IH SFC, 250 mm × 20 mm ID, 5 μmm; mobile phase: CO 2 / MeOH[0.1%(NH 3 )]=70 / 30) and concentrated under reduced pressure to obtain the first fraction 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 1 H NMR (400MHz, DMSO-d 6, ppm) δ: 11.37 (s, 1H), 8.43 - 8.34 (m, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.8, 3.2 Hz, 1H), 3.82 - 3.77 (m, 2H), 3.23 - 3.20 (m, 2H), 3.13 - 3.09 (m, 1H), 3.03 (s, 3H), 2.99 - 2.92 (m, 3H), 2.78 (d, J = 4.8 Hz, 3H), 2.68 - 2.66 (m, 1H), 2.59 - 2.57 (m, 1H), 2.35 - 2.26 (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] + Calculated m / z value: 452.27, Measured value: 452.30. Compound 208b 1 H NMR (400 MHz, DMSO - d 6 , ppm) δ: 11.35 (s, 1H), 8.41 - 8.33 (m, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 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 = 4.8 Hz, 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] + Calculated m / z 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-dihydroisoquinolin-3-yl)pyrrolidine-1-carboxylate (INT-3) [ka] To a solution of tert-butyl 3-(1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidine-1-carboxylate (1) (500 mg, 1.59 mmol) in DMAC (20 mL) was added Selectfluor (563 mg, 1.59 mmol) at room temperature. The mixture was stirred at 150° C. for 10 min. After cooling to room temperature, the reaction mixture was added to cold water and extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine and Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc=100:0 to 50:50) to give tert-butyl 3-(4-fluoro-1-oxo-1,2-dihydroisoquinolin-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: 333.15, found: 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) To a solution of 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) in pyridine (20 mL) was added EDCI (423 mg, 2.21 mmol), 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 EtOAc (150 mL x 3). The combined organic phase was washed with 1M HCl solution and brine, and then extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure to give tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, 56% yield) as a white solid. LCMS(ESI)C18H22FN3O4[M+Na] + m / z calculated: 386.16, found: 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) was added KOH (154 mg, 2.75 mmol). The solution was stirred at 60° C. for 2 h, cooled to room temperature, and the reaction mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 90:10) to give tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (400 mg, 76% yield) as a white solid. LCMS(ESI)C18H20FN3O3[M+H] + m / z calculated: 346.15, measured: 345.85

[0277] Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-6-fluoroquinazolin-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) was added a solution of HCl in dioxane (4 mL, 20 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazolin-4(3H)-one (5) (200 mg, 63% yield) as a white solid. LCMS(ESI)C15H17N3O[M+H] + m / z calculated: 246.10, found: 245.95.

[0278] Preparation of 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide (compound 259) To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-6-fluoroquinazolin-4(3H)-one (5) (60 mg, 0.24 mmol) in MeOH (20 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) (61 mg, 0.24 mmol). Then, 2 drops of acetic acid and NaBH 3 CN (8 mg, 0.13 mmol) was added at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified on a C18 column (mobile phase: ACN-H2O (0.1% FA), gradient: 10-95) to give 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide (259) (45.5 mg, purity 99%, yield 15%) as a white solid. 1 H NMR (400MHz, DMSO-d 6,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: 481.21, found: 481.05.

[0279] Example 22: Synthesis of compound 299

[0280] Synthesis of compound 299 [ka]

[0281] Preparation of tert-butyl ((1-(6-(methylcarbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)carbamate (2) A solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (1) (500 mg, 2.19 mmol) in DCM (20 mL) was added at room temperature with NH 4 Cl (234 mg, 4.38 mmol), DIPEA (1415 mg, 10.95 mmol) and HATU (1249 mg, 3.28 mmol) were added sequentially. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM (50 mL x 3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH / DCM, 3% to 5%) to give tert-butyl 4-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (2) (400 mg, 90% purity, 72% yield) as a white solid. LCMS(ESI)C11H18N2O3[M-56+H] + m / z calculated: 171.13, found: 171.10.

[0282] Preparation of tert-butyl 4-carbamimidoyl-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) was dissolved in Me 3 O + BF 4- (312 mg, 2.1 mmol) was added to a suspension of 10 mL of DCM. The mixture was stirred at room temperature under argon for 2 h. The solvent was removed to give the crude imidate salt. The crude was then reacted with NH 3 The mixture was dissolved in Boc / MeOH (7M, 10 mL) and stirred at room temperature for 16 hours. 2 O (1152 mg, 5.28 mmol) was added. The mixture was stirred at room temperature for 10 min and concentrated to give crude tert-butyl 4-carbamimidoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, 50% purity, 62% yield) as a white solid. LCMS(ESI)C11H19N3O2[M+H] + m / z calculated: 226.15, found: 226.05.

[0283] Preparation of tert-butyl 4-(6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) A solution of tert-butyl 4-carbamimidoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (500 mg, 2.21 mmol) in DMF (20 mL) was added with K 2 CO 3(916 mg, 6.63 mmol) and methyl (E)-3-methoxyacrylate (4) (770 mg, 6.63 mmol) were added in one portion. The reaction mixture was heated at 120 °C with stirring for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (eluted with EtOAc / PE, 50% to 100%) to give tert-butyl 4-(6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (200 mg, 90% purity, 29% yield) as a white solid. LCMS(ESI)C14H19N3O3[M+H] + m / z calculated: 278.15, found: 277.95.

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

[0285] Preparation of tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8) tert-Butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) (180 mg, 0.44 mmol), tributyl(vinyl)stannane (7) (282 mg, 0.89 mmol) and Pd(AMPHOS)Cl 2Dissolve (32 mg, 0.04 mmol) in ACN (10 mL) 2 The mixture was purged with 500 mL of ethyl acetate for 2 min and then stirred at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (eluted with EtOAc / PE, 50% to 70%) to give tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8) (120 mg, 90% purity, 79% yield) as a white solid. LCMS(ESI)C16H21N3O3[M+H] + m / z calculated: 304.16, measured: 304.20

[0286] Preparation of tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9) To a solution of tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8) (120 mg, 0.40 mmol) in MeOH (5 mL) was added 10% Pd / C (12 mg). The mixture was evacuated and filled with nitrogen three times and then filled with hydrogen. The resulting mixture was stirred at room temperature for 16 h. The mixture was then filtered through Celite and concentrated in vacuo to give crude tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9) (120 mg, 90% purity, 89% yield) as a white solid, which was used directly in the next step without further purification. LCMS(ESI)C16H23N3O3[M+H] + m / z calculated: 306.18, found: 306.00.

[0287] Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-ethylpyrimidin-4(3H)-one (10) To a solution of tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9) (120 mg, 0.39 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The resulting mixture was diluted with Et 3 Quenching with N and concentration under reduced pressure gave 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-ethylpyrimidin-4(3H)-one (10) (120 mg, 50% purity, 74% yield). LCMS(ESI)C11H15N3O[M+H] + m / z calculated: 206.12, found: 206.00.

[0288] Preparation of 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide (299) To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-ethylpyrimidin-4(3H)-one (10) (40 mg, 0.19 mmol) in MeOH (5 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (68 mg, 0.29 mmol), followed by addition of 2 drops of acetic acid and NaBH(OAc) at room temperature. 3 (82 mg, 0.39 mmol) was added. After 1 h, NaBH 3 CN (12 mg, 0.19 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 um C18 150×21.2 mm, 0.1% NH 3 H 2 10% to 40% ACN / H2O 2 2H) and preparative TLC (MeOH / DCM, 1 / 20) to give 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide (299) (3.2 mg, 99% purity, 3% yield) as a white solid. 1 H NMR (400MHz, DMSO-d 6,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: 423.25, found: 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-methoxypyridin-4-amine (2) To a solution of 2,6-dichloropyridin-4-amine (1) (1.0 g, 6.1 mmol) in dioxane (15 mL) was added MeONa (3.3 g, 61.0 mmol) and TBAI (230 mg, 0.6 mmol) at room temperature. The reaction mixture was stirred in a sealed tube at 150° C. for 15 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to 95:5) to give 2-chloro-6-methoxypyridin-4-amine (2) (880 mg, purity 90%, yield 81%) as a white solid. LCMS(ESI)C6H7ClNO[M+H] + m / z calculated: 159.02, found: 158.93.

[0292] Preparation of 3-bromo-6-chloro-2-methoxypyridin-4-amine (3) To a solution of 2-chloro-6-methoxypyridin-4-amine (2) (880 mg, 5.5 mmol) in DMF (40 mL) was added NBS (1.2 g, 6.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3) and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to 70:30) to give 3-bromo-6-chloro-2-methoxypyridin-4-amine (3) (950 mg, purity 90%, yield 64%) as a white solid. LCMS(ESI)C6H6BrClN2O[M+H] + m / z calculated: 236.94, found: 236.87.

[0293] Preparation of tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)carbamate (4) A solution of 3-bromo-6-chloro-2-methoxypyridin-4-amine (3) (950 mg, 4.0 mmol) in DCM (30 mL) was added with Boc 2 O (1.31 g, 6.0 mmol), Et 3 N (810 mg, 8.0 mmol) and DMAP (244 mg, 2.0 mmol) were added successively 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 (eluted with PE / EtOAc = 100:0 to 80:20) to obtain a mixture of tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)carbamate (4) and tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate (4a) (750 mg, purity 90%, yield 49%) as a white solid. LCMS(ESI)C11H14BrClN2O3[M+H] + m / z calculated: 336.99, found: 336.92.

[0294] Preparation of ethyl (E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate (6) A mixture of tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)carbamate (4) and tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate (4a) (750 mg, 2.2 mmol) in dioxane / H 2 Ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (5) (751 mg, 3.3 mmol), Pd(dppf)Cl in 25 mL of 2H2O (10:1). 2 DCM (181 mg, 0.22 mmol) and K 3 PO 4 H 2 O (1.5 g, 6.6 mmol) was added sequentially 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 (eluted with PE / EtOAc = 100:0 to 70:30) to obtain a mixture of ethyl (E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate (6) and ethyl (E)-3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate (6a) (410 mg, purity 90%, yield 46%) as a white solid. LCMS(ESI)C16H21ClN2O5[M+H] + m / z calculated: 357.11, found: 357.00.

[0295] Preparation of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate (7) Ethyl (E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate (6) and ethyl (E)-3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate (6a) (410 mg, 0.9 mmol), and PtO 2A mixture of (50 mg) in EtOAc (10 mL) was stirred under a hydrogen atmosphere at room temperature for 1 h. 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 give a mixture of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate (7) and ethyl 3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate (7a) (210 mg, 90% purity, 45% yield) as a colorless oil. LCMS(ESI)C16H23ClN2O5[M+H] + m / z calculated: 359.13, found: 359.08.

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

[0297] Preparation of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10) 7-Chloro-5-methoxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one (8) (110 mg, 0.5 mmol) in dioxane / H 2tert-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)Cl in 1H2O (10 mL, 10:1) 2 (42 mg, 0.06 mmol) and K 3 PO 4 H 2 O (357 mg, 1.6 mmol) was added sequentially 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 (eluted with PE / EtOAc = 100:0 to 20:80) to obtain tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-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: 346.17, found: 346.05.

[0298] Preparation of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (11) A solution of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-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 under hydrogen atmosphere at room temperature for 2 h. 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 give tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (11) (140 mg, purity 90%, yield 83%) as a colorless oil. LCMS(ESI)C18H25N3O4[M+H] + m / z calculated: 348.18, found: 347.95.

[0299] Preparation of 7-(pyrrolidin-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (12) tert-Butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (11) (120 mg, 0.34 mmol) in HBr ( 2 A solution of 48% in 200 (5 mL) was stirred at 110° C. for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and diluted with Et 3 N (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 min. The reaction solution was concentrated under reduced pressure to give 7-(pyrrolidin-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (12) (65 mg, purity 90%, yield 72%) as a brown solid. LCMS(ESI)C12H15N3O2[M+H] + m / z calculated: 234.12, found: 234.06.

[0300] Preparation of 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compounds 309a and 309b) A solution of 7-(pyrrolidin-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (12) (65 mg, 0.3 mmol) in MeOH (10 mL) was added at room temperature with N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (78 mg, 0.3 mmol), AcOH (2 drops), and NaBH 3 CN (35 mg, 0.6 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. 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 (eluted with DCM / MeOH=100:0 to 90:10) to give 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide, a racemic mixture of compounds 309a and 309b (35 mg, 98% purity, 27% yield) as a white solid.

[0301] Chiral separation of 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compounds 309a and 309b) The racemic mixture of compounds 309a and 309b was subjected to SFC (column: Daicel CHIRALPAK IH SFC, 20 mm ID × 250 mm, 5 μmm; mobile phase: CO 2 / MeOH[0.1%(NH 3 ) (7M solution in MeOH] = 60 / 40) and concentrated under reduced pressure to give the first fraction as compound 309a (4.8 mg, purity 95%, ee%: 100, white solid) and the second fraction as compound 309b (8.7 mg, purity 95%, ee%: 98, white solid). Compound 309a 1 H NMR (400MHz, DMSO-d 6 ,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: 451.24, found: 451.40. Compound 309b 1 H NMR (400MHz, DMSO-d 6,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: 451.24, found: 451.20.

[0302] Example 24: Synthesis of compound 324rac

[0303] Synthesis of compound 324rac [ka]

[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) was added t-BuOK (5.25 g, 0.0468 mol). The mixture was stirred at room temperature for 1 h. 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 nitrogen atmosphere for 24 hours. The mixture was diluted with water, acidified to pH = 2 with 1M 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 give 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: 228.06, found: 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) was added ethyl carbonochloridate (2281 mg, 21.12 mmol) dropwise under nitrogen atmosphere at 0° C. The mixture was stirred at this temperature for 1 h and then diluted with NH 3 H 2 2H2O (28%, 1285 mg) was added dropwise and the resulting mixture was stirred at room temperature for 1 h. 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 purified using Biotage Isolera One (C 18 Column, 5%-90% MeCN / H containing 0.1% FA 2 The resulting mixture was purified by column chromatography (eluted with 0) to give 3-fluoro-6,8-dihydro-1,6-naphthyridine-5,7-dione (4) (505 mg, 90% purity, 23% yield) as a white solid. LCMS(ESI)C8H5FN2O2[M+H] + m / z calculated: 181.03, found: 180.90.

[0306] Preparation of 5,7-dichloro-3-fluoro-1,6-naphthyridine (5) 3-Fluoro-6,8-dihydro-1,6-naphthyridine-5,7-dione (4) (300 mg, 1.66 mmol) in PhPOCl 2 The (3 mL) solution was stirred at 110 °C under nitrogen atmosphere for 12 h. 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 brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 100:0 to 50:50) to give 5,7-dichloro-3-fluoro-1,6-naphthyridine (5) (125 mg, purity 90%, yield 31%) as a white solid. LCMS(ESI)C8H3C2FN2[M+H] + m / z calculated: 216.97, found: 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-naphthyridine (5) (195 mg, 0.8985 mmol) in MeOH (20 mL), MeONa (48 mg, 0.8985 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc (20 mL x 3) and brine. The combined organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 95:5) to give 7-chloro-3-fluoro-5-methoxy-1,6-naphthyridine (6) (135 mg, purity 90%, yield 63%) as a white solid. LCMS(ESI)C9H6ClFN2O[M+H] + m / z calculated: 213.02, found: 212.90.

[0308] Preparation of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) 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 Na 2 CO 3 (306mg, 0.941mmol) of dioxane-H 2 The mixture was diluted with N2O (3:1, 2 mL). 2 The mixture was degassed at rt and heated under nitrogen at 80° C. for 3 h. The reaction mixture was concentrated and purified by flash silica chromatography to give tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (100 mg, 90% purity, 24% yield) as a colorless oil. LCMS(ESI)C18H20FN3O3[M+H] + m / z calculated: 346.15, found: 346.15.

[0309] Preparation of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (9) A mixture of 3-(3-fluoro-5-methoxy-1,6-naphthyridin-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) and H 2 Degass with H 2 The mixture was stirred under atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (9) (100 mg, purity 60%, yield 59%) as a yellow oil. LCMS(ESI)C18H22FN3O3[M+H] + m / z calculated: 348.16, found: 348.05.

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

[0311] Preparation of 6-fluoro-5-(4-(3-(3-fluoro-5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (compound 324rac) To a solution of 3-fluoro-7-(pyrrolidin-3-yl)-6H-1,6-naphthyridin-5-one hydrobromide (10) (40 mg, 0.127 mmol) in MeOH (10 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide (INT-2) (32 mg, 0.127 mmol), followed by 2 drops of acetic acid and NaBH 3 CN (40 mg, 0.636 mmol) was 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 to give racemic 6-fluoro-5-(4-(3-(3-fluoro-5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 324rac (13.2 mg, 95% purity, 21% yield) as a white solid. 1 H NMR (400MHz, DMSO-d 6,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: 469.21, measured: 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-tetrahydroisoquinolin-1(2H)-one (2) 2H-Isoquinolin-1-one (8 g, 0.05 mol) and PtO 2 (0.9 g, 0.003 mol) in TFA (80 mL) and 2 The mixture was stirred at 100° C. under (1 MPa) for 12 hours. The precipitate was collected by filtration and extracted with EtOAc (400 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: PE / EtOAc=100:0 to 80:20) to give 5,6,7,8-tetrahydroisoquinolin-1(2H)-one (2) (7.00 g, 77% yield) as a black oil. LCMS(ESI)C9H11NO[M+H] + m / z calculated: 150.08, found: 150.00.

[0315] Preparation of 1-chloro-5,6,7,8-tetrahydroisoquinoline (3) POCl of sodium salt of 5,6,7,8-tetrahydro-2H-isoquinolin-1-one (2) (7 g, 0.047 mmol) 3 (100 mL) solution was stirred at 110° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, placed in ice water, and NH 3 H 2 The mixture was neutralized with O and then extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to 80:20) to give 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: 168.05, found: 168.00.

[0316] Preparation of 1-chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide (4) 1-Chloro-5,6,7,8-tetrahydroisoquinoline (3) (5 g, 0.029 mol) was dissolved in AcOH / H 2 O 2 (100 mL). The reaction mixture was stirred at 70° C. for 2 h. The precipitate was collected by filtration and extracted with EtPAc (200 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: DCM / MeOH=100:0 to 90:10) to give 1-chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide (4) (2.00 g, 73% yield) as a yellow oil. LCMS(ESI)C9H10ClNO[M+H] + m / z calculated: 184.05, found: 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 POCl at room temperature. 3 (50 mL). The mixture was heated to 110° C. and stirred for 3 h. The resulting mixture was diluted with ice water (200 mL) and extracted with EtOAc (400 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: PE / EtOAc=100:0 to 70:30) to give 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline (5) (370 mg, 15% yield) as a yellow oil. LCMS(ESI)C9H9Cl2N[M+H] + m / z calculated: 202.01, found: 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) was added MeONa (280 mg, 5.20 mmol) and the mixture was heated at 60 °C for 3 h with stirring. The precipitate was collected by filtration and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: PE / EtOAc = 100:0 to 90:10) to give 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline (6) (250 mg, 66% yield) as a white solid. LCMS(ESI)C10H12ClNO[M+H] + m / z calculated: 198.06, found: 197.95.

[0319] Preparation of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) 3-Chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline (6) (240 mg, 1.21 mmol) in dioxane / H 2In a 10:1 (60 mL) solution of 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)Cl 2 (88 mg, 0.12 mmol) and Na 2 CO 3 (503 mg, 3.64 mmol) were added sequentially at room temperature. The reaction mixture was diluted with N 2 The mixture was stirred under atmospheric pressure at 90° C. for 3 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (100 mL×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (PE / EtOAc=100:0 to 85:15) to give tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (140 mg, 31% yield) as a yellow solid. LCMS(ESI)C19H26N2O3[M+H] + m / z calculated: 331.19, found: 331.15.

[0320] Preparation of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)pyrrolidine-1-carboxylate (9) To a solution of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8) (130 mg, 0.39 mmol) in MeOH (50 mL) was added Pd / C (30 mg). The mixture was evacuated and refilled with hydrogen three times, then refilled with hydrogen. The resulting mixture was stirred at room temperature for 5 h. The mixture was then filtered through Celite and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography (PE / EtOAc = 100:0 to 50:50) to give tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)pyrrolidine-1-carboxylate (9) (130 mg, 89% yield) as a yellow solid. LCMS(ESI)C19H28N2O3[M+H] + m / z calculated: 333.21, found: 333.10.

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

[0322] Preparation of 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of compounds 337a and 337b) To a solution of 3-(pyrrolidin-3-yl)-5,6,7,8-tetrahydroisoquinolin-1(2H)-one (10) (60 mg, 0.27 mmol), 6-fluoro-N-methyl-5-(4-oxopiperidin-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 stirred at 50° C. for 1 hour, followed by addition of NaBH 3 CN (21 mg, 0.33 mmol) was added and stirred for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH=100:0 to 90:10) to give 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide, a racemic mixture of compounds 337a and 337b (22 mg, 18% yield) as a white solid. LCMS(ESI)C25H32FN5O2[M+H] + m / z calculated: 454.25, found: 454.15.

[0323] Chiral separation of 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of compound 337a and compound 337b) The racemic mixture of compounds 337a and 337b was subjected to SFC (column: DAICEL OD-H 4.6 mm ID*250 mmL 5 μm; mobile phase: CO 2 / MeOH[0.1%(NH 3 ) (7M solution in MeOH)]=70 / 30) and concentrated under reduced pressure to give the first fraction as compound 337a (7 mg, purity 95%, ee%: 100, white solid) and the second fraction as compound 337b (5 mg, purity 92%, ee%: 100, white solid). Compound 337a 11H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.40 (d, J = 4.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 10.6, 8.4 Hz, 1H), 5.83 (s, 1H), 3.55 - 3.44 (m, 2H), 3.14 - 3.04 (m, 1H), 2.86 (t, J = 11.6 Hz, 3H), 2.75 (t, J = 6.4 Hz, 4H), 2.63 (dd, J = 14.8, 8.0 Hz, 2H), 2.44 (s, 2H), 2.27 (s, 3H), 2.21 - 2.10 (m, 1H), 1.95 (d, J = 13.2 Hz, 2H), 1.73 (dd, J = 12.8, 8.4 Hz, 1H), 1.58 (dd, J = 22.4, 12.0 Hz, 6H). LCMS (ESI) C25H32FN5O2 [M + H] + Calculated m / z: 454.25, Found: 454.20. Compound 337b 1 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.70 - 7.45 (m, 1H), 5.83 (s, 1H), 3.49 (d, J = 11.2 Hz, 2H), 3.08 (d, J = 6.4 Hz, 1H), 2.85 (t, J = 11.2 Hz, 3H), 2.76 (d, J = 4.4 Hz, 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 = 12.4 Hz, 2H), 1.80 - 1.68 (m, 1H), 1.68 - 1.51 (m, 6H). LCMS (ESI) C25H32FN5O2 [M + H] + Calculated m / z: 454.25, Found: 454.15.

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

[0325] Synthesis of compounds 343a and 343b

Chem.

[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. This solution was diluted with i-PrNH 2 (2.54 g, 25.0 mmol) was slowly added followed by 4-chloro-3-fluoropyridine (1) (3 g, 22.8 mmol). After stirring at -78 °C for 2 h, crushed dry ice was added in one portion. The reaction mixture was allowed to stir until it warmed to room temperature. The reaction was quenched by the addition of aqueous ammonium chloride, acidified to pH = 2 with concentrated hydrochloric acid, and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried at rt and concentrated under reduced pressure to give 4-chloro-5-fluoronicotinic acid (2) (2.2 g, 70% purity, 36% yield) as a yellow solid. LCMS(ESI)C6H3ClFNO2[M+H] + m / z calculated: 175.99, found: 175.80.

[0327] Preparation of methyl 4-chloro-5-fluoronicotinate (3) A solution of 4-chloro-5-fluoronicotinic acid (2) (2.2 g, 11.6 mmol) in ACN (100 mL) was added with DBU (5.29 g, 34.8 mmol) and CH 3 I (8.2 g, 58.0 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 5 h. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluted with EtOAc / PE, 20%-50%) to give methyl 4-chloro-5-fluoronicotinate (3) (1.5 g, 90% purity, 63% yield) as a white solid. LCMS(ESI)C7H5ClFNO2[M+H] + m / z calculated: 190.00, found: 189.95.

[0328] Preparation of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinate (5) Methyl 4-chloro-5-fluoronicotinate (3) (150 mg, 0.79 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (4) (233 mg, 1.19 mmol), PdCl in ACN (15 mL). 2 (PPh 3 ) 2 A mixture of (55 mg, 0.079 mmol) and DIPEA (511 mg, 3.96 mmol) was added to N 2 The mixture was heated at 85° C. under atmospheric pressure for 5 h. After cooling to ambient temperature, the mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (EtOAc / PE, 20% to 40%) to give methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinate (5) (150 mg, 90% purity, 48% yield) as a yellow solid. LCMS(ESI)C18H21FN2O4[M+H] + m / z calculated: 349.15, found: 348.95.

[0329] Preparation of 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinic acid (6) Methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinate (5) (150 mg, 0.43 mmol) in THF / H 2 To a solution of 2H2O (3 / 1, 10 mL) was added LiOH (31 mg, 1.29 mmol). The mixture was stirred at room temperature for 2 h. The organic solvent was then removed under reduced pressure. The aqueous solution was adjusted to pH 3-4 using 1M HCl and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine and then with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure to give 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinic acid (6) (120 mg, 90% purity, 75% yield) as a yellow oil. LCMS(ESI)C17H19FN2O4[M+H]+ m / z calculated: 335.14, found: 335.00.

[0330] Preparation of tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridin-3-yl)pyrrolidine-1-carboxylate (7) To a solution of 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinic acid (6) (120 mg, 0.36 mmol) in DCM (10 mL) was added TfOH (161 mg, 1.07 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 16 h. The reaction was quenched with DIPEA (231 mg, 1.79 mmol) and then Boc 2 O (156 mg, 0.716 mmol) was added. After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 20% to 40% EtOAc / PE) to give tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridin-3-yl)pyrrolidine-1-carboxylate (7) (70 mg, 90% purity, 52% yield) as a white solid. LCMS(ESI)C17H19FN2O4[M-tBu+H] + m / z calculated: 279.14, found: 278.85.

[0331] Preparation of tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate (8) tert-Butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridin-3-yl)pyrrolidine-1-carboxylate (7) (70 mg, 0.21 mmol) NH 3 A solution of 1.5M MeOH (7 mL) was stirred in a sealed tube at 90 °C for 1 h. The reaction was then concentrated under reduced pressure to give tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate (8) (70 mg, 90% purity, 90% yield) as a yellow solid. LCMS(ESI)C17H20FN3O3[M+H] + m / z calculated: 334.15, found: 333.95.

[0332] Preparation of 5-fluoro-3-(pyrrolidin-3-yl)-2,7-naphthyridin-1(2H)-one (9) A mixture of tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate (8) (70 mg, 0.44 mmol) in a solution of HCl in dioxane (4 M, 5 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and diluted with Et 3 Quenched with N. The resulting solution was concentrated in vacuo to give 5-fluoro-3-(pyrrolidin-3-yl)-2,7-naphthyridin-1(2H)-one (9) (50 mg, 90% purity, 92% yield) as a yellow oil. LCMS(ESI)C12H12FN3O[M+H] + m / z calculated: 234.10, found: 234.05.

[0333] Preparation of 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compounds 343a and 343b) To a solution of 5-fluoro-3-(pyrrolidin-3-yl)-2,7-naphthyridin-1(2H)-one (9) (70 mg, 0.30 mmol) in MeOH (10 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) (113 mg, 0.45 mmol), followed by 2 drops of acetic acid, NaBH 3 CN (19 mg, 0.30 mmol) and NaBH(OAc) 3 (191 mg, 0.90 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 90:10) to give 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-1-yl)piperidin-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-naphthyridin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compound 343a and compound 343b) The racemic mixture of compounds 343a and 343b was subjected to SFC (column: DAICEL CHIRALPAK IH 20 mm ID × 250 mm, 5 μm; mobile phase: CO 2 / MeOH[0.1%(NH 3 )]=70 / 30) and concentrated under reduced pressure to obtain the first fraction as compound 343a (19.7 mg, purity 99%, ee%: 100, white solid) and the second fraction as compound 343b (24.7 mg, purity 98%, ee%: 90, white solid). Compound 343a 1 H NMR (400MHz, DMSO-d 6 ,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: 469.21, found: 469.07. Compound 343b 1 H NMR (400MHz, DMSO-d 6,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: 469.21, found: 469.10.

[0335] Example 27: Synthesis of Compound 361

[0336] Synthesis of compound 361 [ka]

[0337] Preparation of tert-butyl 4-((2-(ethoxycarbonyl)cyclohex-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-aminocyclohex-1-ene-1-carboxylate (2) (160 mg, 0.95 mmol) was added at room temperature, followed by addition of POCl. 3 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 layer was washed with brine (50 mL) and diluted with Na 2 SO 4The mixture was dried at 40° C. and then concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 85:15) to give tert-butyl 4-((2-(ethoxycarbonyl)cyclohex-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (100 mg, 55% yield) as a white solid. LCMS(ESI)C20H30N2O5[M-56+H] + m / z calculated: 323.22, found: 323.05.

[0338] Preparation of 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)cyclohex-1-ene-1-carboxylic acid (4) tert-Butyl 4-((2-(ethoxycarbonyl)cyclohex-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (100 mg, 0.26 mmol) in MeOH:H 2 To the 1:1 O=1 (10 mL) solution was added LiOH (30 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)cyclohex-1-ene-1-carboxylic acid (4) (80 mg, 88% yield) as a white solid. LCMS(ESI)C18H26N2O5[M-56+H] + m / z calculated: 295.18, measured: 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-carboxamido)cyclohex-1-ene-1-carboxylic acid (4) (80 mg, 0.23 mmol) in ACN (10 mL) was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate / TCFH (150 mg, 0.54 mmol) and N-methylimidazole / NMI (50 mg, 0.61 mmol) at room temperature. After 10 min, excess NH 3-MeOH (7M, 5 mL) was added at 50° C. The mixture was stirred at 50° C. for 18 h. The residue was concentrated under reduced pressure and purified by flash chromatography (eluted with DCM / MeOH=100:0 to 96:4) to give 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, 79% yield) as a white solid. LCMS(ESI)C18H25N3O3[M+H] + m / z calculated: 332.19, found: 332.10.

[0340] Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5,6,7,8-tetrahydroquinazolin-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 solution of HCl in dioxane (4 M, 3 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6) (40 mg, 96% yield) as a white solid. LCMS(ESI)C13H17N3O[M+H] + m / z calculated: 232.14, found: 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]hexan-2-yl)piperidin-1-yl)picolinamide (compound 361) To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6) (40 mg, 0.17 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (40 mg, 0.17 mmol) and 3 drops of HOAc, followed by addition of NaBH 3 CN (10 mg, 0.16 mmol) was added. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5 um C18 150×21.2 mm, mobile phase: ACN-H2 0 (0.1% FA), gradient: 10-25) to give N-methyl-5-(4-(4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (361) (30 mg, 97% purity, 38% yield) as a white solid. compound 361 1 H 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: 449.26, found: 449.20.

[0342] Example 28: Synthesis of compound 375

[0343] Synthesis of compound 375 [ka]

[0344] Preparation of tert-butyl 4-((3-carbamoylpyridin-2-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 (2) (500 mg, 2.19 mmol) in DCM (15 mL) was added 2-aminonicotinamide (1) (330 mg, 2.41 mmol), T3P (50% wt in EtOAc, 4.18 g, 6.57 mmol) and DIPEA (850 mg, 6.57 mmol) successively at room temperature. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with DCM / MeOH=100:0 to 90:10) to obtain tert-butyl 4-((3-carbamoylpyridin-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: 347.16, found: 346.85.

[0345] Preparation of tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) To a solution of tert-butyl 4-((3-carbamoylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3) (330 mg, 0.95 mmol) in DME (20 mL) was added KOH (160 mg, 2.85 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 6 h. The reaction solution was filtered to remove KOH. The filtrate was diluted with water and extracted with EtOAc (10 mL × 3). The aqueous phase was purified by column chromatography on a silica gel C18 column (10%-50% MeCN / H2O with 0.1% formic acid). 2 The mixture was purified by elution with 0 (eluting with 2,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (220 mg, 80% purity, 56% yield) as a white solid. LCMS(ESI)C17H20N4O3[M+H] + m / z calculated: 329.15, found: 329.00.

[0346] Preparation of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) tert-Butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4) (200 mg, 0.607 mmol) in THF / H 2 In a 20 mL solution of PtO 2 (41 mg) was added. The mixture was then stirred under hydrogen atmosphere at room temperature for 18 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-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: 333.18, found: 333.25.

[0347] Preparation of tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) A solution of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5) (200 mg, 0.6 mmol) in DMSO (10 mL) was added to the reaction mixture at room temperature. 2 CO 3 (586 mg, 1.8 mmol) and PMBCl (188 mg, 1.2 mmol) were added. The reaction mixture was stirred at 50 °C for 1 h. The reaction solution was quenched with water and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine three times and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 50:50) to give tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-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: 453.24, found: 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]pyrimidin-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]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6) (50 mg, 0.11 mmol) in DMF (10 mL) was added NaH (7 mg, 0.17 mmol, 60% wt) and MeI (24 mg, 0.17 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was quenched with water and extracted with EtOAc (50 mL×3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 70:30) to give tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-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: 467.26, found: 467.30.

[0349] Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-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]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (7) (30 mg, 0.064 mmol) in TFA (5 mL) was added TfOH (0.2 mL). The reaction was stirred at room temperature for 0.5 h. The reaction solution was diluted with NaHCO 3 The pH was adjusted to 8 using a saturated aqueous solution of NaCl. The basic solution was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine and diluted with Na 2 SO 4The mixture was dried at 40° C. for 1 hour and concentrated under reduced pressure to give 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (8) (25 mg, 60% purity, 94% yield) as a yellow oil. LCMS(ESI)C13H18N4O[M+H] + m / z calculated: 247.15, found: 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]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (compound 375) A solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (8) (25 mg, 0.10 mmol) in MeOH (15 mL) and AcOH (0.01 mL) was added at room temperature with 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) (31 mg, 0.12 mmol) and NaBH 3 CN (10 mg, 0.15 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 90:10) and preparative HPLC (Gemini 5 um C18 150×21.2 mm, mobile phase: ACN- H 2 O(0.05%NH 3 ), gradient: 25-95) to give 6-fluoro-N-methyl-5-(4-(4-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (375) (5.0 mg, 97% purity, 10% yield) as a white solid. 1 H NMR (400MHz, DMSO-d 6, 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: 482.26, found: 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) 3-Chloro-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (1) (2000 mg, 6.294 mmol) and Pd(AMPHOS)Cl 2 To a solution of (445 mg, 0.6294 mmol) in ACN (30 mL) was added tributyl(vinyl)stannane (2) (1995 mg, 6.294 mmol). The mixture was heated at 100 °C for 5 h in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with EtOAc / PE, 0-15%) to give 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinolin-1(2H)-one (3) (1500 mg, 90% purity, 69% yield) as a white solid. LCMS(ESI)C19H16FNO2[M+H] + m / z calculated: 310.12, found: 309.90.

[0354] Preparation of 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4) 8-Fluoro-2-(4-methoxybenzyl)-3-vinylisoquinolin-1(2H)-one (3) (1500 mg, 4.85 mmol) in MeOH / H 2 HO (3:1, 80 mL) solution of NaIO 4 (4150mg, 19.40mmol) and K 2 OsO 4 2H 2 O (178 mg, 0.48 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine and added Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluted with EtOAc / PE, 0-25%) to give 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4) (430 mg, 90% purity, 25% yield) as a yellow solid. LCMS(ESI)C18H14FNO3[M+H] + m / z calculated: 312.10, found: 311.90.

[0355] Preparation of 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (5) 8-Fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4) (430 mg, 1.38 mmol), PPh 3 (724 mg, 2.76 mmol) and LiI (369 mg, 2.76 mmol) in DMF / dioxane (8%, 10 mL) were added to a solution of TMSCF 3(491 mg, 3.45 mmol) was added. The mixture was heated in a sealed tube at 130 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with EtOAc / PE, 0-15%) to give 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (5) (200 mg, 60% purity, 25% yield) as a white solid. LCMS(ESI)C19H14F3NO3[M+H] + m / z calculated: 346.10, found: 346.00.

[0356] Preparation of 3-(1-benzyl-4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (7) To a solution of 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (5) (260 mg, 0.75 mmol) and LiF (39 mg, 1.51 mmol) in ACN (50 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (6) (357 mg, 1.51 mmol). The mixture was kept stirring at 60° C. for 16 h. The resulting mixture was diluted with water and extracted with DCM (30 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with 0-15% EtOAc / PE) to give 3-(1-benzyl-4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (7) (25 mg, 90% purity, 6% yield) as a white solid. LCMS(ESI)C28H25F3N2O2[M+H] + m / z calculated: 479.19, found: 479.20.

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

[0358] Preparation of 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (10) To a solution of 3-(4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (8) (100 mg, 0.257 mmol) in MeOH (10 mL), N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT) (90 mg, 0.386 mmol) was added at room temperature, and the mixture was diluted with 2 drops of acetic acid and NaBH 3 CN (24 mg, 0.386 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=100:0 to 90:10) to give 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (10) (80 mg, purity 50%, yield 25%) as a white solid. LCMS(ESI)C33H34F3N5O3[M+H] +m / z calculated: 606.26, found: 606.20.

[0359] Preparation of 5-(4-(3,3-difluoro-4-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-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-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (10) (80 mg, 0.13 mmol) in TFA (5 mL) was added TfOH (1 mL) dropwise at room temperature. The reaction mixture was stirred at 100° C. for 5 min. NaHCO 3 The pH of the resulting mixture was adjusted to around 8.0 by slowly adding a saturated solution of Na 2 SO 4 The residue was purified by preparative HPLC (Gemini 5um C18 150×21.2 mm, 35%-40% ACN / H2O containing 0.1% FA). 2 Purification by HPLC (eluted with 0 mL of 1000 mL) gave 5-(4-(3,3-difluoro-4-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (393rac) (6.2 mg, 93% purity, 9% yield) as a brown solid. 1 H NMR (400MHz, CD 3 OD_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: 486.21, found: 486.40.

[0360] Assay Exemplary compounds of the invention have been prepared and tested to determine their effectiveness as PARP1 and PARP2 inhibitors. Exemplary assays are described below.

[0361] Biochemical dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA assay) of PARP1 Optiplate HB 384-well plates were coated with anti-FLAG antibody, which is supplied as a 4 mg / ml solution, and the coating was performed in 10 mL of NaCl, pH 9.6, with a final immobilization of 0.3 g per well. 2 CO3 / HCO 3 Coating buffer was used for overnight at 4°C. The wells were then washed 3 times for 5 min 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). Prior to the assay, each well was washed 3 times for 5 min with coating wash buffer. For the assay, 2.5 nM recombinant full-length N-terminal FLAG-tagged human PARP1 (20 μL) was added to each well of a 384-well plate and left at room temperature for 30 min, after which a DMSO solution (50 nL) of each compound was added using the pintool technique. After a 30-min incubation at room temperature, 10 μM biotin-NAD + 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. Auto-polyADP-ribosylation (AutoPARylation) was allowed to proceed at room temperature for 2 hours, after which 12 mM NAD +5 μL of quenching solution was added. After 30 min at room temperature, the assay solution was removed, washed 5 times for 3 min, and a 1:1000 dilution of DELFIA Eu-N1 Streptavidin Reagent (100 μL) was added. The plate was then incubated for 30 min at room temperature. The reaction mixture was removed and the plate was washed 5 times for 3 min before adding DELFIA Enhancement Solution (25 μL). After 30 min incubation at room temperature, fluorescence was measured on a PHERAstar FS (Ex: 337 nm, Em: 620 nm, integration start: 60 μs, integration time: 400 μs).

[0362] Typically, compounds are tested in a 12-point concentration-response curve with 3-fold dilution intervals starting from 20 μM and an IC 50 Data was analyzed using ActivityBase software, replicate values ​​from the low control (no enzyme, 0.2% DMSO) and high control (0.2% DMSO) were averaged, and data from test compounds were expressed as a % value of 100% using the following formula: %Value=100-(100*((High Control-Value) / (High Control-Low Control)) The data were fitted with a nonlinear regression equation (log inhibitor vs response - variable slope (4 parameters)) to obtain IC 50 The value was calculated. IC of various test compounds 50 The values ​​are shown in Table 1.

[0363] Activation DNA sequence [ka]

[0364] Probe-displacement homogeneous time-resolved fluorescence assay (HTRF assay) of PARP1 10 nM full-length N-terminal FLAG-tagged PARP1 was incubated with 2 nM anti-FLAG Tb-cryptate antibody and PARP1 / 2 Cy5 fluorescent dye-labeled binding 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)) for 40 min at room temperature. The Cy5-labeled binding probe is shown below and described in Papeo, G. et al. J. Biomol.Screen.2014;19:1212-1219. This reaction mixture (6 μL) was then transferred to each well of a black non-binding surface 384-well plate and DMSO solutions (35 nL) of each compound were added using the pintool technique. After 1 h of incubation at room temperature, fluorescence was measured on a PHERAstar FS (Ex: 337 nm, Em: 620 nm, em: 665 nm, integration start 60 μs, integration time 400 μs) using the HTRF module.

[0365] Typically, compounds are tested in a 12-point concentration-response curve with 3-fold dilution intervals starting from 58.5 μM and an IC 50 Data was analyzed using ActivityBase software, replicate values ​​from low controls (no enzyme, probe and Tb-cryptate antibody, 0.6% DMSO) and high controls (0.6% DMSO) were averaged, and data from test compounds 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 with a nonlinear regression equation to obtain the IC 50 The value was calculated. K d Values ​​were calculated using the Cheng-Prussoff formula: I C 50 = (1 + ([probe concentration] / [K m(probe) ]))*K d Therefore, K d =IC50 / (1+[[probe concentration] / [K m(probe) ]]), and 10 × K m With the probe, this equation becomes d =IC 50 / 11.

[0366] Probe-displacement homogeneous time-resolved fluorescence assay (HTRF assay) of PARP2 The assay uses N-terminally FLAG-tagged PARP2 (amino acids 1-583) instead of PARP1 and uses a PARP1 / 2 binding probe at 10x probe K d The assay conditions were the same as for PARP1, except that the antibody was used at 540 nM. Data analysis was performed in the same manner as for PARP1.

[0367] Cy5 probe structure [ka]

[0368] NanoBRET Cellular Target Occupancy Assay To demonstrate cellular target engagement and selectivity for PARP1 and PARP2, NanoBRET assays were used. These assays bind Nano-luc tagged proteins (e.g., PARP1 or PARP2) to high affinity NADPH. + Such cellular probe displacement assays, which are based on bioluminescence resonance energy transfer (BRET) between fluorescent groups on competitive binding probes, can be used to measure inhibitor affinity and selectivity for PARP1 and 2.

[0369] Frozen HEK293 cells transiently transfected with either PARP1-NanoLuc® or PARP2-NanoLuc® fusion constructs (Promega) were thawed and the suspension was dispensed into 384-well microplates at a density of 1750 cells per well. NanoBRET assays were then performed for PARP1 and PARP2 assays. TMTE PARP Tracer 01 was added to final concentrations of 11 nM and 2 nM, respectively. Compounds were added to 12 points of a concentration-response curve in 3-fold dilution intervals starting from 25 μM and the plate was incubated for 2 hours at 37° C. NanoBRET assay was then performed according to the manufacturer's instructions. TM After addition of Nano-Glo® substrate and extracellular NanoLuc® inhibitor, the BRET ratio was measured using a NanoBRET module (LUM 610-LP 450-80) and a PHERAstar FS or FSX reader. d Values ​​were calculated using the Cheng-Prussoff formula: I C 50 =(1+([Tracer concentration] / [K m(tracer) ]))*K d

[0370] Efficacy, affinity, and selectivity data for a variety of test compounds determined using the DELFIA and probe displacement HTRF assays are summarized in Table 1. Efficacy, affinity, and selectivity data for some test compounds determined using the NanoBRET assay are summarized in Table 2.

[0371] Table 1 PARP1 / 2 Assay Results for Selected Compounds (DELFIA and Probe Displacement 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 PARP1 / 2 Assay Results (NanoBRET) for Selected Compounds [Table 2-1] [Table 2-2]

[0373] Legend: Results from the DELFIA, probe displacement HTRF, and NanoBRET assays are categorized as follows: "-" indicates that the IC50 or Kd value is greater than 10M. "+" 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 an IC50 or Kd value greater than 10 nM and less than or equal to 100 nM. "++++" indicates an IC50 of 10 nM or less. Selectivity is categorized as follows: "-" indicates a value less than 10. "+" indicates a value between 10 and 50. "++" indicates a value between 50 and 100. "+++" indicates a value greater than or equal to 100. Selectivity values ​​are the preference for PARP1 over PARP2. They are based on the ratio of the Kd values ​​for inhibition of PARP1 and PARP2, calculated as Kd(PARP2) / Kd(PARP1).

Claims

1. 1. A PARP1 inhibitor compound for use in medicine, comprising the following structure: 【Chemistry 1】 (In the formula, R １ is selected from H and a substituted or unsubstituted organic group; R ２ is optional and is independently selected from H and a substituted or unsubstituted organic group; R １ and R ２ may be taken together to form a ring; R ３ is independently selected from H and a substituted or unsubstituted organic group; R ６ is optional and is independently selected from H and a substituted or unsubstituted organic group; Z １ and Z ２ is independently selected from C and N; and L comprises a group having the structure: 【Chemistry 2】 (In the formula, 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; and Preferably, both r and s are at least 1; each X １ may be the same or different and are independently selected from C, N, O and S; each X ３ may be the same or different and are independently selected from C, N, O and S; each X ６ may be the same or different and are independently selected from C and N; Each R ４１ may be the same or different, may be present or absent and is selected from H and a substituted or unsubstituted organic group; Each R ４３ may be the same or different, may be present or absent, and are selected from H and substituted or unsubstituted organic groups; and R ４４ is optional and is selected from H and a substituted or unsubstituted organic group; The dotted lines indicate that ring A may have a single bond or a combination of both single and double bonds and may be aliphatic or aromatic; and, independently, ring C may have a single bond or a combination of both single and double bonds and may be aliphatic or aromatic; R ５ is selected from H and a substituted or unsubstituted organic group; Each Q １ may be the same or different, may be present or absent, and comprise groups independently selected from the following structures: 【Chemistry 3】 (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 may be the same or different and are independently selected from H and substituted or unsubstituted organic groups; and R ４６ is selected from H and substituted or unsubstituted organic groups; Q ２ is an optional group having the structure: 【Chemistry 4】 (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 may be the same or different and are independently selected from C, N, O and S; X ５ is independently selected from C and N; Each R ４２ may be the same or different, may be present or absent and is selected from H and a substituted or unsubstituted organic group; The dotted line indicates that Ring B may have single bonds or a combination of both single and double bonds, and may be aliphatic or aromatic; and Q ３ may be present or absent and comprises a group independently selected from the following structures: 【Chemistry 5】 (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; and v+w is a number selected from 0, 1, 2, 3, 4, 5 and 6 (preferably a number selected from 0, 1 and 2)).

2. Q ３ is not present or has the structure: 【Chemistry 6】 (In the formula, Each R ４５ may be the same or different and are independently selected from H and substituted or unsubstituted organic groups; R ４６ is selected from H and substituted or unsubstituted organic groups.

2. The compound of claim 1, wherein R is a group independently selected from the group consisting of:

3. R ４１ , R ４２ , R ４３ , R ４４ and R ４５ 5. The compound of any of the preceding claims, wherein each is independently selected from H and a group selected from the following groups: -deuterium; - halogens (such as -F, -Cl, -Br, and -I); -nitrile group; - substituted or unsubstituted linear or branched C １ ~C ６ alkyl groups (such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and hexyl groups); - substituted or unsubstituted linear or branched C １ ~C ６ Alkyl-aryl groups (-CH ２ Ph, -CH ２ (2, 3 or 4) F-Ph, -CH ２ (2, 3 or 4) Cl-Ph, -CH ２ (2, 3 or 4) Br-Ph, -CH ２ (2, 3 or 4) I-Ph, -CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ CH ２ Ph and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ Ph, etc.); - substituted or unsubstituted linear or branched C １ ~C ６ A halogenated alkyl group (-CH ２ F, -CH ２ Cl, -CH ２ Br, -CH ２ I, -CHF ２ , -CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -CH ２ CH ２ F, -CH ２ CF ３ , -CH ２ CCl ３ , -CH ２ CBr ３ , and -CH ２ C.I. ３ etc.); --NH ２ or substituted or unsubstituted linear or branched primary, secondary or tertiary C １ ~C ６ Amine groups (-NMeH, -NMe ２ , -NEtH, -NEtMe, -NEt ２ , -NPrH, -NPrMe, -NPrEt, -NPr ２ , -NBuH, -NBuMe, -NBuEt, -CH ２ -NH ２ , -CH ２ -NMeH, -CH ２ -NMe ２ , -CH ２ -NEtH, -CH ２ -NEtMe, -CH ２ -N.E.T. ２ , -CH ２ -NPrH, -CH ２ -NPrMe and -CH ２ -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)F ２ -Ph, -NH-2,(3,4,5 or 6)Cl ２ -Ph, -NH-2,(3,4,5 or 6)Br ２ -Ph, -NH-2,(3,4,5 or 6)I ２ -Ph, -NH-2,(3,4,5 or 6)Me ２ -Ph, -NH-2,(3,4,5 or 6)Et ２ -Ph, -NH-2,(3,4,5 or 6)Pr ２ -Ph and -NH-2,(3,4,5 or 6)Bu ２ -Ph, etc.); - substituted or unsubstituted cyclic amine or amide groups, such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl; - substituted or unsubstituted cyclic C ３ ~C ８ alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; -OH group or substituted or unsubstituted linear or branched C １ ~C ６ Alcohol group (-CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ ) CH ２ OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ ) CH ２ CH ２ OH, -CH(CH ３ )CH(CH ３ )OH, -CH(CH ２ CH ３ ) CH ２ OH, -C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ CH ２ OH and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ OH, etc.); - substituted or unsubstituted linear or branched C １ ~C ６ Carboxylic acid group (-COOH, -CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ CH ２ COOH and -CH ２ CH ２ CH ２ CH ２ CH ２ COOH, etc.); - a substituted or unsubstituted straight or branched carbonyl group (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH ２ Ph, -(CO)CH ２ OH, -(CO)CH ２ OCH ３ , -(CO)CH ２ N.H. ２ , -(CO)CH ２ NHMe, -(CO)CH ２ NMe ２ , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl, -(CO)NH ２ , -(CO)NHMe, -(CO)NMe ２ , -(CO)NHEt, -(CO)NET ２ , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH ２ CH ２ OH, -(CO)NHCH ２ CH ２ OMe, -(CO)NHCH ２ CH ２ N.H. ２ , -(CO)NHCH ２ CH ２ NHMe and -(CO)NHCH ２ CH ２ NMe ２ etc.); - substituted or unsubstituted linear or branched C １ ~C ６ Carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH ２ COOMe, -CH ２ CH ２ COOMe, -CH ２ CH ２ CH ２ COOMe and -CH ２ CH ２ CH ２ CH ２ COOMe etc.); - substituted or unsubstituted linear or branched C １ ~C ６ The amide group (—CO—NH ２ , -CO-NMeH, -CO-NMe ２ , -CO-NEtH, -CO-NEtMe, -CO-NEt ２ , —CO-NPrH, —CO-NPrMe, and —CO-NPrEt, etc.; - substituted or unsubstituted linear or branched C １ ~C ７ aminocarbonyl groups (such as -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); - substituted or unsubstituted linear or branched C １ ~C ７ Alkoxy or aryloxy groups (-OMe, -OEt, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH ２ F, -OCHF ２ , -OCF ３ , -OCH ２ Cl, -OCHCl ２ , -OCCl ３ , -O-Ph, -O-CH ２ -Ph, -O-CH ２ -(2, 3 or 4)-F-Ph, -O-CH ２ -(2,3 or 4)-Cl-Ph, -CH ２ OMe, -CH ２ OEt, -CH ２ OPr, -CH ２ OBu, -CH ２ CH ２ OMe, -CH ２ CH ２ CH ２ OMe, -CH ２ CH ２ CH ２ CH ２ OMe and -CH ２ CH ２ CH ２ CH ２ CH ２ OMe, etc.); - a substituted or unsubstituted straight or branched aminoalkoxy group (-OCH ２ N.H. ２ , -OCH ２ NHMe, -OCH ２ NMe ２ , -OCH ２ NHEt, -OCH ２ N.E.T. ２ , -OCH ２ CH ２ N.H. ２ , -OCH ２ CH ２ NHMe, -OCH ２ CH ２ NMe ２ , -OCH ２ CH ２ NHEt, and -OCH ２ CH ２ N.E.T. ２ etc.); -Substituted or unsubstituted sulfonyl group (-SO ２ Me, -SO ２ Et, -SO ２ Pr, -SO ２ iPr, -SO ２ Ph, -SO ２ -(2, 3 or 4)-F-Ph, -SO ２ -Cyclopropyl, -SO ２ CH ２ CH ２ OCH ３ , -SO ２ N.H. ２ , -SO ２ NHMe, -SO ２ NMe ２ , -SO ２ NHEt, -SO ２ N.E.T. ２ , -SO ２ -pyrrolidine-N-yl, -SO ２ -morpholin-N-yl, -SO ２ N.H.C.H. ２ OMe and -SO ２ N.H.C.H. ２ CH ２ OMe, etc.); -Substituted or unsubstituted aminosulfonyl group (-NHSO ２ Me, -NHSO ２ Et, -NHSO ２ Pr, -NHSO ２ iPr, -NHSO ２ Ph, -NHSO ２ -(2,3 or 4)-F-Ph, -NHSO ２ -cyclopropyl and -NHSO ２ CH ２ CH ２ OCH ３ etc.); - 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)-F ２ -Ph-, 2,(3,4,5 or 6)-Cl ２ -Ph-, 2,(3,4,5 or 6)-Br ２ -Ph-, 2,(3,4,5 or 6)-I ２ -Ph-, 2,(3,4,5 or 6)-Me ２ -Ph-, 2,(3,4,5 or 6)-Et ２ -Ph-, 2,(3,4,5 or 6)-Pr ２ -Ph-, 2,(3,4,5 or 6)-Bu ２ -Ph-, 2,(3,4,5 or 6)-(CN) ２ -Ph-, 2, (3, 4, 5 or 6)-(NO ２ ) ２ -Ph-, 2,(3,4,5 or 6)-(NH ２ ) ２ -Ph-, 2,(3,4,5 or 6)-(MeO) ２ -Ph-, 2,(3,4,5 or 6)-(CF ３ ) ２ -Ph-, 3, (4 or 5)-F ２ -Ph-, 3,(4 or 5)-Cl ２ -Ph-, 3,(4 or 5)-Br ２ -Ph-, 3, (4 or 5)-I ２ -Ph-, 3,(4 or 5)-Me ２ -Ph-, 3,(4 or 5)-Et ２ -Ph-, 3,(4 or 5)-Pr ２ -Ph-, 3,(4 or 5)-Bu ２ -Ph-, 3, (4 or 5)-(CN) ２ -Ph-, 3, (4 or 5)-(NO ２ ) ２ -Ph-, 3,(4 or 5)-(NH ２ ) ２ -Ph-, 3,(4 or 5)-(MeO) ２ -Ph-, 3,(4 or 5)-(CF ３ ) ２ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO ２ )-Ph-, 3-(NO ２ )-Ph-, 4-(NO ２ )-Ph-, 2-(NH ２ )-Ph-, 3-(NH ２ )-Ph-, 4-(NH ２ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH ２ -CO)-Ph-, 3-(NH ２ -CO)-Ph-, 4-(NH ２ -CO)-Ph-, 2-CF ３ -Ph-, 3-CF ３ -Ph-, 4-CF ３ -Ph-, 2-CF ３ O-Ph-, 3-CF ３ O-Ph-, and 4-CF ３ O-Ph-, etc.); - saturated or unsaturated, substituted or unsubstituted heterocyclic groups, including aromatic and / or non-aromatic heterocyclic groups (pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4 ... Triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-1-yl, 2-azapiperidin-3-yl, 2-azapiperidin-4-yl, Azapiperidin-4-yl, 3-azapiperidin-1-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-1-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran- zapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl,3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-2-yl, 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, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, and tetrazol-1-yl, tetrazol-2-yl, and tetrazol-5-yl, etc.; where, when there are two R groups attached to the same atom, they may together form a group that is double-bonded to said atom (e.g., a carbonyl group (=O) or an alkene group (=C(R') ２ ) (wherein each R′ group is the same or different and is H or an organic group, preferably H or a linear or branched C １ ~C ６ ) and the like); Also, where a pair of R ４１ The groups may be taken together to form a ring with the atoms of ring A and / or a pair of R ４２ The groups may be taken together to form a ring with the atoms of ring B, optionally where the pair of R ４１ group and / or the pair of R ４２ Each of the groups is independently ７ ) １又は２ where each X ７ may be the same or different and are independently selected from C, N, O, and S; ７ is independently unsubstituted, or ７ is C, H or C １ ~C ６ or an alkyl group of C １ ~C ６ (ii) X is independently substituted with an organic group selected from a halogenated alkyl group of the formula: ７ When is N, H or C １ ~C ６ Alkyl groups of C １ ~C ６ or a halogenated alkyl group of C １ ~C ６ and - where R ５ and R ４４ The groups taken together represent the X of the ring C to which they are attached. ６ and X ３ Together with the atoms, optionally, a ring may be formed, where R ５ and R ４４ The groups together form (X ８ ) ３、４又は５ where each X ８ may be the same or different and are independently selected from C, N, O, and S; ８ is independently unsubstituted, or ８ is C, H or C １ ~C ６ Alkyl groups of C １ ~C ６ (ii) X is independently substituted with an organic group selected from a halogenated alkyl group of the formula: ８ is N, H or C １ ~C ６ Alkyl groups of C １ ~C ６ or a halogenated alkyl group of C １ ~C ６ and the amide groups are independently substituted with organic groups selected from the group consisting of

4. R ４１ , R ４２ , R ４３ and R ４４ are each independently H, deuterium, a halogen (such as -F, -Cl, -Br, and -I, preferably F or Cl), a nitrile group, a substituted or unsubstituted C １ ~C ６ substituted or unsubstituted linear or branched C １ ~C ６ A halogenated alkyl group (preferably CF ３ or CHF ２ ), a cyclopropyl group, an —OH group or a substituted or unsubstituted linear or branched C １ ~C ６ an alcohol group of substituted or unsubstituted straight or branched C １ ~C ７ Aminocarbonyl groups (such as --NH-CO-Me), --NH ２ Group or substituted or unsubstituted C １ ~C ６ and a substituted or unsubstituted C １ ~C ６ an alkoxy group selected from the group consisting of A pair of Rs bonded to different atoms ４１ When the R groups are taken together to form a ring with an atom of ring A, and / or when a pair of R ４２ When the R groups are taken together to form a ring with the atoms of ring B, the pair of R ４１ group, and / or the pair of R ４２ Each of the groups is independently -CH ２ -or-CH ２ CH ２ - comprising; and R ５ and R ４４ When the groups taken together form a ring with the atoms of Ring C, R ５ and R ４４ together form -CH=CH-CH=CH- or -NH-CO-NH- The compound according to claim 3.

5. R ４５ is H, halogen (such as -F, -Cl, -Br and -I, preferably -F), substituted or unsubstituted C １ ~C ６ substituted or unsubstituted linear or branched C １ ~C ６ A halogenated alkyl group (preferably CF ３ ), -NH ２ Group or substituted or unsubstituted C １ ~C ６ an amino group, an —OH group, or a substituted or unsubstituted linear or branched C １ ~C ６ and a substituted or unsubstituted C １ ~C ６ alkoxy groups selected from the group consisting of 5. A compound according to claim 3 or 4.

6. R ４６ A compound according to any of the preceding claims, wherein is selected from H and a group selected from the following groups: - substituted or unsubstituted linear or branched C １ ~C ６ alkyl groups (such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and hexyl groups); - substituted or unsubstituted linear or branched C １ ~C ６ Alkyl-aryl groups (-CH ２ Ph, -CH ２ -(2,3 or 4)F-Ph, -CH ２ -(2,3 or 4)Cl-Ph, -CH ２ -(2,3 or 4)Br-Ph, -CH ２ -(2, 3 or 4)I-Ph, -CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ CH ２ Ph and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ Ph, etc.); - substituted or unsubstituted linear or branched C １ ~C ６ A halogenated alkyl group (-CH ２ F, -CF ３ , -CH ２ CH ２ F and -CH ２ CF ３ etc.); - substituted or unsubstituted cyclic amine or amide groups, such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl; - substituted or unsubstituted C ３ ~C ８ cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; - substituted or unsubstituted linear or branched C ２ ~C ６ Alcohol group (-CH ２ CH ２ OH, -CH(CH ３ ) CH ２ OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ ) CH ２ CH ２ OH, -CH(CH ３ )CH(CH ３ )OH, -CH(CH ２ CH ３ ) CH ２ OH, -C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ CH ２ OH and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ OH, etc.); - substituted or unsubstituted linear or branched C ２ ~C ６ Carboxylic acid group (-CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ CH ２ COOH and -CH ２ CH ２ CH ２ CH ２ CH ２ COOH, etc.); - a substituted or unsubstituted straight or branched carbonyl group (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH ２ Ph, -(CO)CH ２ OH, -(CO)CH ２ OCH ３ , -(CO)CH ２ N.H. ２ , -(CO)CH ２ NHMe, -(CO)CH ２ NMe ２ , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl, -(CO)NH ２ , -(CO)NHMe, -(CO)NMe ２ , -(CO)NHEt, -(CO)NET ２ , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH ２ CH ２ OH, -(CO)NHCH ２ CH ２ OMe, -(CO)NHCH ２ CH ２ N.H. ２ , -(CO)NHCH ２ CH ２ NHMe and -(CO)NHCH ２ CH ２ NMe ２ etc.); - substituted or unsubstituted linear or branched C １ ~C ６ Carboxylic acid ester groups (-COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH ２ COOMe, -CH ２ CH ２ COOMe, -CH ２ CH ２ CH ２ COOMe and -CH ２ CH ２ CH ２ CH ２ COOMe etc.); - substituted or unsubstituted linear or branched C １ ~C ６ The amide group (—CO—NH ２ , -CO-NMeH, -CO-NMe ２ , -CO-NEtH, -CO-NEtMe, -CO-NEt ２ , —CO-NPrH, —CO-NPrMe, and —CO-NPrEt, etc.; -Substituted or unsubstituted sulfonyl group (-SO ２ Me, -SO ２ Et, -SO ２ Pr, -SO ２ iPr, -SO ２ Ph, -SO ２ -(2, 3 or 4)-F-Ph, -SO ２ -Cyclopropyl, -SO ２ CH ２ CH ２ OCH ３ , -SO ２ N.H. ２ , -SO ２ NHMe, -SO ２ NMe ２ , -SO ２ NHEt, -SO ２ N.E.T. ２ , -SO ２ -pyrrolidine-N-yl, -SO ２ -morpholin-N-yl, -SO ２ N.H.C.H. ２ OMe and -SO ２ N.H.C.H. ２ CH ２ OMe, 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)-F ２ -Ph-, 2,(3,4,5 or 6)-Cl ２ -Ph-, 2,(3,4,5 or 6)-Br ２ -Ph-, 2,(3,4,5 or 6)-I ２ -Ph-, 2,(3,4,5 or 6)-Me ２ -Ph-, 2,(3,4,5 or 6)-Et ２ -Ph-, 2,(3,4,5 or 6)-Pr ２ -Ph-, 2,(3,4,5 or 6)-Bu ２ -Ph-, 2,(3,4,5 or 6)-(CN) ２ -Ph-, 2, (3, 4, 5 or 6)-(NO ２ ) ２ -Ph-, 2,(3,4,5 or 6)-(NH ２ ) ２ -Ph-, 2,(3,4,5 or 6)-(MeO) ２ -Ph-, 2,(3,4,5 or 6)-(CF ３ ) ２ -Ph-, 3, (4 or 5)-F ２ -Ph-, 3,(4 or 5)-Cl ２ -Ph-, 3,(4 or 5)-Br ２ -Ph-, 3, (4 or 5)-I ２ -Ph-, 3,(4 or 5)-Me ２ -Ph-, 3,(4 or 5)-Et ２ -Ph-, 3,(4 or 5)-Pr ２ -Ph-, 3,(4 or 5)-Bu ２ -Ph-, 3, (4 or 5)-(CN) ２ -Ph-, 3, (4 or 5)-(NO ２ ) ２ -Ph-, 3,(4 or 5)-(NH ２ ) ２ -Ph-, 3,(4 or 5)-(MeO) ２ -Ph-, 3,(4 or 5)-(CF ３ ) ２ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO ２ )-Ph-, 3-(NO ２ )-Ph-, 4-(NO ２ )-Ph-, 2-(NH ２ )-Ph-, 3-(NH ２ )-Ph-, 4-(NH ２ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH ２ -CO)-Ph-, 3-(NH ２ -CO)-Ph-, 4-(NH ２ -CO)-Ph-, 2-CF ３ -Ph-, 3-CF ３ -Ph-, 4-CF ３ -Ph-, 2-CF ３ O-Ph-, 3-CF ３ O-Ph- and 4-CF ３ O-Ph- etc.); and, - substituted or unsubstituted, saturated or unsaturated, substituted or unsubstituted heterocyclic groups, including aromatic and / or non-aromatic heterocyclic groups (pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-5-yl, pyridin-6-yl, pyridin-6-yl, pyridin-5 ... 3-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-6-yl, pyrazin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-3-yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3 -yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-4-yl, hydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetan-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl,3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6 -yl, 4-azathiopyran-2-yl, 4-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, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, and tetrazol-5-yl, etc.

7. R ４６ is H, substituted or unsubstituted C １ ~C ６ or a substituted or unsubstituted linear or branched C １ ~C ６ wherein the halogenated alkyl group is selected from the halogenated alkyl groups The compound according to claim 6.

8. Ring A of the L group has the following structure: 【Chemistry 7】 (In the formula, R ４１ is as defined in any of the preceding claims.

9. Ring A of the L group has the following structure: 【Chemistry 8】 9. The compound of claim 8, comprising any one of:

10. Ring C of the L group has the following structure: 【Chemistry 9-1】 【Chemistry 9-2】 (In the formula, R ５ , R ４３ , R ４４ and R ４６ is as defined in any of the preceding claims.

11. Ring C of the L group has the following structure: 【Chemistry 10】 (In the formula, R ５ and R ４３ is as defined in claim 10).

12. The R ５ 2. A compound according to any preceding claim, wherein is a substituted or unsubstituted organic group.

13. The R ５ The group is H, —F, —Cl, —Br, —I, —CN, or —CONR ５１ R ５１ , -NR ５１ C.O.R. ５２ , -SO ２ N.R. ５１ R ５１ , -NR ５１ SO ２ R ５３ , -O-CR ５２ R ５２ R ５２ , -CR ５２ R ５２ N.R. ５１ R ５１ and the following structure: 【Chemistry 11】 (In the formula, R ５１ , R ５２ and R ５３ wherein each of the groups may be the same or different and is independently selected from H and a substituted or unsubstituted organic group.

14. Said R ５ group 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: 【Chemistry 12】 14. The compound of claim 13, selected from:

15. Q ２ exists, Each Q １ is independently absent or has the structure: 【Chemistry 13】 (In the formula, Each R ４５ may be the same or different and are independently selected from H and substituted or unsubstituted organic groups; R ４６ is a group independently selected from H and a substituted or unsubstituted organic group.

16. Q of the L group ２ group is present, and X ５ The compound of claim 15 , wherein is N.

17. Q of the L group ２ has the following structure: 【Chemistry 14】 (In the formula, R ４２ is as defined in any of the preceding claims.

18. Q of the L group ２ has the following structure: 【Chemistry 15】 18. The compound of claim 17, comprising any one of:

19. The L group has the following structure: 【Chemistry 16】 (In the formula, Q １ is absent or a group as defined in claim 3; Q ３ is absent or a group as defined in claim 2; 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 in any preceding claim.

20. The L group has the following structure: 【Chemistry 17】 (In the formula, n, m, p, q, r, s, X １ , X ２ , X ３ , X ５ , R ４１ , R ４２ , R ４３ , R ４４ , R ５ , Q １ , Q ３ and rings A, B and C are as defined in claim 19.

21. The L group has the following structure: 【Chemistry 18】 (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 and rings A, B and C are as defined in claim 20.

22. The L group has the following structure: 【Chemistry 19】 (In the formula, n, m, p, q, r, s, X ３ , X ５ , R ４１ , R ４２ , R ４３ , R ４４ , R ５ and rings A, B and C are as defined in claim 21.

23. The L group has the following structure: 【Chemistry 20】 (In the formula, n, m, p, q, r, s, X ３ , X ５ , R ４１ , R ４２ , R ４３ , R ４４ , R ５ and Ring C is as defined in claim 22.

24. The L group has the following structure: 【Chemistry 21】 (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 and Ring C is as defined in claim 19.

25. The L group has the following structure: 【Chemistry 22-1】 【Chemistry 22-2】 (In the formula, n, m, p, q, X ３ , R ４１ , R ４２ , R ４３ , R ４４ and R ５ The compound according to claim 24, comprising a group selected from:

26. m is selected from 1 or 2; n is selected from 2 or 3; p is selected from 1, 2 or 3; q is selected from 1 or 2; 26. A compound according to any one of claims 15 to 25.

27. The L group has the following structure: 【Chemistry 23-1】 【Chemistry 23-2】 (In the formula, R ４１ , R ４２ , R ４３ , R ４４ and R ５ 27. The compound according to claim 25 or 26, comprising a group having any of the following formulas:

28. Q of the L group ２ There is no group, Q １ There is only one group, and said Q １ 15. A compound according to any one of claims 1 to 14, wherein the group separates ring A from ring C in the linear direction by 3 or 4 atoms.

29. Q １ The group has the structure: 【Chemistry 24】 (In the formula, R ４５ and R ４６ is as defined in any of the preceding claims.

30. Q １ The group has the structure: 【Chemistry 25】 30. The compound of claim 29, comprising any one of:

31. The L group has the following structure: 【Chemistry 26-1】 【Chemistry 26-2】 【Chemistry 26-3】 【Chemistry 26-4】 【Chemistry 26-5】 【Chemistry 26-6】 【Chemistry 26-7】 【Chemistry 26-8】 【Chemistry 26-9】 【Chemistry 26-10】 The compound according to any one of claims 1 to 11 and 13 to 14, comprising a group having any one of the following formulas:

32. The structure: 【Chemistry 27】 (In the formula, The dotted line indicates that Ring D may contain single bonds or a combination of both single and double bonds and may be aliphatic or aromatic; each X ４ may be the same or different and are independently selected from C, N, O and S; Each R １１ 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 is as defined in any of the preceding claims.

33. The structure: 【Chemistry 28】 (Wherein, the rings D and X ４ , R １１ , R ３ , R ６ and L are as defined in claim 32, preferably with at least one X ４ is C).

34. The structure: 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 (In the formula, R １４ may or may not be present, and R １４ If H, C １ ~C ３ or an alkyl group of C １ ~C ３ is selected from the fluoroalkyl groups R １１ , ring D, R ３ , R ６ and L is as defined in claim 33.

34. The compound of claim 33, comprising any one of:

35. The structure: 【Chemistry 30-1】 【Chemistry 30-2】 【Chemistry 30-3】 【Chemistry 30-4】 【Chemistry 30-5】 (In the formula, R ３ , R １１ , R １４ , R ６ and L is as defined in claim 34.

36. Each R １１ is H, halogen, a nitrile group, a linear or branched C １ ~C ３ Alkyl groups of the formula (I) １ ~C ３ a halogenated alkyl group (preferably a fluoroalkyl group), an —OH group, a linear or branched C １ ~C ３ alcohol group, halogenated (preferably fluorinated) linear or branched C １ ~C ３ an alcohol group of -NH ２ , linear or branched primary, secondary or tertiary C １ ~C ３ A linear or branched amine group of １ ~C ３ Alkoxy group, linear or branched C １ ~C ３ a halogenated alkoxy group (preferably a fluoroalkoxy group), and / or a pair of R １１ groups; and a pair of R １１ When the R groups are taken together to form a ring with the atoms of ring D, the pair of R １１ The group is -CH ２ CH ２ CH ２ The compound according to any one of claims 32 to 35, comprising:

37. Each R １１ H, Cl, F, CHF ２ , C.F. ３ , C.H. ３ , O.H., C.H. ３ O and NH ２ and / or a pair of R bonded to the same atom forming =O １１ are independently selected from the group Independently, a pair of R １１ When the R groups are taken together to form a ring with the atoms of ring D, the pair of R １１ The group is -CH ２ CH ２ CH ２ The compound of claim 36, comprising:

38. The structure: 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 【Chemistry 31-5】 【Chemistry 31-6】 【Chemistry 31-7】 【Chemistry 31-8】 【Chemistry 31-9】 38. The compound of claim 37, comprising any one of:

39. The structure: 【Chemistry 32】 (In the formula, Each R １２ is H and a substituted or unsubstituted organic group, preferably a lower (C １ ~C ６ ) an alkyl, alkoxy or haloalkyl group, substituted or unsubstituted C ３ ~C ６ and a halogen group; １２ is not H; Each R １３ may be the same or different and are independently selected from H and substituted or unsubstituted organic groups; R ３ , R ６ and L is as defined in any of the preceding claims.

40. At least one R １２ But -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -F, -Cl, -CH ２ CF ３ , -CH ２ CH ２ F, -CH ２ CH ２ 40. The compound of claim 39, wherein the aryl group is selected from OH, a methoxy group, a methoxymethyl group, a methoxyethyl group, an isopropyl group, a cyclopropyl group, or a cyclopropylmethyl group.

41. R １３ But H, F, C １ ~C ３ or an alkyl group of １ ~C ３ 41. The compound according to claim 39 or 40, wherein the fluoroalkyl group is selected from the group consisting of:

42. The structure: 【Chemistry 33-1】 【Chemistry 33-2】 42. The compound of any one of claims 39 to 41, comprising any one of:

43. R ３ 42. The compound of any one of claims 32-37 or 39-41, wherein is H.

44. R ６ H, halogen, C １ ~C ３ Alkyl groups of C １ ~C ３ haloalkyl group of C １ ~C ３ or an alcohol group of C １ ~C ３ 42. The compound of any one of claims 32 to 37 or 39 to 41, wherein the aminoalkyl group is selected from the group consisting of:

45. 2. A compound for use in medicine according to any preceding claim, having a chemical formula selected from any one of the following: 【Chemistry 34-1】 【Chemistry 34-2】 【Chemistry 34-3】 【Chemistry 34-4】 【Chemistry 34-5】 【Chemistry 34-6】 【Chemistry 34-7】 【Chemistry 34-8】 【Chemistry 34-9】 【Chemistry 34-10】 【Chemistry 34-11】 【Chemistry 34-12】 【Chemistry 34-13】 【Chemistry 34-14】 【Chemistry 34-15】 【Chemistry 34-16】 【Chemistry 34-17】 【Chemistry 34-18】 【Chemistry 34-19】 【Chemistry 34-20】 【Chemistry 34-21】 【Chemistry 34-22】 【Chemistry 34-23】 【Chemistry 34-24】 【Chemistry 34-25】 【Chemistry 34-26】 【Chemistry 34-27】 【Chemistry 34-28】 【Chemistry 34-29】 【Chemistry 34-30】 【Chemistry 34-31】 【Chemistry 34-32】 【Chemistry 34-33】 【Chemistry 34-34】 【Chemistry 34-35】 【Chemistry 34-36】 【Chemistry 34-37】 【Chemistry 34-38】 【Chemistry 34-39】 【Chemistry 34-40】 【Chemistry 34-41】 【Chemistry 34-42】 【Chemistry 34-43】 【Chemistry 34-44】 【Chemistry 34-45】 【Chemistry 34-46】 【Chemistry 34-47】 【Chemistry 34-48】 【Chemistry 34-49】 【Chemistry 34-50】 【Chemistry 34-51】 【Chemistry 34-52】 【Chemistry 34-53】 【Chemistry 34-54】 【Chemistry 34-55】

46. The compound - isolated enantiomers, or a mixture of two or more enantiomers, or a mixture of two or more diastereomers and / or epimers, or a racemic mixture, or - tautomers of said compounds 2. A compound for use in medicine according to any of the preceding claims, comprising:

47. 2. A compound according to any of the preceding claims, which exhibits selectivity for PARP1 over PARP2.

48. 13. A compound according to any preceding claim for use in treating cancer.

49. 49. The compound of claim 48, wherein the cancer is a cancer selected from: Solid or liquid tumors, including cancer of the eye, brain (including glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma), 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, bronchus, 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, hemangiomatosis, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, and PTEN hamartoma syndrome. (PHTS) (such as 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 prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma), nasopharyngeal carcinoma and gastrointestinal cancer.

50. 50. The compound of claim 48 or 49, wherein the cancer is deficient in a DNA damage repair pathway, such as homologous recombination dependent DNA double strand break DNA repair activity.

51. 51. A compound according to any one of claims 48 to 50, wherein the cancer is deficient in BRCA1 and / or BRCA2 function.

52. 48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47.

53. 53. The pharmaceutical composition of claim 52, further comprising a pharma- ceutically acceptable additive and / or excipient, and / or wherein the compound is in the form of a pharma- ceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

54. 54. A pharmaceutical composition according to claim 52 or 53 for treating a cancer according to any one of claims 48 to 51.

55. Further, the method further comprises providing a further agent for treating cancer; Preferably, said further agent for treating cancer is selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody drug conjugates, immunotherapeutic agents, hormone ablation therapy, apoptosis inducers and cell cycle signaling inhibitors.

55. A pharmaceutical composition for treating cancer according to claim 54.

56. the further agent is an immunotherapeutic agent selected from anti-tumor 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, 56. A pharmaceutical composition for treating cancer according to claim 55.

57. A pharmaceutical kit for treating cancer, comprising: (a) a compound as defined in any one of claims 1 to 47; and (b) an additional agent for treating cancer; and preferably said further agent for treating cancer is selected from the group consisting of microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody drug conjugates, hormone ablation therapy, immunotherapeutic agents (anti-tumor vaccines; oncolytic viruses; anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX immunostimulatory antibodies such as anti-CD40, 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; selected from chimeric antigen receptor T cell therapy (CAR-T cell therapy), small molecule immunomodulators, tumor microenvironment modifiers and anti-angiogenic agents), apoptosis inducers and cell cycle signaling inhibitors; The compound and the further agent are suitable for simultaneous, sequential or separate administration. kit.

58. 13. A method of treating a disease and / or condition and / or disorder comprising administering to a patient a compound or composition or kit according to any preceding claim.

59. 59. The method of claim 58, wherein the disease, condition, or disorder is a disease, condition, or disorder according to any one of claims 48 to 51.

60. 60. The method of claim 59 for treating cancer, comprising: Administering to a patient a compound or composition according to any one of claims 1 to 50 and a further agent for treating cancer according to claim 55 or claim 56, Preferably, the compound or composition and the further agent are administered simultaneously, sequentially or separately. method.

61. 61. The method of any of claims 58 to 60, wherein the patient is an animal, preferably a mammal, including dogs, horses and cats, more preferably a human.

62. 46. ​​A compound selected from any of the compounds defined in claim 45.

63. The compound - isolated enantiomers, or a mixture of two or more enantiomers, or a mixture of two or more diastereomers and / or epimers, or a racemic mixture, or - Tautomer 63. The compound of claim 62 comprising:

64. 50. A method of synthesizing a PARP1 inhibitor compound according to any one of claims 1 to 47, comprising the steps of: reacting between (i) a first reactant comprising a ring E having a portion of a substituent L, and (ii) a second reactant comprising a remaining portion of the substituent L, to form the PARP1 inhibitor compound; method.

65. the first reactant comprises a ring E and a ring A; the second reactant comprises a precursor of Q1 or Q2 having a reactive group; The method comprises binding a N atom of Ring A to a precursor of Q1 or Q2.

65. The method of claim 64.

66. 66. The method of claim 65, wherein the reactive group of the precursor of Q1 or Q2 comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.

67. 67. The method of any of claims 64 to 66, wherein the reaction comprises alkylation, reductive amination, or amide formation to form an L group.

68. The first reactant is Ring E, Ring A, and At least one of Q1 and Q2 Equipped with The second reactant is a derivative of Ring C having a leaving group such as a halide or sulfonate; 65. The method of claim 64.

69. 69. The method of claim 68, wherein the reaction comprises a nucleophilic substitution reaction, such as an aromatic nucleophilic substitution reaction, to form an L group.

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