Pharmaceutical Compounds

Abstract

Formula I below: [Formula 1] TIFF2024514539000484.tif72153 (in the formula, X 1 are each independently the same or different and are selected from C, N, O and S; Each Y is independently the same or different and is C or N; Z 1 are independently C or N; X 1 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; each Y is independently unsubstituted or substituted with H or a substituted or unsubstituted organic group; m may be 1, 2, 3 or 4; n may be 1, 2, or 3; the bonds between all atoms of ring A may independently be single or double bonds; The bonds between all atoms of Ring B may independently be single or double bonds, and R 1 is connected to Z by a single bond or a double bond. 1 (may be combined with It is a compound comprising:

Description

[Technical Field]

[0001] The present invention relates to PARP7 inhibitor compounds, particularly for use in medicine. The inhibitors of the present invention can be used in pharmaceutical compositions, particularly for treating cancer, infectious diseases, central nervous system diseases or disorders, pain conditions, and other diseases, conditions, and disorders. The present invention also relates to methods of making the inhibitors and methods of treatment using the inhibitors. [Background technology]

[0002] Monoclonal antibody-based therapies targeting immune checkpoints, particularly the PDL1-PD1 axis, are transforming approaches to cancer treatment. These agents have been demonstrated to induce complete and durable regression of metastatic disease, particularly in the setting of malignant melanoma. PDL1, expressed by tumor (and other) cells, transmits inhibitory signals through ligation of PD1 on T cells. Blockade of this interaction with antibodies targeting PD1 or PDL1 results in T cell reactivation, recognition of tumor cell neoantigens, and CD8+ T cell-mediated tumor cell killing (Non-Patent Document 1). Despite this progress, tumor responses are observed in only a minority of cancer patients. Furthermore, the responses of many responding patients are not sustained. There is an urgent need to identify and develop complementary therapies that will expand the population that benefits from immunomodulatory therapies.

[0003] Immune checkpoint inhibitors (ICIs), such as anti-PD1 and anti-PDL1, work by alleviating checkpoint restrictions on antitumor T cell responses. They work best against immunogenic, T cell-inflamed, or hyperthermic tumors. In contrast, ICIs are less effective in the hypothermic tumor microenvironment (TME), where T cells are scarce and immunosuppressive cells are infiltrated. In the hyperthermic TME, increased expression of T cell-attracting chemokines, such as type I interferon (IFN-I) and IFN-stimulated genes (ISGs), contributes to potent antitumor responses. One novel therapeutic strategy to convert hypothermic tumors to hyperthermic tumors utilizes pattern recognition receptor (PRR) agonists. Indeed, the combination of ICIs with agonists of RIG-I helicase, Toll-like receptor 9 (TLR9), or stimulator of interferon genes (STING) is currently undergoing clinical evaluation.

[0004] The innate immune system provides the first line of host defense and plays a critical role in initiating and promoting adaptive immune responses. The cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS) is activated by double-stranded DNA derived from the genomes of invading pathogens and by abnormal cytoplasmic levels of host DNA generated in tumor cells (Non-Patent Document 2). Activation of cGAS leads to the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which induces 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), promoting the production of type I interferons and supporting the generation of immunity (Non-Patent Document 3). Thus, activation of the STING pathway has attracted increasing interest from the cancer drug discovery community as a potential strategy to promote the development of adaptive immune responses against tumor cell neoantigens (Non-Patent Document 4). Cytoplasmic DNA sensing has also been associated with the inactivation of cell proliferation, providing an additional mechanistic axis that may contribute to the control of tumorigenesis (Non-Patent Document 5).

[0005] Cancer cells can exhibit a chronic interferon-stimulated gene (ISG) signature induced by STING-dependent pathways, resulting in a unique primed cancer cell state that is sensitized to respond to abnormal nucleic acid accumulation (Non-Patent Document 6). Genomic instability in the form of unrepaired DNA double-strand breaks or micronucleus disruption has recently been shown to induce STING-dependent antitumor responses. For example, chemotherapy increases the level of abnormal DNA in the cytoplasm, which then induces cancer cell-specific STING signaling and leads to antitumor immunity. Indeed, the efficacy of the commonly used chemotherapy drug 5-fluorouracil (5-FU) has recently been shown to depend on antitumor immunity induced by the activation of cancer cell-specific STING (Non-Patent Document 7). Furthermore, PARP inhibitor-induced STING pathway activation and antitumor immune responses have been demonstrated in multiple tumor models, providing a rationale for combining immunotherapy with PARP inhibitors to improve therapeutic efficacy. For example, the PARP inhibitor olaparib has recently been shown to induce synthetic lethal effects in DNA damage repair-deficient cancer cells and BRCA-deficient breast cancer models when combined with a synthetic cyclic dinucleotide STING agonist (Non-Patent Document 8). The authors hypothesize that STING agonists could enhance the therapeutic efficacy of PARP inhibitors in BRCA-associated triple-negative breast cancer (TNBC). Overall, modulation of nucleic acid sensing pathways through multiple mechanisms has been shown to promote antitumor effects in various cell and animal models, demonstrating therapeutic potential for enhancing immunotherapy efficacy and overcoming resistance to immune checkpoint inhibition.

[0006] Poly-ADP-ribose polymerase 7 (PARP7, TIPARP, ARTD14), a member of the broader PARP enzyme family, regulates protein function by using nicotinamide adenine dinucleotide (NAD) as a substrate to transfer ADP-ribose monomers to specific amino acid acceptor residues in target proteins (Non-Patent Document 9). PARP7 catalyzes the mono-ADP-ribosylation (MARylation) of its target substrate and is thus a member of the mono(ADP-ribosyl)transferase (MART) enzymes, a subclass of the PARP enzyme family (Non-Patent Document 10). PARP7 is a target gene of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and is a member of the basic helix-loop-helix / Per-AHR nuclear translocator (ARNT)-Sim (PAS) protein family, which plays a central role in regulating immune responses. Thus, PARP7 has emerged as a key regulator of innate immune responses. The PARP7 gene is amplified in many cancers, particularly those of the upper aerodigestive tract (Non-Patent Document 11). It has been reported that PARP7 is ADP-ribosylated, inactivating the kinase domain of TBK1 and suppressing the central pathway for interferon production (Non-Patent Document 12). The potential use of PARP7 inhibitors in cancer treatment, particularly lung squamous cell carcinoma, is described in Patent Document 1. The discovery of RBN-2397, a potent and selective inhibitor of PARP7, was recently reported (Non-Patent Documents 11, 13, and 14). RBN-2397 potently inhibited the growth of cancer cell lines with high baseline expression of interferon-stimulated genes, restored type I interferon responses both in vitro and in vivo, and led to tumor regression and the establishment of specific antitumor immunity in animal models. Patent Document 2 reports pyridazinone compounds as PARP7 inhibitors for cancer treatment. The monocyclic pyridazinone ring has been reported as an essential feature for interaction with PARP7 targets. This observation provides a rational basis for generating novel agents that inhibit PARP7 and induce therapeutic anti-tumor responses. There is also a growing body of literature establishing and highlighting the important role of PARP7 in other diseases.

[0007] infectious disease PARP13, an inactive PARP family member that plays a key role in regulating antiviral innate immune responses, is a major substrate of PARP7 (Non-Patent Document 15). PARP13 is preferentially MARYlated on cysteine ​​residues in its RNA-binding zinc finger domain. PARP13 stimulates interferon responses in response to influenza A virus infection through direct activation of the cytosolic nucleic acid sensor RNA helicase RIG-I. This interaction is dependent on the finger domain of PARP13. Therefore, CysMARYlation of PARP13 by PARP7 potentially disrupts the interaction between PARP13 and RIG-I, modulating its antiviral and immunoregulatory roles.

[0008] Furthermore, PARP7 promotes influenza A virus infection by ADP-ribosylating TBK1, which inhibits type I IFN (IFN-I) production (Non-Patent Document 12). The same study found that constitutive AHR signaling negatively regulates type I interferon (IFN-I) responses during various types of virus infection. Therefore, the physiological importance of endogenous activation of AHR signaling in shaping IFN-I-mediated innate responses was revealed, and furthermore, the AHR-PARP7 axis is suggested to be a potential therapeutic target for controlling antiviral responses.

[0009] More recently (Non-Patent Document 16), SARS-CoV-2 infection was shown to significantly upregulate MARylating PARPs, including PARP7. It induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. Furthermore, infection with the coronavirus (CoV), mouse hepatitis virus (MHV), stimulates upregulation of the downstream effector PARP7 via activation of AhR. Knockdown of PARP7 reduced viral replication and increased interferon expression, suggesting that PARP7 functions in a proviral manner during MHV infection (Non-Patent Document 17). AhR is also overexpressed after infection with coronaviruses, including SARS-CoV-2, and regulates PARP gene expression, suggesting that the latter is likely activated in COVID-19 (Non-Patent Document 18). Therefore, given its important role in the innate immune system, PARP7 inhibition could be used to improve patient outcomes with a wide variety of infectious diseases, including those induced by viral infections.

[0010] Central nervous system disorders PARP7 affects the proliferation and migration of neural progenitor cells, and its loss leads to abnormal organization of the developing mouse cortex (Non-Patent Document 19). PARP7 is highly expressed in the brain, and increased expression has been reported in various neurological disorders. PARP7 has been identified as a highly upregulated protein after trace fear conditioning and in neurological disorders such as epilepsy (Non-Patent Document 20). In an integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, PARP7 was shown to be strongly upregulated (Non-Patent Document 21). The phenotype and expression pattern of PARP7- / - mice suggest that alterations in PARP7 expression or function may increase susceptibility to a wide range of both developmental and degenerative neurological disorders, and that inhibitors may have beneficial effects in these conditions.

[0011] pain Recently, it has been reported that STING is a key regulator of pain through the induction of type I interferon production in sensory neurons and subsequent activation of type I interferon receptors (Non-Patent Document 22). STING-deficient mice exhibit hypersensitivity to pain stimuli, whereas STING activation induces significant anti-pain responses in mice and non-human primates. PARP7 is a negative regulator of the STING pathway, and PARP7 inhibitors have been shown to activate this pathway. Such inhibitors are useful as anti-pain drugs and for the treatment of chronic pain conditions, including cancer-related pain and peripheral neuropathy.

[0012] Furthermore, the use of PARP7 inhibitors in canine cancer has therapeutic potential, especially since recent data show that intratumoral delivery of STING agonists resulted in clinical responses in canine glioblastoma (Non-Patent Document 23). [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2016 / 116602 [Patent Document 2] International Publication No. 2019 / 212937 [Non-patent literature]

[0014] [Non-Patent Document 1] Hashem O. et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. FrontPharmacol. 8: 561, (2017) [Non-patent document 2] Chen Q et al. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 17: 1142-9, (2016) [Non-patent document 3] ZhuY et al. STING: a master regulator in the cancer-immunity cycle. MolCancer 18: 152 (2019) [Non-patent document 4] Sivick KE et al. Magnitude ofTherapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumorImmunity. Cell Reports. 25: 3074, (2018) [Non-patent document 5] Paludan SR et al. DNA-stimulated cell death: implications for host defense, inflammatory diseases and cancer.Nat Rev Immunol. 19: 141-153, (2019) [Non-patent document 6] Liu H et al. Tumor-derived IFNtriggers chronic pathway agonism and sensitivity to ADAR loss. Nat Medicine.25: 95-102, 2019 [Non-Patent Document 7] Tian J et al. 5-Fluorouracil efficacyrequires anti-tumor immunity triggered by cancer-cell-intrinsic STING. EMBO J.40: e106065 (2021) [Non-patent document 8] Pantelidou C et al. STING agonismenhances anti-tumor immune responses and therapeutic efficacy of PARPinhibition in BRCA-associated breast cancer. bioRxiv (2021) [Non-Patent Document 9] Gomez A et al. Characterization ofTCDD-inducible poly-ADP-ribose polymerase (TIPARP / ARTD14) catalytic activity.Biochemical Journal. 475: 3827-3846, (2018) [Non-Patent Document 10] Challa L. et al. MARTs and MARylationin the Cytosol: Biological Functions, Mechanisms of Action, and TherapeuticPotential. Cells 10, 313 (2021) [Non-Patent Document 11] Vasbinder, MM et al. RBN-2397: AFirst-in-class PAPR7 inhibitor targeting a newly discovered cancer vulnerability in stress-signalling pathways. Cancer Res. 80: 16 suppl DDT02-01,(2020) [Non-Patent Document 12] Yamada T et al. Constitutive arylhydrocarbon receptor signaling constraints type I interferon-mediated antiviralinnate defense. Nature Immunol. 17: 687-694, (2016) [Non-Patent Document 13] Gozgit J et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition leads to tumor regression. Cancer Res. 80: 16 suppl 3405, (2020); [Non-Patent Document 14] Gozgit J et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell 39: 1-13, 2021 [Non-Patent Document 15] Rodriguez, K et al. Chemicalgenetics and proteome-wide site mapping reveal cysteine ​​MARylation by PARP-7 onimmune-relevant protein targets. Elife. 10:e60480, (2021) [Non-Patent Document 16] Heer C. et al. Coronavirus infectionand PARP expression dysregulate the NAD Metabolome: an actionable component ofinnate immunity. J Biol Chem. 195, 17986-17996 (2020) [Non-Patent Document 17] Grunewald ME et al. MurineCoronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression. J. Virology 94: e01743-19 (2020) [Non-Patent Document 18] Badawy A. Immunotherapy of COVID-19with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide.Bioscience Reports. 40: BSR20202856 (2020) [Non-Patent Document 19] Grimaldi G et al. Loss of TiparpResults in Aberrant Layering of the Cerebral Cortex. ENeuro 6(6) 0239-19.2019 [Non-Patent Document 20] Dachet et al. Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. Brain 138:356-370, (2015) [Non-Patent Document 21] Li et al. Integrated multi-cohorttranscriptional meta-analysis of neurodegenerative diseases. Acta NeuropatholCommun 2:93 (2014) [Non-Patent Document 22] Donnelly CR et al. STING controlsnociception via type I interferon signaling in sensory neurons. Nature. 591:275-280 (2021) [Non-Patent Document 23] Boudreau CE et al. Delivery ofSTING Agonist Results in Clinical Responses in Canine Glioblastoma. Clin Cancer Res (2021) Summary of the Invention [Problem to be solved by the invention]

[0015] In view of the above, it is an object of the present invention to provide PARP7 inhibitors, particularly PARP7 inhibitors for use in medicine. A further object of the present invention is to provide pharmaceutical compositions containing such inhibitors, particularly compounds and pharmaceutical compositions for treating cancer, infectious diseases, central nervous system diseases or disorders, and other diseases, conditions, and disorders. A further object of the present invention is also to provide methods for synthesizing such compounds. [Means for solving the problem]

[0016] Thus, the present invention provides a compound of the formula:

[0017] [ka] (In the formula, X 1 are each independently the same or different and are selected from C, N, O and S; each Y is independently the same or different and is C or N; Z 1 are independently C or N; X 1 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; each Y independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; Z 1 each independently may be further substituted with H or a substituted or unsubstituted organic group; m can be 1, 2, 3 or 4; n may be 1, 2, or 3; The bonds between all atoms of ring A may independently be single or double bonds, but X 1 When is O or S, the X 1 The bond to is a single bond, The bonds between all atoms of ring B may independently be single or double bonds, but X 1 When is O or S, the X 1 The bond to is a single bond, and, R 1 is connected to Z by a single or double bond 1 and can be bonded to the following formula:

[0018] [ka] (In the formula, Each Q may be the same or different and is selected from C, N, O and S, and is connected to another Q or Z by a single or double bond. 3 and may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; two or more Q atoms may together with their substituents form a ring; p is an integer from 2 to 8; Z 3 are each independently the same or different and are C or N, and may be further substituted with H or a substituted or unsubstituted organic group; X 2 are each independently the same or different and are selected from C, N, O and S; r is an integer from 1 to 5; s is independently an integer from 1 to 5; Here, Q1 is selected from C, N, O and S, and is connected to Z by a single or double bond. 3 and R 4 and may be unsubstituted or substituted with H or an organic group; R 4 is a substituted or unsubstituted organic group containing a substituted or unsubstituted carbocyclic or heterocyclic ring, Z 3 and X 2 Each bond in the ring containing the atom may independently be a double bond or a single bond, provided that X 2 If is O or S, then the X 2 The bond to is a single bond, R 5 are each independently the R 5 X bonded to 2 (It may or may not be present depending on the number of bonds to the atom and its valence, and may be substituted with H or a substituted or unsubstituted organic group.) is a substituent of R 2 is a substituted or unsubstituted organic group that can be attached to Ring B by a single or double bond, and R 16 may be present or absent, and if present is selected from H, a C1-C6 alkyl group, or a linear or branched C1-C6 halogenated alkyl group. The present invention provides a PARP7 inhibitor compound comprising: Usually, R 5 When a group is a substituent on a C atom, the R 5 is R 7 or R 8 and R may be selected from any substituent that may be 5 When a group is a substituent on an N atom, the R 5 is R 6 or R 9 The substituent may be selected from any of the following:

[0019] In the present invention, both above and below, where substituents are possible but not shown in the formula, the number of substituents on any atom is the number necessary to maintain the valence of that atom. For example, in the formula above, the group X 1 and Y may be unsubstituted or substituted. The number of such substituents (and their presence or absence) is determined by the ratio of X to Y, including the substituents. 1 Substituents are not explicitly shown in the formula because they depend on the number of bonds to the atom or Y atom and their valence. In general, where substituents may be present but are not shown in the formula, both above and below, the number of substituents any atom has is the number necessary to maintain the valence of that atom. Similarly, while substituents may be shown, the number of such substituents (and their presence or absence) depends on the number of bonds to the atom containing the substituent and the valence. Both above and below, the number of substituents an atom has is the number necessary to maintain the valence of the atom.

[0020] In the context of the present invention, maintaining valence means ensuring that atoms have the normal (typically most common) valence in organic compounds (e.g., 2 for oxygen and sulfur, 3 for nitrogen, and 4 for carbon). Nitrogen atoms may occasionally have four bonds, in which case they typically have a positive charge so that the compound has a counterion. The valence of sulfur atoms may occasionally be greater than six, for example, when forming a sulfonyl group. Such compounds are also considered part of the present invention. It will be apparent that if there is a positive charge on the nitrogen, the nitrogen atom still maintains its normal valence of three. For the avoidance of doubt, where the number of R groups varies with the selection of X, Y, or Z groups, it varies as follows: R 5 are respectively X 2 is N and is double bonded to a ring atom, R 5 If does not exist, X 2 :R 5 may be the same or different, and one R 5 is X 2is N and is not double-bonded to a ring atom, and one R 5 is X 2 is C and is double bonded to a ring atom, and one R 5 is X 2 It exists when is C and is not double bonded to a ring atom. R 16 does not exist when the N bonded to ring B is double-bonded to a ring atom. 16 exists when N is not double bonded to a ring atom. R 11 are respectively X 4 is O or divalent S, then R 11 If does not exist, then for each X 4 may be the same or different, and R 11 is X 4 is N and is absent when double-bonded to the adjacent atom, R 11 is X 4 is present if N is not double-bonded to an adjacent atom, and R 11 is X 4 is C and is double-bonded to the adjacent atom, R 11 is X 4 is present if C is not double-bonded to an adjacent atom, and R 11 is X 4 When is a hexavalent S, it exists as a double bond O. R 12 Z with 6 If is O or S, then R 12 does not exist, and Z 6 If N is double-bonded to a ring atom, R 12 does not exist. Z 6 If N is not double-bonded to a ring atom, R 12 exists, and Z 6 If C is double-bonded to a ring atom, R 12 exists, and Z 6 is single-bonded to a ring atom at C and has further substituents, R 12 exists.

[0021] In certain embodiments of the compounds and elsewhere herein, (R 1 Any R group (except for R) can form a ring with other R groups on adjacent and / or proximal atoms, although in most embodiments this is not preferred unless explicitly stated. Thus, in some embodiments, the following substituents: R 5 and other R 5 ;R 5 and R 4 ;R 6 and other R 6 ;R 6 and R 7 ;R 7 and other R 7 ;R 8 and other R 8 ;R 8 and R 9 ;R 9 and other R 9 ;R 6 and R 8 ;R 6 and R 11 ; and R 11 and other R 11 , can together form a ring. In the context of the present invention, adjacent and / or proximal atoms may mean another atom directly bonded to an atom (adjacent), may mean two atoms with only a single atom between them (proximal), or may mean two atoms that are sterically close enough to form a ring (proximal). Preferably, R groups bonded to the same atom do not together form a ring, although this is not excluded. In this context, the present invention includes compounds in which a single R group on an atom or two R groups on the same atom form a double-bonded group to that atom. Thus, the R group or two R groups bonded to the same atom may together form a =O group or a =C(R')2 group (where each R' group is the same or different and is H or an organic group, preferably H or a straight-chain or branched C1-C6 alkyl group). More typically, the R groups are bonded to a C atom and together form a C=O group or a C=C(R')2 group. Thus, the C ring atom in the ring may be bonded to any X, any Z and / or R 2 , R 5 , R 7 , R 8 and R 11may contain ═O groups, such as one or more of: In this context, any part of a structure that appears within parentheses (either regular parentheses or square brackets) is 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 case of, the C-R group may be absent, may be present only once, i.e., -C(R)-; or may be present twice, i.e., -C(R)-C(R)-. Additionally, if a structural moiety is shown with a wavy line over a bond, that bond is a bond that attaches to another structural moiety of the compound. In the context of the present invention, a compound is considered to be a PARP7 inhibitor if its presence is capable of inhibiting or reducing the ability of immobilized PARP7 to undergo automono-ADP-ribosylation (auto-MARylation) after incubation with biotinylated NAD+, compared to the same process in its absence. Typically, a compound exhibits an IC 50 If the concentration is <10 μM, the compound is considered a PARP7 inhibitor. A suitable assay can be performed using a 10-30 nM PARP7 (amino acids 456-657) and 2 μM biotin-NAD assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v) assay buffer. MARylation is performed at room temperature for 2-3 hours and can be detected using a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) readout. This assay format has recently been utilized to screen for modulators of PARP7 and other MonoPARP enzymes (Wigle T. et al. Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes. SLAS Discovery. 25; 241-252, (2020)). A particularly suitable assay is described in the following example.

[0022] In all embodiments of the present invention (both above and below in this specification), the substituents (each R group) are not particularly limited as long as they do not interfere with the occurrence of the PARP7 inhibitory function. In all embodiments mentioned in connection with the present invention, both above and below, the substituents are selected from H and organic groups. Therefore, both above and below, the terms "substituent" and "organic group" are not particularly limited and may be any functional group or any atom, particularly any functional group or atom common in organic chemistry. Therefore, "substituent" and "organic group" may have any of the following meanings:

[0023] Organic groups are groups containing B, Si, N, P, O, or S atoms (e.g., OH, OR, NH2, NHR, NR2, SH, SR, SO2R, SO3H, PO4H) 2) or any one or more atoms from any of Groups IIIA, IVA, VA, VIA or VIIA of the periodic table, such as a halogen atom (e.g., F, Cl, Br or I), where R is a linear or branched lower hydrocarbon (1-6 C atoms) or a linear or branched higher hydrocarbon (7 or more C atoms, e.g., 7-40 C atoms). The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight-chain, branched-chain, or cyclic group. The hydrocarbon group may independently comprise an aliphatic group or an aromatic group. The hydrocarbon group may also independently comprise a saturated group or an unsaturated group. If the hydrocarbon contains unsaturated groups, it may contain one or more alkene functionalities and / or one or more alkyne functionalities. If the hydrocarbon contains straight or branched chain groups, it may contain one or more primary, secondary and / or tertiary alkyl groups. When the hydrocarbon contains a cyclic group, it may contain aromatic rings, non-aromatic rings, aliphatic rings, heterocyclic groups, and / or fused ring derivatives of such groups. The rings may be fully saturated, partially saturated, or fully unsaturated.The cyclic groups each independently represent 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, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, and isoxazoline. ol, furazan, 1,2,4 oxadiazole, 1,3,4 oxadiazole, thiophene, isothiazole, thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, oxetan-2-yl, oxetan-3-yl, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-azatetrahydropyran, 3-azatetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-Azathiopyran, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaiisoindole, 5-azaiisoindole, 6-azaiisoindole, 7-azaiisoindole, indolizine, 1-azaiindolizine, 2-azaiindolizine, 3-azaiindolizine, 5-azaiindolizine, 6-azaiindolizine, 7-azaiindolizine, 8-azaiindolizine, 9-azaiindolizine, purine, carbamate The group may include azole, 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. The group may generally be attached at any point on the group and may be attached to a heteroatom or a carbon atom.In some instances, particular points of attachment are preferred, such as 1-yl, 2-yl, etc., and these are explicitly designated where appropriate. All tautomeric ring forms are included in the definition. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole, and 3H-pyrrole. The number of carbon atoms in the hydrocarbon group is not particularly limited, but the hydrocarbon group preferably contains 1 to 40 C atoms. Therefore, 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, ethyl group, propyl group, butyl group, pentyl group, or hexyl group, or a positional isomer thereof, such as an isopropyl group, an isobutyl group, or a tert-butyl group. The number of atoms in the ring of the cyclic group is not particularly limited, but preferably the ring of the cyclic group contains 3 to 10 atoms, such as 3, 4, 5, 6, 7, 8, 9, or 10 atoms.

[0024] The heteroatom-containing groups, as well as the other groups defined above, may contain one or more heteroatoms consisting of any of Groups IIIA, IVA, VA, VIA, or VIIA of the Periodic Table, such as B, Si, N, P, O, or S atoms, or halogen atoms (e.g., F, Cl, Br, or I). Accordingly, the substituents may include one or more of the common functional groups in organic chemistry, such as hydroxyl groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulfate groups, sulfonate groups, sulfonyl groups, and phosphate groups. The substituents may also include derivatives of such groups, such as carboxylic acid anhydrides and carboxylic acid halides. Additionally, any substituent may contain a combination of two or more of the above-defined substituents and / or functional groups.

[0025] The present invention will now be described in more detail with reference to certain preferred embodiments. Rings A and B of the compounds of the present invention form a bicyclic fused ring structure (which may further include fused rings when a substituent on either ring itself forms a ring). Each of rings A and B is not necessarily limited as long as they do not interfere with the occurrence of PARP7 inhibitory function. Rings A and B may independently be composed of aromatic rings, non-aromatic rings, aliphatic rings, and / or heterocyclic rings. The rings may be fully saturated, partially saturated, or fully unsaturated.Thus, each ring independently represents 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, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazoline, ol, 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-azatetrahydropyran, 3-azatetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-azathiopyran anthane, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaiisoindole, 5-azaiisoindole, 6-azaiisoindole, 7-azaiisoindole, indolizine, 1-azaiindolizine, 2-azaiindolizine, 3-azaiindolizine, 6-azaiindolizine, 6-azaiindolizine, 7-azaiindolizine, 8-azaiindolizine, 9-azaiindolizine, 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, phenoxanthine, and / or thianthrene, as well as positional isomers of the above groups. The rings may generally be substituted at any point in the group and may be substituted at a heteroatom or a carbon atom. All tautomeric rings are included in the definition.For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole and 3H-pyrrole.

[0026] In a typical embodiment, the present invention provides a compound in which Ring B is:

[0027] [ka] (In the formula, each Y may be independently selected from C and N; X 1 may each independently be selected from C, N, O and S; The bonds between all atoms in ring B are X 1 when the bond to is a single bond, it may independently be a single bond or a double bond; X 1 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; R 16 may be present or absent and are as defined herein) The compound as defined above is selected from:

[0028] In one preferred embodiment, ring B is:

[0029] [ka] (In the formula, Y, X 1 and R 16 is as defined anywhere in this specification, and the bonds between all atoms of ring B are X 1 If X is O or S, 1 When the bond to is a single bond, it may independently be a single bond or a double bond. may be selected from: In a more preferred embodiment, ring B is:

[0030] [ka]

[0031] [ka]

[0032] [ka]

[0033] [ka]

[0034] [ka]

[0035] [ka] (In the formula, R 6 and R 7 are independently selected from H or a substituted or unsubstituted organic group; R 16 is as defined herein) may be selected from:

[0036] In a further preferred embodiment, independently of ring B, ring A is:

[0037] [ka] (In the formula, Y, X 1 , Z 1 and R 1 is as defined herein) may be selected from: In a further preferred embodiment, ring A is:

[0038] [ka]

[0039]

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[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] [ka] (In the formula, R 1 is as defined herein, and R 8 and R 9 are independently selected from H and substituted or unsubstituted organic groups. may be selected from:

[0054] In a preferred embodiment, independently of ring A and ring B, R 1 is as follows:

[0055] [ka] (In the formula, Q, Q 1 , p, Z 3 , X 2 , R 4 and R 5 are as defined herein) It may be selected from any of the structures. In a further preferred embodiment, R 1 is the following:

[0056] [ka]

[0057] [ka]

[0058] [ka] (In the formula, Q, p, R 7 and R 4 is as defined herein) may be selected from:

[0059] In one preferred embodiment, the linking group -(Q)p- is:

[0060] [ka] (In the formula, X 3 are each independently the same or different and are selected from C, N, O and S, and, if C or N, may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; X 4 are each independently the same or different and are selected from C, N, O and S; Z 4 are each independently the same or different and are C or N, X 3 is O or S, and the X 3 is a single bond, then the bonds between all atoms of any ring may independently be single or double bonds; R 11 is R 11 Contains X 4 are present or absent depending on the number of bonds and valence of the atom, and are each independently substituted with H or a substituted or unsubstituted organic group; R 15 is selected from H, a linear or branched C1-C6 alkyl group, or a linear or branched C1-C6 halogenated alkyl group; Z 5 can be linked via a single or double bond, as follows:

[0061] [ka] (In the formula, R 3 may be the same or different and are each independently substituted with H or a substituted or unsubstituted organic group. and p and Z 3 are as defined herein) It may be selected from any of the structures.

[0062] In a further preferred embodiment, the linking group -(Q)p- is one of the following:

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] [ka] (In the formula, Z 3 , R 6 , R 8 and R11 is as defined herein. may be selected from:

[0069] In a preferred embodiment of the present invention, R 4 may be linked via a single or double bond and may be linked via the following:

[0070] [ka] (In the formula, X 5 are each independently the same or different and are selected from C, N, O and S, and when C or N, X 5 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; Z 6 are each independently the same or different and are selected from C, N, O and S; X 5 or Z 6 is O or S, and the X 5 or Z 6 is a single bond, then the bonds between all atoms of any ring may independently be single or double bonds; R 12 is R 12 Contains Z 6 Present or absent depending on the number of bonds and valence of the atom, and if present, R 12 are each independently selected from H or a substituted or unsubstituted organic group; where R 8 and R 11 is as defined herein) may be selected from:

[0071] In one preferred embodiment, R 4 is as follows:

[0072] [ka]

[0073] [ka]

[0074] [ka] (In the formula, R 6 , R 7 and R 12 are each independently H or a substituted or unsubstituted organic group. may be selected from either Q1 may be present or absent, and is preferably R 4 Z 3 Q to bind directly to 1 is absent. When present, Q1 is usually O, S, CH2 or NH.

[0075] R 2 can be linked via a single or double bond, as follows:

[0076] [ka] (In the formula, R 3 and each independently may be the same or different and are selected from H or a substituted or unsubstituted organic group. is selected from.

[0077] In one preferred embodiment, R 1 is as follows:

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082]

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[0092] [ka]

[0093] [ka]

[0094] [ka]

[0095] [ka] (In the formula, R 6 , R 7 and R 12 are each independently H or a substituted or unsubstituted organic group. may be selected from:

[0096] The present invention further provides a compound of formula:

[0097] [ka] (In the formula, X 1 are each independently the same or different and are selected from C, N, O and S; each Y is independently the same or different and is C or N; Z 1 are independently C or N; X 1 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; each Y independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; Z 1 each independently may be further substituted with H or a substituted or unsubstituted organic group; m can be 1, 2, 3 or 4; n may be 1, 2, or 3, or alternatively 1 or 2; The bonds between all atoms of ring A may independently be single or double bonds, but X 1 When is O or S, the X 1 The bond to is a single bond, The bonds between all atoms of ring B may independently be single or double bonds, but X 1 When is O or S, the X 1 The bond to is a single bond, and R 2 and R 16 is as defined in claim 1, and, R 1 is connected to Z by a single or double bond 1 and can be bonded to the following formula:

[0098] [ka] (wherein L is the following:

[0099] [ka]

[0100] [ka] (In the formula, Each Q is independently the same or different and is selected from C, N, O, and S, and is connected to another Q or Z by a single or double bond. 3 and may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; R 8 are each independently selected from H and a substituted or unsubstituted organic group; R 11 are each independently the number of bonds and the R 11 may be present or absent depending on the valence of the Q atom, including: Z3 are each independently the same or different and are C or N, X 2 are each independently the same or different and are selected from C, N, O and S; r is an integer from 1 to 3; s is independently an integer from 1 to 3; Here, Q 1 is selected from C, N, O and S, and is connected to Z by a single or double bond. 3 and R 4 and may be unsubstituted or substituted with H or an organic group; Z 3 and X 2 Each bond in the ring containing the atom may independently be a double bond or a single bond, provided that X 2 If is O or S, then the X 2 The bond to is a single bond, R 5 are each independently the R 5 X bonded to 2 It is present or absent depending on the number of bonds to the atom and its valence, and is selected from H and substituted or unsubstituted organic groups. R 4 is as follows:

[0101] [ka]

[0102] [ka]

[0103] [ka] and, (In the formula, each R 6 are each independently selected from H and a substituted or unsubstituted organic group; R 12are independently selected from H and substituted or unsubstituted organic groups, or the following: -H, -CH3, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OMe, -CH2CF3, -CF2CH3, -OCH2F, -F, -Cl, -Br, -I, -SO2Me, -CONHMe, t-Bu, cyclopropyl, and

[0104] [ka] is a group selected from is a group selected from is a group selected from is a substituent represented by the formula: The present invention provides a PARP7 inhibitor compound comprising: In compounds according to this formula, preferably R 1 Contains the following:

[0105] [ka] (In the formula, L, Z 3 , X 2 , Q 1 , R 4 and R 5 is as defined herein) There is one of the structures represented by

[0106] R 1 contains the following:

[0107] [ka]

[0108] [ka] (Here, L, R 4 and R 7 are as defined herein.) There is one of the structures represented by

[0109] Advantageously, the compounds according to the invention have the general formula

[0110] [ka] (In the formula, X 1 , Z 1 , R 1 , R 16 , m and n are as defined herein. may include: Usually, m is 1, 2 or 3. n is 1, 2 or 3. Preferably, m is 1 or 2. Preferably, n is 1 or 2, most preferably 2.

[0111] The present invention will now be described in more detail. First, the general structure of many of the compounds of the present invention will be described. Below are common general structures of many of the compounds of this invention.

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka] (In the formula, R 1 , R 6 , R 7 , R 8 , R9 and R 16 is as defined herein).

[0117] The following is one preferred general structure according to the present invention:

[0118] [ka]

[0119] [ka]

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

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[0170] [ka] (R 6 , R 7 , R 8 , R 11 , R 12 and R 16 is as defined herein).

[0171] The R groups referred to in the compounds and structures herein are described in more detail below. As noted above, the number of R substituents on X, Y, Z, or a ring atom depends on its valence. Thus, in any of the above and below embodiments, it will be clear that if X, Y, or Z, or a ring atom, has three ring bonds (either three single bonds or one bond and two bonds), then N has no substituents and C has one substituent (H or an organic group as defined herein); and if X, Y, or Z, or a ring atom has three ring bonds (two single bonds), then N has one substituent (H or an organic group as defined herein) and C has two substituents (each independently selected from H or an organic group as defined herein). Of course, when X or Z is O, there are no substituents. When X or Z is S, there can be no substituents or a sulfonyl group.

[0172] As mentioned above, in all embodiments of the present invention (both above and below), the substituents are not particularly limited as long as they do not prevent the occurrence of PARP7 inhibitory function. However, in a typical embodiment, the substituents can be independently selected as follows: R 5 , R 7 , R 8 , R 11 and R 12 is usually H and the following group: -deuterium -halogens (-F, -Cl, -Br, and -I); - substituted or unsubstituted straight or branched C1-C6 alkyl groups (Me, Et, Pr, iPr, n-Bu, i-Bu, tBu, pentyl, hexyl, etc.); - substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (-CH2Ph, -CH2(2,3, or 4)F-Ph, -CH2(2,3, or 4)Cl-Ph, -CH2(2,3, or 4)Br-Ph, -CH2(2,3, or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2CH2Ph, etc.); - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (CH2F, CHF 2、 CH2CH2F, CH2Cl, CH2Br, CH2I, CF3, CCl3-CBr3, -CI3, -CH2CF3, -CH2CCl3, -CH2CBr3, -CH2CI3, etc.); -NH2 or a substituted or unsubstituted linear or branched primary, secondary or tertiary C1 to C6 amine group (-NMeH, -NMe2, -NEtH, -NEtMe, -NEt 2、 -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, -CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and -CH2-NPrEt, etc.); - substituted or unsubstituted aminoaryl groups (-NH-Ph, -NH-(2,3, or 4)F-Ph, -NH-(2,3, or 4)Cl-Ph, -NH-(2,3, or 4)Br-Ph, -NH-(2,3, or 4)I-Ph, -NH-(2,3, or 4)Me-Ph, -NH-(2,3, or 4)Et-Ph, -NH-(2,3, or 4)Pr-Ph, -NH-(2,3, or 4)Bu-Ph, NH-(2,3, or 4)OMe-Ph, -NH-(2,3, or 4)OEt-Ph, -NH-(2,3 , or 4) OPr-Ph, -NH-(2,3, or 4)OBu-Ph, -NH-2,(3,4,5, or 6)F2-Ph, -NH-2,(3,4,5, or 6)Cl2-Ph, -NH-2,(3,4,5, or 6)Br2-Ph, -NH-2,(3,4,5, or 6)I2-Ph, -NH-2,(3,4,5, or 6)Me2-Ph, -NH-2,(3,4,5, or 6)Et2-Ph, -NH-2,(3,4,5, or 6)Pr2-Ph, -NH-2,(2,3, or 4)Bu2-Ph, etc.; - substituted or unsubstituted cyclic amine or amide groups (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 C3-C8 alkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.); an -OH group or a substituted or unsubstituted straight-chain or branched C1 to C6 alcohol group (-CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and CH2CH2CH2CH2CH2CH2CH2OH); - substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid groups (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, CH2CH2CH2CH2COOH, and CH2CH2CH2CH2CH2COOH); - substituted or unsubstituted straight-chain or branched carbonyl groups (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CHOCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt 2、 -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methylpiperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2, etc.); - substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and CH2CH2CH2COOMe); - substituted or unsubstituted linear or branched C1-C6 amide groups (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, -CO-NPrEt, etc.); - substituted or unsubstituted, straight-chain or branched C1-C7 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, NMe-CO-Ph, etc.); - substituted or unsubstituted straight-chain or branched C1-C7 alkoxy or aryloxy groups (such as -OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2, 3, or 4)-F-Ph, -O-CH2-(2, 3, or 4)-Cl-Ph, -CH2OMe, -CH2OEt, -CH2OPr, -CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe, and -CH2CH2CH2CH2CH2CH2OMe); - substituted or unsubstituted straight or branched aminoalkoxy groups (such as OCH2NH2, OCH2NHMe, OCH2NMe2, OCH2NHEt, OCH2NEt2, OCH2CH2NH2, OCH2CH2NHMe, OCH2CH2NMe2, OCH2CH2NHEt and OCH2CH2NEt2); - a substituted or unsubstituted sulfonyl group (-SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3, or 4)-F-Ph, -SO 2- cyclopropyl, -SO2CH2CH2OCH3, etc.), -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidin-N-yl, -SO2-morpholin-N-yl, -SO2NHCH2OMe and SO2NHCH2CH2OMe, etc.); - substituted or unsubstituted aminosulfonyl groups (-NHSOMe, -NHSOEt, -NHSOPr, -NHSOiPr, -NHSOPh, -NHSO 2- (2, 3, or 4)-F-Ph, -NHSO 2-cyclopropyl, NHSO2CH2CH2OCH3, etc.); -substituted or unsubstituted aromatic groups (Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2- Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)-Pr2-Ph-, 2,(3,4,5, or 6)-Bu2-Ph-, 2,(3,4,5, or 6)-(CN)2-Ph-, 2,(3,4,5, or 6))-(NO2)2-Ph-, 2,(3,4,5, or 6)-(NH2)2-Ph-, 2,(3,4,5, or 6)-(MeO)2-Ph-, 2,(3,4,5,or 6)-(CF3)2-Ph-, 3, (4 or 5)-F2-Ph-, 3, (4 or 5)-Cl2-Ph-, 3, (4 or 5)-Br2-Ph-, 3, (4 or 5)-I2-Ph-, 3, (4 or 5)-Me2-Ph-, 3, (4 or 5)-Et2-Ph-, 3, (4 or 5)-Pr2-Ph-, 3, (4 or 5)-Bu2-Ph-, 3 , (4 or 5)-(CN)2-Ph-, 3, (4 or 5)-(NO2)2-Ph-, 3, (4 or 5)-(NH2)2-Ph-, 3, (4 or 5)-(MeO)2-Ph-, 3, (4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph- , 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph -, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-( NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2 -CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, 4-CF3O-Ph-, etc.);, saturated or unsaturated, substituted or unsubstituted heterocyclic groups, including aromatic and / or non-aromatic heterocyclic groups (e.g., 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, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrimidin-7-yl, pyrimidin-8-yl, pyrimidin-9-yl, pyrimidin-10-yl, pyrimidin-11-yl, pyrimidin-12-yl, pyrimidin-13-yl, pyrimidin-14-yl, pyrimidin-15-yl, pyrimidin-16-yl, pyrimidin-17-yl, pyrimidin-18-yl, pyrimidin-19-yl, pyrimidin-20-yl, pyrimidin-21-yl, pyrimidin-22-yl, pyrimidin-23-yl, pyrimidin-24-yl, pyrimidin-25-yl, pyrimidin-26-yl, pyrimidin-27-yl, pyrimidin-28-yl, pyrimidin-29-yl, pyrimidin-30-yl, pyrimidin-31-yl, pyrimidin-29-yl, pyrimidin-32-yl, pyrimidin-29-yl, pyrimidin-33-yl, pyrimidin-29-yl, pyrimidin-34-yl, pyrimidin-29-yl, pyrimidin-35-yl, pyrimidin-29-yl, pyrimidin-31- Pyrazin-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 -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, 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 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; and -When two R groups are attached to the same atom, they are both double-bonded to that atom (carbonyl group (=O) or alkene group (=C(R')). 2) where each R' group is the same or different and is H or an organic group, preferably H or a straight or branched C 1- is a C6 alkyl group; are each independently selected from the group selected from:

[0173] R 7 and R 8 may be independently selected from nitrile groups. More typically, R 5are independently selected from H, deuterium, halogen (such as -F, -Cl, -Br, -I), a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted straight-chain or branched C1-C6 halogenated alkyl group, an -OH group or a substituted or unsubstituted straight-chain or branched C1-C6 alcohol group, an NH2 group or a substituted or unsubstituted C1-C6 amino group, and a substituted or unsubstituted C1-C6 alkoxy group, or two R 5 groups, which together form a carbonyl group. More typically, R 7 and R 8 are each independently selected from H, deuterium, halogen (such as -F, -Cl, -Br, -I), a substituted or unsubstituted C1-C6 alkyl group or cycloalkyl group, a substituted or unsubstituted straight-chain or branched C1-C6 halogenated alkyl group, an -OH group or a substituted or unsubstituted straight-chain or branched C1-C6 alcohol group, an NH2 group or a substituted or unsubstituted C1-C6 amino group, and a substituted or unsubstituted C1-C6 alkoxy group, and a nitrile group, or two R 7 and R 8 groups, which together form a carbonyl group. More typically, R 11 is selected from H, deuterium, halogen (such as -F, -Cl, -Br, -I), a substituted or unsubstituted C1 to C6 alkyl group, a substituted or unsubstituted straight-chain or branched C1 to C6 halogenated alkyl group, a CF3;NH2 group or a substituted or unsubstituted C1 to C6 amino group, an -OH group or a substituted or unsubstituted straight-chain or branched C1 to C6 alcohol group, and a substituted or unsubstituted C1 to C6 alkoxy group. More typically, R 12 are independently selected from H and substituted or unsubstituted organic groups, or the following: -H, -CH3, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OMe, -CH2CF3, -CF2CH3, -OCH2F, -F, -Cl, -Br, -I, -SO2Me, -CONHMe, t-Bu, cyclopropyl, and

[0174] [ka] is selected from. Usually, R 3 , R 6 and R 9 are each independently selected from H and: - substituted or unsubstituted straight or branched C1-C6 alkyl groups (Me, Et, Pr, iPr, n-Bu, i-Bu, tBu, pentyl, hexyl, etc.); - substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (-CH2Ph, -CH2(2,3, or 4)F-Ph, -CH2(2,3, or 4)Cl-Ph, -CH2(2,3, or 4)Br-Ph, -CH2(2,3, or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2CH2Ph, etc.); - substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (CH2F, CH2F3, CH2CH2F, 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 cyclic C3-C8 alkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.); -OH group or a substituted or unsubstituted straight-chain or branched C1 to C6 alcohol group (-CH2CH2OH, -CH(CH3)CH2OH, C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and CH2CH2CH2CH2CH2CH2CH2OH); - substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, CH2CH2CH2CH2COOH, and CH2CH2CH2CH2CH2COOH); - substituted or unsubstituted straight-chain or branched carbonyl groups (-(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CHOCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt 2、 -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methylpiperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2, etc.); - substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and CH2CH2CH2COOMe); - substituted or unsubstituted linear or branched C1-C6 amide groups (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, -CO-NPrEt, etc.); - a substituted or unsubstituted sulfonyl group (-SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3, or 4)-F-Ph, -SO 2-cyclopropyl, -SO2CH2CH2OCH3, etc.), -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidin-N-yl, -SO2-morpholin-N-yl, -SO2NHCH2OMe and SO2NHCH2CH2OMe, etc.); -substituted or unsubstituted aromatic groups (Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2- Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)-Pr2-Ph-, 2,(3,4,5, or 6)-Bu2-Ph-, 2,(3,4,5, or 6)-(CN)2-Ph-, 2,(3,4,5, or 6))-(NO2)2-Ph-, 2,(3,4,5, or 6)-(NH2)2-Ph-, 2,(3,4,5, or 6)-(MeO)2-Ph-, 2,(3,4,5,or 6)-(CF3)2-Ph-, 3, (4 or 5)-F2-Ph-, 3, (4 or 5)-Cl2-Ph-, 3, (4 or 5)-Br2-Ph-, 3, (4 or 5)-I2-Ph-, 3, (4 or 5)-Me2-Ph-, 3, (4 or 5)-Et2-Ph-, 3, (4 or 5)-Pr2-Ph-, 3, (4 or 5)-Bu2-Ph-, 3 , (4 or 5)-(CN)2-Ph-, 3, (4 or 5)-(NO2)2-Ph-, 3, (4 or 5)-(NH2)2-Ph-, 3, (4 or 5)-(MeO)2-Ph-, 3, (4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph- , 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph -, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-( NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2 -CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, 4-CF3O-Ph-, etc.);, saturated or unsaturated, substituted or unsubstituted heterocyclic groups, including aromatic and / or non-aromatic heterocyclic groups (e.g. 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 ... ,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-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, 3-azapiperidin azinzin-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-6-yl, 4-azapyran-2-yl 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-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, thia oxazol-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, tetrazol-5-yl, etc.); The group is selected from the group selected from the group.

[0175] Preferably, R 3 , R6 and R 9 are each independently selected from H, a substituted or unsubstituted C1 to C6 alkyl group, or a substituted or unsubstituted straight or branched C1 to C6 halogenated alkyl group.

[0176] Preferably, R 16 is absent or selected from the group consisting of H, C1-C3 alkyl groups, and C1-C3 halogenated alkyl groups. More preferably, R 16 is H.

[0177] In one embodiment, the present invention provides a method for producing a composition comprising:

[0178] [ka]

[0179] [ka]

[0180] [ka]

[0181] [ka]

[0182] [ka]

[0183] [ka]

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[0235] [ka]

[0236] [ka] The present invention provides a PARP7 inhibitor compound comprising a formula selected from any of:

[0237] The compounds of the present invention have been described in detail above with respect to their structures. For the avoidance of doubt, the compounds used in the present invention may be those having the following structure: 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 -one or more tautomers The compound or composition may include a compound or composition according to In the case of compound 116, this is the active enantiomer and elutes as the first fraction when the racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAK chiral chromatography column. In the case of compounds 33, 62, 63 and 273, each of which is the active enantiomer, elutes as the second fraction when the racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAK chiral chromatography column.

[0238] The following compound pairs: 64 and 65, 70 and 71, 72 and 73, 75 and 76, 85 and 86, 87 and 88, 89 and 90, 119 and 120, 122 and 123, 129 and 130, 137 and 138, 142 and 143, 148 and 149, 151 and 152, 155 and 156, 160 and 161, 162 and 163, 168 and 169, 174 and 175, 176 and 177, 178 and 179, 185 and 186, 187 and 188, 189 and 190, 201 and 202, 209 and 210, 211 and 212, 221 and 222, 223 and 224, 243 and 244, 245 and 246, 248 and 249, 250 and 251, 253 and 254, 255 and 256, 258 and 259, 262 and 263, 264 and 265, 266 and 267, 274 and 275, 278 and 279, 280 and 281, 283 and 284, 286 and 287, 288 and 289, 291 and 292, 293 and 294, 297 and 298, 30 4 and 305, 306 and 307, 308 and 309, 310 and 311, 312 and 313, 318 and 319, 321 and 322, 323 and 324, 325 and 326, 327 and 328, 329 and 330, 331 and 332, 335 and 336, 338 and 339, 342 and 343, 344 and 345, 347 and 348, 349 and 350, 351 and 352, 353 and 354, 355 and 356, 365 and 366, 368 and 389, 370 and 371, 372 and 373, 374 and 375, 376 and 377, 378 and 379, 380 and 381, 382 and 383, 384 and 385, 386 and 387, 388 and 389, 389 and 390, 391 and 392, 393 and 394, 395 and 396, 397 and 398, 399 and 400, 401 and 402, 403 and 404, 405 and 406, 407 and 408, 409 and 410, 411 and 412, 413 and 414, 415 and 416, 417 and 418, 419 and 420, 421 and 422, 423 and 424, 42 72 and 373, 374 and 375, 376 and 377, 386 and 387, 388 and 389, 392 and 393, 395 and 396, 397 and 398, 399 and 400, 405 and 406, 411 and 412, 414 and 415, 416 and 417, 418 and 419, 420 and 421, 422 and 423, 426 and 427, 429 and 430, 431 and 432, 435 and 436, 437 and 438, 439 and 440, 442 and 443, 444 and 445,In the case of 448 and 449, 450 and 451, 452 and 453, 454 and 455, 456 and 457, 458 and 459, 460 and 461, 462 and 463, 464 and 465, 466 and 467, 468 and 469, 472 and 473, 474 and 475, 476 and 477, 479 and 480, 481 and 482, 483 and 484, 485 and 486, 490 and 491, 492 and 493, 494 and 495, 496 and 497, 498 and 499, and 500 and 501, each of these is a pair of enantiomers, and when a racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAK chiral chromatography column, it elutes as the first and second fractions, respectively.

[0239] The compounds described herein 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 promoted by the PARP7 inhibitory effect of the compound.Therefore, the compounds of the present invention can be used for any disease, condition or disorder that can be prevented, improved or treated with a PARP7 inhibitor.Usually, this includes disease conditions and / or disorders selected from cancer, infectious diseases, central nervous system diseases or disorders, and pain conditions.

[0240] When the disease, condition, or disorder is cancer, there are no particular limitations as long as the cancer can be treated, prevented, or ameliorated by using a PARP7 inhibitor. Therefore, cancers include the following: solid or liquid tumors, including cancer of the eye, brain (glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, astrocytoma, etc.), spinal cord, kidney, lip, 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, adrenal gland; endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, hemangiomatosis, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, striated muscle, hepatocellular carcinoma, PTEN hematoma-tumor Syndrome (PHTS) (Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, Proteus-like syndrome, etc.), 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, Hodgkin's lymphoma, diffuse B-cell lymphoma, Burkitt's lymphoma, and cutaneous T-cell lymphoma), preferably the cancer is selected from esophageal cancer, head and neck cancer, non-small cell lung cancer, squamous cell lung cancer, breast cancer, acute myeloid leukemia (AML), small cell lung cancer, melanoma, ovarian cancer, colorectal cancer, pancreatic cancer, endometrial cancer, and skin papilloma.

[0241] When the disease is an infectious disease, the disease is not particularly limited as long as it can be treated, prevented, or improved by using a PARP7 inhibitor. However, the infectious disease is usually selected from bacterial infections and viral infections, preferably respiratory infections, immune system infections, intestinal infections, and sepsis. The viral respiratory infections include influenza and coronavirus infections, particularly influenza A and SARS-CoV-2 infections. When the disease, condition, or disorder is a central nervous system disease, condition, or disorder, the disease, condition, or disorder is not particularly limited as long as it can be treated, prevented, or improved by using a PARP7 inhibitor. However, the central nervous system disease, condition, or disorder typically includes amyotrophic lateral sclerosis (AML), Huntington's disease, Alzheimer's disease, pain, psychiatric disorders, multiple sclerosis, Parkinson's disease, and HIV-associated neurocognitive decline. When the disease, condition, or disorder is a pain state, the condition is not particularly limited as long as it can be treated, prevented, or improved by using a PARP7 inhibitor. Typically, the pain state is acute pain or neuropathic pain, and is a chronic pain state such as cancer-related pain and peripheral neuropathy.

[0242] The present invention also provides a pharmaceutical composition comprising the compound defined above. The pharmaceutical composition typically further comprises, but is not limited to, a pharmaceutically acceptable additive and / or excipient. 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 the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternatively suitable form. Typically, the composition is intended for treating a disease, condition, or disorder defined above. In some embodiments, the compound may be present in the composition as a pharmaceutically acceptable salt or other alternative form of the compound to improve pharmaceutical formulation.

[0243] In one embodiment, 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. However, typically, the additional agent for treating cancer is selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, anti-aging agents, hormones and hormone analogs, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptive tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents (anti-tumor vaccines, oncolytic viruses; anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX-40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-T immunostimulatory antibodies such as IM3 and anti-GITR; novel adjuvants, peptides, cytokines, chimeric antigen receptor T-cell therapy (CAR-T), small molecule immunomodulators such as IDO and TDO inhibitors, or pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists, tumor microenvironment modifiers, and anti-angiogenic agents), cell proliferation inhibitors such as receptor tyrosine kinase inhibitors, Ras inhibitors and Raf inhibitors, pro-apoptotic agents, and cell cycle signaling inhibitors.

[0244] In yet another embodiment, the present invention provides a pharmaceutical kit for treating cancer, the pharmaceutical kit comprising: (a) a compound as defined above; and (b) an additional agent for treating cancer, preferably, the additional agent for treating cancer is selected from the following: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, anti-aging agents, hormones and hormone analogs, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents (anti-tumor vaccines, oncolytic viruses; anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX-40, anti-41BB, anti-CD27, anti-C immunostimulatory antibodies such as D40, anti-LAG3, anti-TIM3, and anti-GITR; novel adjuvants, peptides, cytokines, chimeric antigen receptor T-cell therapy (CAR-T), small molecule immunomodulators such as IDO and TDO inhibitors, or pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists, tumor microenvironment modifiers, and anti-angiogenic agents), cell proliferation inhibitors such as receptor tyrosine kinase inhibitors, Ras inhibitors, and Raf inhibitors, pro-apoptotic agents, and cell cycle signaling inhibitors; wherein said compound and said further agent are suitable for simultaneous, sequential or separate administration.

[0245] The present invention further provides a method for treating a disease and / or condition and / or disorder, the method comprising administering to a patient (or subject) a compound, composition, or kit as defined above. The method is typically a method for treating any disease state or disorder described herein. In a typical embodiment, the method is a method for 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 can be administered simultaneously, sequentially, or separately, depending on the agents involved, the patient, and the indicated cancer. Generally, in all embodiments of the present invention, both above and below, the patient (or subject) is an animal, usually a mammal, including dogs and cats, and more typically a human. The present invention further provides a method for synthesizing the compounds defined above, the method comprising: (i) providing a substituent R 1 and (ii) a first reactant comprising rings A and B having a moiety 1 to form a PARP7 inhibitor compound.

[0246] In one conventional method, the first reactant is a compound of the general formula:

[0247] [ka] and the second reactant comprises a compound represented by the following general formula:

[0248] [ka] (In the formula, R 13 and R 14 are each independently a substituent that is removed during the reaction; and X 1 , Y, Z 1 , Z 2 , R 2 , R 4 , R 5 , Q, m, n and p are as defined herein. The compound includes compounds represented by the formula:

[0249] In a typical embodiment, the synthesis method is carried out by reacting under conditions suitable for amide formation, nucleophilic substitution, or Michael addition reaction. Those skilled in the art can select reaction conditions based on the appropriate starting materials, with reference to known synthesis techniques. In some embodiments, the method includes one or more additional substitution steps. Exemplary syntheses are shown in the examples herein. Generally, the above formula (and all formulas herein) 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, and all possible mixtures of the corresponding enantiomers. Additionally, the above formula (and all formulas herein) are intended to represent all tautomers corresponding to the corresponding formula.

[0250] Additionally, a PARP7 inhibitor compound is disclosed, which has the following formula:

[0251] [ka] (In the formula, X 1 are each independently the same or different and are selected from C, N, O and S; each Y is independently the same or different and is C or N; Z 1 and Z 2 may be the same or different, Z 1 are independently C or N; Z 2 are independently selected from C, N, O and S; X 1 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; each Y independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; Z 1 each independently may be further substituted with H or a substituted or unsubstituted organic group; Z 2 may independently be further substituted with H or a substituted or unsubstituted organic group; m can be 1, 2, 3 or 4; n may be 1, 2, 3 or 4; The bonds between all atoms of ring A may independently be single or double bonds, but X 1 When is O or S, the X 1 The bond to is a single bond, The bonds between all atoms of ring B may independently be single or double bonds, but X 1 or Z 2 When is O or S, the X 1 or Z2 The bond to is a single bond, and, R 1 is connected to Z by a single or double bond 1 and can be bonded to the following formula:

[0252] [ka] (In the formula, Each Q may be the same or different and is selected from C, N, O and S, and is connected to another Q or Z by a single or double bond. 3 and may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; two or more Q atoms may together with their substituents form a ring; p is an integer from 2 to 8; Z 3 are each independently the same or different and are C or N, and may be further substituted with H or a substituted or unsubstituted organic group; X 2 are each independently the same or different and are selected from C, N, O and S, preferably C and N; r is an integer from 1 to 5; s is independently an integer from 1 to 5; Here, Q 1 is selected from C, N, O and S, and is connected to Z by a single or double bond. 3 and R 4 and may be unsubstituted or substituted with H or an organic group; R 4 is a substituted or unsubstituted organic group containing a substituted or unsubstituted carbocyclic or heterocyclic ring, Z 3 and X 2 Each bond in the ring containing the atom may independently be a double bond or a single bond, provided that X 2 If is O or S, then the X 2 The bond to is a single bond, R 5 are each independently the R5 X bonded to 2 (It may or may not be present depending on the number of bonds to the atom and its valence, and may be substituted with H or a substituted or unsubstituted organic group.) is a substituent of R 2 may be present or absent, and if present, is separated from Z by a single or double bond. 2 and substituted with H or a substituted or unsubstituted organic group) Includes. Usually, Z 2 If C, then R 2 is present and is selected from substituted or unsubstituted organic groups.

[0253] Additionally, the following formula:

[0254] [ka] (In the formula, X 1 are each independently the same or different and are selected from C, N, O and S; each Y is independently the same or different and is C or N; Z 1 and Z 2 may be the same or different, Z 1 are independently C or N; Z 2 are independently selected from C, N, O and S; X 1 each independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; each Y independently may be unsubstituted or substituted with H or a substituted or unsubstituted organic group; Z 1 each independently may be further substituted with H or a substituted or unsubstituted organic group; Z 2 may independently be further substituted with H or a substituted or unsubstituted organic group; m can be 1, 2 or 3; n can be 1, 2 or 3; The bonds between all atoms of ring A may independently be single or double bonds, but X 1 When is O or S, the X 1 The bond to is a single bond, The bonds between all atoms of ring B may independently be single or double bonds, but X 1 or Z 2 When is O or S, the X 1 or Z 2 The bond to is a single bond, and R 1 is as defined herein) Disclosed is a PARP7 inhibitor compound, which is a compound comprising:

[0255] The term "comprises" is used throughout this specification and claims to mean "including (includes) or consisting of." The term indicates the inclusion of at least the features that follow the term, and does not exclude the inclusion of other features not expressly mentioned. The term can also indicate an entity consisting only of the features that follow the term. [Brief explanation of the drawings]

[0256] [Figure 1] FIG. 1 shows that type I interferon production is induced in CT26 and MC38 cancer cells in the presence of a compound according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0257] The present invention will now be described in more detail, by way of example only, with reference to the following specific embodiments and the accompanying drawings, in which: [Example]

[0258] Exemplary Synthesis of Compounds of the Invention The compounds of the present invention can be synthesized using readily available starting materials and known reactions. Exemplary syntheses of various compounds are provided below. 1. Synthesis of 6-(4-(3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoyl)piperazin-1-yl)nicotinonitrile (Compound 1)

[0259] [ka] Preparation of 4-bromo-3-hydroxyisobenzofuran-1(3H)-one (1002) To a stirred solution of 2,2,6,6-tetramethylpiperidine (1.9 mL, 11.5 mMol) in anhydrous THF (10 mL) was added nBuLi (2.4 M in hexane, 4.8 mL, 11.5 mMol) dropwise at -20 °C under N2. After cooling to -50 °C, 3-bromobenzoic acid 1001 (1 g, 5 mMol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at -50 °C for 2 h. N,N-dimethylformamide (1.9 mL, 25.0 mMol) was then added dropwise at this temperature. The resulting reaction mixture was slowly warmed to room temperature and stirred for an additional 14 h. The reaction mixture was carefully poured into ice water (20 mL) and stirred for 10 min. The mixture was then washed twice with EtOAc (20 mL). The resulting aqueous layer was acidified with 1 M aqueous HCl at 0 °C and extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluting with petroleum ether / EtOAc = 80:20 to 0:100). After concentration, the resulting solid was triturated with PE (x mL) to give 4-bromo-3-hydroxyisobenzofuran-1(3H)-one 1002 (0.2 g, 95% purity, 16% yield) as a pale yellow solid. LCMS (ESI) calculation for C8H5BrO3[MH]-m / z 226.93 was 227.

[0260] Preparation of 5-bromophthalazin-1(2H)-one (1003) To a solution of 4-bromo-3-hydroxyisobenzofuran-1(3H)-one 1002 (100 mg, 0.44 mMol) in ethanol (5 mL) was added hydrazine hydrate (80%, 136.3 mg, 2.18 mMol) in one portion. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and then filtered. The filter cake was rinsed with EtOH (5 mL × 2) and then dried in vacuo to give 5-bromophthalazin-1(2H)-one 1003 (90 mg, 95% purity, 87% yield) as white needles. LCMS (ESI) calculation for C8H5BrN2O [M+H]+ m / z 224.97 was 225.

[0261] Preparation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-1(2H)-one (1004) A three-neck flask equipped with a stir bar, a condenser, and a rubber septum thoroughly purged with N was charged with 5-bromophthalazin-1(2H)-one 1003 (2 g, 8.9 mmol), Pd(dppf)Cl2 (0.65 g, 0.8 mMol), B2Pin2 (5.65 g, 22.2 mMol), and potassium acetate (2.62 g, 26.7 mMol). The flask was purged with N2 once more before adding DMF (100 mL) via syringe. The resulting mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into cold water and then extracted with EtOAc (200 mL × 4). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting petroleum ether / EtOAc = 20:80 to 0:100) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-1(2H)-one 1004 (0.5 g, 95% purity, 19% yield) as a white solid. C 14 H 17 LCMS (ESI) calculation for BN2O3 [M+H]+ m / z 272.14 was 273.

[0262] Preparation of methyl 3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoate (1005) To a stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-1(2H)-one 1004 (500 mg, 1.84 mMol) and methyl 3-(bromomethyl)benzoate (463 mg, 2.02 mMol) in 1,4-dioxane / HO (50 mL, 4:1) was added KPO (1170 mg, 5.51 mMol) at room temperature. Pd(pdf)Cl 2. Nitrogen was purged through the reaction mixture for 5 min before adding DCM (150 mg, 0.18 mMol), and then the mixture was purged with N for another 5 min. The reaction mixture was stirred at 80 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (eluting with PE / EtOAc = 60:40 to 0:100) to give methyl 3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoate 1005 (500 mg, 85% purity, 78% yield) as a brown solid. C 17 H 14 LCMS (ESI) calculation for N2O3 [M+H]+ m / z 295.11 was 295.

[0263] Preparation of 3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoic acid (1006) To a solution of methyl 3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoate 1005 (500 mg, 1.70 mMol) in THF / HO (40 mL, 3:1) was added LiOH (203 mg, 8.49 mMol). The mixture was stirred at 50 °C for 1 h. The THF was removed under reduced pressure, and the aqueous phase was acidified with 1 M aqueous HCl to pH = 4–5. The resulting solid was collected by filtration and dried in vacuo to give 3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoic acid 1006 (350 mg, 85% purity, 62% yield) as a gray solid. C 16 H 12 LCMS (ESI) calculation for N2O3+ m / z 281.09 was 281.

[0264] Preparation of 6-(4-(3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoyl)piperazin-1-yl)nicotinonitrile (1) To a solution (15 mL) of 3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoic acid 1006 (150 mg, 0.54 mMol) in DCM, HATU (305 mg, 0.80 mMol), DIPEA (208 mg, 1.61 mMol), and 6-(piperazin-1-yl)pyridine-3-carbonitrile hydrochloride (132 mg, 0.59 mMol) were added successively at room temperature. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-HPLC (column: Sympaq GIST 5 um C18 20 x 250 mM, mobile phase: ACN-HO (0.1% FA), gradient: 35-75) to give 6-(4-(3-((1-oxo-1,2-dihydrophthalazin-5-yl)methyl)benzoyl)piperazin-1-yl)nicotinonitrile 1 (35.7 mg, purity 99%, yield 14%) as a white solid.

[0265] [ka] C 26 H 22 LCMS (ESI) calculation for N6O2 [M+H]+ m / z 451.19 was 451.

[0266] 2. Synthesis of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 10)

[0267] [ka] Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (1102) Ethyl 2-methyl-1H-pyrrole-3-carboxylate 1101 (5 g, 32.6 mMol) was added in portions to a stirred solution of NaH (60% mass, 1.56 g, 39.1 mMol) in THF (100 mL) at 0 °C. After stirring for 15 min at 0 °C, ethyl 2-bromoacetate (6 g, 35.9 mMol) was added dropwise, and the reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (eluting with petroleum ether / EtOAc = 90:10 to 60:40) to give ethyl 1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate 1102 (7 g, 90% purity, 80% yield) as an off-white solid. C 12 H 17 LCMS (ESI) calculation for NO4 [M+H]+ m / z 240.12 was 240.

[0268] Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate (1103) Ethyl 1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (7 g, 29.3 mMol) 1102 was dissolved in THF (120 mL) with stirring, followed by the addition of a solution of AcOH (140 mL) and HO (120 mL). The mixture was homogenously stirred at 0 °C, and cerium(IV) ammonium nitrate (64 g, 117.2 mol) was added in portions. After stirring at room temperature for 1 h, the reaction mixture was poured into ice water (300 mL) and stirred for an additional 30 min. The resulting solution was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting petroleum ether / EtOAc=100:0 to 80:20) to give the title compound ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1103 (3 g, purity 95%, yield 38%) as a yellow solid. C 12 H 15LCMS (ESI) calculation for NO5 [M+H]+ m / z 254.10 was 254.

[0269] Preparation of 2-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]-pyridazin-1-yl)-ethyl acetate (1104) To a solution of ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1103 (3 g, 11.8 mMol) in AcOH (30 mL), H2NNH2·HO (80% by mass, 1.11 g, 17.7 mMol) was added in one portion. The reaction mixture was heated with stirring at 100 °C for 1 h. Most of the solvent was removed by evaporation under reduced pressure (55 °C). The residue was cooled in an ice-water bath. The resulting precipitate was collected and washed with water (10 mL × 2). The solid was dried in vacuo (55 °C) to give ethyl 2-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)-acetate 1104 (1.9 g, 95% purity, 69% yield) as a yellow solid. C 10 H 11 LCMS (ESI) calculation for N3O3+ m / z 222.09 was 222.

[0270] Preparation of ethyl acetate 2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) (1105) To a solution of ethyl 2-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)-acetate 1104 (1.45 g, 6.6 mMol) and DIPEA (4.26 g, 33.0 mMol) in DMF (20 mL) at room temperature was added SEMCl (5.5 g, 33.0 mMol). After the addition, the reaction solution was heated at 80 °C for 1 h. The resulting reaction solution was poured into cold water and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 70:30 to 40:60) to give ethyl acetate 2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1105 (2 g, 95% purity, 81% yield) as an off-white solid. C 16 H25 N3O4Si[M+H] + The LCMS (ESI) calculation for m / z 352.17 was 352.

[0271] Preparation of 1-(2-hydroxyethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1106) To a suspension of LiAlH4 (0.31 g, 8.1 mMol) in THF (35 mL) was added dropwise 2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethyl acetate 1105 (1.9 g, 5.4 mMol) in THF (15 mL) under a N2 atmosphere while maintaining the temperature at 0-5 °C. The reaction mixture was stirred at this temperature for an additional 1 h. Water (0.3 mL) and 13% aqueous NaOH (0.6 mL) were added dropwise, and the mixture was stirred for an additional 30 min. The resulting mixture was filtered through diatomaceous earth, and the filter cake was thoroughly washed with DCM. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give 1-(2-hydroxyethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1106 (1 g, purity 85%, yield 59%) as a yellow solid. C 14 H 23 LCMS (ESI) calculation for N3O3Si[M+H]+ m / z 310.16 was 310.

[0272] Preparation of tert-butyl 3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate (1107) To a solution of 1-(2-hydroxyethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1106 (500 mg, 1.61 mMol, 1 eq) in THF (50 mL) was added Na (74 mg, 3.22 mMol, 2 eq) in portions at room temperature. After stirring for 30 min, tert-butyl acrylate (619 mg, 4.83 mMol, 3 eq) was added in portions. The reaction mixture was stirred at room temperature for an additional 5 h. The reaction solution was evacuated (the remaining Na was suspended in fresh THF and quenched with EtOH and HO), poured into cold water, and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with petroleum ether / EtOAc = 60:40 to 30:70) to give tert-butyl 3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate 1107 (530 mg, 95% purity, 71% yield) as a colorless oil. C 21 H 35 LCMS (ESI) calculation for N3O5Si[M+H]+ m / z 438.24 was 438.

[0273] Preparation of 3-(2-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid (1108) A solution of tert-butyl 3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate 1107 (530 mg, 1.21 mMol) in HCl-dioxane (4 M, 30 mL) was stirred at room temperature under a N atmosphere for 16 h. The resulting reaction mixture was evaporated under reduced pressure to give 3-(2-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid 1108 (300 mg, 85% purity, 84% yield) as a yellow solid. C 11 H 13LCMS (ESI) calculation for N3O4 [M+H]+ m / z 252.10 was 252.

[0274] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (10) To a solution of 3-(2-(4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid 1108 (150 mg, 0.60 mMol) in MeCN (10 mL) were added 2-methylimidazole (123 mg, 1.49 mMol), TCFH (201 mg, 0.71 mMol), and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (209 mg, 0.78 mMol) successively at room temperature. The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluent: DCM / MeOH = 100:0 to 90:10) and pre-HPLC (column: Gemini 5 um C18 150 × 21.2 mM, mobile phase: ACN-HO (0.1% FA), gradient: 30-70) to give 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 10 (30.9 mg, purity 99%, yield 10%) as a white solid.

[0275] [ka] C 20 H 22 LCMS (ESI) for F3N7O3 [M+H]+ m / z 466.18 calculated to be 466.

[0276] 3. Synthesis of the enantiomers of 5-(((1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)phthalazin-1(2H)-one (compound 33)

[0277] [ka] Preparation of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one (1201) To a stirred suspension of NaH (60%, 0.78 g, 19.6 mMol) in THF (60 mL) under nitrogen at 0 °C, 5-bromophthalazin-1(2H)-one 1003 (2.2 g, 9.8 mMol) was added in portions and stirred for an additional 10 min. After adding SEM-Cl (2.45 g, 14.7 mmol), the reaction mixture was warmed to room temperature and stirred for an additional 16 h. The resulting reaction mixture was poured into cold water (30 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography (eluting with petroleum ether / EtOAc = 70:30 to 40:60) gave 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1201 (1.3 g, 95% purity, 35% yield) as a pale yellow oil. C 14 H 19 LCMS (ESI) calculation for BrN2O2Si[M+H]+ m / z 355.05 was 355,357.

[0278] Preparation of 5-hydroxy-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one (1202) To a solution of 5-bromo-2-((2(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1201 (500 mg, 1.41 mMol) in dioxane / HO (10 mL, 1:1) was added Pd(dba) (64 mg, 0.07 mMol), t-BuXPHOS (60 mg, 0.14 mMol), and KOH (240 mg, 4.23 mMol). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 100:0 to 90:10) to give 5-hydroxy-2-((2(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1202 (321 mg, 90% purity, 78% yield) as a yellow solid. C 14 H 20LCMS (ESI) calculation for N2O3Si[M+H]+ m / z 293.13 was 293.

[0279] Preparation of methyl 2-((1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)oxy)propanoate (1203) To a solution of 5-hydroxy-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1202 (200 mg, 0.685 mMol) in acetone (5 mL) was added KCO (171 mg, 2.058 mMol) and methyl 2-bromopropanoate (235 mg, 1.029 mMol). The reaction mixture was stirred at 80 °C for 3 h. The reaction solution was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether eluent / EtOAc = 95:5 to 75:25) to give methyl 2-((1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)oxy)propanoate 1203 (246 mg, 90% purity, 95% yield) as a yellow solid. C 18 H 26 LCMS (ESI) calculation for N2O5Si[M+H]+ m / z 379.17 was 379.

[0280] Preparation of 5-((1-hydroxypropan-2-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one (1204) To a solution of methyl 2-((1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)oxy)propanoate 1203 (500 mg, 1.322 mMol) in EtOH (5 mL) was added LiCl (224 mg, 5.291 mMol). The reaction mixture was stirred at room temperature for 1 h. Then, NaBH4 (200 mg, 5.291 mMol) was added in portions. The reaction mixture was then stirred at room temperature overnight. The resulting mixture was quenched with water and extracted with DCM (10 mL × 3). The organic phase was concentrated under reduced pressure to give 5-((1-hydroxypropan-2-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1204 (460 mg, 90% purity, 99% yield) as a white solid. C 17 H 26LCMS (ESI) calculation for N2O4Si[M+H]+ m / z 351.17 was 351.

[0281] Preparation of 5-(((1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one (1205) To a solution of 5-((1-hydroxypropan-2-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1204 (200 mg, 0.571 mMol) in THF (2 mL) was added NaH (60% by weight, 46 mg, 1.143 mMol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, and then 2-chloro-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (211 mg, 0.685 mMol) was added portionwise to the mixture at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified on a silica gel column (eluent DCM / MeOH=95:5) to give 5-(((1-(2-oxo-2-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1205 (170 mg, purity 90%, yield 48%) as a white solid. C 28 H 37 LCMS (ESI) calculation for F3N6O5Si[M+H]+ m / z 623.25 was 623.

[0282] Preparation of 5-(((1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)phthalazin-1(2H)-one (racemic 33) 5-((1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 1205 (150 mg, 0.241 mMol) was dissolved in HCl-dioxane (4 M, 4 mL). The reaction mixture was stirred at room temperature under N overnight. The solvent was removed and the residue was purified by preparative HPLC (column: Gemini 5 um C18 150 × 21.2 mM, mobile phase: ACN-HO (0.1% FA), gradient: 25-65) to give 5-(((1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)phthalazin-1(2H)-one 33 racemic as a white solid (84 mg, purity 97%, yield 71%). C 22 H 23 LCMS (ESI) calculation for F3N6O4 [M+H]+ m / z 493.18 was 493.

[0283] Chiral resolution of 5-(((1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)propan-2-yl)oxy)phthalazin-1(2H)-one (33) Compound 33 (racemate) was purified by SFC (column: Daicel Chiral Pack OJ-H 250 mm × 20 mm ID, 5 μm; mobile phase: CO 2 / MeOH [0.2% (NH 3) The mixture was separated by filtration (mixture of 200 ml ...

[0284] Compound 33 Enantiomer 1

[0285] [ka] C 22 H 23 LCMS (ESI) calculation for F3N6O4 [M+H]+ m / z 493.18 was 493.

[0286] Compound 33 Enantiomer 2

[0287] [ka] C 22 H 23 LCMS (ESI) calculation for F3N6O4 [M+H]+ m / z 493.18 was 493.

[0288] 4. Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 50)

[0289] [ka] Preparation of ethyl (Z)-2-((dimethylamino)methylene)-4,4-diethoxy-3-oxobutanoate (1302) To a solution of ethyl 4,4-diethoxy-3-oxobutanoate 1301 (4 g, 0.0183 mol) in xylene (40 mL) was added DMF-DMA (4.36 g, 0.0366 mol). The mixture was stirred at 140 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into cold water and extracted with EtOAc (50 mL × 4). The combined organic layers were washed three times with brine, dried over NaSO, and concentrated under reduced pressure to give (Z)-ethyl 2-((dimethylamino)methylene)-4,4-diethoxy-3-oxobutanoate 1302 (4 g, 60% purity, 48% yield) as a brown liquid, which was used directly in the next step. C 13 H 23 LCMS (ESI) calculation for NO5 [M+H]+ m / z 274.16 was 274.

[0290] Preparation of ethyl 5-(diethoxymethyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (1304) To a stirred solution of ethyl (Z)-2-((dimethylamino)methylene)-4,4-diethoxy-3-oxobutanoate 1302 (4 g, 0.0146 mol) and ethyl aminoglycinate hydrochloride 1303 (2.23 g, 0.0146 mMol) in DMF (40 mL) was added DIPEA (5.66 g, 0.0438 mMol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was poured into cold water and extracted with EtOAc (50 mL × 4). The combined organic layers were washed three times with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 50:50) to give ethyl 5-(diethoxymethyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate 1304 (3.2 g, purity 90%, yield 60%) as a yellow liquid. C 15 H 24 LCMS (ESI) calculation for N2O6 [M+H]+ m / z 329.17 was 329.

[0291] Preparation of 2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) ethyl acetate (1305) To a solution of ethyl 5-(diethoxymethyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate 1304 (3.2 g, 0.0097 mol) in AcOH (50 mL) was added HCl (0.18 g, 0.0048 mMol) and H2NNH2·H2O (80% mass, 0.61 g, 0.0097 mMol). The mixture was stirred at 100 °C for 2 h. AcOH was removed under reduced pressure. The residue was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent DCM / MeOH = 90:10 to 80:20) to give ethyl acetate 2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) 1305 (0.7 g, purity 90%, yield 28%) as a white solid. C9H 10 LCMS (ESI) calculated for N4O3 [M+H]+ m / z 223.08.

[0292] Preparation of ethyl 2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate (1306) To a solution of ethyl acetate 2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) (1305) (730 mg, 3.285 mMol) in DMF (20 mL) was added SEMCl (821 mg, 4.928 mMol) and DIPEA (1273.78 mg, 9.856 mol) at room temperature. The reaction mixture was then stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into cold water and then extracted with EtOAc (50 mL × 4). The combined organic layers were washed three times with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 50:50) to give ethyl acetate 2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) 1306 (700 mg, purity 95%, yield 57%) as a white solid. LCMS (ESI) calculation for C15H24N4O4Si[M+H]+ m / z 353.16 was 353.

[0293] Preparation of 1-(2-hydroxyethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1307) To a stirred solution of ethyl acetate 2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) 1306 (690 mg, 1.952 mMol) in 20 mL of THF was added LiAlH (114 mg, 2.928 mMol) in portions at 0 °C. The mixture was stirred at 0 °C for 5 min, and the reaction mixture was quenched sequentially with HO (0.1 mL), NaOH (15% by weight in water, 0.3 mL), and HO (0.3 mL). The resulting mixture was filtered through diatomaceous earth and washed several times with DCM. The filtrate was concentrated under reduced pressure to give 1-(2-hydroxyethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1307 (600 mg, 90% purity, 88% yield) as a yellow oil. C 13 H 22The LCMS (ESI) calculation for N4O3Si [M+H]+ m / z 311.15 was 311.

[0294] Preparation of ethyl (E)-3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acrylate (1309) To a solution of 1-(2-hydroxyethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1307 (300 mg, 0.963 mMol) in DCM (15 mL) was added sequentially at room temperature, followed by ethyl propionate 1308 (94 mg, 0.963 mMol) and P(n-Bu) (19 mg, 0.0963 mMol). The solution was then stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 70:30 to 30:70) to give ethyl (E)-3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acrylate 1309 (200 mg, 95% purity, 48% yield) as a yellow oil. C 18 H 28 The calculated value of LCMS (ESI) for N4O5Si [M+Na]+ m / z 431.17 was 431.

[0295] Preparation of ethyl 3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate (1310) To a solution of ethyl (E)-3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acrylate 1309 (200 mg, 0.488 mMol) in MeOH (10 mL) was added Pd / C (17 mg) at room temperature. The reaction mixture was stirred at room temperature under a H atmosphere for 16 h. The reaction solution was filtered through diatomaceous earth. The filtrate was then concentrated under reduced pressure to give ethyl 3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate 1310 (190 mg, 95% purity, 89% yield) as a yellow oil. C18 H 30 The LCMS (ESI) calculation for N4O5Si [M+H]+ m / z 411.20 was 411.

[0296] Preparation of ethyl 3-(2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate (1311) To a solution of ethyl 3-(2-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate 1310 (190 mg, 0.4617 mMol) in HCl-dioxane (4 M, 20 mL) was added at room temperature, and the reaction was stirred for an additional 16 h. The resulting reaction mixture was evaporated under reduced pressure to give ethyl 3-(2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate 1311 (200 mg, 60% purity, 92% yield) as a yellow oil. C 12 H 16 The LCMS (ESI) calculation for N4O4 [M+H]+ m / z 281.12 was 281.

[0297] Preparation of 3-(2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid (1312) To a solution of ethyl 3-(2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate 1311 (200 mg, 0.7136 mMol) in THF / HO (20 mL, 3:1) was added LiOH (51 mg, 2.141 mMol). The mixture was stirred at 50 °C for 1 h. The THF was removed under reduced pressure, and the aqueous phase was acidified to pH = 4-5 with 1 M aqueous HCl. The residue was purified on a C18 column (mobile phase: ACN-HO (0.1% FA), gradient: 40-60) to give 3-(2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 1312 (35 mg, purity 97%, yield 18%) as a white solid. C 10 H 12 LCMS (ESI) calculation for N4O4 [M+H]+ m / z 253.09 was 253.

[0298] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (compound 50) To a solution of 3-(2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 1312 (35 mg, 0.139 mMol) in DCM (5 mL) were added 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride Int 3 (48 mg, 0.208 mMol), DIPEA (89 mg, 0.694 mMol), and T3P (132 mg, 0.208 mMol in 50% EtOAc) successively at room temperature. The mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on a C18 column (mobile phase: ACN-HO (0.1% FA), gradient: 40-60) to give 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 50 (10 mg, purity 97%, yield 14%) as a white solid.

[0299] [ka] C 19 H 21 LCMS (ESI) calculation of F3N8O3 [M+H]+ m / z 467.17 was 467 5. Synthesis of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 60)

[0300] [ka] Preparation of ethyl 5-bromo-1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (1404) To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate 1401 (5.0 g, 32.64 mMol) in THF (300 mL) was added NBS (5.8 g, 32.64 mMol). The reaction mixture was stirred at -78 °C for 1 h. After LCMS showed complete formation of 1402, NaH (6.5 g, 163.20 mMol, 60% by mass) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 30 min, and then ethyl 2-bromoacetate 1403 (6.5 g, 39.17 mMol) was added. The reaction solution was stirred at room temperature for 16 h until 1402 was completely consumed. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (200 mL × 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 85:15 to 70:30) to give ethyl 5-bromo-1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate 1404 (9.29 g, 90% purity, 81% yield) as a white solid. C 12 H 16 LCMS (ESI) calculation for BrNO4 [M+H]+ m / z 318.03 was 318 / 320.

[0301] Preparation of ethyl 5-bromo-1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate (1405) Ethyl 5-bromo-1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate 1404 (4.0 g, 12.62 mMol) was dissolved in THF (50 mL) with stirring, followed by the addition of a solution of AcOH (50 mL) and HO (50 mL). The mixture was homogenized at 0 °C, and ceric ammonium nitrate (CAN) was added in portions (28 g, 50.47 mMol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water (200 mL) and stirred for an additional 30 min. The resulting solution was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 80:20) to give ethyl 5-bromo-1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1405 (2.3 g, 90% purity, 49% yield) as a yellow solid. C 12 H 14 LCMS (ESI) calculation for BrNO5 [M+H]+ m / z 332.0 was 332 / 334.

[0302] Preparation of ethyl acetate 2-(2-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) (1406) To a solution of ethyl 5-bromo-1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1405 (2.0 g, 6.04 mMol) in AcOH (20 mL) was added H2NNH2·HO (80% mass, 1.2 g, 30.20 mMol) in one portion. The reaction mixture was heated with stirring at 80 °C for 1 h. The solvent was removed by evaporation under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 40:60 to 20:80) to give ethyl 2-(2-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1406 (900 mg, 90% purity, 45% yield) as a yellow solid. C 10 H 10 LCMS (ESI) calculation for BrN3O3 [M+H]+ m / z 299.99 was 300 / 302.

[0303] Preparation of ethyl acetate 2-(2-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) (1407) To a solution of ethyl acetate 2-(2-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1406 (1.88 g, 6.3 mMol) and DIPEA (4.10 g, 31.5 mMol) in DMF (15 mL) was added SEMCl (2.10 g, 12.6 mMol) at room temperature. After the addition was complete, the reaction solution was heated at 50 °C for 1 h. The resulting reaction solution was poured into cold water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 70:30 to 40:60) to give ethyl 2-(2-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)acetate 1407 (2.5 g, 90% purity, 82% yield) as an off-white solid. C 16 H 24 LCMS (ESI) calculation for BrN3O4Si[M+H]+ m / z 430.1 was 430 / 432. Preparation of ethyl acetate 2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) (1409) To a solution of ethyl acetate 2-(2-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1407 (1.10 g, 2.5 mMol) in DMF (20 mL) was added CuI (0.95 g, 5.1 mMol), HMPA (2.24 g, 12.5 mMol), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 1408 (2.40 g, 12.5 mMol) sequentially. The reaction mixture was stirred at 100 °C for 48 h. The resulting reaction solution was poured into cold water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 70:30 to 40:60) to give ethyl acetate 2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1409 (455 mg, 90% purity, 40% yield) as an off-white solid. C 17 H 24 LCMS (ESI) calculation for F3N3O4Si [M+H]+ m / z 420.1 was 420.

[0304] Preparation of 1-(2-hydroxyethyl)-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1410) To a solution of ethyl acetate 2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1409 (450 mg, 1.07 mMol) in THF (10 mL) was added LiAlH4 (81 mg, 2.14 mMol) in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 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 column chromatography (eluting with PE / EtOAc = 50:50 to 40:60) to give 1-(2-hydroxyethyl)-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1410 (297 mg, 90% purity, 66% yield) as a white solid. C 15 H 22 LCMS (ESI) calculation for F3N3O3Si [M+H]+ m / z 378.1 was 378. Preparation of ethyl (E)-3-(2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)acrylate (1412) To a solution of 1-(2-hydroxyethyl)-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1, 5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1410 (270 mg, 0.71 mMol) in DCM (10 mL) was added ethyl propionate 1411 (70 mg, 0.71 mMol) and P(n-Bu) (72 mg, 0.36 mMol) in succession. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 70:30 to 60:40) to give ethyl (E)-3-(2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)acrylate 1412 (302 mg, purity 90%, yield 83%) as a white solid. C 20 H 28 LCMS (ESI) calculation for F3N3O5Si[M+Na]+ m / z 498.2 was 498. Preparation of ethyl 3-(2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate (1413) A solution of ethyl (E)-3-(2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)acrylate 1412 (300 mg, 0.63 mMol) and Pd / C (30 mg, 10% by mass) in MeOH (15 mL) was stirred at room temperature under a H atmosphere for 1 h. The resulting solution was filtered through diatomaceous earth, and the filter cake was washed with DCM (5 mL × 4). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent DCM / MeOH = 97:3 to 95:5) to give ethyl 3-(2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate 1413 (238 mg, purity 90%, yield 71%) as an off-white solid. C 20 H 30 LCMS (ESI) calculation for F3N3O5Si[M+H]+ m / z 478.2 was 478. Preparation of ethyl 3-(2-(four-oxo-2-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate (1414) Ethyl 3-(2-(4-oxo-2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate 1413 (230 mg, 0.48 mMol) was dissolved in HCl-dioxane (4 M, 15 mL). The reaction mixture was stirred at room temperature for 12 hours. The resulting reaction mixture was evaporated under reduced pressure to give ethyl 3-(2-(4-oxo-2-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoate 1414 (180 mg, 90% purity, 97% yield) as a colorless oil. C 14 H 16 LCMS (ESI) calculation for F3N3O4 [M+H]+ m / z 348.1 was 348. Preparation of 3-(2-(4-oxo-2-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid (1415) To a solution of ethyl 3-(2-(4-oxo-2-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid 1414 (200 mg, 0.57 mMol) in THF / HO (15 mL, 1:1) was added LiOH (72 mg, 1.72 mMol). The mixture was stirred at room temperature for 2 h. The THF was removed under reduced pressure, and the aqueous phase was acidified with 1 M aqueous HCl to pH = 4–5. The resulting solid was collected by filtration and dried in vacuo to give 3-(2-(4-oxo-2-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid 1415 (82 mg, 90% purity, 40% yield) as a white solid. C 12 H 12 LCMS (ESI) calculation for F3N3O4 [M+H]+ m / z 320.0 was 320.

[0305] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-2-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 60) To a solution of 3-(2-(4-oxo-2-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethoxy)propanoic acid 1415 (40 mg, 0.12 mMol) and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride 1416 (35 mg, 0.15 mMol) in DCM (5 mL) was added DIPEA (658 mg, 0.50 mMol) and T3P (50% by mass in EtOAc, 160 mg, 0.25 mMol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was quenched with water (20 mL) and extracted with DCM (20 mL × 3). The organic phase was concentrated and purified by prep-HPLC (column: Gemini 5 um C18 150 × 21.2 mM, mobile phase: ACN-HO (0.1% FA), gradient: 30-95) to give 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 60 (23.4 mg, 100% purity, 35% yield) as a white solid.

[0306] [ka] C 21 H 21 LCMS (ESI) calculation for F6N7O3 [M+H]+ m / z 534.1 was 534. 6. Synthesis of 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (Compounds 64 and 65)

[0307] [ka] Preparation of methyl 5-bromo-2-methylnicotinate (1502) To a solution of 5-bromo-2-methylnicotinic acid 1501 (20 g, 92.4 mMol) in MeOH (300 mL) was added SOCl2 (66 mL, 924 mMol) at 0 °C, and the resulting mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. Water (100 mL) was added, and the mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried (Na2SO4 4) The mixture was concentrated in vacuo to give methyl 5-bromo-2-methylnicotinate 1502 (17.2 g, 90% purity, 73% yield) as a colorless oil. LCMS (ESI) calculation for C8H8BrNO2 [M+H]+ m / z 229.98 was 230.

[0308] Preparation of methyl 5-bromo-2-(dibromomethyl)nicotinate (1503) To a solution of methyl 5-bromo-2-methylnicotinate 1502 (15 g, 65.1 mMol) in CCl4 (350 mL) at room temperature was added NBS (46.4 g, 260.4 mMol) and AIBN (2.1 g, 13.0 mMol). The reaction mixture was stirred at 85 °C for 30 h. After cooling to room temperature, water (400 mL) was added and the mixture was extracted with EtOAc (3 × 350 mL). The combined organic layers were dried (NaSO 4)The residue was concentrated in vacuo and purified by flash chromatography (silica gel, eluted with PE / EtOAc = 100:0 to 10:90) to give methyl 5-bromo-2-(dibromomethyl)nicotinate 1503 (12 g, 85% purity, 41% yield) as a white solid. LCMS (ESI) calculation for C8H6Br3NO2 [M+H]+ m / z 385.80 was 386.

[0309] Preparation of 3-bromopyrido[2,3-d]pyridazin-5(6H)-one (1504) To a solution of methyl 5-bromo-2-(dibromomethyl)nicotinate 1503 (10 g, 25.8 mMol) in AcOH (150 mL) was added NH2NH2·HO (6.46 g, 129 mMol) at room temperature. The resulting mixture was stirred at 100 °C for 10 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluted with PE / EtOAc = 100:0 to 20:80) to give 3-bromopyrido[2,3-d]pyridazin-5(6H)-one 1504 (5 g, 80% purity, 69% yield) as a white solid. LCMS (ESI) calculation for C7H4BrN3O [M+H]+ m / z 225.96 was 226. Preparation of 3-methylpyrido[2,3-d]pyridazin-5(6H)-one (1505) To a solution of 3-bromopyrido[2,3-d]pyridazin-5(6H)-one 1504 (4.8 g, 21.2 mMol) in dioxane-HO (60 mL, v / v = 3:1) was added KPO (27 g, 127.2 mMol), methylboronic acid (5.08 g, 84.8 mMol), and Pd(dppf)Cl (1.56 g, 2.12 mMol) at room temperature. The resulting mixture was degassed for 5 min, and the mixture was stirred at 100 °C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluted with PE / EtOAc = 100:0 to 0:100) to give 3-methylpyrido[2,3-d]pyridazin-5(6H)-one 1505 (2.4 g, 85% purity, 59% yield) as a white solid. LCMS (ESI) calculation for C8H7N3O [M+H]+ m / z 162.07 was 162. Preparation of 3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (1506) To a solution of 3-methylpyrido[2,3-d]pyridazin-5(6H)-one 1505 (1.2 g, 7.4 mMol) in TFA (100 mL) was added PtO (170 mg, 0.74 mMol) at room temperature. The resulting mixture was stirred at room temperature under an H atmosphere for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo to give crude 3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one as a white solid as the TFA salt 1506 (1.2 g, 80% purity, 67% yield). C8H 11 LCMS (ESI) calculation for N3O [M+H] + m / z 166.10 was 166.

[0310] Preparation of 6-(4-methoxybenzyl)-3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (1507) To a solution of 3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one as the TFA salt (1506) (2.1 g, 0.0075 mol) in DMSO (80 mL) was added PMBCl (2.35 g, 0.015 mol) and CsCO (9.77 g, 0.03 mol). The reaction mixture was stirred at 50 °C for 18 h. The reaction solution was quenched with water and extracted with EtOAc (3 × 100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PE / EtOAc = 90:10 to 80:20) to give 6-(4-methoxybenzyl)-3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1507 (0.5 g, purity 95%, yield 22%) as a white solid. C 16 H 19 LCMS (ESI) calculation for N3O2 [M+H]+ m / z 286.15 was 286. Preparation of ethyl acetate 2-(6-(4-methoxybenzyl)-3-methyl-5-oxo-3,4,5,6-tetrahydropyrido[2,3-d]-pyridazin-1(2H)-yl) (1508) To a solution of 6-(4-methoxybenzyl)-3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1507 (500 mg, 1.75 mMol) in DMF (40 mL) at 0 °C was added t-BuOK (590 mg, 5.26 mMol) in DMF (10 mL). The reaction mixture was stirred at 0 °C for 10 min. Ethyl 2-bromoacetate (878 mg, 5.25 mMol) in DMF (25 mL) was then added at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then warmed to room temperature and stirred at room temperature for 1 h. The reaction solution was quenched with water and extracted with EtOAc (3 × 50 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (elution with PE / EtOAc = 90:10 to 0:100) to give 2-(6-(4-methoxybenzyl)-3-methyl-5-oxo-3,4,5,6-tetrahydropyrido[2,3-d]-pyridazin-1(2H)-yl)ethyl acetate 1508 (560 mg, purity 90%, yield 77%) as a yellow oil. C 20 H 25 LCMS (ESI) calculation for N3O4 [M+H]+ m / z 372.18 was 372. Preparation of 1-(2-hydroxyethyl)-6-(4-methoxybenzyl)-3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (1509) To a 0 °C solution of ethyl acetate 2-(6-(4-methoxybenzyl)-3-methyl-5-oxo-3,4,5,6-tetrahydropyrido[2,3-d]-pyridazin-1(2H)-yl) 1508 (500 mg, 1.34 mMol) in THF (30 mL) was added LiAlH4 (102 mg, 2.69 mMol). The reaction mixture was stirred at 0 °C for 15 min. The reaction solution was quenched with water and filtered. The filtrate was extracted with EtOAc (3 × 20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluent DCM / MeOH = 100:0 to 95:5) to give 1-(2-hydroxyethyl)-6-(4-methoxybenzyl)-3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1509 (250 mg, purity 95%, yield 53%) as a white solid. C 18 H 23LCMS (ESI) calculation for N3O3 [M+H]+ m / z 330.17 was 330.

[0311] Preparation of (E)-6-(4-methoxybenzyl)-3-methyl-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (1510) To a solution of 1-(2-hydroxyethyl)-6-(4-methoxybenzyl)-3-methyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazine-5(1H)-one 1509 (140 mg, 0.42 mMol) in DCM (10 mL) was added 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (133 mg, 0.47 mMol) and P(n-Bu) (43 mg, 0.21 mMol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by pre-TLC (eluting DCM / MeOH=95:5) to give (E)-6-(4-methoxybenzyl)-3-methyl-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1510 (310 mg, 60% purity, 71% yield) as a white solid. C 30 H 34 LCMS (ESI) calculation for F3N7O4 [M+H]+ m / z 614.26 was 614.35.

[0312] Preparation of 6-(4-methoxybenzyl)-3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (1511) To a room temperature solution of (E)-6-(4-methoxybenzyl)-3-methyl-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1510 (310 mg, 0.50 mMol) in MeOH (10 mL) was added Pd / C (32 mg, 0.30 mMol). The reaction mixture was stirred at room temperature for 18 h. The reaction solution was filtered and concentrated under reduced pressure to give 6-(4-methoxybenzyl)-3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1511 (200 mg, 80% purity, 50% yield) as a yellow oil. C 30 H 36 LCMS (ESI) for F3N7O4 [M+H]+ m / z 616.28 calculated to be 616.

[0313] Preparation of 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (mixture of 64 and 65) A solution of 6-(4-methoxybenzyl)-3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one 1511 (200 mg, 0.32 mMol) in TFA (20 mL) was stirred at 100 °C overnight. The solvent was removed under reduced pressure. The reaction was then quenched with water, and the pH was adjusted to 7-8 with 1 M aqueous NaOH. The aqueous phase was purified on a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 50-95) to give 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (mixture of 64 and 65) (40 mg, purity 97%, yield 24%) as a white solid. C 22 H28 LCMS (ESI) calculation for F3N7O3 [M+H]+ m / z 496.22 was 496. Chiral Resolution of 3-Methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one (64 and 65) Compounds 64 and 65 were purified by SFC (column: Daicel Chiral Pack OJ-H 250 mm x 20 mm ID, 5 μm; mobile phase: CO 2 / MeOH [0.2% (NH 3) ]=70 / 30) and concentrated under reduced pressure to give 64 (20.5 mg, purity 99%, ee%: 100, white solid) as the first fraction, and 65 (16.1 mg, purity 100%, ee%: 99, white solid) as the second fraction. Two fractions were obtained, but this information did not allow the absolute stereochemistry to be assigned to each enantiomer.

[0314] compound 64

[0315] [ka] C 22 H 28 LCMS (ESI) calculation for F3N7O3 [M+H]+ m / z 496.22 was 496.

[0316] compound 65

[0317] [ka] C 22 H 28 LCMS (ESI) calculation for F3N7O3 [M+H]+ m / z 496.22 was 496. 7. Synthesis of 5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)phthalazin-1(2H)-one (Compounds 72 and 73)

[0318] [ka] Preparation of 5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)phthalazin-1(2H)-one (mixture of 72 and 73) To a solution of 3-(2-(1-oxo-1,2-dihydrophthalazin-5-yl)proxy)propanoic acid 1601 (150 mg, 0.543 mMol) in DCM (15 mL), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (220 mg, 0.814 mMol), DIPEA (351 mg, 2.715 mMol), and T3P (50% in EtOAc, 518 mg, 0.814 mMol) were added successively at room temperature. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 40-60) to give 5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)propan-2-yl)phthalazin-1(2H)-one (mixture of 72 and 73) (80 mg, purity 99%, yield 30%) as a white solid. C 23 H 25 LCMS (ESI) calculation for F3N6O3 [M+H]+ m / z 491.20 was 491.

[0319] Chiral resolution of 5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)phthalazin-1(2H)-one (72 and 73) Compounds 72 and 73 were subjected to SFC (column: Daicel Chiral Pack AS-H 250 mm x 20 mm, inner diameter 5 μm; mobile phase: CO 2 / MeOH [0.1% (NH 3) ]=70 / 30) and concentrated under reduced pressure to give the first fraction as 72 (34.9 mg, purity 100%, ee%: 100, white solid) and the second fraction as 73 (37.2 mg, purity 99%, ee%: 100, white solid).

[0320] compound 72

[0321] [ka] C 23 H 25LCMS (ESI) calculation for F3N6O3 [M+H]+ m / z 491.20 was 491.

[0322] compound 73

[0323] [ka] C 23 H 25 LCMS (ESI) calculation for F3N6O3 [M+H]+ m / z 491.20 was 491.

[0324] 8. Synthesis of 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 74)

[0325] [ka] Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (1702) To a stirred solution of NaH (60% oil, 3.2 g, 80.0 mMol) in THF (100 mL) at 0 °C, ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate (1701) (2 g, 11.8 mmol) was added in portions. After stirring at 0 °C for 15 min, ethyl 2-bromoacetate (10.1 g, 60.9 mMol) was added dropwise, and the reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (elution with PE / EtOAc = 100:0 to 95:5) to give ethyl 1-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate 1702 (2.63 g, 98% purity, 72% yield) as an off-white solid. C 13 H 19LCMS (ESI) calculation for NO4 [M+H]+ m / z 254.13 was 254.10.

[0326] Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-4-methyl-1H-pyrrole-3-carboxylate (1703) Ethyl 1-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 1702 (2.63 g, 10.38 mMol) was dissolved in THF (120 mL) with stirring, followed by the addition of a solution of AcOH (120 mL) and HO (120 mL). The mixture was stirred homogeneously at 0 °C, and then CAN (33.66 g, 61.54 mol) was added in portions. After stirring at room temperature for 1 h, the reaction mixture was poured into ice water (120 mL) and stirred for an additional 30 min. The resulting solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 90:10) to give the title compound ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-4-methyl-1H-pyrrole-3-carboxylate 1703 (1.20 g, purity 98%, yield 46%) as a white solid.

[0327] Preparation of 2-(3-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) ethyl acetate (1704) To a solution of ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-4-methyl-1H-pyrrole-3-carboxylate 1703 (1.20 g, 4.47 mMol) in AcOH (5 mL) was added H2NNH2·HO (80% mass, 0.46 g, 6.73 mMol) in one portion. The reaction mixture was heated with stirring at 100 °C for 1 h. Most of the solvent was removed by evaporation under reduced pressure (55 °C). The resulting solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 50:50) to give the title compound ethyl 2-(3-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)acetate 1704 (603 mg, purity 97%, yield 47%) as a white solid. C11 H 13 N3O 3[ LCMS (ESI) calculation for M+H]+ m / z 236.10 was 236.

[0328] Preparation of ethyl acetate 2-(3-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) (1705) To a solution of 2-(3-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)acetate (1704) (603 mg, 2.58 mMol) and DIPEA (1664 mg, 12.8 mMol) in DMF (42 mL) at room temperature was added SEMCl (2127 mg, 12.8 mMol) in portions. After the addition was complete, the reaction solution was heated at 80 °C for 1 h. The resulting reaction solution was poured into cold water and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 60:40) to give ethyl acetate 2-(3-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1705 (565 mg, purity 98%, yield 82%) as a white solid. C 17 H 27 LCMS (ESI) calculation for N3O4Si[M+H]+ m / z 366.18 was 366.15.

[0329] Preparation of 1-(2-hydroxyethyl)-3-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1706) LiAlH 4(To a suspension of 2-(3-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)ethyl acetate 1705 (350 mg, 0.956 mMol) in THF (5 mL) was added dropwise under a N atmosphere, maintaining the temperature at 0-5°C. The reaction mixture was stirred at this temperature for an additional 1 h. Water (0.1 mL) and 13% NaOH (0.2 mL) were added dropwise, and the mixture was stirred for an additional 30 min. The resulting mixture was filtered through diatomaceous earth, and the filter cake was thoroughly washed with DCM. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give 1-(2-hydroxyethyl)-3-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1706 (280 mg, purity 98%, yield 75%) as a yellow oil. C 15 H 25 LCMS (ESI) calculation for N3O3Si [M+H]+ m / z 324.17 was 324.15.

[0330] Preparation of (E)-3-methyl-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1707) A round-bottom flask containing a mixture of 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (80 mg, 0.282 mMol), 1-(2-hydroxyethyl)-3-methyl-5-(2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1706 (90 mg, 0.279 mMol), and P(n-Bu) (49 mg, 0.241 mMol) in DCM (9 mL) was placed in an oil bath heated to 25 °C and stirred at 25 °C for 18 h. The resulting reaction solution was poured into cold water and then extracted with DCM (100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give (E)-3-methyl-1-(2-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1707 (172 mg, purity 98%, yield 79%) as a yellow solid. C 27 H 36 LCMS (ESI) calculation for F3N7O4Si [M+H]+ m / z 608.26 was 608.25.

[0331] Preparation of 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1708) A mixture of compound (E)-3-methyl-1-(2-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-1-en-1-yl)oxy)ethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1707 (152 mg, 0.250 mMol) and Pd / C (31 mg) was stirred in MeOH (20 mL) under 1 atmosphere at room temperature for 6 hours. The resulting mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 98:2) to give 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1708 (120 mg, purity 98%, yield 78%) as a yellow solid. C 27 H 38 LCMS (ESI) calculation for F3N7O4Si [M+H]+ m / z 610.27 was 610.30.

[0332] Preparation of 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 74) A round-bottom flask containing a mixture of 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-5((2(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1708 (120 mg, 0.197 mMol) and HCl-dioxane (4 M, 10 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness under reduced pressure. The residue was purified on a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 30-70) to give 3-methyl-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 74 (40 mg, purity 99%, yield 40%) as a white solid.

[0333] [ka] C 21 H 24 LCMS (ESI) calculation for F3N7O3 [M+H]+ m / z 480.19 was 480.25.

[0334] 9. Synthesis of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 131)

[0335] [ka] Preparation of ethyl-1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylic acid (1802) To a solution of ethyl-2-methyl-1H-pyrrole-3-carboxylate (10 g, 0.065 mol) 1801 in THF (100 mL) was added ethyl 2-bromoacetate (16.3 g, 0.097 mol) and NaH (60% oil, 3.9 g, 0.097 mol) at 0 °C. After the addition was complete, the reaction solution was warmed to room temperature and stirred at room temperature for an additional 16 h. Water was added to quench the reaction. The resulting solution was extracted with EtOAc (50 mL × 4). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to give ethyl 1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate 1802 (14 g, 90% purity, 80% yield) as a yellow solid. C 12 H 17 LCMS (ESI) calculation for NO4 [M+H]+ m / z 240.12 was 240.

[0336] Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate (1803) To a stirred solution of ethyl 1-(2-ethoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylic acid 1802 (10 g, 0.041 mol) in THF:CHCOOH:HO (1:1:1, 150 mL) was added CAN (91.6 g, 0.167 mol) at room temperature. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was carefully poured into an ice-bath cooled solution and extracted with EtOAc (2 × 500 mL). The combined extracts were washed with NaHCO solution (500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (eluting with PE / EtOAc = 99:1 to 50:50) to give ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylic acid 1803 (6 g, 90% purity, 50% yield) as a yellow oil. C 12 H 15 LCMS (ESI) calculation for NO5 [M+H]+ m / z 254.10 was 254.

[0337] Preparation of ethyl 4-bromo-1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate (1804) To a solution of ethyl 1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1803 (3.0 g, 0.011 mol) in MeCN (50 mL) was added NBS (1.0 g, 0.005 mMol) at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 70:30) to give ethyl 4-bromo-1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1804 (1 g, 90% purity, 22% yield) as a yellow oil. C 12 H 14 LCMS (ESI) calculation for BrNO5 [M+H]+ m / z 332.01 was 332,334.

[0338] Preparation of 2-(3-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) ethyl acetate (1805) To a solution of ethyl 4-bromo-1-(2-ethoxy-2-oxoethyl)-2-formyl-1H-pyrrole-3-carboxylate 1804 (1.2 g, 0.003 mol) in AcOH (20 mL) was added H2NNH2·H2O (80% mass, 0.54 g, 0.010 mol) at room temperature. ° The mixture was stirred at RT for 1 h. The resulting light brown solution was concentrated under reduced pressure to remove most of the AcOH. The residue was diluted with DCM (50 mL) and the pH was adjusted to 8 with saturated aqueous NaHCO3 at 0 °C. The basified solution was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give ethyl acetate 2-(3-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1805 (1.1 g, 90% purity, 91% yield) as a yellow solid. C 10 H 10 LCMS (ESI) calculation for BrN3O3 [M+H]+ m / z 299.99 was 300,302.

[0339] Preparation of ethyl acetate 2-(3-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) (1806) To a solution of 2-(3-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) ethyl acetate 1805 (2 g, 0.006 mol) in DMF (30 mL) was added DIPEA (2.6 g, 0.020 mol) and SEMCl (2.2 g, 0.013 mol) at room temperature. The reaction mixture was then stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into cold water and then extracted with EtOAc (50 mL × 4). The combined organic layers were washed three times with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 40:60) to give ethyl acetate 2-(3-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1806 (2 g, 90% purity, 62% yield) as a yellow oil. C 16 H 24 LCMS (ESI) calculation for BrN3O4Si[M+H]+ m / z 430.07 was 430,432.

[0340] Preparation of ethyl 2-(4-oxo-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)acetate (1807) To a stirred solution of ethyl 2-(3-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)acetate 1806 (300 mg, 0.69 mMol), CuI (131 mg, 0.69 mMol), and HMPA (621 mg, 3.45 mMol) in NMP (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (662 mg, 3.45 mMol) at room temperature. The solution was then stirred in a microwave at 160 °C for 1 h. The resulting reaction solution was filtered, and the filtrate was directly purified by flash silica chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to give ethyl acetate 2-(4-oxo-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1807 (150 mg, purity 30%, yield 12%) as a yellow oil. C 17 H 24 LCMS (ESI) calculation for F3N3O4Si [M+H]+ m / z 420.15 was 420.

[0341] Preparation of 1-(2-hydroxyethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1808) To a solution of ethyl acetate 2-(4-oxo-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) 1807 (900 mg, 2.13 mMol) in MeOH (20 mL) were added LiCl (362 mg, 8.54 mMol) and NaBH (323 mg, 8.54 mMol) successively. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give 1-(2-hydroxyethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1808 (150 mg, purity 90%, yield 16%) as a colorless oil. C 15 H 22 LCMS (ESI) calculation for F3N3O3Si [M+H]+ m / z 378.14 was 378.15.

[0342] Preparation of (E)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1809) To a solution of 1-(2-hydroxyethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1808 (100 mg, 0.26 mMol) and 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (112 mg, 0.39 mMol) in DCM (10 mL) was added P(n-Bu) (5 mg, 0.026 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 0:100) to give (E)-1-(2-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1809 (180 mg, purity 90%, yield 92%) as a colorless oil. C 27 H 33 LCMS (ESI) calculation for F6N7O4Si[M+H]+ m / z 662.23 was 662.25.

[0343] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (1810) A solution of (E)-1-(2-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1809 (150 mg, 0.22 mMol) and Pd / C (30 mg) in MeOH / DCM (15 mL, 2:1) was stirred under a H atmosphere at room temperature for 1 h. The resulting solution was filtered through diatomaceous earth, and the filter cake was washed with DCM (5 mL × 4). The filtrate was concentrated under reduced pressure to give 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1810 (140 mg, 90% purity, 83% yield) as a colorless oil. C 27 H 35 LCMS (ESI) calculated for F6N7O4Si[M+H]+ m / z 664.24 was 664.25.

[0344] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compound 131) A solution of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1) in HCl-dioxane (4 M, 40 mL) was added with 5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1810 (100 mg, 0.15 mMol) and stirred at room temperature for 16 h. The resulting reaction solution was basified (pH 8) with saturated aqueous NaHCO at 0 °C and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The crude was purified on a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 30-60) to give 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 131 (21.5 mg, purity 98%, yield 23%) as a white solid.

[0345] [ka] C 21 H 21 LCMS (ESI) calculation for F6N7O3 [M+H]+ m / z 534.16 was 534.

[0346] 10. Synthesis of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 153)

[0347] [ka] Preparation of 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1902) To a solution of 4,5-dichloropyridazin-3(2H)-one 1901 (8 g, 48.5 mMol) in DMF (100 mL) was added PMBCl (19 g, 121.3 mMol) and DIPEA (31.4 g, 242.5 mMol) at room temperature. The resulting mixture was stirred at 50 °C for 6 h. After cooling to room temperature, water (400 mL) was added and the mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried (NaSO 4) The residue was purified by flash chromatography (silica gel, eluting with PE / EtOAc = 100:0 to 80:20) to give 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one 1902 (8 g, 90% purity, 52% yield) as a white solid. C 12 H 10 LCMS (ESI) calculation for Cl2N2O2 [M+H]+ m / z 285.02 was 285.

[0348] Preparation of 4-chloro-5-(dimethylamino)-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1903) To a solution of 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one 1902 (8 g, 28.1 mMol) in EtOH (100 mL) and HO (50 mL) was added dimethylamine in MeOH (2 M, 70.5 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried (NaSO 4) The residue was concentrated in vacuo and purified by flash chromatography (silica gel, eluted with PE / EtOAc = 100:0 to 20:80) to give 4-chloro-5-(dimethylamino)-2-(4-methoxybenzyl)pyridazin-3(2H)-one 1903 (8 g, 85% purity, 82% yield) as a white solid. C 14 H 16 LCMS (ESI) calculation for ClN3O2 [M+H]+ m / z 294.1 was 294.

[0349] Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-vinylpyridazin-3(2H)-one (1904) To a solution of 4-chloro-5-(dimethylamino)-2-(4-methoxybenzyl)pyridazin-3(2H)-one 1903 (8 g, 27.2 mMol) in ACN (100 mL) was added tributyl(vinyl)stannane (17.3 g, 54.4 mMol) and Pd(AMPHOS)Cl (1.93 g, 2.72 mMol) at room temperature. The resulting mixture was stirred at 100 °C for 10 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluted with PE / EtOAc = 100:0 to 10:90) to give 5-(dimethylamino)-2-(4-methoxybenzyl)-4-vinylpyridazin-3(2H)-one 1904 (6 g, 90% purity, 69% yield) as a white solid. C 16 H 19 LCMS (ESI) calculation for N3O2 [M+H]+ m / z 286.16 was 286.

[0350] Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbaldehyde (1905) To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-vinylpyridazin-3(2H)-one 1904 (3 g, 0.01 mol) in MeOH / HO (2:1, 30 mL) was added KOsO·2HO (0.39 g, 0.001 mol) and NaIO (8.9 g, 0.04 mol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give 5-(dimethylamino)-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbaldehyde 1905 (1.8 g, 90% purity, 53% yield) as a yellow oil. C 15 H 17 LCMS (ESI) calculation for N3O3 [M+H]+ m / z 288.13 was 288.10.

[0351] Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2 trifluoro-1-hydroxyethyl)pyridazin-3(2H)-one (1906) To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbaldehyde 1905 (1.8 g, 0.006 mol) and trimethyl(trifluoromethyl)silane (0.9 g, 0.006 mol) in THF (20 mL) was added TBAF / THF (1 M, 0.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 30:70) to give 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2 trifluoro-1-hydroxyethyl)pyridazin-3(2H)-one 1906 (1.6 g, purity 90%, yield 63%) as a yellow oil. C 16 H 18 LCMS (ESI) calculation for F3N3O3 [M+H]+ m / z 358.13 was 358.10.

[0352] Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2 trifluoroacetyl)pyridazin-3(2H)-one (1907) To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)pyridazin-3(2H)-one 1906 (1.6 g, 0.004 mol) in DCM (30 mL) was added Dess-Martin peridinane (3.8 g, 0.009 mol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoroacetyl)pyridazin-3(2H)-one 1907 (1.5 g, 90% purity, 84% yield) as a yellow oil. C 16 H 16 LCMS (ESI) calculation for F3N3O3 [M+H]+ m / z 356.11 was 356.10.

[0353] Preparation of 5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1908) To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoroacetyl)pyridazin-3(2H)-one 1907 (1.6 g, 0.004 mol) in EtOH (30 mL) was added H2NNH2·HO (80% mass, 1.0 g, 0.020 mol) at room temperature. The reaction mixture was stirred at 80 °C for 3 h. The resulting light brown solution was concentrated under reduced pressure to remove most of the EtOH and give the crude product. The crude was purified on a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 30-60) to give 5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1908 (0.9 g, purity 90%, yield 55%) as a white solid. C 14 H 11 LCMS (ESI) calculation for F3N4O2 [M+H]+ m / z 325.08 was 325.05.

[0354] Preparation of ethyl acetate 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) (1909) To a solution of 5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1908 (200 mg, 0.61 mMol), 2-bromoethyl acetate (308 mg, 1.84 mMol) and t-BuOK (206 mg, 1.84 mMol) were added 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 (20 mL × 3). The organic phase was concentrated and purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethyl acetate 1909 (200 mg, purity 90%, yield 71%) as a yellow oil. C 18 H 17 LCMS (ESI) calculated for F3N4O4 [M+H]+ m / z 411.12 was 411.10.

[0355] Preparation of 1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1910) To a solution of ethyl acetate 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) 1909 (200 mg, 0.48 mMol) in MeOH (20 mL) was added LiCl (82 mg, 1.94 mMol) and NaBH (73 mg, 1.94 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give 1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1910 (140 mg, purity 90%, yield 70%) as a yellow oil. C 16 H 15 LCMS (ESI) calculation for F3N4O3 [M+H]+ m / z 369.11 was 369.05.

[0356] Preparation of (E)-5-(4-methoxybenzyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1911) To a solution of 1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1910 (140 mg, 0.37 mMol) and 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (108 mg, 0.37 mMol) in DCM (10 mL) was added P(n-Bu) (15 mg, 0.075 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 0:100) to give (E)-5-(4-methoxybenzyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1911 (200 mg, purity 90%, yield 72%) as a yellow oil. C 28 H 26 LCMS (ESI) calculation for F6N8O4 [M+H]+ m / z 653.20 was 653.

[0357] Preparation of 5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1912) A solution of (E)-5-(4-methoxybenzyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1911 (150 mg, 0.22 mMol) and Pd / C (30 mg) in MeOH / DCM (15 mL, 2:1) was stirred at room temperature under a H atmosphere for 1 h. The resulting solution was filtered through diatomaceous earth, and the filter cake was washed with DCM (5 mL × 4). The filtrate was concentrated under reduced pressure to give 5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1912 (140 mg, 90% purity, 83% yield) as a yellow oil. C 28 H 28 LCMS (ESI) calculation for F6N8O4 [M+H]+ m / z 655.21 was 655.

[0358] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 153) To a solution of 5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1912 (140 mg, 0.21 mMol) in TFA (10 mL) was added TfOH (64 mg, 0.42 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with DCM (50 mL), and then the pH was adjusted to 8 with saturated aqueous NaHCO at 0 °C. The basified solution was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The crude product was purified on a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 30-60) to give 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 153 (47 mg, purity 99%, yield 40%) as a white solid.

[0359] [ka] C 20 H 20 LCMS (ESI) calculation for F6N8O3 [M+H]+ m / z 535.16 was 535.20.

[0360] 11. Synthesis of 7-chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)phthalazin-1(2H)-one (Compound 80)

[0361] [ka] Preparation of 5-allyl-7-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one (2002) To a solution of 5-bromo-7-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 2001 (400 mg, 1.02 mMol) in ACN (10 mL) was added allyltributylstannane (339 mg, 1.02 mMol) and Pd(AMPHOS)Cl (73 mg, 0.10 mMol) at room temperature under N. The reaction mixture was stirred at 100 °C in a sealed tube for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 80:20 to 70:30) to give 5-allyl-7-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 2002 (300 mg, 90% purity, 75% yield) as a colorless oil. C 17 H 23 LCMS (ESI) calculated for ClN2O2Si [M+H]+ m / z 351.12 was 351.15.

[0362] Preparation of 2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)acetaldehyde (2003) To a solution of 5-allyl-7-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 2002 (1.0 g, 2.8 mMol) in MeOH / HO (3:1, 40 mL) was added KOsO·2HO (100 mg, 0.28 mMol) and NaIO (2.4 g, 11.2 mMol) successively at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure to give crude 2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)acetaldehyde 2003 (500 mg, 80% purity, 39% yield) as a yellow oil. C 16 H 21 LCMS (ESI) calculation for ClN2O3Si[M-27]+ m / z 325.10 was 325.

[0363] Preparation of 7-chloro-5-(2-hydroxyethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one (2004) To a solution of 2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)acetaldehyde 2003 (500 mg, 1.41 mMol) in methanol was added NaBH4 (160 mg, 4.24 mMol) in portions at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 60:40) to give 7-chloro-5-(2-hydroxyethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 2004 (413 mg, 90% purity, 74% yield) as a white solid. C 16 H 23 LCMS (ESI) calculation for ClN2O3Si[M+H]+ m / z 355.12 was 355.

[0364] Preparation of ethyl (E)-3-(2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)ethoxy)acrylate (2005) To a solution (20 mL) of 7-chloro-5-(2-hydroxyethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one 2004 (410 mg, 1.16 mMol) and ethyl propionate (114 mg, 1.16 mMol) in DCM was added P(n-Bu) (117 mg, 0.58 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to give ethyl (E)-3-(2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)ethoxy)acrylate 2005 (262 mg, purity 90%, yield 45%) as a white solid. C 21 H 29 LCMS (ESI) calculation for ClN2O5Si[M+Na]+ m / z 475.15 was 475.

[0365] Preparation of ethyl 3-(2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)ethoxy)propanoate (2006) A solution of ethyl (E)-3-(2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)ethoxy)acrylate 2005 (240 mg, 0.53 mMol) in toluene (10 mL) was added to the solution of RhCl (PPh) at room temperature. 3)3 (25 mg) was added. The reaction mixture was stirred under an atmosphere of H for 50 ° The mixture was stirred at RT for 2 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to give ethyl 3-(2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)ethoxy)propanoate 2006 (250 mg, purity 90%, yield 93%) as a colorless oil. C 21 H 31 LCMS (ESI) calculation for ClN2O5Si[M+Na]+ m / z 477.17 was 477.

[0366] Preparation of ethyl 3-(2-(7-chloro-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)propanoate (2007) A solution of ethyl 3-(2-(7-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-5-yl)ethoxy)propanoate 2006 (350 mg, 0.77 mMol) in HCl-dioxane (4 M, 20 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to give crude ethyl 3-(2-(7-chloro-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)propanoate 2007 (152 mg, 90% purity, 55% yield) as a colorless oil. C 15 H 17 LCMS (ESI) calculation for ClN2O4 [M+H]+ m / z 325.09 was 325.

[0367] Preparation of 3-(2-(7-chloro-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)propanoic acid (2008) To a solution of ethyl 3-(2-(7-chloro-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)propanoic acid 2007 (150 mg, 0.46 mMol) in THF / HO (15 mL, 1:1) was added LiOH (58 mg, 0.14 mMol). The mixture was stirred at room temperature for 2 h. The THF was removed under reduced pressure, and the aqueous phase was acidified with 1 M aqueous HCl to pH = 4-5. The resulting solid was collected by filtration and dried in vacuo to give 3-(2-(7-chloro-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)propanoic acid 2008 (58 mg, 95% purity, 40% yield) as a white solid. C 13 H 13 LCMS (ESI) calculation for ClN2O4 [M+H]+ m / z 297.06 was 297.

[0368] Preparation of 7-chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)phthalazin-1(2H)-one (Compound 80) To a solution of 3-(2-(7-chloro-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)propanoic acid 2008 (29 mg, 0.10 mMol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (25 mg, 0.11 mMol) in DCM (5 mL) was added DIPEA (51 mg, 0.39 mMol), T3P (50% by mass in EtOAc, 124 mg, 0.20 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with water (20 mL) and extracted with DCM (20 mL × 3). The organic phase was concentrated and purified by prep-HPLC (column: Gemini 5 um C18 150 × 21.2 mM, mobile phase: ACN-HO (0.1% FA), gradient: 40-95) to give 7-chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)phthalazin-1(2H)-one 80 (19.3 mg, purity 99%, yield 38%) as a white solid.

[0369] [ka] C 22 H 22LCMS (ESI) calculation for ClF3N6O3 [M+H]+ m / z 511.14 was 511.

[0370] 12. Synthesis of 5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)phthalazin-1(2H)-one (Compound 98)

[0371] [ka] Preparation of tert-butyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (2102) To a stirred mixture of 2-chloro-5-(trifluoromethyl)pyridine 2101 (500 mg, 2.739 mMol) in DMSO (10 mL) was added tert-butyl piperazine-1-carboxylate (513 mg, 2.739 mMol) and potassium carbonate (946 mg, 6.8475 mMol). The resulting mixture was stirred at 100 °C for 5 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate (30 mL). The reaction was filtered, and the filtrate was washed with saturated aqueous NaHCO (2 × 10 mL). The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 100:0 to 85:15). tert-Butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate 2102 (600 mg, 90% purity, 59% yield) was obtained as a white solid.

[0372] [ka] Preparation of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (2103) A mixture of tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate 2102 (300 mg, 0.9 mMol) in 4 M HCl / dioxane (10 mL) was added, and the mixture was stirred at 20 °C for 5 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine 2103 (210 mg, 90% purity, 78% yield) as a white solid. The crude mixture was used directly in the next step without further purification. C 10 H 12 The LCMS (ESI) calculation for F3N3 [M+H] + m / z 232.10 was 232.

[0373] Preparation of 5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)phthalazin-1(2H)-one (Compound 98) To a stirred solution of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine 2103 (60 mg, 0.2233 mMol) in DCM (5 mL) was added 3-[2-(1-oxo-2H-phthalazin-5-yl)ethoxy]propanoic acid 2104 (59 mg, 0.2233 mMol), T3P (107 mg, 0.3349 mMol), and DIPEA (87 mg, 0.6699 mMol). The reaction mixture was stirred at 20 °C for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-HPLC (column: Gemini 5um C18 150*21.2mm, mobile phase: ACN-HO (0.1% FA), gradient: 20-95) to give 5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)phthalazin-1(2H)-one 98 (51.8 mg, purity 95%, yield 46%) as a white solid.

[0374] [ka] C 23 H 24 LCMS (ESI) calculation for F3N5O3 [M+H]+ m / z 476.18 was 476.

[0375] 13. Preparation of 7-chloro-5-(1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (Compounds 174 and 175)

[0376] [ka] Preparation of 7-chloro-5-(1-ethoxyvinyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one (2203) To a solution of 5-bromo-7-chloro-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2201 (620 mg, 1.63 mMol) in dioxane (15 mL) at room temperature was added tributyl(1-ethoxyvinyl)stannane 2202 (141 mg, 1.63 mMol), CuI (31 mg, 0.16 mMol), and Pd(PPh 3)4 (189 mg, 0.16 mMol) was added sequentially. The reaction mixture was stirred at 100 °C under N2 atmosphere for 1 h. The reaction mixture was poured into cold water and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to give 7-chloro-5-(1-ethoxyvinyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2203 (410 mg, 90% purity, 61% yield) as a yellow solid. C 20 H 19 LCMS (ESI) calculated for ClN2O3 [M+H]+ m / z 371.11 was 371.15.

[0377] Preparation of 5-acetyl-7-chloro-2-(4-methoxybenzyl)phthalazin-1(2H)-one (2204) A solution of 7-chloro-5-(1-ethoxyvinyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2203 (400 mg, 1.08 mMol) in DCM (5 mL) was added to HCl-dioxane (4 M, 5 mL) at room temperature. The reaction solution was stirred at room temperature for 4 h. The resulting reaction mixture was evaporated under reduced pressure, and the residue was purified by flash column chromatography (eluted with PE / EtOAc = 85:15 to 70:30) to give 5-acetyl-7-chloro-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2204 (347 mg, 90% purity, 84% yield) as a colorless oil. C 18 H 15 LCMS (ESI) calculation for ClN2O3 [M+H]+ m / z 343.08 was 343.10.

[0378] Preparation of 7-chloro-5-(1-hydroxyethyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one (2205) To a solution of 5-acetyl-7-chloro-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2204 (340 mg, 0.99 mMol) in MeOH (5 mL) was added NaBH (75 mg, 1.98 mMol) in portions at 0 °C, and the reaction was stirred at 0 °C for 10 min. The reaction solution was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated NH Cl solution, dried over Na SO , and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 85:15 to 70:30) to give 7-chloro-5-(1-hydroxyethyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2205 as a white solid (335 mg, 90% purity, 88% yield). C 18 H 17 LCMS (ESI) calculation for ClN2O3 [M+H]+ m / z 345.09 was 345.10.

[0379] Preparation of methyl (E)-4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)but-2-enoate (2207) To a solution of 7-chloro-5-(1-hydroxyethyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2205 (330 mg, 0.96 mMol) in n-hexane (15 mL) was added AgO (887 mg, 3.83 mMol), followed by MgSO (459 mg, 3.83 mMol) at room temperature. The reaction mixture was heated at 80 °C for 1 h, and then AgO (887 mg, 3.83 mMol) was added to the solution, followed by methyl (E)-4-bromobut-2-enoate 2206 (857 mg, 4.79 mMol). The resulting solution was heated under reflux for 18 h. The reaction mixture was poured into cold water and extracted with EtOAc (50 mL × 4). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography (elution with EtOAc / PE 30%–50%) to give methyl (E)-4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)but-2-enoate 2207 (85 mg, 90% purity, 18% yield) as a white solid. C 23 H23 LCMS (ESI) calculated for ClN2O5 [M+H]+ m / z 443.13 was 443.10.

[0380] Preparation of methyl 4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoate (2208) To a solution of methyl (E)-4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)but-2-enoate 2207 (95 mg, 0.21 mMol) in toluene (5 mL) was added RhCl(PPh) (10 mg) at room temperature. The reaction mixture was stirred at 50 °C under a H atmosphere for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc = 70 / 30 to 40 / 60) to give methyl 4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoate 2208 (70 mg, 90% purity, 66% yield) as a white solid. C 23 H 25 LCMS (ESI) calculated for ClN2O5 [M+H]+ m / z 445.15 was 445.20.

[0381] Preparation of 4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoic acid (2209) To a solution of methyl 4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoate 2208 (70 mg, 0.16 mMol) in THF / HO (3 / 1, 5 mL) was added LiOH (20 mg, 0.47 mMol) at room temperature. The mixture was stirred at room temperature for 4 h. The THF was removed under reduced pressure, and the aqueous phase was acidified to pH = 4-5 with 1 M aqueous HCl. The precipitate was collected by filtration and dried in vacuo to give 4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoic acid 2209 (55 mg, 90% purity, 73% yield) as a white solid. C 22 H 23LCMS (ESI) calculated for ClN2O5 [M+H]+ m / z 431.13 was 431.20.

[0382] Preparation of 7-chloro-2-(4-methoxybenzyl)-5-(1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (2210) To a solution of 4-(1-(7-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoic acid 2209 (50 mg, 0.12 mMol) and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (47 mg, 0.17 mMol) in DMF (10 mL) was added DIPEA (60 mg, 0.46 mMol) and HATU (87 mg, 0.23 mMol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (20 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 90:10 to 40:60) to give 7-chloro-2-(4-methoxybenzyl)-5-(1-(4-oxo-4-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one 2210 (70 mg, purity 90%, yield 84%) as a white solid. C 31 H 32 LCMS (ESI) calculated for ClF3N6O4 [M+H]+ m / z 645.21 was 645.35.

[0383] Preparation of 7-chloro-5-(1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (mixture of 174 and 175) To a solution of 7-chloro-2-(4-methoxybenzyl)-5-(1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one 2210 (70 mg, 0.09 mMol) in TFA (2 mL) was added TfOH (28 mg, 0.19 mMol) at 0 °C. The reaction solution was stirred at room temperature for 1 h. The mixture was adjusted to pH = 8-9 with aqueous NaHCO3 at 0 °C, and then the aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was C 18 Purification by column chromatography (mobile phase: ACN-HO (0.1% FA), gradient: 10%-95%) gave 7-chloro-5-(1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (mixture of 174 and 175) as a white solid.

[0384] Chiral Resolution of 7-Chloro-5-(1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (174 and 175) Compounds 174 and 175 were analyzed by SFC (column: Daicel Chiral Pack AS-H 250 mm x 20 mm, 5 μm inner diameter; mobile phase: CO 2 / MeOH (0.1% NH 3) The mixture was separated by a solvent mixture of 174 (60 / 40) and concentrated under reduced pressure to give the first fraction 174 (5.9 mg, purity 99%, ee 100%, white solid), and the second fraction 175 (8.2 mg, purity 99%, ee 98%, white solid).

[0385] compound 174

[0386] [ka] C 23 H 24 LCMS (ESI) calculated for ClF3N6O3 [M+H]+ m / z 525.16 was 525.30.

[0387] compound 175

[0388] [ka] C 23 H 24 LCMS (ESI) calculated for ClF3N6O3 [M+H]+ m / z 525.16 was 525.30.

[0389] 14. Synthesis of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 176 and 177)

[0390] [ka] Preparation of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)propanoate (2303) To a solution of 5-(4-methoxybenzyl)-3-(trifluoromethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1908 (1 g, 0.0031 mol) was added t-BuOK (1.04 g, 0.0093 mMol) and ethyl 2-bromopropanoate 2302 (2.24 g, 0.0124 mol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction solution was quenched with cold water and extracted with EtOAc (20 mL × 3). The organic phase was concentrated under reduced pressure and purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)propanoate 2303 (1 g, purity 90%, yield 68%) as a white solid. C 19 H 19 LCMS (ESI) calculated for F3N4O4 [M+H]+ m / z 425.14 was 425.15.

[0391] Preparation of 1-(1-hydroxypropan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2304) To a solution of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)propanoate 2303 (1 g, 0.00235 mol) in EtOH (30 mL) was added LiCl (0.394 g, 0.0094 mol) and NaBH (0.355 g, 0.0094 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 50:50) to give 1-(1-hydroxypropan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2304 (0.8 g, purity 90%, yield 56%) as a white solid. C 17 H 17 LCMS (ESI) calculation for F3N4O3 [M+H]+ m / z 383.13 was 383.15.

[0392] Preparation of (E)-5-(4-methoxybenzyl)-1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-1-en-1-yl)oxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2305) To a solution of 1-(1-hydroxypropan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2304 (139 mg, 0.3626 mMol), 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (101 mg, 0.356 mMol) in DCM (15 mL) was added P(n-Bu) (37 mg, 0.183 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with PE / EtOAc = 100:0 to 0:100) to give (E)-5-(4-methoxybenzyl)-1-(1-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-1-en-1-yl)oxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2305 (200 mg, purity 90%, yield 74%) as a white solid. C 29 H 28 LCMS (ESI) calculation for F6N8O4 [M+H]+ m / z 667.21 was 667.25.

[0393] Preparation of 5-(4-methoxybenzyl)-1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2306) To a solution of (E)-5-(4-methoxybenzyl)-1-(((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)propan-2-yl)-3-(trifluoromethyl)-1 (10 mL), 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2305 (200 mg, 0.300 mMol) in MeOH was added 10% Pd / C (20 mg). The mixture was evacuated and filled with hydrogen three times, then backfilled with hydrogen. The resulting mixture was stirred at room temperature for 2 h. The mixture was then filtered through Celite and concentrated in vacuo to give crude 5-(4-methoxybenzyl)-1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2306 (190 mg, 90% purity, 85% yield), which was used directly in the next step without further purification. C 29 H 30 LCMS (ESI) calculation for F6N8O4 [M+H]+ m / z 669.23 was 669.25.

[0394] Preparation of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (mixture of 176 and 177) To a solution of 5-(4-methoxybenzyl)-1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2306 (190 mg, 0.284 mMol) in TFA (8 mL) was added TfOH (0.3 mL) at room temperature. The reaction solution was stirred at room temperature for 0.5 hours. The mixture was then cooled to room temperature and stirred for 1 hour. 0°The pH was adjusted to 8-9 with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was 18 Purification by column chromatography (mobile phase: ACN-HO (0.1% FA), gradient: 10%-95%) gave 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (mixture of 176 and 177) (90 mg) as a white solid.

[0395] Chiral Resolution of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (176 and 177) Compounds 176 and 177 were analyzed by SFC (column: DAICEL AD-H 4.6 mm I.D. * 250 mm L 5 μm; mobile phase: CO 2 / The mixture was separated with MEOH (0.1% FA) = 65 / 35) and concentrated under reduced pressure to give the first fraction 176 (31.6 mg, purity 95%, ee 100%, white solid), and the second fraction 177 (27.5 mg, purity 100%, ee 100%, white solid).

[0396] compound 176

[0397] [ka] C 21 H 22 LCMS (ESI) calculation for F6N8O3 [M+H]+ m / z 549.17 was 549.25.

[0398] compound 177

[0399] [ka] C21 H 22 LCMS (ESI) calculation for F6N8O3 [M+H]+ m / z 549.17 was 549.30.

[0400] 15. Synthesis of 1-ethyl-3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (Compound 203)

[0401] [ka] Preparation of 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylic acid (2402) To a solution of (tert-butoxycarbonyl)proline 2401 (74.0 g, 0.34 mol) in DMF (444 mL) at 0 °C, K2CO3 (165 g, 1.20 mol) and MeI (97 g, 0.68 mol) were added. The reaction mixture was stirred at room temperature for 18 h. The reaction solution was quenched with water and extracted with EtOAc (300 mL × 3). The organic phase was concentrated and purified on a silica gel column to give 1-(tert-butyl)2-methylpyrrolidine-1,2-dicarboxylic acid 2402 (65 g, 90% purity, 74% yield) as a yellow oil.

[0402] [ka] Preparation of 1-(tert-butyl) 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylic acid (2403) To a solution of 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylic acid 2402 (32.0 g, 0.139 mol) in CCl4 (8 L) was added NBS (86.6 g, 0.486 mol). The reaction mixture was stirred at 85 °C for 1 h. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (eluted with PE / EtOAc = 90:10) to give 1-(tert-butyl) 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylic acid 2403 (22.8 g, 95% purity, 51% yield) as a yellow oil. C 11 H 14LCMS (ESI) [M -55] + m / z calcd for BrNO4 was 248.01, 248.0.

[0403] Preparation of 1-(tert-butyl) 2-methyl-3-vinyl-1H-pyrrole-1,2-dicarboxylic acid (2405) To a solution of 1-(tert-butyl) 2-methyl-3-bromo-1H-pyrrole-1,2-dicarboxylic acid 2403 (4.2 g, 0.014 mol) in 1,4-dioxane / HO (5:1, 182 mL) at room temperature, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 2404 (5.31 g, 0.035 mol), KCO (3.81 g, 0.028 mol), and Pd(dppf)Cl (1.01 g, 0.0014 mol) were added. The reaction mixture was stirred at 100 °C under N for 3 h. After cooling to room temperature, the reaction solution was quenched with water and extracted with EtOAc (100 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PE / EtOAc = 90:10 to 60:40) to give 1-(tert-butyl) 2-methyl-3-vinyl-1H-pyrrole-1,2-dicarboxylic acid 2405 (1.96 g, purity 80%, yield 45%) as a yellow solid. C 13 H 17 LCMS (ESI) calculation for NO4 [M-55]+ m / z 196.12 was 195.95.

[0404] Preparation of 1-(tert-butyl) 2-methyl 3-formyl-1H-pyrrole-1,2-dicarboxylic acid (2406) To a solution of 1-(tert-butyl)2-methyl-3-vinyl-1H-pyrrole-1,2-dicarboxylic acid 2405 (7.4 g, 0.03 mol) in MeOH / HO (3:1, 400 mL) at 0 °C, KOsO 2HO (1.08 g, 0.003 mol) and NaIO (25.08 g, 0.12 mol) were added. 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. The residue was purified on a silica gel column (elution with PE / EtOAc = 90:10 to 0:100) to give 1-(tert-butyl)2-methyl-3-formyl-1H-pyrrole-1,2-dicarboxylic acid 2406 (3.5 g, 95% purity, 44% yield) as a yellow oil. C 12 H 15 LCMS (ESI) calculation for NO5 [M-99]+ m / z 154.10 was 154.15.

[0405] Preparation of methyl 3-formyl-1H-pyrrole-2-carboxylate (2407) To a solution of methyl 1-(tert-butyl) 2-methyl-3-formyl-1H-pyrrole-1,2-dicarboxylate 2406 (4.3 g, 0.017 mol) in DCM (100 mL) at room temperature was added ZnBr (7.65 g, 0.034 mol). The reaction mixture was stirred at room temperature under N for 18 h. The reaction solution was quenched with water and extracted with EtOAc (50 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (eluting with PE / EtOAc = 90:10 to 60:40) to give methyl 3-formyl-1H-pyrrole-2-carboxylate 2407 (1.2 g, 90% purity, 24% yield) as a yellow oil. LCMS (ESI) calculated for C7H7NO3 [M+H]+ m / z 154.04 was 154.10.

[0406] Preparation of methyl 4-bromo-3-formyl-1H-pyrrole-2-carboxylate (2408) To a solution of methyl 3-formyl-1H-pyrrole 2407-2-carboxylate (320 mg, 2.1 mMol) in THF (12 mL) was added NBS (409 mg, 2.3 mMol) in portions at 0 °C. The reaction was stirred at 0 °C for 2 h. Water was added to quench the reaction. The resulting solution was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 85:15) to give methyl 4-bromo-3-formyl-1H-pyrrole-2-carboxylate 2408 (260 mg, 90% purity, 48% yield) as a white solid. LCMS (ESI) calculated for C7H6BrNO3 [M+H]+ m / z 231.95 was 232.00.

[0407] Preparation of 3-bromo-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (2410) To a room temperature solution of methyl 4-bromo-3-formyl-1H-pyrrole-2-carboxylate 2408 (310 mg, 1.34 mMol) in AcOH (2 mL) was added (4-methoxybenzyl)hydrazine hydrochloride 2409 (504 mg, 2.67 mMol). The reaction mixture was stirred at 80 °C for 18 h. The reaction solution was quenched with water and extracted with EtOAc (50 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (eluting with PE / EtOAc = 90:10 to 60:40) to give 3-bromo-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2410 (125 mg, 90% purity, 25% yield) as a yellow solid. C 14 H 12 LCMS (ESI) calculation for BrN3O2 [M+H]+ m / z 334.01 was 334.10.

[0408] Preparation of 3-bromo-1-ethyl-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (2411) To a 0 °C solution of 3-bromo-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2410 (445 mg, 1.33 mMol) in THF (10 mL) was added NaH (60%, 266 mg, 6.66 mMol). The reaction mixture was stirred with N2 at 0 °C for 10 min. Iodoethane (2076 mg, 13.00 mMol) was then added. The reaction mixture was stirred with N2 at 70 °C for 5 h. After cooling to room temperature, the reaction solution was quenched with ice water and extracted with EtOAc (50 mL × 3). The organic phase was concentrated and purified on a silica gel column to give 3-bromo-1-ethyl-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2411 (410 mg, 1.02 mMol, 76% yield) as a yellow oil. C 16 H 16 LCMS (ESI) calculated for BrN3O2 [M+H]+ m / z 362.04 was 362.00.

[0409] Preparation of 3-allyl-1-ethyl-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (2413) To a solution of 3-bromo-1-ethyl-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2411 (300 mg, 0.83 mMol) in ACN (15 mL) at room temperature was added allyltributylstannane 2412 (822 mg, 2.48 mMol) and Pd(AMPHOS)Cl (117 mg, 0.17 mMol). The reaction mixture was stirred at 100 °C under N in a sealed tube for 3 h. After cooling to room temperature, the resulting reaction mixture was poured into cold saturated aqueous NH Cl and stirred for 5 min. The mixture was then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na SO , and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with PE / EtOAc = 100:0 to 55:45) to give 3-allyl-1-ethyl-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2413 (300 mg, 70% purity, 78% yield) as a yellow oil. C 19 H 21 LCMS (ESI) calculation for N3O2 [M+H]+ m / z 324.16 was 324.20.

[0410] Preparation of 2-(1-ethyl-6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-3-yl)acetaldehyde (2414) To a 0 °C solution of 3-allyl-1-ethyl-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2413 (150 mg, 0.46 mMol) in dioxane / HO (3:1, 10 mL) was added NaIO (397 mg, 1.85 mMol) and KOsO·2HO (17 mg, 0.046 mMol). The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was quenched with water and extracted with EtOAc (20 mL × 3). The organic phase was concentrated under reduced pressure to give 2-(1-ethyl-6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-3-yl)acetaldehyde 2414 (100 mg, 70% purity, 45% yield) as a yellow oil. C 18 H 19LCMS (ESI) calculation for N3O3 [M+H]+ m / z 326.14 was 326.15.

[0411] Preparation of 1-ethyl-3-(2-hydroxyethyl)-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (2415) To a solution of 2-(1-ethyl-6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-3-yl)acetaldehyde 2414 (100 mg, 0.30 mMol) in MeOH (5 mL) at 0 °C was added NaBH4 (46 mg, 1.23 mMol). The reaction mixture was stirred at 0 °C for 1 h. The reaction solution was quenched with water and extracted with EtOAc (10 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 1-ethyl-3-(2-hydroxyethyl)-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2415 (70 mg, 40% purity, 27% yield) as a yellow oil. C 18 H 21 LCMS (ESI) calculation for N3O3 [M+H]+ m / z 328.16 was 328.15.

[0412] Preparation of (E)-1-ethyl-6-(4-methoxybenzyl)-3-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (2416) To a solution of 1-ethyl-3-(2-hydroxyethyl)-6-(4-methoxybenzyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2415 (70 mg, 0.21 mMol) in DCM (5 mL) at room temperature was added 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (79 mg, 0.28 mMol) and P(n-Bu) (22 mg, 0.11 mMol). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with DCM (10 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 95:5) to give (E)-1-ethyl-6-(4-methoxybenzyl)-3-(2-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2416 (70 mg, purity 50%, yield 26%) as a yellow oil. C 30 H 32 LCMS (ESI) calculation for F3N7O4 [M+H]+ m / z 612.25 was 612.20.

[0413] Preparation of 1-ethyl-6-(4-methoxybenzyl)-3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (2417) To a solution of (E)-1-ethyl-6-(4-methoxybenzyl)-3-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-1, 6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2416 (70 mg, 0.057 mMol) in MeOH (10 mL) at rt, Pd / C (24 mg) was added. The reaction mixture was stirred at room temperature under H for 24 h. The reaction solution was filtered and washed with MeOH (10 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 95:5) to give 1-ethyl-6-(4-methoxybenzyl)-3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2417 (30 mg, purity 70%, yield 29%) as a yellow oil. C 30 H 34 LCMS (ESI) calculation for F3N7O4 [M+H]+ m / z 614.26 was 614.20.

[0414] Preparation of 1-ethyl-3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (203) To a solution of 1-ethyl-6-(4-methoxybenzyl)-3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1, 6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 2417 (30 mg, 0.04 mMol) in TFA (3 mL) at room temperature was added TfOH (30 mg, 0.20 mMol). The reaction mixture was stirred at room temperature for 1 h. The reaction solution was quenched with water, and the aqueous solution was adjusted to pH 7-8. The Na2CO3 was concentrated at 0 °C, and the aqueous phase was purified on a Biotage Isolera One (C18 column eluted with 20%–50% MeCN / HO containing 0.1% formic acid) and prep-TLC (DCM / MeOH = 25:1) to give 1-ethyl-3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one 203 (2.8 mg, 93% purity, 13% yield) as a yellow solid.

[0415] [ka] C 22 H 26 LCMS (ESI) calculation for F3N7O3 [M+H]+ m / z 494.20 was 494.25.

[0416] 16. Synthesis of 1-(2-(3-(4-(4-(5-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 215)

[0417] [ka] Preparation of tert-butyl 4-(5-fluorobenzo[d]oxazol-2-yl)piperazine-1-carboxylic acid (2503) tert-Butyl piperazine-1-carboxylic acid (5.54 g, 0.030 mol) (2502) was added to a solution of 5-fluorobenzo[d]oxazole-2(3H)-thione 2501 (2.5 g, 0.015 mol) in xylene (50 mL). The reaction mixture was stirred at 140 °C for 2 h and then concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE, 0-37%) to give tert-butyl 4-(5-fluorobenzo[d]oxazol-2-yl)piperazine-1-carboxylate 2503 (4.42 g, 90% purity, 83% yield) as a white solid. C 16 H 20 LCMS (ESI) calculation for FN3O3 [M+H]+ m / z 322.16 was 322.20.

[0418] Preparation of 5-fluoro-2-(piperazin-1-yl)benzo[d]oxazole hydrochloride (2504) To a round-bottom flask containing tert-butyl 4-(5-fluorobenzo[d]oxazol-2-yl)piperazine-1-carboxylate 2503 (4.42 g, 0.013 mol) was added HCl-dioxane (4 mol / L, 50 mL). The reaction mixture was stirred at room temperature for 20 minutes and concentrated under reduced pressure. The residue was triturated with DCM (30 mL). The precipitate was collected and dried under reduced pressure to give 5-fluoro-2-(piperazin-1-yl)benzo[d]oxazole hydrochloride 2504 (3.41 g, 90% purity, 86% yield) as a white solid. C 11 H 12 LCMS (ESI) calculation for FN3O [M+H]+ m / z 222.10 was 222.20.

[0419] Preparation of 1-(2-(3-(4-(4-(5-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2506) DIPEA (147 mg, 1.135 mMol), 5-fluoro-2-(piperazin-1-yl)benzo[d]oxazole hydrochloride 2504 (70 mg, 0.272 mMol), and T3P (289 mg, 0.454 mMol, 50% in EtOAc) were added to a solution of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 2505 (100 mg, 0.227 mMol) in DCM (10 mL). The mixture was stirred at room temperature for 30 min, washed with water (20 mL), and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE, 0–100%) to give 1-(2-(3-(4-(4-(5-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2506 (150 mg, 90% purity, 92% yield) as a colorless oil. C 30 H 29 LCMS (ESI) calculation for F4N7O5 [M+H]+ m / z 644.22 was 644.15.

[0420] Preparation of 1-(2-(3-(4-(4-(5-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 215) TfOH (0.2 mL) was added to a solution of 1-(2-(3-(4-(5-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2506 (140 mg, 0.217 mMol) in TFA (5 mL) at room temperature. The mixture was stirred at room temperature for 10 min. The pH of the resulting mixture was then adjusted to approximately 8.0 by gradually adding saturated aqueous NaHCO at 0 °C, and the resulting mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. Elute the residue with Biotage Isolera One (30%-40% MeCN / HO containing 0.1% formic acid). 18 Purification on a column afforded 1-(2-(3-(4-(5-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 215 (54.7 mg, 99% purity, 47% yield) as a white solid.

[0421] [ka] C 22 H 21 LCMS (ESI) calculation for F4N7O4 [M+H]+ m / z 524.17 was 524.25.

[0422] 17. Synthesis of 5-(2,2,2-trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (Compounds 221 and 222)

[0423] [ka] Preparation of 2-(4-methoxybenzyl)-5-vinylphthalazin-1(2H)-one (2602) To a solution of 5-bromo-2-(4-methoxybenzyl)phthalazin-1(2H)-one 2601 (1.50 g, 0.0043 mol) in MeCN (50 mL) was added tributyl(vinyl)stannane (2.73 g, 0.0086 mol) and Pd(AMPHOS)Cl (0.15 g, 0.0002 mol). The mixture was heated under reflux for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by flash silica chromatography (elution with EtOAc / PE, 0-15%) to give 2-(4-methoxybenzyl)-5-vinylphthalazin-1(2H)-one 2602 (1.01 g, 74% purity, 60% yield) as a pale yellow solid. C 18 H 16 LCMS (ESI) calculation for N2O2 [M+H]+ m / z 293.13 was 293.16.

[0424] Preparation of 2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazine-5-carbaldehyde (2603) To a solution of 2-(4-methoxybenzyl)-5-vinylphthalazin-1(2H)-one 2602 (1.0 g, 0.0034 mol) in MeOH / HO (3 / 1, 120 mL) was added KOsO·2HO (0.13 g, 0.0003 mol) at 0 °C. After stirring at 0 °C for 10 min, NaIO (2.91 g, 0.0136 mol) was added to the mixture, which was then stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE, 0–56%) to give 2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazine-5-carbaldehyde 2603 (0.43 g, 90% purity, 38% yield) as a white solid. C 17 H 14 LCMS (ESI) calculation for N2O3 [M+H]+ m / z 295.11 was 295.13.

[0425] Preparation of 2-(4-methoxybenzyl)-5-(2,2,2-trifluoro-1-hydroxyethyl)phthalazin-1(2H)-one (2604) TBAF (0.1 mL, 0.139 mMol in THF, 1 mol / L) and TMSCF (297 mg, 2.090 mMol) were added to a solution of 2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazine-5-carbaldehyde 2603 (410 mg, 1.393 mMol) in THF (20 mL). The mixture was stirred at room temperature for 30 min, acidified with HCl (1 mol / L) at 0 °C, and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE, 0–19%) to give 2-(4-methoxybenzyl)-5-(2,2,2 trifluoro-1-hydroxyethyl)phthalazin-1(2H)-one 2604 (300 mg, 90% purity, 53% yield) as a white solid. C 18 H 15 LCMS (ESI) calculation for F3N2O3 [M+H]+ m / z 365.11 was 365.00.

[0426] Preparation of methyl (E)-4-(2,2,2 trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)but-2-enoate (2606) AgO (951 mg, 4.106 mMol) and MgSO (493 mg, 4.106 mMol) were added to a solution of 2-(4-methoxybenzyl)-5-(2,2,2-trifluoro-1-hydroxyethyl)phthalazin-1(2H)-one 2604 (300 mg, 0.821 mMol) in hexane (40 mL). The mixture was heated under reflux for 1 h, and then methyl (E)-4-bromobut-2-enoate 2605 (294 mg, 1.642 mMol) was added. The mixture was heated under reflux for 16 h. After cooling to room temperature, the mixture was filtered to remove AgO, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE, 0–35%) to give methyl (E)-4-(2,2,2 trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)but-2-enoate 2606 (270 mg, 70% purity, 50% yield) as a pale yellow oil. C 23 H 21LCMS (ESI) calculation for F3N2O5 [M+Na]+ m / z 485.11 was 485.22.

[0427] Preparation of methyl 4-(2,2,2-trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoate (2607) To a solution of methyl (E)-4-(2,2,2 trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)but-2-enoate 2606 (260 mg, 0.561 mMol) in MeOH (20 mL) was added Pd / C (10%, 50 mg) at room temperature. The suspension was degassed with H 6 times. The reaction mixture was stirred under an H 2 atmosphere at room temperature for 3 h. The resulting reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give methyl 4-(2,2,2 trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoate 2607 (240 mg, 59% purity, 54% yield) as a yellow oil. LCMS(ESI)C 23 H 23 The F3N2O5[M+H]+ m / z calcd was 465.16, 465.19.

[0428] Preparation of 4-(2,2,2-trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoic acid (2608) To a solution of methyl 4-(2,2,2-trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoate 2607 (230 mg, 0.494 mMol) in THF / HO (3 / 1, 16 mL) was added LiOH (35 mg, 1.483 mMol). The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure to remove THF, acidified with HCl solution (1 mol / L), and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 4-(2,2,2 trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoic acid 2608 (240 mg, 60% purity, 64% yield) as a pale yellow oil. C 22 H 21LCMS (ESI) [M+H]+ m / z calcd of F3N2O5 was 451.15, 451.15.

[0429] Preparation of 2-(4-methoxybenzyl)-5-(2,2,2 trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (2609) To a solution of 4-(2,2,2-trifluoro-1-(2-(4-methoxybenzyl)-1-oxo-1,2-dihydrophthalazin-5-yl)ethoxy)butanoic acid 2608 (230 mg, 0.509 mMol) in DCM (10 mL) was added DIPEA (329 mg, 2.547 mMol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (164 mg, 0.611 mMol), and T3P (50% in EtOAc, 648 mg, 1.019 mMol). The mixture was stirred at room temperature for 30 min, diluted with water (20 mL), and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give 2-(4-methoxybenzyl)-5-(2,2,2 trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one 2609 (300 mg, 70% purity, 62% yield) as a pale yellow oil. C 31 H 30 LCMS (ESI) calculation for F6N6O4 [M+H]+ m / z 665.23 was 665.15.

[0430] Preparation of 5-(2,2,2 trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (Compounds 221 and 222) To a solution of 2-(4-methoxybenzyl)-5-(2,2,2 trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one 2609 (300 mg, 0.451 mMol) in TFA (10 mL) was added TfOH (0.2 mL). The reaction mixture was stirred at room temperature for 10 min, adjusted to pH = 8 by slow addition of saturated aqueous NaHCO3, and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was C 18Purification by column (Agela 40 g, mobile phase: MeCN-HO (0.1% FA), gradient: 40%-50%) gave 5-(2,2,2 trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one 221 and 222 (93 mg, 99%, 37% yield) as a white solid.

[0431] Chiral Resolution of 5-(2,2,2-Trifluoro-1-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)ethyl)phthalazin-1(2H)-one (Compounds 221 and 222) Compounds 221 and 222 were analyzed by SFC (column: Daicel Chiral Pack IC 250 mm x 20 mm, 5 μm inner diameter; mobile phase: CO 2 / MeOH (0.1% NH 3) =65 / 35) and concentrated under reduced pressure to give 221 (24.7 mg, purity 99%, ee 100%, white solid) as the first fraction, and 222 (32.7 mg, purity 99%, ee 100%, white solid) as the second fraction.

[0432] compound 221

[0433] [ka] C 23 H 22 LCMS (ESI) calculation for F6N6O3 [M+H]+ m / z 545.17 was 545.15.

[0434] compound 222

[0435] [ka] C 23 H 22 LCMS (ESI) calculation for F6N6O3 [M+H]+ m / z 545.17 was 545.10.

[0436] 18. Synthesis of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compounds 223 and 224)

[0437] [ka] Preparation of ethyl 1-(1-ethoxy-1-oxopropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (2703) To a stirred solution of NaH (60% mass, 5.95 g, 148.8 mMol) in THF (400 mL) at 0 °C was added ethyl 2-methyl-1H-pyrrole-3-carboxylate (2701) (4.06 g, 26.5 mMol) in portions. After stirring at 0 °C for 15 min, ethyl 2-bromopropanoate (2702) (24.4 g, 134.8 mMol) was added dropwise, and the reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (200 mL × 4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (elution with PE / EtOAc = 100:0 to 95:5) to give ethyl 1-(1-ethoxy-1-oxopropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate 2703 (7.38 g, 98% purity, 72% yield) as an off-white solid. C 13 H 19 LCMS (ESI) calculation for NO4 [M+H]+ m / z 254.13 was 254.10.

[0438] Preparation of ethyl 1-(1-ethoxy-1-oxopropan-2-yl)-2-formyl-1H-pyrrole-3-carboxylate (2704) Ethyl 1-(1-ethoxy-1-oxopropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate 2703 (7.38 g, 28.88 mMol) was dissolved in THF (885 mL) with stirring, and then a solution of AcOH (148 mL) and HO (148 mL) was added. The mixture was stirred homogeneously at 0 °C, and then CAN (94.4 g, 172.5 mMol) was added in portions. After stirring at room temperature for 1 h, the reaction mixture was poured into ice water (2000 mL) and stirred for an additional 30 min. The resulting solution was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 90:10) to give the title compound ethyl 1-(1-ethoxy-1-oxopropan-2-yl)-2-formyl-1H-pyrrole-3-carboxylate 2704 (9.09 g, purity 90%, yield 86%) as a white solid. C 13 H 17 LCMS (ESI) calculation for NO5 [M+H]+ m / z 268.11 was 268.15.

[0439] Preparation of ethyl 4-bromo-1-(1-ethoxy-1-oxopropan-2-yl)-2-formyl-1H-pyrrole-3-carboxylate (2705) To a solution of ethyl 1-(1-ethoxy-1-oxopropan-2-yl)-2-formyl-1H-pyrrole-3-carboxylate 2704 (9.09 g, 33.9 mMol) in ACN (500 mL) was added NBS (5.8 g, 32.5 mMol) in portions. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 70:30) to give ethyl 4-bromo-1-(1-ethoxy-1-oxopropan-2-yl)-2-formyl-1H-pyrrole-3-carboxylate 2705 (3.23 g, 90% purity, 26% yield) as a white solid.

[0440] [ka] Preparation of ethyl 2-(3-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (2706) To a solution of ethyl 4-bromo-1-(1-ethoxy-1-oxopropan-2-yl)-2-formyl-1H-pyrrole-3-carboxylate 2705 (3.23 g, 9.37 mMol) in AcOH (50 mL) was added H2NNH2·HO (80% mass, 630 mg, 15.75 mMol) in one portion. The reaction mixture was heated at 80 °C with stirring for 2 h. The solvent was removed by evaporation under reduced pressure (55 °C). The residue was diluted with DCM (50 mL) and adjusted to pH 8 with saturated aqueous NaHCO3 at 0 °C. The basified solution was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give ethyl 2-(3-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 2706 (2.06 g, 95% purity, 67% yield) as a white solid. C 11 H 12 LCMS (ESI) calculation for BrN3O3 [M+H]+ m / z 314.01 was 314.05.

[0441] Preparation of ethyl 2-(3-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (2707) To a solution of ethyl 2-(3-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 2706 (2.06 g, 6.6 mMol) and DIPEA (4.3 g, 33.3 mMol) in DMF (100 mL) at room temperature was added SEMCl (5.40 g, 32.5 mMol). After the addition was complete, the reaction solution was heated at 80 °C for 1 h. The resulting reaction solution was cooled, poured into cold water, and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 70:30 to 40:60) to give ethyl 2-(3-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 2707 (3 g, 90% purity, 89% yield) as a white solid. C17 H 26 LCMS (ESI) calculated for BrN3O4Si [M+H]+ m / z 444.09 was 444.05.

[0442] Preparation of ethyl 2-(4-oxo-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (2709) A solution of ethyl 2-(3-bromo-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 2707 (2.24 g, 5.0 mMol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 2708 (4.86 g, 25.2 mMol), CuI (1.92 g, 10.1 mMol), and HMPA (4.51 g, 25.2 mMol) in NMP (30 mL) was prepared at room temperature. The mixture was heated at 170 °C in a microwave reactor under a N atmosphere for 1.5 h. The resulting reaction solution was poured into cold water and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography to give ethyl 2-(4-oxo-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 2709 (0.665 g, 65% purity, 33% yield) as a yellow solid. C 18 H 26 LCMS (ESI) calculation for F3N3O4Si [M+H]+ m / z 434.16 was 434.10.

[0443] Preparation of 1-(1-hydroxypropan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (2710) To a suspension of ethyl 2-(4-oxo-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 2709 (665 mg, 1.53 mMol) and LiCl (265 mg, 6.25 mMol) in MeOH (20 mL) was added NaBH (243 mg, 6.42 mMol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with saturated aqueous NH Cl and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give 1-(1-hydroxypropan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 2710 (365 mg, purity 65%, yield 73%) as a yellow oil. C 16 H 24 LCMS (ESI) calculation for F3N3O3Si [M+H]+ m / z 392.15 was 392.17.

[0444] Preparation of (E)-1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-1-en-1-yl)oxy)propan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (2711) A round-bottom flask containing a mixture of 1-(1-hydroxypropan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 2710 (130 mg, 0.332 mMol), 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (124 mg, 0.437 mMol), and P(n-Bu) (68 mg, 0.337 mMol) in DCM (20 mL) was stirred at room temperature for 16 h. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH=90:10) to give (E)-1-(((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-1-en-1-yl)oxy)propan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 2711 (156 mg, 70% purity, 69% yield) as a yellow solid. C 28 H 35 LCMS (ESI) calculation for F6N7O4Si[M+H]+ m / z 676.24 was 676.20.

[0445] Preparation of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (2712) A mixture of compound (E)-1-(1-((3-oxo-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)propan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 2711 (156 mg, 0.231 mMol) and Pd(OH) (150 mg) was stirred in MeOH (20 mL) under a H atmosphere at room temperature for 16 hours. The resulting mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent DCM / MeOH=98:2) to give 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 2712 (83 mg, 80% purity, 70% yield) as a white solid. C 28 H 37 LCMS (ESI) calculation for F6N7O4Si[M+H]+ m / z 678.26 was 678.30.

[0446] Preparation of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (223 and 224) A round-bottom flask containing a mixture of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 2712 (83 mg, 0.123 mMol), HCl in 1,4-dioxane (4 M, 15 mL) was stirred at room temperature for 12 hours. The resulting mixture was concentrated to dryness under reduced pressure. The mixture was adjusted to pH 8-9 with saturated aqueous NaHCO3 and then extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by C 18Purification on an Agela 40 g column (mobile phase: ACN-HO (0.1% FA), gradient: 10%-95%) afforded 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 223 and 224 (54 mg, purity 88%, yield 77%) as a white solid. C 22 H 23 LCMS (ESI) calculation for F6N7O3 [M+H]+ m / z 548.18 was 548.27.

[0447] Chiral Separation of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (223 and 224) Compounds 223 and 224 were purified by SFC (column: DAICEL AD-H 4.6 mM ID × 250 mM 5 μm; mobile phase: CO 2 / MeOH (0.1% NH 3) =70 / 30) and concentrated under reduced pressure to give the first fraction as 223 (14.0 mg, purity 99%, ee 100%, off-white solid) and the second fraction as 224 (15.2 mg, purity 99%, ee 93%, white solid).

[0448] compound 223

[0449] [ka] C 22 H 23 LCMS (ESI) calculation for F6N7O3 [M+H]+ m / z 548.18 was 548.15.

[0450] compound 224

[0451] [ka] C 22 H 23 LCMS (ESI) calculation for F6N7O3 [M+H]+ m / z 548.18 was 548.15. [ka]

[0452] Preparation of ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2802) Ethyl 2-chloro-4,4,4-trifluorooxobutanoate 2801 (2180 mg, 10 mMol) was mixed with formamide (4492 mg, 100 mMol) and water (0.4 mL). 30° The mixture was heated at RT for 1.5 h. The mixture was then cooled to room temperature, and 8 mL of ice water was added. The resulting solid was collected, washed with water, and then dried under reduced pressure to give ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate 2802 (440 mg, 90% purity, 19% yield) as a brown solid. LCMS (ESI) calculation for C7H7F3N2O2 [M+H]+ m / z 209.05 was 209.10.

[0453] Preparation of ethyl 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2803) To a solution of ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate 2802 (1500 mg, 7.2 mMol) in CHCN (15 mL) was added NBS (1530 mg, 8.4 mMol). 5° The mixture was stirred at RT for 2 h. Water was added to quench the reaction. The resulting solution was extracted with EtOAc (40 mL × 4). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 95:5) to give ethyl 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate 2803 (1560 mg, 90% purity, 67% yield) as a white solid. LCMS (ESI) calculated for C7H6BrF3N2O2 [M+H]+ m / z 286.95 was 287.00.

[0454] Preparation of ethyl 2-bromo-1-(cyanomethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2804) To a solution of NaH (60%, 600 mg, 15 mMol) in DMF (5 mL) was added dropwise a solution of ethyl 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (2803) (1440 mg, 5 mMol) and 2-bromoacetonitrile (600 mg, 5 mMol) in DMF (20 mL) at 0 °C under a N atmosphere. The reaction mixture was warmed to 70 °C and stirred for an additional 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into cold saturated aqueous NH4Cl. The resulting solution was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with PE / EtOAc = 100:0 to 90:10) to give ethyl 2-bromo-1-(cyanomethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate 2804 (1250 mg, 90% purity, 68.8% yield) as a white solid. LCMS (ESI) calculated for C9H7BrF3N3O2 [M+H]+ m / z 325.97 was 326.05.

[0455] Preparation of 3-bromo-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (2805) To a solution of ethyl 2-bromo-3-(cyanomethyl)-5-(trifluoromethyl)imidazole-4-carboxylate 2804 (1280 mg, 4 mMol) in THF (40 mL) was slowly added BH3-THF (1 M, 20 mL, 20 mMol) at 0 °C. After the addition was complete, the reaction solution was warmed to room temperature and continued stirring at room temperature for an additional 5 h. MeOH (15 mL) was added dropwise to the resulting reaction solution to quench the BH3-THF at rt (CAUTION: gas evolved), then concentrated under reduced pressure to give ethyl 1-(2-aminoethyl)-2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (600 mg, 85% purity, 40% yield) as a white oil. C9H 11 LCMS (ESI) calculation for BrF3N3O2 [M+H]+ m / z 330.0 was 330.05.

[0456] Ethyl 1-(2-aminoethyl)-2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (1200 mg, 3.6 mMol) was diluted with NH3-MeOH (7 M, 7 mL) and stirred at room temperature overnight. LCMS monitored the formation of the product, and the reaction mixture was evaporated under reduced pressure to give 3-bromo-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2805 (700 mg, 75% purity, 51% yield) as a white solid. LCMS (ESI) calculated for C7H5BrF3N3O [M+H]+ m / z 283.96 was 284.00.

[0457] Preparation of 3-bromo-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (2806) To a solution of t-BuOK (664 mg, 6 mMol) in DMF (12 mL) was slowly added a solution of 3-bromo-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2805 (560 mg, 2 mMol) and PMBCl (926 mg, 6 mMol) in DMF (8 mL) at 0 °C under a N atmosphere. After the addition was complete, the reaction was warmed to room temperature and stirred at room temperature for an additional 1.5 h. The resulting reaction mixture was poured into cold saturated aqueous NH4Cl and stirred for 5 min. The solution was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with PE / EtOAc = 100:0 to 55:45) to give 3-bromo-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2806 (600 mg, 90% purity, 67% yield) as a yellow solid. C 15 H 13 LCMS (ESI) calculated for BrF3N3O2 [M+H]+ m / z 404.01 was 404.10.

[0458] Preparation of (E)-3-(2-ethoxyvinyl)-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (2807) A solution of 3-bromo-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2806 (480 mg, 1.2 mMol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (471 mg, 2.4 mMol), KPO (278 mg, 1.2 mMol), and Pd(dppf)Cl (87 mg, 0.12 mMol) in dioxane / HO (30 mL, 3:1) was stirred at 80 °C for 4 h under a N atmosphere. After cooling to room temperature, the reaction mixture was added to cold water and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to give (E)-3-(2-ethoxyvinyl)-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2807 (480 mg, 70% purity, 74% yield) as a colorless oil. C 19 H 20 LCMS (ESI) calculation for F3N3O3 [M+H]+ m / z 396.15 was 396.0.

[0459] Preparation of 2-7-(4-methoxybenzyl)-8-oxo-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)acetaldehyde (2808) To a solution of (E)-3-(2-ethoxyvinyl)-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6, 7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2807 (390 mg, 1 mMol) in THF (30 mL) was added in portions with 2 M aqueous HCl (15 mL). The solution was then stirred at 70 °C for 5 h. The resulting reaction solution was basified (pH 8) with saturated aqueous NaHCO at 0 °C and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The crude 2-7-(4-methoxybenzyl)-8-oxo-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)acetaldehyde 2808 (crude 200 mg, 80% purity, 44.3% yield) was used directly as a brown oil in the next step. C 17 H 16 LCMS (ESI) calculation for F3N3O3 [M+H]+ m / z 368.11 was 368.20.

[0460] Preparation of 3-(2-hydroxyethyl)-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (2809) To a solution of 2-7-(4-methoxybenzyl)-8-oxo-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)acetaldehyde 2808 (900 mg, 2.5 mMol) in MeOH (10 mL) was added NaBH4 (140 mg, 3.6 mMol) in portions at 0 °C. The solution was warmed to room temperature and stirred for 1 h. Saturated aqueous NH4Cl (15 mL) was added to the reaction solution and stirred for 5 min. The resulting solution was extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with PE / EtOAc = 50:50 to 0:100) to give 3-(2-hydroxyethyl)-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2809 (620 mg, 90% purity, 62% yield) as a yellow solid. C 17 H18 LCMS (ESI) calculation for F3N3O3 [M+H]+ m / z 370.13 was 370.15.

[0461] Preparation of (E)-7-(4-methoxybenzyl)-3-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (2810) To a solution of 3-(2-hydroxyethyl)-7-(4-methoxybenzyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2809 (200 mg, 0.56 mMol) and 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (168 mg, 0.60 mMol) in DCM (20 mL) was added P(n-Bu). 3( To the resulting solution was added dropwise (56 mg, 0.28 mMol). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. The resulting solution was evaporated under reduced pressure to give a crude deep brown solid, which was purified by flash silica chromatography (elution with PE / EtOAc = 50:50 to 0:100) to give (E)-7-(4-methoxybenzyl)-3-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)ethyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2810 (228 mg, 90% purity, 58% yield) as a yellow solid. C 29 H 29 LCMS (ESI) calculation for F6N7O4 [M+Na]+ m / z 676.21 was 676.75.

[0462] Preparation of 2-(4-methoxybenzyl)-6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (2811) A solution of (E)-7-(4-methoxybenzyl)-3-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one 2810 (280 mg, 0.43 mMol) and Pd / C (46 mg) in MeOH (10 mL) was stirred at room temperature under a H atmosphere for 1 h. The resulting solution was filtered through diatomaceous earth, and the filter cake was washed with MeOH (10 mL × 4). The filtrate was concentrated under reduced pressure to give 2-(4-methoxybenzyl)-6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 2811 (99 mg, 90% purity, 32% yield) as a colorless oil, which was used directly in the next step without further purification. C 29 H 31 LCMS (ESI) calculation for F6N7O4 [M+H]+ m / z 656.23 was 656.30.

[0463] Preparation of 3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (Compound 235) To a solution of 2-(4-methoxybenzyl)-6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-3, 4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 2811 (100 mg, 0.15 mMol) in TFA (10 mL) was added TfOH (228 mg, 1.5 mMol) at room temperature. After the addition was complete, the reaction solution was stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure to remove most of the TFA. The residue was diluted with DCM (20 mL) and then adjusted to pH 8 with saturated aqueous NaHCO3 at 0 °C. The basified solution was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash silica chromatography (eluent: DCM / MeOH = 100:0 to 90:10) and a C18 column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 30-60°C) to give 3-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-1-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (compound 235, 14.6 mg, purity 100%, yield 17%) as a white solid.

[0464] [ka] C 21 H 23 LCMS (ESI) calculation for F6N7O3 [M+H]+ m / z 536.18 was 536.30.

[0465] 20. Synthesis of 3-(difluoromethyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 236)

[0466] [ka] Preparation of 5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2902) To a solution of 5-(dimethylamino)-2-(2-methoxy-5-methylphenyl)-3-oxopyridazine-4-carbaldehyde 1905 (2.6 g, 0.009 mol) in EtOH (50 mL) was added H2NNH2·HO (80% mass, 2.0 g, 0.050 mol) at room temperature. The reaction mixture was stirred at 80 °C for 24 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (elution with PE / EtOAc = 20:80 to 0:100) to give 5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2902 (1.5 g, 90% purity, 59% yield) as a white solid. C 13 H 12 LCMS (ESI) calculation for N4O2 [M+H]+ m / z 257.10 was 257.13.

[0467] Preparation of 3-bromo-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2903) To a solution of 5-(2-methoxy-5-methylphenyl)-1H-pyrazolo[3,4-d]pyridazin-4-one 2902 (1.13 g, 4.4 mMol) in EtOH / HO (1:1, 20 mL) was added NaOAc (2.53 g, 30.8 mMol) and Br (2.81 g, 17.6 mMol) successively at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with saturated aqueous NaSO and extracted with EtOAc (50 mL × 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 85:15 to 70:30) to give 3-bromo-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2903 (1.08 g, 90% purity, 66% yield) as a yellow solid. C 13 H 11 LCMS (ESI calculation) for BrNO [M+H] m / z 335.01 was 335.10.

[0468] Preparation of ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate (2905) To a solution of 3-bromo-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2903 (1.0 g, 3.0 mMol) in DMF (20 mL) was added t-BuOK (1.01 g, 9.0 mMol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and 2-bromoethyl acetate 2904 (1.5 g, 9.0 mMol) was added dropwise at 0 °C. The reaction solution was stirred at room temperature for 2 h. The reaction solution was quenched with ice water and extracted with EtOAc (20 mL × 3). The organic phase was concentrated and purified by flash column chromatography (eluting with PE / EtOAc = 85:15 to 50:50) to give ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate 2905 (1.3 g, 90% purity, 97% yield) as a white solid. C 17 H 17 LCMS (ESI) calculated for BrN4O4 [M+H]+ m / z 421.04 was 421.15.

[0469] Preparation of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-vinyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate (2907) To a solution of ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate 2905 (1.35 g, 3.2 mMol) in ACN (30 mL) was added tributyl(vinyl)stannane 2906 (1.52 g, 4.8 mMol) and Pd(AMPHOS)Cl (230 mg, 0.3 mMol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 40:60) to give 2-(5-(4-methoxybenzyl)-4-oxo-3-vinyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethyl acetate 2907 (1.0 g, 90% purity, 75% yield) as a yellow solid. C 19 H 20LCMS (ESI) calculation for N4O4 [M+H]+ m / z 369.15 was 369.20.

[0470] Preparation of ethyl 2-(3-formyl-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate (2908) To a solution of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-vinyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate 2907 (770 mg, 2.09 mMol) in dioxane / HO (3:1, 20 mL) was added KOsO·2HO (77 mg, 0.21 mMol) and NaIO (1.8 g, 8.36 mol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was diluted with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to 50:50) to give 2-(3-formyl-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethyl acetate 2908 (520 mg, purity 90%, yield 60%) as a yellow oil. C 18 H 18 LCMS (ESI) calculation for N4O5 [M+H]+ m / z 371.13 was 371.20.

[0471] Preparation of ethyl 2-(3-(difluoromethyl)-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)acetate (2909) To a solution of 2-(3-formyl-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethyl acetate 2908 (0.5 g, 1.35 mMol) in DCM (20 mL) was added DAST (1.74 g, 10.8 mMol) dropwise at 0 °C under a N atmosphere. The reaction solution was stirred at room temperature for 2 h. The reaction was quenched with aqueous NaHCO3, and the aqueous layer was extracted with DCM (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 70:30 to 50:50) to give 2-(3-(difluoromethyl)-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethyl acetate 2909 (420 mg, purity 90%, yield 71%) as a white solid. C 18 H 18 LCMS (ESI) calculation for F2N4O4 [M+H]+ m / z 393.13 was 393.18.

[0472] Preparation of 3-(difluoromethyl)-1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2910) To a solution of ethyl acetate 2-(3-(difluoromethyl)-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl) 2909 (320 mg, 0.81 mMol) in EtOH (10 mL) was added LiCl (138 mg, 3.26 mMol) and NaBH (123 mg, 3.26 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with EtOAc / PE, 0–50%) to give 3-(difluoromethyl)-1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2910 (270 mg, purity 80%, yield 75%) as a white solid. C 16 H 16LCMS (ESI) calculation for F2N4O3 [M+H]+ m / z 351.12 was 351.20.

[0473] Preparation of (E)-3-(difluoromethyl)-5-(4-methoxybenzyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2911) To a solution of 3-(difluoromethyl)-1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2910 (150 mg, 0.42 mMol) and 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one (122 mg, 0.42 mMol) in DCM (15 mL) was added P(n-Bu) (43 mg, 0.21 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified on a silica gel column (elution with EtOAc / PE, 0–100%) to give (E)-3-(difluoromethyl)-5-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2911 (190 mg, 90% purity, 63% yield) as a white solid. C 28 H 27 LCMS (ESI) calculation for F5N8O4 [M+H]+ m / z 635.21 was 635.40.

[0474] Preparation of 3-(difluoromethyl)-5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (2912) To a solution of (E)-3-(difluoromethyl)-5-(4-methoxybenzyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2911 (100 mg, 0.15 mMol) in MeOH (10 mL) was added 10% Pd / C (10 mg). The mixture was evacuated and filled with hydrogen three times, then backfilled with hydrogen. The resulting mixture was stirred at room temperature under N for 2 h. The mixture was then filtered through Celite and concentrated in vacuo to give 3-(difluoromethyl)-5-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2912 (100 mg, 90% purity, 90% yield), which was used directly in the next step without further purification. C 28 H 29 LCMS (ESI) calculation for F5N8O4 [M+H]+ m / z 637.22 was 637.35.

[0475] Preparation of 3-(difluoromethyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compound 236) To a solution of 3-(difluoromethyl)-5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 2912 (100 mg, 0.15 mMol) in TFA (1 mL) was added dropwise with TfOH (707 mg, 4.71 mMol). The mixture was stirred at room temperature for 2 h. The resulting light brown solution was concentrated under reduced pressure to remove most of the TFA. The residue was diluted with DCM (10 mL) and the pH was adjusted to 8 with saturated aqueous NaHCO3 at 0 °C. The basified solution was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was C 18Purification on an Agela 40 g column (mobile phase: ACN-HO (0.1% FA), gradient: 30%-60%) afforded 3-(difluoromethyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 236 (39.4 mg, 100% purity, 48% yield) as a white solid.

[0476] [ka] C 20 H 21 LCMS (ESI) calculation for F5N8O3 [M+H]+ m / z 517.17 was 517.29.

[0477] 21. Synthesis of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridine-2,5(1H,3H)-dione (Compound 240)

[0478] [ka] Preparation of 2-((benzyloxy)methyl)-4,5-dichloropyridazin-3(2H)-one (3002) To a solution of 4,5-dichloropyridazin-3(2H)-one 1901 (10 g, 0.061 mol) in DMF (100 mL) at 0 °C, BOMCl (11.39 g, 0.073 mol) and DBU (11.07 g, 0.073 mol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was quenched with water and extracted with EtOAc (50 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (eluting with PE / EtOAc = 100:0 to 95:5) to give 2-((benzyloxy)methyl)-4,5-dichloropyridazin-3(2H)-one 3002 (13.5 g, 90% purity, 70% yield) as a white solid. C 12 H 10 LCMS (ESI) calculated for Cl2N2O2 [M+H]+ m / z 285.01 was 284.95.

[0479] Preparation of ethyl (1-((benzyloxy)methyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)glycinate (3004) To a solution of 2-((benzyloxy)methyl)-4 in DMF (230 mL) at room temperature, 5-dichloropyridazin-3(2H)-one 3002 (13.5 g, 0.047 mol), ethyl 2-aminoacetate HCl salt 3003 (5.37 g, 0.052 mol), and DIPEA (18.34 g, 0.14 mol) were added. The reaction mixture was stirred at 100 °C for 3 h. The reaction solution was quenched with water and extracted with EtOAc (300 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 70:30) to give ethyl (1-((benzyloxy)methyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)glycinate 3004 (15 g, 90% purity, 81% yield) as a yellow solid. C 16 H 18 LCMS (ESI) calculated for ClN3O4 [M+H]+ m / z 352.10 was 352.05.

[0480] Preparation of 2-((benzyloxy)methyl)-4-chloro-5-((2-hydroxyethyl)amino)pyridazin-3(2H)-one (3005) To a solution of ethyl (1-((benzyloxy)methyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)glycinate 3004 (4.2 g, 0.012 mol) in EtOH (300 mL) at 0 °C, NaBH4 (1.80 g, 0.048 mol) and LiCl (2.02 g, 0.048 mol) were added. 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. The residue was purified on a silica gel column (eluted with PE / EtOAc = 100:0 to 0:100) to give 2-((benzyloxy)methyl)-4-chloro-5-((2-hydroxyethyl)amino)pyridazin-3(2H)-one 3005 (3.4 g, 90% purity, 83% yield) as a yellow solid. C 14 H 16 LCMS (ESI) calculated for ClN3O3 [M+H]+ m / z 310.09 was 310.00.

[0481] Preparation of ethyl (E)-3-(2-((benzyloxy)methyl)-5-((2-hydroxyethyl)amino)-3-oxo-2,3-dihydropyridazin-4-yl)acrylate (3007) To a solution of 2-((benzyloxy)methyl)-4-chloro-5-((2-hydroxyethyl)amino)pyridazin-3(2H)-one 3005 (3.0 g, 0.0097 mol) in t-BuOH (120 mL) at room temperature, ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate 3006 (2.63 g, 0.012 mol), Pd(dba) (0.27 g, 0.0003 mol), XPhos (0.55 g, 0.0012 mol), and KPO·HO (5.58 g, 0.024 mol) were added. The reaction mixture was stirred with N under microwave heating at 130 °C for 10 min. The reaction solution was quenched with water and extracted with EtOAc (100 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution with PE / EtOAc = 90:10 to 0:100) to give ethyl (E)-3-(2-((benzyloxy)methyl)-5-((2-hydroxyethyl)amino)-3-oxo-2,3-dihydropyridazin-4-yl)acrylate 3007 (1.2 g, purity 95%, yield 32%) as a yellow solid. C 19 H 23 LCMS (ESI) calculation for N3O5 [M+H]+ m / z 374.16 was 374.10.

[0482] Preparation of ethyl 3-(2-((benzyloxy)methyl)-5-((2-hydroxyethyl)amino)-3-oxo-2,3-dihydropyridazin-4-yl)propanoate (3008) To a solution of ethyl (E)-3-(2-((benzyloxy)methyl)-5-((2-hydroxyethyl)amino)-3-oxo-2,3-dihydropyridazin-4-yl)acrylate 3007 (1.2 g, 0.0032 mol) in DCM (5 mL) and MeOH (20 mL) at rt was added Pd / C (0.29 g, 0.0013 mol). The reaction mixture was stirred at room temperature for 4 h. The reaction solution was filtered and concentrated under reduced pressure to give ethyl 3-(2-((benzyloxy)methyl)-5-((2-hydroxyethyl)amino)-3-oxo-2,3-dihydropyridazin-4-yl)propanoate 3008 (1.1 g, 95% purity, 87% yield) as a yellow oil. C 19 H 25LCMS (ESI) calculation for N3O5 [M+H]+ m / z 376.18 was 376.05.

[0483] Preparation of 6-((benzyloxy)methyl)-1-(2-hydroxyethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione (3009) To a solution of ethyl 3-(2-((benzyloxy)methyl)-5-((2-hydroxyethyl)amino)-3-oxo-2,3-dihydropyridazin-4-yl)propanoate 3008 (1.1 g, 0.0029 mol) in EtOH (50 mL) at room temperature was added 10% aqueous HCl (20 mL). The reaction mixture was stirred at 80 °C for 8 h. The reaction was then quenched with water, and the pH was adjusted to 7-8 with 1 M aqueous NaOH at 0 °C. The reaction solution was 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 0:100) to give 6-((benzyloxy)methyl)-1-(2-hydroxyethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 3009 (0.85 g, purity 95%, yield 86%) as a yellow solid.

[0484] [ka] C 17 H 19 LCMS (ESI) calculation for N3O4 [M+H]+ m / z 330.14 was 330.10.

[0485] Preparation of (E)-6-((benzyloxy)methyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione (3010) To a solution of 6-((benzyloxy)methyl)-1-(2-hydroxyethyl)-4, 6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 3009 (140 mg, 0.425 mMol) in DCM (100 mL) was added 1-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)prop-2-yn-1-one (120 mg, 0.425 mMol) and P(n-Bu) (135 mg, 0.425 mMol) successively at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with EtOAc / PE from 50% to 100%) to give (E)-6-((benzyloxy)methyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)prop-1-en-1-yl)oxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 3010 (150 mg, purity 90%, yield 52%) as a yellow solid. C 30 H 31 LCMS (ESI) calculation for F3N6O5 [M+H]+ m / z 613.23 was 613.10.

[0486] Preparation of 6-((benzyloxy)methyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione (3011) To a solution of (E)-6-((benzyloxy)methyl)-1-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-4, 6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 3010 (140 mg, 0.229 mMol) in MeOH (20 mL) was added 10% Pd / C (140 mg). The mixture was evacuated and filled with hydrogen three times, then back-filled with hydrogen. The resulting mixture was stirred at room temperature for 2 h. The mixture was then filtered through Celite, concentrated under vacuum, and purified by flash column chromatography (eluent MeOH / DCM, 0% to 10%) to give 6-((benzyloxy)methyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 3011 (115 mg, 90% purity, 74% yield) as a yellow solid. C 30 H 33 LCMS (ESI) calculation for F3N6O5 [M+H]+ m / z 615.25 was 615.30.

[0487] Preparation of 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)proxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione (Compound 240) A solution of 6-((benzyloxy)methyl)-1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 3011 (115 mg, 0.187 mMol) in TFA (5 mL) was stirred at room temperature for 2 h. The pH was adjusted to approximately 8 by slow addition of saturated aqueous NaHCO3 at 0 °C, and the mixture was then extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by Biotage Isolera One (C) eluting with 0% to 55% MeCN / HO containing 0.1% formic acid. 18Purification on a column afforded 1-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)proxy)ethyl)-4,6-dihydropyrido[2,3-d]pyridazine-2,5(1H,3H)-dione 240 (34.0 mg, 93% purity, 35% yield) as a solid.

[0488] [ka] C 22 H 25 LCMS (ESI) calculation for F3N6O4 [M+H]+ m / z 495.19 was 495.25.

[0489] 22. Synthesis of 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 248 and 249)

[0490] [ka] Preparation of tert-butyl 4-(5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (3103) 2-Chloro-5-fluoropyrimidine 3101 (500 mg, 3.77 mMol), tert-butyl piperazine-1-carboxylate 3102 (843.28 mg, 4.53 mMol), and DIPEA (975.28 mg, 7.55 mMol) were dissolved in IPA (10 mL). The resulting mixture was heated in a microwave reactor at 120 °C for 2 h. The mixture was then cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (2 × 30 mL). The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with EtOAc / PE, 0–20%) to give tert-butyl 4-(5-fluoropyrimidin-2-yl)piperazine-1-carboxylate 3103 (300 mg, 85% purity, 24% yield) as a white solid. C 13 H 19 LCMS (ESI) calculation for FN4O2 [Mt-Bu+H]+ m / z 227.16 was 227.0.

[0491] Preparation of 5-fluoro-2-(piperazin-1-yl)pyrimidine hydrochloride (3104) To a 50 mL round-bottom flask was added tert-butyl 4-(5-fluoropyrimidin-2-yl)piperazine-1-carboxylate 3103 (300 mg, 1.059 mMol) and HCl-dioxane (4 M, 15 mL). The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to give 5-fluoro-2-(piperazin-1-yl)pyrimidine hydrochloride 3104 (225 mg, 85% purity, 82.6% yield) as a white solid. C8H 11 The LCMS (ESI) calculation for FN4 [M+H] + m / z 183.11 was 183.0.

[0492] Preparation of 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (3105) To a solution of 5-fluoro-2-(piperazin-1-yl)pyrimidine hydrochloride 3104 (200 mg, 0.44 mMol) in DCM (10 mL) was added 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 2505 (116 mg, 0.52 mMol), T3P (50% in EtOAc, 560 mg, 0.88 mMol), and DIPEA (284 mg, 2.2 mMol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Gemini 5 μm C 18 Purification with 150 × 21.2 mM, mobile phase: ACN-HO (0.1% FA), gradient: 50%-95% yielded 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 3105 (116 mg, 98% purity, 42% yield) as a white solid. C 28 H 30 LCMS (ESI) calculation for F4N8O4 [M+H]+ m / z 619.24 was 619.0.

[0493] Preparation of 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 248 and 249) TfOH (0.2 mL) was added to a solution of 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 3105 (100 mg, 0.16 mMol) in TFA (10 mL). The reaction mixture was stirred at room temperature for 10 h, and then the pH was adjusted to 8 by slowly adding saturated aqueous NaHCO3 at 0 °C. The mixture was then extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was C 18 Purification twice on an Agela 40 g column (mobile phase: ACN-HO (0.1% FA), gradient: 40%-50%) gave 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (compounds 248 and 249) (50 mg, purity 98%, yield 61%) as a white solid. C 20 H 22 LCMS (ESI) calculation for F4N8O3 [M+H]+ m / z 499.19 was 499.0.

[0494] Chiral Resolution of 1-(1-(3-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 248 and 249) Compounds 248 and 249 were purified by SFC (column: DAICEL OJ-H 4.6 mM ID × 250 mM 5 μm; mobile phase: CO 2 / The mixture was separated with MeOH (0.1% FA) = 60 / 40) and concentrated under reduced pressure to give the first fraction 248 (16.7 mg, purity 98%, ee 100%, white solid), and the second fraction 249 (19.3 mg, purity 98%, ee 97%, white solid).

[0495] compound 248

[0496] [ka] C 20 H 22 LCMS (ESI) calculation for F4N8O3 [M+H]+ m / z 499.19 was 499.0.

[0497] compound 249

[0498] [ka] C 20 H 22 LCMS (ESI) calculation for F4N8O3 [M+H]+ m / z 499.19 was 499.0.

[0499] 23. Synthesis of 6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Compound 316)

[0500] [ka] Preparation of methyl 3-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate (3202) To a suspension of NaH (60%, 0.98 g, 0.0245 mol) in DMF (50 mL) was added dropwise a solution of methyl 3-bromo-1H-pyrrole-2-carboxylate (1 g, 0.0049 mol) and 2-bromoacetonitrile (2.94 g, 0.0245 mMol) in DMF 3201 (10 mL) under a N atmosphere at 0 °C. The reaction mixture was warmed to 70 °C and stirred at 70 °C for an additional 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into cold saturated aqueous NH4Cl. The resulting solution was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE 0% to 10%) to give methyl 3-bromo-1-(cyanomethyl)-1H-pyrrole-2-carboxylate 3202 (0.8 g, 90% purity, 31% yield) as a white solid.

[0501] Preparation of methyl 1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (3204) To a stirred solution of methyl 3-bromo-1-(cyanomethyl)pyrrole-2-carboxylate 3202 (800 mg, 3.29 mMol), CuI (626 mg, 3.29 mMol), and HMPA (2949 mg, 16.46 mMol) in NMP (20 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 3203 (3161 mg, 16.46 mMol) at room temperature. The solution was then stirred at 110 °C for 3 h. The resulting reaction solution was filtered, and the filtrate was directly purified by flash silica chromatography (elution with EtOAc / PE, 10%-20%) to give 1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid 3204 (250 mg, 90% purity, 29% yield) as a yellow solid.

[0502] Preparation of methyl 5-bromo-1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (3205) To a solution of methyl 1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 3204 (100 mg, 0.429 mMol) in DCE (5 mL) was added NBS (114 mg, 0.643 mMol) and TFA (24 mg, 0.214 mMol) at room temperature. The mixture was heated at 80 °C for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with DCM (10 mL × 3). The combined organic phase was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (elution with EtOAc / PE, 10%–20%) to give methyl 5-bromo-1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 3205 (40 mg, 90% purity, 26% yield) as a white solid.

[0503] Preparation of 6-bromo-8-(trifluoromethyl)-3,4-dihydropyrrole[1,2-a]pyrazin-1(2H)-one (3206) A solution of methyl 5-bromo-1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 3205 (600 mg, 1.9289 mMol) in THF (10 mL) was treated with BH at 0 °C. 3-THF (1M, 9.6 mL, 9.6 mMol) was slowly added. After the addition was complete, the reaction solution was warmed to room temperature and continued to stir at room temperature for an additional 16 hours. MeOH (50 mL) was added dropwise to the resulting reaction solution to quench the BH3-THF at room temperature and concentrated under reduced pressure. The residue was treated with NH 3- The mixture was diluted with MeOH (7 M, 12.3 mL) and stirred overnight at room temperature. LCMS monitored the formation of the product, and the reaction mixture was concentrated and purified by silica gel column chromatography (elution with EtOAc / PE, 30% to 70%) to give 6-bromo-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3206 (250 mg, 90% purity, 41% yield) as a white solid. LCMS (ESI) calculated for C8H6BrF3N2O [M+H]+ m / z 282.96 was 282.95.

[0504] Preparation of 6-bromo-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3207) To a solution of t-BuOK (0.2 g, 1.77 mMol) in DMF (10 mL) was slowly added a solution of 6-bromo-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3206 (0.25 g, 0.883 mMol) and PMBCl (0.28 g, 1.77 mMol) in DMF (5 mL) at 0 °C under a N atmosphere. After the addition was complete, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The resulting reaction mixture was poured into cold saturated aqueous NH4Cl and stirred for 5 min. The solution was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with bottles (30 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE 20%–40%) to give 6-bromo-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3207 (0.2 g, 90% purity, 50% yield) as a white solid. C 16 H 14LCMS (ESI) calculated for BrF3N2O2 [M+H]+ m / z 403.02 was 403.10.

[0505] Preparation of (E)-6-(2-ethoxyvinyl)-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3209) A suspension of 6-bromo-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3207 (200 mg, 0.50 mMol), KCO (137 mg, 0.99 mMol), and Pd(dppf)Cl (36 mg, 0.496 mMol) in dioxane / HO (10 / 1, 10 mL) was heated at 100 °C for 2 h under N. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (elution with EtOAc / PE, 0–35%) to give (E)-6-(2-ethoxyvinyl)-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3209 (120 mg, 90% purity, 55% yield) as a white solid. C 20 H 21 LCMS (ESI) calculation for F3N2O3 [M+H]+ m / z 395.15 was 395.10.

[0506] Preparation of 2-(4-methoxybenzyl)-1-oxo-8-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)acetaldehyde (3210) To a solution of (E)-6-(2-ethoxyvinyl)-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3 (8 mL) in DCM, 4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3209 (120 mg, 0.304 mMol) was added dropwise with HCl in dioxane (4 M, 2 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes. The resulting mixture was concentrated under reduced pressure to give 2-2-(4-methoxybenzyl)-1-oxo-8-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)acetaldehyde 3210 (100 mg, 50% purity, 44% yield) as a yellow oil. C18 H 17 LCMS (ESI) calculation for F3N2O3 [M+H]+ m / z 367.12 was 367.10.

[0507] Preparation of 6-(2-hydroxyethyl)-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3211) To a solution of 2-(4-methoxybenzyl)-1-oxo-8-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)acetaldehyde 3210 (100 mg, 0.273 mMol) in MeOH (10 mL) was added NaBH (20 mg, 0.546 mMol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. The resulting reaction solution was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography (elution with EtOAc / PE 30%–60%) to give 6-(2-hydroxyethyl)-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3211 (40 mg, 90% purity, 35% yield) as a white solid. C 18 H 19 LCMS (ESI) calculation for F3N2O3 [M+H]+ m / z 369.14 was 369.00.

[0508] Preparation of (E)-2-(4-methoxybenzyl)-6-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3212) To a solution of 6-(2-hydroxyethyl)-2-(4-methoxybenzyl)-8-(trifluoromethyl)-3, 4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3211 (40 mg, 0.11 mMol) in DCM (5 mL) was added sequentially at room temperature, followed by 1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-2-yn-1-one (34 mg, 0.12 mMol), and P(n-Bu) (2 mg, 0.011 mMol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent MeOH / DCM, 0% to 5%) to give (E)-2-(4-methoxybenzyl)-6-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3212 (60 mg, purity 90%, yield 76%) as a white solid. C 30 H 30 LCMS (ESI) calcd of F6N6O4 [M+Na]+ m / z 675.22 was 675.25.

[0509] Preparation of 2-(4-methoxybenzyl)-6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3213) A solution of (E)-2-(4-methoxybenzyl)-6-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pro-1-en-1-yl)oxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3212 (60 mg, 0.09 mMol) and Pd / C (10%, 6 mg) in MeOH (6 mL) was stirred at room temperature under a H atmosphere for 16 h. The resulting solution was filtered, and the filter cake was washed three times with MeOH. The filtrate was concentrated under reduced pressure to give 2-(4-methoxybenzyl)-6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3213 (50 mg, 90% purity, 74% yield) as a white solid. C 30 H 32 LCMS (ESI) calculation for F6N6O4 [M+H]+ m / z 655.24 was 655.35.

[0510] Preparation of 6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Compound 316) TfOH (0.5 mL) was added to a solution of 2-(4-methoxybenzyl)-6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 3213 (50 mg, 0.076 mMol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 min. The pH of the resulting mixture was adjusted to approximately 8 by slowly adding saturated aqueous NaHCO3 at 0 °C and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was C 18Purification on a column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 40-60) gave 6-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)proxy)ethyl)-8-(trifluoromethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 316 (14.5 mg, purity 94%, yield 34%) as a white solid.

[0511] [ka] C 22 H 24 LCMS (ESI) calculation for F6N6O3 [M+H]+ m / z 535.18 found 535.05.

[0512] 24. Synthesis of N-methyl-2-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (Compound 317)

[0513] [ka] Preparation of 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)ethyl acetate (3303) To a solution of 1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1910 (100 mg, 0.27 mMol) in n-hexane (2 mL) was added AgO (252 mg, 1.09 mMol) and MgSO (130 mg, 1.08 mMol) sequentially at 80 °C under N. After refluxing the reaction mixture for 1 h, ethyl 2-bromoacetate 3302 (317 mg, 1.90 mMol) was added to the solution. The mixture was refluxed for an additional 18 h and then cooled to room temperature. The reaction mixture was poured into cold water, then extracted with EtOAc (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (eluting with PE / EtOAc = 70:30 to 30:70) to give 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)ethyl acetate 3303 (80 mg, purity 90%, yield 58%) as a colorless oil. C 20 H 21 LCMS (ESI) calculation for F3N4O5 [M+H]+ m / z 455.15 was 455.20.

[0514] Preparation of 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acetic acid (3304) To a solution of 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)ethyl acetate 3303 (80 mg, 0.18 mMol) in THF / HO (THF:HO=3:1, 4 mL) LiOH (13 mg, 0.53 mMol) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to remove THF. The resulting aqueous solution was acidified with HCl solution (1 mol / L) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acetic acid 3304 (70 mg, 80% purity, 74% yield) as a colorless oil. C 18 H 17 LCMS (ESI) calculation for F3N4O5 [M+H]+ m / z 427.12 was 427.25.

[0515] Preparation of 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (3306) To a solution of 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acetic acid 3304 (70 mg, 0.16 mMol) in DCM (2 mL) were added N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride 3305 (51 mg, 0.20 mMol), DIPEA (106 mg, 0.82 mMol), and T3P (50% in EtOAc, 157 mg, 0.25 mMol) successively at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by C 18 Purification by column chromatography (mobile phase: ACN-HO (0.1% FA), gradient: 0%-100%) gave 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide 3306 (80 mg, purity 90%, yield 65%) as a white solid. C 29 H30 LCMS (ESI) calculation for F6N8O4 [M+H]+ m / z 669.23 was 669.33.

[0516] Preparation of N-methyl-2-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (Compound 317) To a solution of 2-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide 3306 (80 mg, 0.12 mMol) in TFA (3 mL) was added TfOH (1 mL) dropwise at room temperature. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes. The resulting mixture was adjusted to pH 8 with saturated aqueous NaHCO3 at 0°C and then extracted with DCM (30 mL x 3). The combined organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 um C). 18 Column, 150 × 21.2 mm, eluted with 30% to 95% MeCN / HO containing 0.1% FA) and C 18 Purification by column chromatography (mobile phase: ACN-HO (0.1% FA), gradient: 0%-100%) afforded N-methyl-2-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide 317 (9.9 mg, purity 100%, yield 15%) as a white solid.

[0517] [ka] C 21 H 22 LCMS (ESI) calculation of F6N8O3 [M+H]+ m / z 549.17 detected 549.25.

[0518] 25. Synthesis of 2-(4-(3-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile (Compounds 321 and 322)

[0519] [ka] Preparation of 2-(4-(3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile (3403) To a solution of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 2505 (150 mg, 0.33 mMol) in DMF (5 mL) were added 2-(piperazin-1-yl)pyrimidine-5-carbonitrile hydrochloride 3402 (112 mg, 0.50 mMol), DIPEA (2123 mg, 1.65 mMol), and HATU (158 mg, 0.50 mMol) successively. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine and dried over Na2SO4. The combined organic layers were concentrated and purified by C 18 Purification by column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 47-50) gave 2-(4-(3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile 3403 (90 mg, purity 95%, yield 41%) as a yellow solid. C 29 H 30 LCMS (ESI) calculation for F3N9O4 [M+H]+ m / z 626.24 was 626.39.

[0520] Preparation of 2-(4-(3-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile (Compounds 321 and 322) To a stirred solution of 2-(4-(3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile 3403 (80 mg, 0.13 mMol) in TFA (5 mL) was added TfOH (0.1 mL) at room temperature. The mixture was stirred at room temperature for 10 min. The resulting solution was adjusted to pH 7-8 with saturated aqueous NaHCO3 at 0 °C and extracted with DCM. The combined organic phase was washed with water and brine, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC. 18 Purification on a column (Agela 40 g, mobile phase: ACN-HO (0.1% FA), gradient: 45-47) gave 2-(4-(3-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile (mixture of compounds 321 and 322) (20 mg, purity 95%) as a green solid.

[0521] Chiral Resolution of 2-(4-(3-(2-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)proxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile (Compounds 321 and 322) Compounds 321 and 322 were purified by SFC (column: Daicel OJ-H 20 mM ID x 250 mM 5 μm; mobile phase: CO 2 / The mixture was separated with MeOH (0.1% FA) = 60 / 40) and concentrated under reduced pressure to give 321 (6.3 mg, purity 98%, ee 100%, green solid) as the first fraction, and 322 (8.9 mg, purity 98%, ee 100%, green solid) as the second fraction.

[0522] Compound 321

[0523] [ka] C 21 H 22 LCMS (ESI) calculation for F3N9O3 [M+H]+ m / z 506.18 was 506.25.

[0524] Compound 322

[0525] [ka] C 21 H 22 LCMS (ESI) calculation for F3N9O3 [M+H]+ m / z 506.18 was 506.25.

[0526] 26. Synthesis of 1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 327 and 328)

[0527] [ka] Preparation of ethyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)butanoate (3503) To a solution of 5-(4-methoxybenzyl)-3-(trifluoromethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1908 (1.0 g, 0.0030 mol) in MeCN (50 mL) was added ethyl (E)-but-2-enoate 3502 (0.99 g, 0.0086 mol) and KF (0.36 g, 0.0062 mol) at room temperature. The reaction mixture was stirred at 80 °C for 18 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 (eluting with PE / EtOAc = 100:0 to 80:20) to give ethyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)butanoate 3503 (0.7 g, 70% purity, 35% yield) as a yellow oil. C 20 H 21 LCMS (ESI) calculation for F3N4O4 [M+H]+ m / z 439.15 was 439.05.

[0528] Preparation of 1-(4-hydroxybutan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (3504) To a solution of ethyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)butanoate 3503 (1 g, 0.0023 mol) in EtOH (100 mL) was added NaBH4 (0.35 g, 0.0092 mol) and LiCl (0.39 g, 0.0092 mol) 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 combined organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to give 1-(4-hydroxybutan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 3504 (0.68 g, 90% purity, 65% yield) as a yellow solid. C 18 H 19 LCMS (ESI) calculation for F3N4O3 [M+H]+ m / z 397.14 was 397.25.

[0529] Preparation of 2-(3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-1-yl)butoxy)ethyl acetate (3506) To a solution of 1-(4-hydroxybutan-2-yl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 3504 (680 mg, 1.72 mMol) in hexane (50 mL) was added ethyl 2-bromoacetate 3505 (2.86 g, 17.2 mMol), AgO (3.18 g, 13.72 mMol), and MgSO (0.823 g, 6.86 mMol) at room temperature. The reaction mixture was stirred at 80 °C for 18 h. The resulting solution was filtered through Celite, and the filter cake was washed with DCM (5 mL × 4). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to give 2-(3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-1-yl)butoxy)ethyl acetate 3506 (520 mg, 70% purity, 43% yield) as a yellow oil. C 22 H 25 LCMS (ESI) calculation for F3N4O5 [M+H]+ m / z 483.15 was 483.35.

[0530] Preparation of 2-(3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)butoxy)acetic acid (3507) To a solution of ethyl 2-(3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-1-yl)butoxy)acetate 3506 (500 mg, 1.036 mMol) in THF / HO (3:1, 30 mL) was added LiOH (25 mg, 1.03 mMol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The pH of the reaction solution was adjusted to 4 with 1 M aqueous hydrochloric acid. The aqueous phase was purified by Biotage Isolera One (C) eluting with 60%-90% MeCN / HO containing 0.1% formic acid. 18 Column) to give 2-(3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)butoxy)acetic acid 3507 (300 mg, 50% purity, 31% yield) as a white solid. C 20 H 21 LCMS (ESI) calculation for F3N4O5 [M+H]+ m / z 455.15 was 455.25.

[0531] Preparation of 5-(4-methoxybenzyl)-1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (3508) To a solution of 2-(3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)butoxy)acetic acid 3507 (300 mg, 0.33 mMol) in DCM (10 mL), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (92 mg, 0.40 mMol), T3P (50% by mass in EtOAc, 420 mg, 0.66 mMol), and DIPEA (128 mg, 0.99 mMol) were added sequentially at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Elute the residue with Biotage Isolera One (60%-90% MeCN / HO containing 0.1% formic acid). 18 Purification on a column afforded 5-(4-methoxybenzyl)-1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 3508 (110 mg, 80% purity, 39% yield) as a white solid. C 29 H 30 LCMS (ESI) calculation for F6N8O4 [M+H]+ m / z 669.23 was 669.20.

[0532] Preparation of 1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (mixture of compounds 327 and 328) To a solution of 5-(4-methoxybenzyl)-1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1, 5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 3508 (110 mg, 0.16 mMol) in TFA (5 mL) was added TfOH (123 mg, 0.82 mMol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The pH of the reaction solution was adjusted to 7-8 with saturated aqueous NaHCO3 at 0 °C, and the solution was extracted with EtOAc. The combined organic phases were concentrated and purified on a Biotage Isolera One (C18 column eluted with 60%–90% MeCN / HO containing 0.1% formic acid) to give 1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 327 and 328 (60 mg, 95% purity, 63% yield) as a white solid. C 21 H 22 LCMS (ESI) calculation for F6N8O3 [M+H]+ m / z 549.17 was 549.10.

[0533] Chiral Resolution of 1-(4-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethoxy)butan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 327 and 328) Compounds 327 and 328 were analyzed by SFC (column: CHIRALPAK OJ-H, 250 mm × 20 mm ID, 5 μm; mobile phase: CO 2 / The mixture was separated using a HPLC with HCl (IPA = 85 / 15) and concentrated under reduced pressure to give the first fraction as 327 (20.2 mg, purity 100%, ee 100%, white solid) and the second fraction as 328 (17.9 mg, purity 99%, ee 95%, white solid).

[0534] Compound 327

[0535] [ka] C 21 H 22LCMS (ESI) calculation for F6N8O3 [M+H]+ m / z 549.17 was 549.30.

[0536] Compound 328

[0537] [ka] C 21 H 22 LCMS (ESI) calculation for F6N8O3 [M+H]+ m / z 549.17 was 549.30.

[0538] 27. Synthesis of 3-(difluoromethyl)-1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compounds 395 and 396)

[0539] [ka] Preparation of ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (3602) To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (3601) (45 g, 293.8 mMol) in THF (1000 mL) was added NaH (23.5 g, 587.6 mMol, 60% by mass) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. SEMCl (58.8 g, 352.5 mMol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with cold water and extracted with EtOAc (300 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 85:15 to 70:30) to give ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate 3602 (52 g, 90% purity, 56% yield) as a yellow oil. C 14 H 25 LCMS (ESI) calculation for NO3Si[M+H]+ m / z 284.16 was 284.25.

[0540] Preparation of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (3603) To a solution of ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate 3602 (50 g, 175.8 mMol) in THF / AcOH / HO (800 mL, 1:1:1) was added CAN (385.5 g, 703.2 mMol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (500 mL) and stirred for an additional 30 min. The resulting solution was extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to 80:20) to give ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate 3603 (18 g, 90% purity, 31% yield) as a yellow oil. C 14 H 23 LCMS (ESI) calculation for NO4Si[M+H]+ m / z 298.14 was 298.18.

[0541] Preparation of ethyl 4-bromo-2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (3604) To a solution of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate 3603 (18 g, 60.3 mMol) in ACN (300 mL) was added NBS (10.7 g, 60.3 mMol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 85:15 to 70:30) to give ethyl 4-bromo-2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate 3604 (15 g, 90% purity, 59% yield) as a yellow oil.

[0542] [ka] Preparation of 3-bromo-5-(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (3606) To a solution of ethyl 4-bromo-2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate 3604 (10 g, 26.5 mMol) in EtOH (50 mL) was added (2-methoxy-5-methylphenyl)hydrazine 3605 (8.1 g, 53 mMol) at room temperature. The reaction mixture was stirred at 80 °C for 1 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 85:15 to 20:80) to give 3-bromo-5-(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 3606 (8.3 g, 90% purity, 60% yield) as a yellow solid. C 20 H 26 LCMS (ESI) calculated for BrN3O3Si [M+H]+ m / z 464.09 was 464.18.

[0543] Preparation of 3-bromo-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (3608) A solution of 3-bromo-5-(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 3606 (8.2 g, 17.6 mMol) in HCl-dioxane (150 mL, 4 M) was prepared at room temperature. The reaction mixture was stirred in a sealed tube at 50 °C for 16 h. After LCMS showed the formation of 3607, the reaction solution was concentrated under reduced pressure. The residue was dissolved in EtOH / HO (100 mL, 5:1) and KCO (24.3 g, 0.18 mMol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was diluted with HO (200 mL), and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure to give 3-bromo-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 3608 (5.8 g, 80% purity, 79% yield) as a yellow solid. C 14 H 12LCMS (ESI) calculation for BrN3O2 [M+H]+ m / z 334.01 was 334.07.

[0544] Preparation of ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (3610) To a solution of 3-bromo-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 3608 (6 g, 18 mMol) in THF (100 mL) was added NaH (2.2 g, 54 mMol, 60% mass) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Ethyl 2-bromopropanoate 3609 (4.9 g, 27 mMol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with cold water and extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) to give ethyl 2-propanoate 15 3610 (3.0 g, 90% purity, 34% yield) as a yellow solid 60. C 19 H 20 LCMS (ESI) calculated for BrN3O4 [M+H]+ m / z 434.06 was 434.15.

[0545] Preparation of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-vinyl-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (3612) To a solution of ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 3610 (4.0 g, 9.2 mMol) in ACN (30 mL) was added tributyl(vinyl)stannane 3611 (5.83 g, 18.4 mMol) and Pd(AMPHOS)Cl (650 mg, 0.9 mMol) at room temperature. The resulting mixture was stirred in a sealed tube at 100 °C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 60:40) to give 2-(5-(4-methoxybenzyl)-4-oxo-3-vinyl-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate ethyl 3612 (2.96 g, 90% purity, 76% yield) as a white solid. C 21 H 23 LCMS (ESI) calculation for N3O4 [M+H]+ m / z 382.17 was 382.19.

[0546] Preparation of ethyl 2-(3-formyl-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (3613) To a solution of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-vinyl-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 3612 (3 g, 7.9 mMol) in 1,4-dioxane / HO (2:1, 50 mL) was added KOsO·2HO (290 mg, 0.8 mMol) and NaIO (6.76 g, 31.6 mMol) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 100:0 to 50:50) to give ethyl 2-(3-formyl-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 3613 (1.7 g, 90% purity, 51% yield) as a yellow oil. C 20 H 21LCMS (ESI) calculation for N3O5 [M+H]+ m / z 384.15 was 384.19.

[0547] Preparation of ethyl 2-(3-(difluoromethyl)-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate (3614) To a solution of ethyl 2-(3-formyl-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 3613 (1.7 g, 4.4 mMol) in DCM (50 mL) was added DAST (7.1 g, 44.0 mMol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction solution was adjusted to pH 8-9 with saturated aqueous NaHCO3 and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 85:15 to 70:30) to give ethyl 2-(3-(difluoromethyl)-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 3614 (1.36 g, 90% purity, 68% yield) as a white solid. C 20 H 21 LCMS (ESI) calculation for F2N3O4 [M+H]+ m / z 406.15 was 406.14.

[0548] Preparation of 3-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-5-(4-methoxybenzyl)-1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (3615) To a solution of ethyl 2-(3-(difluoromethyl)-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)propanoate 3614 (1.35 g, 3...

Claims

1. The following formula: 【Chemistry 1】 (In the formula, X １A and X １B are each independently selected from C, N, O, and S; Z １ is C or N, X １Ａ are each unsubstituted or X １Ａ If N, then R ６ or X １Ａ If C, then up to two R ７ is replaced by X １Ｂ are each unsubstituted or X １Ｂ If C, then up to two R ８ or X １Ｂ If N, then R ９ is replaced by Z １ is further R ８ may be substituted with m is 1 or 2; n is 1, 2 or 3; The bonds between all atoms of ring A are each independently a single bond or a double bond, and X １Ａ When is O or S, the X １Ａ The bond to is a single bond, The bonds between all atoms of ring B are each independently a single bond or a double bond, and X １B When is O or S, the X １B The bond to is a single bond, and, R １ has the following formula: 【Chemistry 2】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (In the formula, R １２ is the number of bonds and the R １２ Z containing ６ may be present or absent depending on the valence of the atom and include the following: -H, -CH ３ , -CN, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OMe, -CH ２ CF ３ , -CF ２ CH ３ , -OCHF ２ , -OCH ２ F, -F, -Cl, -Br, -I, -SO ２ Me, -CONHMe, t-Bu, cyclopropyl and 【Transformation 3】 is selected from R ６ and R9 are each independently H, C １ ~C ６ Alkyl group and C １ ~C ６ selected from halogenated alkyl groups, R ７ and R ８ are each independently H, deuterium, halogen, or C １ ~C ６ Alkyl group or cycloalkyl group, C １ ~C ６ Halogenated alkyl group, —OH group, C １ ~C ６ Alcohol group, NH ２ Group, C １ ~C ６ Amino group, C １ ~C ６ an alkoxy group, a nitrile group, and two R ７ or R ８ The group, if present, is an oxo group, and R １１ are each independently H, deuterium, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Halogenated alkyl group, NH ２ Group, C １ ~C ６ Amino group, —OH group, C １ ~C ６ Alcohol group and C １ ~C ６ alkoxy groups) (The structure is expressed as 10. A PARP7 inhibitor compound comprising:

2. below: 【Chemistry 4】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (In the formula, R １６ is H) 2. The compound of claim 1 selected from:

3. Ring B is: 【Transformation 5】 3. The compound according to claim 1 or 2, selected from:

4. The compound according to any one of claims 1 to 3, wherein m is 1, 2 or 3.

5. Ring A is: 【Transformation 6】 【change】 【change】 【change】 The compound according to any one of claims 1 to 4, selected from:

6. The compound according to any one of claims 1 to 5, wherein n is 1 or 2.

7. below: 【Transformation 7】 【change】 【change】 (In the formula, R １６ is H) The compound according to any one of claims 1 to 6, selected from:

8. below: 【Transformation 8】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound selected from any one of:

9. below: an 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 Tautomers of Compounds The compound according to any one of claims 1 to 8, comprising:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9.

11. 11. The pharmaceutical composition of claim 10, further comprising a pharmaceutically acceptable additive and / or excipient, and / or wherein the compound is a pharmaceutically acceptable salt or hydrate.

12. 12. The pharmaceutical composition of claim 11, further comprising an additional agent for treating cancer, wherein the additional agent for treating cancer is selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, anti-aging agents, hormones and hormone analogs, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, receptor tyrosine kinase inhibitors, cell proliferation inhibitors, pro-apoptotic agents, and cell cycle signaling inhibitors.

13. 13. The pharmaceutical composition of claim 12, further comprising an agent selected from the group consisting of: an anti-tumor vaccine; a cancer immunotherapy therapeutic; an immunomodulator; an immunosuppressant, a cytokine therapy, a tyrosine kinase inhibitor, and a chimeric antigen receptor T cell therapy.

14. below: (a) a compound according to any one of claims 1 to 9; and (b) an additional agent for treating cancer, wherein said additional agent for treating cancer is selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, anti-aging agents, hormones and hormone analogs, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, receptor tyrosine kinase inhibitors, cell proliferation inhibitors, pro-apoptotic agents, cell cycle signaling inhibitors. A pharmaceutical kit for treating cancer, comprising: A kit, wherein said compound and said further agent are suitable for simultaneous, sequential or separate administration.

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