Novel phthalazine derivatives having the activity of inhibiting ectonucleotide pyrophosphatase-phosphodiesterase and their uses

Abstract

The present invention relates to a compound for inhibiting ENPP1, a composition for inhibiting ENPP1, and a novel phthalazine derivative compound related to a method for inhibiting ENPP1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof.

Description

Technical Field

[0001] The present invention relates to a compound selected from a novel phthalazine derivative compound having the activity of inhibiting ectonucleotide pyrophosphatase-phosphodiesterase (ENPP), a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof, a method for preparing the compound and a pharmaceutical composition comprising the compound for preventing, alleviating or treating cancer. Background Art

[0002] Cancer is a disease associated with uncontrolled cell proliferation, and is a disease that can invade or spread to other parts of the body and reduce the quality of life and ultimately lead to death. Although genetic aberrations are the direct cause of the uncontrolled proliferation of cancer cells, the failure of immune surveillance and / or the lack of appropriate immune counterattacks by the immune system to cancer cells are also the cause of cancer cell proliferation, and lead to the formation of a tumor microenvironment (TME) in which the anti-cancer immune response is suppressed. The therapeutic agent for treating the fatal disease as described above is mainly developed into two categories. The first category is to use the cancer cell itself as a direct target, and the second category is to use the constituent elements of the tumor microenvironment (TME) as a target to prevent further proliferation or survival of cancer cells.

[0003] Cancer immunotherapy is one of the treatment methods that targets immune factors present in the TME to induce immune cells to attack tumor cells. In some cases, the purpose of cancer immunotherapy is to promote the recognition of tumor cells by releasing tumor-associated antigens in the TME (e.g., cancer vaccines). In other cases, the purpose of cancer immunotherapy is to promote the attack on tumor cells by regulating the activity of innate and / or adaptive immune cells (e.g., immune checkpoint blockade).

[0004] Microbial infections can cause a variety of diseases around the world. There are many types of pathogenic microorganisms, including viruses, bacteria, fungi and protozoa. In some cases, therapeutic agents are chemicals that directly prevent the proliferation of microorganisms. In other cases, therapeutic agents are therapeutic substances used to enhance or stimulate the host's immune function against pathogenic microorganisms.

[0005] The tumor microenvironment (TME) consists of malignant tumor cells and various types of immune cells (e.g., macrophages, lymphocytes, NK cells, dendritic cells) and non-immune cells (e.g., cancer-associated fibroblasts, pericytes, endothelial cells, adipocytes). In addition, it is reported that the presence of tumor-infiltrating lymphocytes can respond to various approaches to immunotherapy in different types of cancer, resulting in positive clinical outcomes. It is reported that the regulation or increase of other types of immune cells other than lymphocytes, especially innate immune cells, regulates the responsiveness of anticancer therapy to tumors in preclinical studies. The innate immune system is one of the two main components of the host immune defense system in vertebrates. The main functions of innate immunity are as follows: 1) recognition and removal of foreign bodies (e.g., bacteria, viruses) in body tissues, 2) recruitment of immune cells to specific sites by producing cytokines and promoting adaptive immune responses, and 3) activation of the complement cascade reaction. Innate immunity as described above is activated by recognizing molecular patterns derived from microbial pathogens (pathogen-associated molecular patterns (PAMPs)) or remnants of damaged cells (damage-associated molecular patterns (DAMPs)).

[0006] Pattern recognition receptors (PRRs) are several different types of receptors expressed primarily by innate immune cells and can recognize specific PAMPs or DAMPs depending on their ligand specificity. Cytoplasmic DNA is the type of molecular pattern recognized by cytoplasmic DNA sensors (a type of PRR) and induces an innate immune response. The cGAS-STING pathway (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes) is involved in: 1) recognition of cytoplasmic DNA due to microbial infection or self-DNA damage, and 2) the formation of chemokines, primarily type I interferons (IFNs) through the activation of the IRE3 transcription factor.

[0007] Type I IFNs produced in the TME by transformed cancer cells recruit and activate inflammatory cells, including NK cells, at the tumor site and induce the production of chemoattractants that promote tumor cell death and adaptive immune responses.

[0008] Systemic administration of type I IFNs has demonstrated efficacy in the cancer setting, with systemic injection of IFN-β showing tumor regression and improved survival in preclinical mouse models. However, systemic administration of type I IFNs has the problem of requiring high doses to achieve a therapeutically effective amount that shows therapeutic efficacy. In this case, tolerability issues have been reported.

[0009] Recently published reports on clinical results of exogenous STING agonists (modified cyclic dinucleotides) showed lower-than-expected disease control rate results despite a significant increase in the production of pro-inflammatory cytokines.

[0010] Therefore, novel therapeutic approaches that can activate the cGAS-STING pathway need to be investigated.

[0011] [Prior art literature]

[0012] [Patent Document]

[0013] (Patent Document 1) Chinese Publication Patent CN110575458A

[0014] (Patent Document 2) International Publication No. WO2019 / 233300A1

[0015] (Patent Document 3) International Publication No. WO2018 / 119325A1

[0016] (Patent Document 4) International Publication No. WO2018 / 119328A1

[0017] (Patent Document 5) International Publication No. WO2019 / 046778A1

[0018] (Patent Document 6) International Publication No. WO2019 / 177971A1

[0019] (Patent Document 7) Japanese Patent Application JP2020-15670

[0020] (Patent Document 8) International Publication No. WO2019 / 051269A1

[0021] (Patent Document 9) U.S. Patent Application No. US2020 / 0039979A1

[0022] (Patent Document 10) International Publication No. WO2019 / 023635A1

[0023] (Patent Document 11) International Publication No. WO2019 / 051269A1 Summary of the invention

[0024] Technical issues to be solved

[0025] In order to solve the above-mentioned problems, an object of the present invention is to provide a method for increasing the activity of the cGAS-STING pathway.

[0026] Therefore, one aspect of the present invention is to provide a novel phthalazine derivative compound having the activity of inhibiting ENPP1. In addition, one aspect of the present invention is to provide a novel phthalazine derivative compound that increases and / or regulates the production of type I interferons (IFNs) in vivo.

[0027] In addition, another object of the present invention is to provide a pharmaceutical composition containing a novel phthalazine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof as an active ingredient and being effective for treating, preventing and alleviating cancer.

[0028] In addition, another object of the present invention is to provide a method for preventing, alleviating or treating cancer, which comprises the step of administering a novel phthalazine derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof.

[0029] In addition, another object of the present invention is to provide a method for preventing, alleviating or treating infectious diseases, which comprises the step of administering a novel phthalazine derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof.

[0030] In addition, another object of the present invention is to provide a method for preventing, alleviating or treating periodontal disease, which comprises the step of administering a novel phthalazine derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof.

[0031] In addition, another object of the present invention is to provide a method for preventing, alleviating or treating pathological mineralization of soft tissue, which comprises the step of administering a novel phthalazine derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof.

[0032] In addition, another object of the present invention is to use a novel phthalazine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or an isomer thereof as an active ingredient to achieve the following mechanism. In one aspect, the method includes the case where an agonist that induces immunogenic cell death (ICD) is used to induce cancer before stimulating the cGAS-STING pathway. In another aspect, the method includes the case where the degradation of endogenous STING ligands is blocked before inducing cancer with an agonist that induces ICD. In another aspect, the method includes the case where an agonist that induces ICD and an inhibitor of 2'3'-cGAMP degradation polypeptide are used simultaneously for the treatment of cancer. In one aspect, the present invention provides a method for designing an inhibitor of 2'3'-cGAMP degradation polypeptide and a detailed analysis method for evaluating the enzymatic activity of cGAMP degradation polypeptides.

[0033] Technical Solution

[0034] In order to solve the above-mentioned technical problems, the present invention provides a compound selected from the group consisting of a phthalazine derivative compound represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof and a stereoisomer thereof.

[0035] [Chemical formula 1]

[0036]

[0037] In the chemical formula 1,

[0038] Y 1 and Y 2 are independently hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 3 -C 10 Cyclic group; C 1 -C 6 Alkoxy; C 3 -C 10 Cyclic group; or C 3 -C 10 Heterocyclic group;

[0039] R 1 or R 2 are independently hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C10 Heteroaryl; C 3 -C 10 Heterocyclyl; -C(O)-(C 1 -C 13 alkyl); or R 1 Connect with R 2 The nitrogen atoms together form a four- to seven-membered saturated, unsaturated or aromatic ring, which may optionally contain N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 at least one of, and may optionally be C 1 -C 13 Alkyl, C 6 -C 10 Aryl, C 3 -C 10 Substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group and a cyano group;

[0040] R 3 is hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C 10 Heteroaryl; C 3 -C 10 heterocyclic group; or -C(O)-(C 1 -C 13 alkyl);

[0041] R 4 is hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; C 1 -C 6 Alkenyl; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C 10 Heteroaryl; C 3 -C 10 heterocyclic group; amino group; nitro group; amide group; carboxylic acid group; nitrile group; urea group; sulfonamide group; thioether group; sulfone group; or phosphine group;

[0042] The C 1 -C 6 Alkyl, C 1 -C 13 Alkyl or C 3 -C 10 The ring group contains a group selected from hydrogen; a hydroxyl group; a halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; amino (-NR 5 R 6 ); nitro (-N(O) 2 ); Amide (-(C=O)NR 5 R 6 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 5 (C=O)NR 6 -); sulfonamide (-NHS(O) 2 -); sulfide group (-S-); sulfone group (-S(O) 2 -); phosphinyl (-P(O)R 5 R 6 );C 6 -C 10 Aryl; C 3 -C 10 heteroaryl; and C 3 -C 10 One or more substituents in the heterocyclic group,

[0043] The C 6 -C 10 Aryl, C 3 -C 10 Heteroaryl or C 3 -C 10 The heterocyclic group contains a group selected from hydrogen; a hydroxyl group; a halogen group; a carbonyl group (-(C=O)R 5 R 6 );halogen or C 3 -C 10 Heterocyclic substituted or unsubstituted C 1 -C 3 Alkyl; halogen or C 3 -C 10 Heterocyclic substituted or unsubstituted C 1 -C 3 Alkoxy; C 6 -C 10 Phenoxy; amino (-NR 5 R 6 ); nitro (-N(O) 2 ); Amide (-(C=O)NR 5 R6 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 5 (C=O)NR 6 -); sulfonamide (-NHS(O) 2 -); sulfide group (-S-); sulfone group (-S(O) 2 -); phosphinyl (-P(O)R 5 R 6 );C 6 -C 10 Aryl; C 3 -C 10 Heteroaryl and C 3 -C 10 One or more substituents in the heterocyclic group,

[0044] The R 5 and R 6 are each independently hydrogen; C 1 -C 6 Alkyl; C 1 -C 6 Alkenyl; C 1 -C 6 Alkynyl; C 6 -C 10 Aryl; C 3 -C 10 Heteroaryl; C 3 -C 10 heterocyclic group; or R 5 Connect with R 6 The nitrogen atoms or carbon atoms of the amines or amines are taken together to form a three- to seven-membered saturated ring, which may optionally contain N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 At least one of, and may optionally be replaced by hydrogen, C 1 -C 13 Alkyl, C 6 -C 10 Aryl, C 3 -C 10 is substituted by at least one of a heteroaryl group, a hydroxyl group, a halide group and a cyano group,

[0045] The C 3 -C 10 Heteroaryl and C 3 -C 10 The heterocyclic group contains one or more heteroatoms selected from N, O and S.

[0046] Beneficial Effects

[0047] The compounds according to the present invention have excellent ability to inhibit the activity of ENPP1. Therefore, they can be used for the purpose of treating, preventing and alleviating cancer caused by abnormal cell growth.

[0048] The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an effective ingredient effectively inhibits ENPP1 to activate the STING pathway, and thus can be usefully used for preventing or treating cancer.

[0049] Cancers that can be treated, prevented and alleviated by using the compounds of the present invention may include gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestinal cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma and myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis or fibroadenoma, etc.

[0050] In particular, the compounds according to the present invention are effective for preventing, alleviating or treating diseases in which ENPP1 is involved.

[0051] Best Mode for Carrying Out the Invention

[0052] definition

[0053] Unless otherwise stated, all numerals, values ​​and / or expressions representing the content of composition, reaction conditions and composition used in this specification are approximate values ​​reflecting the various uncertainties of measurement occurring when these numerals are obtained in essentially different values, and therefore should be understood to be modified by the term "about" in all cases. In addition, in the case of numerical ranges disclosed herein, unless otherwise stated, these ranges are continuous and include all values ​​from the minimum value of these ranges to the maximum value (including the maximum value). Further, in the case where these ranges refer to integers, unless otherwise stated, all integers from the minimum value of these ranges to the maximum value (including the maximum value) are included.

[0054] In this specification, when a range of a variable is recorded, it should be understood that the variable includes all values ​​within the recorded range, including the endpoints within the range. For example, a range of "5 to 10" is understood to include not only values ​​of 5, 6, 7, 8, 9, and 10, but also any sub-ranges, such as 6 to 10, 7 to 10, 6 to 9, and 7 to 9, and also any values ​​between reasonable integers in the scope of the recorded range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9, etc. In addition, for example, a range of "10% to 30%" is understood to include not only values ​​of 10%, 11%, 12%, 13%, and all integers including 30%, but also any sub-ranges, such as 10% to 15%, 12% to 18%, 20% to 30%, etc., and also any values ​​between reasonable integers in the scope of the recorded range, such as 10.5%, 15.5%, 25.5%, etc.

[0055] As used herein, the terms "individual(s), "subject(s), and "patient(s)" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by supervision (e.g., continuous or intermittent) by a healthcare management practitioner (e.g., a physician, registered nurse, nurse trainee, physician assistant, caregiver, or hospice staff).

[0056] "Treatment" is an attempt to prevent the development or change of pathological changes in a disease. Therefore, "treatment" refers to all treatments in terms of treatment and prevention using a treatment method. The state in which treatment is needed includes the state in which the disease is already present and the state in which the disease needs to be prevented. In the treatment of tumors, a therapeutic agent can refer to a treatment that directly reduces the pathology of tumor cells or makes tumor cells more susceptible to other therapeutic agents (e.g., radiation and / or chemotherapy and / or immunotherapy). The terms "relieve" or "treatment" used in this specification refer to signs close to normalized values ​​measured by conventional statistical tests. Among them, signs close to normalized values ​​can be, for example, values ​​that differ by less than 50% from values ​​normalized with values ​​obtained in healthy patients or individuals, preferably values ​​that differ by less than 25%, more preferably values ​​that differ by less than 10%, and further preferably values ​​that differ little.

[0057] "Treatment of cancer" refers to any one or more of the following effects: 1) inhibiting tumor growth, including i) slowing growth or ii) completely stopping growth; 2) reducing the number of tumor cells; 3) maintaining tumor size; 4) reducing tumor size; 5) inhibiting tumor cell infiltration into peripheral organs, including i) reducing or ii) slowing down or iii) completely preventing; 6) inhibiting metastasis, including i) reducing or ii) slowing down or iii) completely preventing; 7) enhancing anti-tumor immune response, which can lead to i) maintaining tumor size or ii) reducing tumor size or iii) slowing tumor growth or iv) reducing, slowing down or preventing invasion by enhancing anti-tumor immune response.

[0058] "Effective amount" or "therapeutically effective amount" used in this specification refers to a sufficient amount of the compound disclosed in this specification that alleviates the symptoms of the disease or condition to be treated (e.g., cancer or inflammatory disease, periodontal disease or soft tissue mineralization) to a certain extent. In some specific embodiments, the result is 1) reducing and / or alleviating the signs, symptoms or causes of the disease, or 2) any other preferred changes in the biological system in a clinical setting. In some specific embodiments, in individual cases, the appropriate "effective" amount is determined using techniques such as dose increase studies.

[0059] In some specific embodiments, an "effective amount" is an amount of a disclosed compound in monotherapy or combination therapy, i.e., an amount effective to inhibit ENPP1 by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), about 60% or more (60% inhibition), about 70% or more (70% inhibition), about 80% or more (80% inhibition), about 90% or more (90% inhibition), when compared to ENPP1 activity in an individual not treated with the compound, or compared to ENPP1 activity in an individual before or after treatment with the compound, when administered at one or more doses.

[0060] In some embodiments, a "therapeutically effective amount" is an amount of a disclosed compound in a monotherapy or combination therapy, i.e., an amount effective to reduce the tumor burden of an individual by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or more when compared to the tumor burden of an individual not treated with the compound, or compared to the tumor burden of an individual before or after treatment with the compound, when administered at one or more doses. The term "tumor burden" as used herein is the total mass of tumor tissue possessed by an individual with cancer.

[0061] In some embodiments, a "therapeutically effective amount" is an amount of a disclosed compound in monotherapy or combination therapy, i.e., an amount effective to reduce the amount of radiation therapy required to observe tumor shrinkage in a subject by about 20%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, when administered in one or more doses, compared to the dose of radiation therapy required to observe tumor shrinkage in a subject not treated with the compound.

[0062] Hereinafter, the present invention will be described in detail.

[0063] As a result of continuous research conducted by the inventors to solve the above-mentioned problems, compounds for inhibiting ENPP1, compositions for inhibiting ENPP1, and methods for inhibiting ENPP1 have been developed. In one aspect, the novel phthalazine derivative compound for inhibiting ENPP1, its pharmaceutically acceptable salt, its hydrate, and its stereoisomer, or its preparation method, and a pharmaceutical composition for preventing or treating cancer containing it as an active ingredient are developed. In a specific embodiment, the method comprises inhibiting the hydrolysis of cGAMP caused by ENPP1 by treating the sample with a cell-permeable ENPP1 inhibitor. In a specific embodiment, the method comprises the step of administering a therapeutically effective amount of a cell-permeable ENPP1 inhibitor to a patient or subject to treat cancer. The compound according to one aspect of the present invention, the composition comprising the compound, or the compound and the composition can be used for various uses or diseases requiring the inhibition of ENPP1.

[0064] cGAS-STING pathway, immunogenic cell death, and production of type I IFNs

[0065] Cytoplasmic double-stranded DNA can be introduced from outside the cell by vesicular transfer from microbial infection or nearby dead cells. In addition, cytoplasmic DNA can be generated from damaged genomic DNA or mitochondrial DNA inside the cell. If cytoplasmic DNA is generated, it can be detected by various DNA sensors such as RNA polymerase III, DDX41, DAI, IFI6, cGAS, LEEFIP1, DHX9, DHX36, Ku70, and AIM2.

[0066] cGAS (cyclic GMP-AMP synthase) is a cytoplasmic protein that exists as a dimer and consists of two DNA binding domains and a nucleotidyl transferase domain (which converts ATP and GTP into a cyclic dinucleotide 2'3-cGAMP with 2'5' and 3'5' phosphodiester bonds). In addition, cGAMP acts as a second messenger and binds to STING with high affinity (Kd to 4 nM) to induce the expression of type I IFN.

[0067] STING (also known as TMEM173, MITA, MPYS) is an endoplasmic reticulum (ER)-immobilized protein containing four transmembrane domains at the N-terminus and a dimerization domain at the C-terminus. Upon binding to cGAMP, STING forms a tetramer and translocates from the ER to the ER-Golgi intermediate compartment. In the Golgi, STING recruits and activates TANK binding kinase 1 (TBK1), which phosphorylates the C-terminal domain of STING, and STING collects and activates interferon regulator factor 3 (IRF3). Afterwards, the activated IRF3 moves to the nucleus and increases the expression of immune-stimulated genes (ISGs) and type I IFNs. After activation, STING is transferred to endolysosomes and degraded, thereby terminating the activation of the cGAS-STING pathway.

[0068] Immunogenic Cell Death (ICD)

[0069] Immunogenic cell death (ICD) is a form of cell death, and is a cell phenomenon that induces the activation of a controlled immune response. The cell death is characterized by apoptotic morphology, and maintains the integrity of the biofilm. ICD is also characterized by exposing the polypeptide formed by the secretion of DAMP (e.g., Calreticulin, high mobility group box 1 (HMGB1), ATP and Hsp70 / 90 protein) and cell-specific protein or mutated protein. The exposed polypeptide (playing the role of antigen) is recognized by dendritic cells (dendritic cells, DC), and subsequently sensitizes effector T lymphocytes to activate adaptive immune response.

[0070] ICD can be further classified by different types of ICD inducers, including 1) radiation (e.g., UV rays or gamma rays), 2) chemotherapy small molecules (e.g., doxorubicin or paclitaxel), and 3) biologics (e.g., peptides, oligosaccharides, lipids, or nucleic acids).

[0071] Radiation therapy

[0072] Radiation therapy is a well-known therapy and is used to treat patients with various diseases. Radiation therapy is generally used for the death or growth inhibition of unpreferred tissues (e.g., cancerous tissues). The purpose of a determined amount of high-energy electromagnetic rays and / or high-energy particles is to directly cause damage to unpreferred tissues or lesions on the path of the rays, and to minimize undesirable damage to preferred or healthy tissues.

[0073] According to the results of studies so far, the fraction size has a greater impact on normal tissues than the administration amount, so that the fraction size of 1.8-2.0Gy is regarded as the standard of existing radiotherapy, and the treatment time is prolonged. In fact, a small amount of each administration can induce tumor effects through mitotic death of cancer cells and restore sublethal damage to normal tissues after administration. Stereotactic body radiation therapy (SBRT) is an improved radiotherapy that uses precise image guidance to accurately locate the three-dimensional position of the tumor, so that the radiation can be delivered to cancer cells more accurately. In addition to direct cytotoxicity, SBRT has a substantial effect on tumor cell death at high doses accompanied by microvascular damage, which can increase the new mechanism of radiation-induced damage. However, according to recent reports, high doses of radiation can induce the expression of nucleases, thereby weakening the effect of radiation on STING-mediated innate immune activation.

[0074] Pathogens

[0075] As described above, nucleic acids from pathogens invade cells and activate the cGAS-STING pathway, thereby increasing the immune response to pathogens. In some cases, the pathogen is a virus, for example, a DNA virus or an RNA virus. In some cases, the pathogen is a retrovirus. Exemplary viruses that activate the cGAS-STING pathway include, but are not limited to, herpes simplex virus 1 (HSV-1), Kaposi's sarcoma-associated herpes virus (KSHV), vaccinia virus (VACV), adenovirus, human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), influenza A virus (IAV), human immunodeficiency virus (HIV) or human cytomegalovirus (HCMV). In other cases, the pathogen is a bacterium. Exemplary bacteria include, but are not limited to, Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae or gonococci.

[0076] Phosphodiesterases

[0077] Phosphodiesterases (PDEs) include cyclic nucleotide phosphodiesterases, phospholipase C and phospholipase D, autotoxins, sphingomyelin phosphodiesterases, DNases, RNases, restriction endonucleases, and many lesser-known classes of small molecule phosphodiesterases. An exemplary group of PDE enzymes is an important family of enzymes that hydrolyze the cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inert 5' monophosphates.

[0078] Cyclic nucleotide phosphodiesterases comprise a family of enzymes that degrade the phosphodiester bonds of cAMP and cGMP, cyclic nucleotide second messenger molecules. They regulate the localization, persistence, and amplification of cyclic nucleotide signals in subcellular domains.

[0079] Ecto-nucleotide pyrophosphatases / phosphodiesterases

[0080] The category of phosphodiesterase also includes ectonucleotide pyrophosphatase / phosphodiesterase. Ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) or nucleotide pyrophosphatase / phosphodiesterase (NPP) is an enzyme family of ectonucleotide enzymes that hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to form nucleotide 5'-monophosphates (or phospholipids and phosphorylcholine). In some embodiments, the ENPP enzyme family includes seven enzyme members (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP-5, ENPP-6 and ENPP-7) of ectonucleotide enzymes with similar protein structures present on the cell surface.

[0081] ENPP enzymes have a modular structure with a catalytic domain of about 400 amino acids. This catalytic domain is not related to phospholipases, Nudix hydrolases, or exonucleoside triphosphate diphosphohydrolases, even though they exhibit partially overlapping activities. ENPP1 and ENPP3 have a transmembrane domain at the N-terminus and a nuclease-like domain at the C-terminus, and the catalytic domains contained are predicted to be type II single transmembrane proteins directed to the extracellular space. ENPP2, which does not have a transmembrane domain at the N-terminus or C-terminus, has a signal peptide at the N-terminus and is predicted to be secreted outside the cell. The catalytic domains of ENPP4, ENPP5, ENPP6, and ENPP7, which contain a putative N-terminal signal peptide and a C-terminal transmembrane domain, are also predicted to be type I single transmembrane proteins directed to the extracellular space.

[0082] ENPP1, ENPP2 and ENPP3 are known to use nucleotides and their derivatives as substrates to form nucleoside monophosphates (ENPP1, ENPP2, ENPP3) or nucleoside diphosphates (ENPP1, ENPP2). Only ENPP2 is known to utilize lysophospholipids. ENPP6 and ENPP7 are known to use choline phosphate as substrate and form phosphocholine. In the case of ENPP4 and ENPP5, there are no known substrates.

[0083] ENPP1, also known as NPP1 or PC-1, is a type II transmembrane glycoprotein and is expressed in many tissues (pancreas, kidney, bladder and liver). ENPP1 is important for purinergic signaling transduction, which plays an important role in the regulation of cardiovascular, neural, immune and hematological functions in mammals. ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP to form inorganic pyrophosphate (PPi). Normally, inorganic pyrophosphate regulates the mineralization of bone and cartilage, so the production of PPi by ENPP1 plays a role in making ENPP1 a central regulator of bone and cartilage development. Calcium phosphate formed by PPi produced by ENPP1 is necessary for the mineralization of bone tissue, compared to the inhibitory effect of excess PPi produced by ENPP1 in joint tissue. ENPP1 has a wide range of specificity and hydrolyzes a variety of substrates including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars.

[0084] In recent years, ENPP1 has been found to play an important role in the immune response to various external signals that activate the cGAS-STING pathway. Studies exploring the activity of enzymes that degrade cGAMP molecules have shown that ENPP1 functions as the main hydrolase of cGAMP. As a result consistent with these findings, it has been reported that the half-life of cGAMP is highly dependent on ENPP1 by verifying a longer half-life of cGAMP in ENPP1 knockout mice.

[0085] Bisphosphonate analogs of cGAMP that are resistant to ENPP1 hydrolysis activate STING more than tenfold as much as cGAMP, suggesting that delaying or reducing cGAMP hydrolysis by inhibiting ENPP1 would significantly increase STING activation. ENPP1 inhibition has been reported to attenuate pseudorabies virus infection and reduce Mycobacterium tuberculosis infection by inducing the presence of sustained cGAMP to activate the STING pathway.

[0086] Therefore, one aspect of the present invention provides an inhibitor of ENPP1 which is a cGAMP degrading polypeptide.

[0087] In one aspect, the ENPP1 inhibitor is a reversible inhibitor.

[0088] In one aspect, the ENPP1 inhibitor is a competitive inhibitor.

[0089] In another aspect, the ENPP1 inhibitor is an allosteric inhibitor.

[0090] In another aspect, the ENPP1 inhibitor is an irreversible inhibitor.

[0091] In one aspect, the ENPP1 inhibitor binds to the catalytic domain of phosphodiesterase (PDE) bound to AMP or GMP.

[0092] In one aspect, the ENPP1 inhibitor binds to the PDE catalytic domain, but binds weakly to AMP.

[0093] In another aspect, the ENPP1 inhibitor does not inhibit the ATP hydrolysis activity of the catalytic domain or only weakly inhibits the ATP hydrolysis activity.

[0094] Methods to inhibit ENPP1

[0095] As described above, the present invention includes the following: 1) ENPP1 inhibitors; 2) methods of inhibiting ENPP1 enzymes using the ENPP1 inhibitors; 3) methods of inhibiting the hydrolase activity of ENPP1 towards cGAMP; 4) methods of increasing the signal output of STING pathway activation; 5) methods of inhibiting tumor growth in appropriate mouse tumor models in the context of monotherapy or combination therapy.

[0096] In some embodiments, the inhibition of ENPP1 refers to a decrease in the activity of ENPP1 by more than 10%, such as more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, compared to a control group not treated with the compound. In some embodiments, the inhibition of ENPP1 refers to a decrease in the activity of ENPP1 by more than 2 times, such as more than 3 times, more than 5 times, more than 10 times, more than 100 times, or more than 1000 times, compared to a control group not treated with the compound.

[0097] In some embodiments, the cell-permeable ENPP1 inhibitor is an inhibitor mentioned in the specification. In some embodiments, the cell-permeable ENPP1 inhibitor is any inhibitor selected from the phthalazine derivative compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, its hydrate and its stereoisomer.

[0098] [Chemical formula 1]

[0099]

[0100] In some embodiments, the permeable ENPP1 inhibitor is any one of the following compounds.

[0101] Compound No. 1: 4-phenylphthalazin-1(2H)-one;

[0102] Compound No. 2: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate;

[0103] Compound No. 3: tert-butyl (3(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate;

[0104] Compound No. 4: tert-butyl (3(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate;

[0105] Compound No. 5: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)carbamate;

[0106] Compound No. 6: tert-butyl 3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0107] Compound No. 7: tert-butyl (3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0108] Compound No. 8: tert-butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0109] Compound No. 9: tert-butyl (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0110] Compound No. 10: tert-butyl (4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0111] Compound No. 11: tert-butyl 4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0112] Compound No. 12: tert-butyl (4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0113] Compound No. 13: tert-butyl (4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0114] Compound No. 14: tert-butyl (4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0115] Compound No. 15: tert-butyl (4-(7z-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0116] Compound No. 16: tert-butyl 4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0117] Compound No. 17: tert-butyl 4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0118] Compound No. 18: tert-butyl (4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0119] Compound No. 19: tert-butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0120] Compound No. 20: tert-butyl (4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0121] Compound No. 21: tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate;

[0122] Compound No. 22: (R)-tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate;

[0123] Compound No. 23: tert-butyl (2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)carbamate;

[0124] Compound No. 24: tert-butyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzylcarbamate;

[0125] Compound No. 25: tert-butyl methyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0126] Compound No. 26: tert-butyl 6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0127] Compound No. 27: tert-butyl 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0128] Compound No. 28: tert-butyl 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0129] Compound No. 29: tert-butyl 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0130] Compound No. 30: 4-(3-aminophenyl)phthalazin-1(2H)-one hydrochloride;

[0131] Compound No. 31: 4-(3-aminophenyl)-2-methylphthalazin-1(2H)-one hydrochloride;

[0132] Compound No. 32: 4-(3-aminophenyl)-2-benzylphthalazin-1(2H)-one hydrochloride;

[0133] Compound No. 33: 4-(3-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0134] Compound No. 34: 4-(3-(aminomethyl)phenyl)-2-methylphthalazin-1-(2H)-one hydrochloride;

[0135] Compound No. 35: 4-(3-(aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride;

[0136] Compound No. 36: 4-(4-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0137] Compound No. 37: 4-(4-aminomethyl)phenyl)-2-methylphthalazin-1(2H)-one hydrochloride;

[0138] Compound No. 38: 4-(4-(aminomethyl)phenyl)-2-ethylphthalazin-1(2H)-one hydrochloride;

[0139] Compound No. 39: 4-(4-(aminomethyl)phenyl)-2-isopropylphthalazin-1-(2H)-one hydrochloride;

[0140] Compound No. 40: 4-(4-aminomethyl)phenyl)-2-phenylphthalazin-1(2H)-one hydrochloride;

[0141] Compound No. 41: 4-(4-aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride;

[0142] Compound No. 42: 4-(4-(aminomethyl)phenyl)-2-(4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride;

[0143] Compound No. 43: 4-(4-(aminomethyl)phenyl)-6-methoxyphthalazin-1(2H)-one hydrochloride;

[0144] Compound No. 44: (4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride;

[0145] Compound No. 45: (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride;

[0146] Compound No. 46: 4-(4-(aminomethyl)phenyl)-7-methoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0147] Compound No. 47: 4-(4-(Aminomethyl)-phenyl)-7-methoxyphthalazin-1(2H)-one hydrochloride;

[0148] Compound No. 48: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0149] Compound No. 49: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0150] Compound No. 50: 4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0151] Compound No. 51: (R)-4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0152] Compound No. 52: 4-(4-(2-aminopropan-2-yl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0153] Compound No. 53: 4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0154] Compound No. 54: 4-(4-((methylamino)methyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0155] Compound No. 55: 4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0156] Compound No. 56: 2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0157] Compound No. 57: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0158] Compound No. 58: 6,7-dimethoxy-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0159] Compound No. 59: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroquinolin-7-yl)phthalazin-1(2H)-one;

[0160] Compound No. 60: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate;

[0161] Compound No. 61: tert-butyl (N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate;

[0162] Compound No. 62: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate;

[0163] Compound No. 63: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0164] Compound No. 64: tert-butyl N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0165] Compound No. 65: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0166] Compound No. 66: tert-butyl (N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0167] Compound No. 67: tert-butyl (N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0168] Compound No. 68: tert-butyl N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0169] Compound No. 69: tert-butyl (N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0170] Compound No. 70: tert-butyl (N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0171] Compound No. 71: tert-butyl (N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0172] Compound No. 72: tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0173] Compound No. 73: tert-butyl N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0174] Compound No. 74: tert-butyl N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0175] Compound No. 75: tert-butyl (N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0176] Compound No. 76: tert-butyl (N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0177] Compound No. 77: tert-butyl (N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0178] Compound No. 78: tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0179] Compound No. 79: (R)-tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0180] Compound No. 80: tert-butyl (N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamoyl)carbamate;

[0181] Compound No. 81: tert-butyl N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamoylcarbamate;

[0182] Compound No. 82: tert-butyl (N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0183] Compound No. 83: tert-butyl ((6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0184] Compound No. 84: tert-butyl ((6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0185] Compound No. 85: tert-butyl ((6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0186] Compound No. 86: tert-butyl ((6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0187] Compound No. 87: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0188] Compound No. 88: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride;

[0189] Compound No. 89: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride;

[0190] Compound No. 90: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0191] Compound No. 91: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0192] Compound No. 92: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0193] Compound No. 93: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0194] Compound No. 94: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate;

[0195] Compound No. 95: N-(3-(3-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0196] Compound No. 96: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0197] Compound No. 97: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0198] Compound No. 98: N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0199] Compound No. 99: N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate;

[0200] Compound No. 100: N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0201] Compound No. 101: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0202] Compound No. 102: N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0203] Compound No. 103: N-(4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0204] Compound No. 104: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0205] Compound No. 105: N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0206] Compound No. 106: N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0207] Compound No. 107: N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0208] Compound No. 108: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0209] Compound No. 109: N-(3-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide;

[0210] Compound No. 110: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide;

[0211] Compound No. 111: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)sulfonamide hydrochloride;

[0212] Compound No. 112: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)sulfonamide hydrochloride;

[0213] Compound No. 113: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)-N-methylsulfonamide hydrochloride;

[0214] Compound No. 114: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)-N-methylsulfonamide hydrochloride;

[0215] Compound No. 115: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)sulfonamide hydrochloride;

[0216] Compound No. 116: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)sulfonamide hydrochloride;

[0217] Compound No. 117: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)-N-methylsulfonamide hydrochloride;

[0218] Compound No. 118: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride;

[0219] Compound No. 119: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride;

[0220] Compound No. 120: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride;

[0221] Compound No. 121: 7-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide hydrochloride;

[0222] Compound No. 122: 7-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0223] Compound No. 123: N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride;

[0224] Compound No. 124: (R)-N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride;

[0225] Compound No. 125: N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfonamide hydrochloride;

[0226] Compound No. 126: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride;

[0227] Compound No. 127: N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide;

[0228] Compound No. 128: 6-(4-oxo-3,4-dihydrophthalazin-1-yl-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0229] Compound No. 129: 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0230] Compound No. 130: 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0231] Compound No. 131: 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0232] Compound No. 132: tert-butyl ((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate;

[0233] Compound No. 133: tert-butyl ((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate;

[0234] Compound No. 134: 4-(4-(aminomethyl)piperidin-1-yl)phthalazin-1(2H)-one hydrochloride;

[0235] Compound No. 135: 4-(4-(aminomethyl)piperidin-1-yl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0236] Compound No. 136: tert-butyl N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate;

[0237] Compound No. 137: tert-butyl N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate;

[0238] Compound No. 138: N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride;

[0239] Compound No. 139: N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride;

[0240] Compound No. 140: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride;

[0241] Compound No. 141: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride;

[0242] Compound No. 142: N-(2-(1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)ethyl)sulfonamide trifluoroacetate;

[0243] Compound No. 143: 4-Benzylphthalazin-1(2H)-one;

[0244] Compound No. 144: 4-benzyl-6,7-dimethoxyphthalazin-1(2H)-one;

[0245] Compound No. 145: tert-butyl (3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0246] Compound No. 146: tert-butyl (3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0247] Compound No. 147: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0248] Compound No. 148: tert-butyl (4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0249] Compound No. 149: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0250] Compound No. 150: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0251] Compound No. 151: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate;

[0252] Compound No. 152: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate;

[0253] Compound No. 153: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate;

[0254] Compound No. 154: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate;

[0255] Compound No. 155: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate;

[0256] Compound No. 156: 4-(3-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0257] Compound No. 157: 4-(3-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0258] Compound No. 158: 4-(4-aminobenzyl)-phthalazin-1(2H)-one hydrochloride;

[0259] Compound No. 159: 4-(4-aminobenzyl)-2-methylphthalazin-1(2H)-one hydrochloride;

[0260] Compound No. 160: 4-(4-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0261] Compound No. 161: 4-(4-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0262] Compound No. 162: 4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride;

[0263] Compound No. 163: 6,7-dimethoxy-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride;

[0264] Compound No. 164: 6,7-dimethoxy-2-methyl-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride;

[0265] Compound No. 165: 4-(Indolin-5-ylmethyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0266] Compound No. 166: 4-(Indolin-5-ylmethyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0267] Compound No. 167: tert-butyl (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0268] Compound No. 168: tert-butyl (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0269] Compound No. 169: tert-butyl (N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0270] Compound No. 170: tert-butyl (N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0271] Compound No. 171: tert-butyl (N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0272] Compound No. 172: tert-butyl (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0273] Compound No. 173: tert-butyl N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoylcarbamate;

[0274] Compound No. 174: tert-butyl N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate;

[0275] Compound No. 175: tert-butyl N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate;

[0276] Compound No. 176: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate;

[0277] Compound No. 177: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate;

[0278] Compound No. 178: (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0279] Compound No. 179: (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0280] Compound No. 180: N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0281] Compound No. 181: N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0282] Compound No. 182: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0283] Compound No. 183: (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0284] Compound No. 184: N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0285] Compound No. 185: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride;

[0286] Compound No. 186: N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride;

[0287] Compound No. 187: 5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride;

[0288] Compound No. 188: 5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride;

[0289] Compound No. 189: N-(3-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0290] Compound No. 190: N-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0291] Compound No. 191: N-(3-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0292] Compound No. 192: N-(2-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0293] Compound No. 193: 4-(3-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one;

[0294] Compound No. 194: 4-(4-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one;

[0295] Compound No. 195: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)methanesulfonamide;

[0296] Compound No. 196: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)cyclopropanesulfonamide;

[0297] Compound No. 197: 4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)benzenesulfonamide;

[0298] Compound No. 198: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)thiophene-2-sulfonamide;

[0299] Compound No. 199: (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0300] Compound No. 200: N-methyl-1-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanesulfonamide;

[0301] Compound No. 201: 2-methyl-4-(4-((morpholinesulfonyl)methyl)phenyl)phthalazin-1(2H)-one;

[0302] Compound No. 202: 2-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethane-1-sulfonamide; and

[0303] Compound No. 203: 4-(4-(Aminomethyl)-3-(trifluoromethyl)phenyl-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride.

[0304] In some embodiments, the compounds of the invention have ENPP1 inhibitory properties that reflect activity on additional enzymes. In some embodiments, the compounds of the invention specifically inhibit ENPP1 without intentionally inhibiting more than one other enzyme.

[0305] In some embodiments, the compounds of the invention inhibit ENPP1 as follows: by inhibition assay, e.g., measuring IC50 or EC50, respectively, compared with a control, by assays for determining the activity of the enzyme in a cell-free system or a cell system after treatment with the compounds of the invention. In some embodiments, the compounds of the invention have an IC50 value (or EC50 value) of 10 μM or less, e.g., 3 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower values.

[0306] The analysis steps that can be used to determine the activity of ENPP1 may include many steps as described below, but the analysis steps are not limited to the following analysis steps. It can be a cell-free analysis system, such as a binding assay, an assay using a purified enzyme, a cell-based assay that measures the expression type of a cell, such as a gene expression assay, and an in vivo assay related to a specific animal.

[0307] In some specific embodiments, the method of the present invention is a method for reducing cancer cell proliferation, the method comprising treating cells with an effective amount of the compound of the present invention to reduce cancer cell proliferation. In some specific embodiments, the method can be used in combination with chemotherapy. As long as it is an available cancer cell, any cancer cell can be used.

[0308] Treatment

[0309] As described above, the present invention includes methods for increasing cGAMP levels and / or modulating sub-factors of the STING pathway by inhibiting ENPP1 activity towards cGAMP. According to recent reports, ENPP1 inhibition can modulate STING activity in vivo and thus can be used as a therapeutic for various diseases, such as cancer immunotherapy or treatment of infectious diseases. As described above, the methods of the present invention are methods for increasing STING-mediated responses and modulating immune responses in an individual.

[0310] In some embodiments, the STING-mediated response includes increasing the production of interferons (e.g., type I interferons, type III interferons) in an individual. Interferons (IFNs) are a group of signaling proteins produced and released by host cells in response to the presence of one or more pathogens in order to enhance the defense of surrounding cells against one or more pathogens. IFNs also have various other functions. 1) Activate immune cells, such as NK cells and macrophages; 2) Upregulate antigen presentation by increasing the expression of major histocompatibility complex (MHC) antigens, thereby increasing host defense. IFNs are generally divided into three categories: type I IFNs, type II IFNs, and type III IFNs. Mammalian type I INFs include IFN-α (alpha), IFN-β (beta), IFN-δ (delta), IFN-ε (epsilon), IFN-κ (kappa), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta). All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α / β receptor (IFNAR), which consists of the IFNAR1 and IFNAR2 chains.

[0311] Interferon has been studied as a cancer therapy because it exhibits two different effects, namely tumor-intrinsic effects and / or immunomodulatory effects, which are anti-tumor activities. IFN regulates the expression of many genes that directly affect tumor cell growth, proliferation, differentiation, survival, migration, and other special functions. In some cases, all phases of the cell cycle are prolonged due to IFN, so in vitro treatment with type I IFN has a direct anti-proliferative effect. In some cases, CRKL, one of the CRK proteins activated by type I IFN, interacts with the small G protein RAP1A, a tumor suppressor gene, to inhibit the RAS family GTPase, thereby causing cancer cells to stop growing. IFNs are known to regulate two major apoptotic responses. The two apoptotic responses are extrinsic (apoptotic receptor-mediated pathways) and intrinsic (mitochondrial) pathways. In response to type I IFN, upregulation of sensor protein activation (e.g., DR receptors) occurs, which triggers apoptosis of tumor cells.

[0312] IFN exerts an external influence on tumors by regulating processes such as angiogenesis, osteoclast formation, and immunity. Both endogenous and exogenous type I IFNs play a major role in the activity of anticancer immunity. For example, they not only enhance the activity of α / βT cells, γ / δT cells, NK cells, and dendritic cells, but also inhibit the activity of immunosuppressive cells, such as the transformation of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Type I IFN also acts directly on tumor cells to improve antigen expression and upregulate many immune interaction molecules (e.g., stress ligands recognized by class I major histocompatibility complex (MHCⅠ) and germline-encoded immune receptors).

[0313] One aspect of the method includes administering a therapeutically effective amount of an ENPP1 inhibitor to an individual suffering from cancer to treat the individual. In a specific embodiment, the individual can be an individual diagnosed with cancer or suspected of having cancer. Any suitable ENPP1 inhibitor can be used for the individual. In a specific embodiment, the cancer is selected from any cancer of the adrenal gland, liver, kidney, bladder, breast, colon, stomach, ovary, cervix, uterus, esophagus, colorectum, prostate, pancreas, lung (small cell and non-small cell), thyroid, carcinoma, sarcoma, glioblastoma, melanoma and various head and neck. In a specific embodiment, the cancer is lymphoma.

[0314] In a specific embodiment, the effective amount of the compound can be in the range of about 10 ng to about 100 mg, for example, it can be in the range of about 10 ng to about 50 ng, about 50 ng to about 150 ng, about 150 ng to about 250 ng, about 250 ng to about 500 ng, about 500 ng to about 750 ng, about 750 ng to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 50 μg, about 50 μg to about 150 μg, about 150 μg to about 250 μg, about 250 μg to about 500 μg, about 500 μg to about 750 μg, about 750 μg to about 1 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, about 50 mg to about 100 mg. The amount can be a single dose or a total daily dose. The total daily dose may be in the range of 10 ng to 100 mg, or may be in the range of 100 mg to about 500 mg, or may be in the range of 500 mg to about 1000 mg.

[0315] In one embodiment, a single dose of the compound is administered. In another embodiment, multiple doses of the compound are administered. When the multiple doses are administered for a period of time, the compound can be administered twice a day (bid), once a day (qd), once every other day (qod), every three days, three times a week (tiw), or twice a week (biw).

[0316] Combination therapy

[0317] The ENPP1 inhibitor compounds of the present invention can be administered alone or in combination with additional activators or additional therapies (e.g., radiotherapy) to an individual. The terms "agent", "compoud" and "drug" are used interchangeably in this specification. In a specific embodiment, the method of the present invention further comprises the following steps: administering to an individual simultaneously or in combination or in sequence an additional agent, such as a small molecule, a chemotherapeutic agent, an antibody, an antibody-drug conjugate, an aptamer, a protein, an immune checkpoint inhibitor or radiotherapy.

[0318] "Co-administration" or "in combination with" includes the simultaneous, joint or sequential administration of two or more therapeutic agents without specific time limits. In some embodiments, the agonists or agents are present in the body of a cell or individual at the same time, or exert biological or therapeutic effects at the same time. In some embodiments, the therapeutic agents are in the same composition or unit dosage form. In some embodiments, the therapeutic agents are in the form of separate compositions or unit dosage forms. In some embodiments, the first formulation can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks after) administration of the second therapeutic agent.

[0319] "Concomitant administration" using a known therapeutic agent or an adjunctive therapy comprising a composition of a compound disclosed in the present invention refers to the administration of a compound and a second agonist or adjunctive therapy so that both a known preparation and a composition of a disclosed compound have a therapeutic effect. Such concomitant administration may include administering a drug simultaneously with the administration of the compound of the present invention or administering a drug in advance. The route of administration of the two preparations may be a variety of routes, representative of which are described in detail below. Those skilled in the art will have no difficulty in determining the appropriate time, sequence, and dosage of administration of a drug or therapy and a compound disclosed in the present invention.

[0320] For the treatment of cancer, the ENPP1 inhibitor compound can be administered in combination with a chemotherapeutic agent selected from alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, taxanes, nucleoside analogs, anthracyclines, thymidylate targeting drugs, cell death regulators, cell cycle regulation inhibitors, colony stimulating factor-1 receptor inhibitors, CD47 inhibitors and others.

[0321] To treat cancer, ENPP1 inhibitor compounds may be administered in combination with immunotherapeutic agents.

[0322] Immunotherapeutic agents are any suitable agonists for treating cancer by inducing, improving or suppressing immune responses. In some specific embodiments, immunotherapeutic agents are immune checkpoint inhibitors. Any immune checkpoint inhibitors can be used, for example, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed death 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors can be used, but are not limited thereto. Exemplary immune checkpoint inhibitors can include ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, etc., but are not limited thereto. In some specific embodiments, immunotherapeutic agents are immune cell therapies. Any suitable cell therapy can be used, and chimeric antigen receptor T cell therapy, chimeric antigen receptor NK cell therapy and other cell therapies can be included, but are not limited thereto.

[0323] For the treatment of cancer, ENPP1 inhibitor compounds may be administered in conjunction with suitable cancer vaccine therapies, such as dendritic cell vaccine formulations that promote Th1 / Th17 immunity. In some cases, ENPP1 inhibitor compounds are suitable for use as adjunctive therapeutics in conjunction with Th-17 inducing vaccination.

[0324] Combination with radiotherapy

[0325] In the method for treating cancer, the ENPP1 inhibitor compound can be administered together with radiotherapy. In some specific embodiments, the ENPP1 inhibitor compound can be administered before or after the administration of radiotherapy. The administration combination of radiotherapy and the compounds of the present invention can provide a synergistic therapeutic effect. When the individual is subjected to radiotherapy (RT) with a suitable dosage and / or frequency during radiotherapy (RT), cGAMP can be induced in the individual. The induced cGAMP level improves the level by preventing the degradation of cGAMP by the ENPP1 inhibitor compound, for example, compared with the level achieved by RT alone, thereby improving the therapeutic efficacy of the subject. As described above, the details of the method of the present invention include the administration of a reduced dosage and / or the frequency / therapy of radiotherapy compared with the dosage and / or frequency / reduction of the therapeutic effect of radiotherapy alone. In some specific embodiments, the dosage and / or frequency of the compound of the present invention are administered in combination with the dosage and / or frequency of the risk of radiation damage to the subject in radiotherapy, for example, effectively reducing the risk of radiation damage expected to occur under the therapeutically effective dosage.

[0326] In one embodiment, the method comprises the step of administering an ENPP1 inhibitor to a subject prior to radiotherapy. In one embodiment, the method comprises the step of administering an ENPP1 inhibitor to a subject after exposing the subject to radiotherapy. In another embodiment, the method comprises administering radiotherapy, an ENPP1 inhibitor, and an immune checkpoint inhibitor sequentially to a subject in need thereof.

[0327] Pharmaceutical composition

[0328] Those skilled in the art can easily use pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents. Those skilled in the art can easily use pharmaceutically acceptable auxiliary substances such as pH adjusters, buffers, isotonicity adjusters, stabilizers, wetting agents, etc.

[0329] In some specific embodiments, the compounds of the present invention are formulated as aqueous buffers. Suitable aqueous buffers include various acetates, succinates, citrates and phosphate buffers with a strength of 5-1000mM, but are not limited thereto. In some specific embodiments, aqueous buffers include reagents that provide isotonic solutions. Such reagents include sodium chloride, sugars, such as mannitol, dextrose, sucrose, etc., but are not limited thereto. In some specific embodiments, aqueous buffers further include nonionic surfactants such as polysorbate 20 or polysorbate 80. Optionally, the preparation may further include a preservative. Suitable preservatives include benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, etc., but are not limited thereto. In another specific example, the preparation is stored at about 4°C. The preparation can also be freeze-dried, and they typically include antifreeze agents such as sucrose, trehalose, lactose, maltose, mannitol, etc. Freeze-dried preparations can also be stored for a long time at room temperature.

[0330] A pharmaceutical composition is provided in this specification, which may include a compound disclosed in the present invention or a pharmaceutically acceptable salt thereof, an isomer thereof, a tautomer thereof, or must consist of them, and further, the pharmaceutical composition may include one or more additional activators of interest or must consist of them. Any convenient activator can be used in this method together with the compound of the present invention. In a specific embodiment, for combination therapy, the additional therapeutic agent, the compound of the present invention, and the immune checkpoint inhibitor recorded in the present invention can be administered orally, subcutaneously, intramuscularly, intranasally, non-orally or by other routes. In another specific embodiment, the compound of the present invention and the chemotherapeutic preparation (particularly a chemotherapeutic preparation that can induce the production of cGAMP in vivo) and the additional therapeutic agent recorded in the present invention for combination therapy can be administered orally, subcutaneously, intramuscularly, intranasally, non-orally or by other routes. The compound of the present invention and the second activator (if present) can be administered by the same route of administration or by different routes of administration. The therapeutic agent can be administered to the affected organ by any suitable method, including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, intratumoral injection.

[0331] The compounds of the present invention can be administered in unit dosage form and can be prepared by any method known in the art. This method includes the step of combining the compounds of the present invention with a pharmaceutically acceptable carrier or diluent of one of the auxiliary components of one or more. Pharmaceutically acceptable carriers are selected based on the selected route of administration and standard pharmaceutical practice. Each carrier should be "pharmaceutically acceptable" in terms of being compatible with the other ingredients of the preparation and not damaging the individual or patient. The carrier can be solid or liquid, and the type is usually selected according to the type of administration used.

[0332] Examples of suitable solid carriers include lactose, sucrose, gelatin, agar and bulk powders. Examples of suitable liquid carriers include water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, such as esters, emulsions, syrups or elixirs, suspensions, and solutions and / or suspensions reconstituted by non-foam particles. These liquid carriers may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners and melting agents.

[0333] Various aspects of the present invention are described below.

[0334] One aspect of the present invention provides a compound selected from the group consisting of a phthalazine derivative compound represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0335] [Chemical formula 1]

[0336]

[0337] In the chemical formula 1,

[0338] Y 1 and Y 2 are independently hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 3 -C 10 Cyclic group; C 1 -C 6 Alkoxy; C 3 -C 10 Cyclic group; or C 3 -C 10 Heterocyclic group;

[0339] R 1 or R 2 are independently hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C 10 Heteroaryl; C 3 -C 10 Heterocyclyl; -C(O)-(C 1 -C 13 alkyl); or R 1 Connect with R 2The nitrogen atoms together form a four- to seven-membered saturated, unsaturated or aromatic ring, which may optionally contain N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 at least one of, and may optionally be C 1 -C 13 Alkyl, C 6 -C 10 Aryl, C 3 -C 10 Substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group and a cyano group;

[0340] R 3 is hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C 10 Heteroaryl; C 3 -C 10 heterocyclic group; or -C(O)-(C 1 -C 13 alkyl);

[0341] R 4 is hydrogen; hydroxyl; halogen group; C 1 -C 13 Alkyl; C 1 -C 6 Alkoxy; C 1 -C 6 Alkenyl; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C 10 Heteroaryl; C 3 -C 10 heterocyclic group; amino group; nitro group; amide group; carboxylic acid group; nitrile group; urea group; sulfonamide group; thioether group; sulfone group; or phosphine group;

[0342] The C 1 -C 6 Alkyl, C 1 -C 13 Alkyl or C 3 -C 10 The ring group contains a group selected from hydrogen; a hydroxyl group; a halogen group; C 1 -C13 Alkyl; C 1 -C 6 Alkoxy; amino (-NR 5 R 6 ); nitro (-N(O) 2 ); Amide (-(C=O)NR 5 R 6 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 5 (C=O)NR 6 -); sulfonamide (-NHS(O) 2 -); sulfide group (-S-); sulfone group (-S(O) 2 -); phosphinyl (-P(O)R 5 R 6 );C 6 -C 10 Aryl; C 3 -C 10 heteroaryl; and C 3 -C 10 One or more substituents in the heterocyclic group,

[0343] The C 6 -C 10 Aryl, C 3 -C 10 Heteroaryl or C 3 -C 10 The heterocyclic group contains a group selected from hydrogen; a hydroxyl group; a halogen group; a carbonyl group (-(C=O)R 5 R 6 );halogen or C 3 -C 10 Heterocyclic substituted or unsubstituted C 1 -C 3 Alkyl; halogen or C 3 -C 10 Heterocyclic substituted or unsubstituted C 1 -C 3 Alkoxy; C 6 -C 10 Phenoxy; amino (-NR 5 R 6 ); nitro (-N(O) 2 ); Amide (-(C=O)NR 5 R 6 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 5 (C=O)NR 6 -); sulfonamide (-NHS(O) 2 -); sulfide group (-S-); sulfone group (-S(O) 2-); phosphinyl (-P(O)R 5 R 6 );C 6 -C 10 Aryl; C 3 -C 10 Heteroaryl and C 3 -C 10 One or more substituents in the heterocyclic group,

[0344] The R 5 and R 6 are each independently hydrogen; C 1 -C 6 Alkyl; C 1 -C 6 Alkenyl; C 1 -C 6 Alkynyl; C 6 -C 10 Aryl; C 3 -C 10 Heteroaryl; C 3 -C 10 heterocyclic group; or R 5 Connect with R 6 The nitrogen atoms or carbon atoms of the amines or amines are taken together to form a three- to seven-membered saturated ring, which may optionally contain N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 At least one of, and may optionally be replaced by hydrogen, C 1 -C 13 Alkyl, C 6 -C 10 Aryl, C 3 -C 10 is substituted by at least one of a heteroaryl group, a hydroxyl group, a halide group and a cyano group,

[0345] The C 3 -C 10 Heteroaryl and C 3 -C 10 The heterocyclic group contains one or more heteroatoms selected from N, O and S.

[0346] In the definition of substituents of the present invention, the term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl group may be a "saturated alkyl" that does not contain an alkenyl or alkynyl moiety, or may be an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety. "Alkenyl" refers to a group containing at least one carbon-carbon double bond, and "alkynyl" refers to a group containing at least one carbon-carbon triple bond. When used alone or in combination, the alkyl groups may each be cyclic, branched or straight chain.

[0347] The term "aryl" refers to a carbocyclic aromatic monocyclic group containing six carbon atoms, which may be fused alone or in combination with other groups to a second aromatic, saturated or unsaturated five-membered or six-membered carbocyclic group. Examples of aryl groups may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, etc. Aryl groups may be connected to other groups at appropriate positions of the aromatic ring.

[0348] The term "alkoxy" refers to an alkyl group (i.e., -O-alkyl) connected to other groups via an oxygen atom. The alkoxy group may be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6) alkoxy groups, for example, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1- The invention also includes, but is not limited to, pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

[0349] The term "phenoxy" refers to a phenyl group connected to another group through an oxygen atom (ie, -O-aryl). The phenoxy group may be unsubstituted or substituted with one or more halogen, alkyl, aryl, and heteroaryl groups, but is not limited thereto.

[0350] The term "amino" refers to an alkyl group (i.e., -NH- or -N-alkyl) connected to other groups via a nitrogen atom. The amino group may be unsubstituted or substituted with one or more suitable substituents. Examples of amino groups include (C1-C6) amino groups, for example, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl-2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl, -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2 -methyl-2-pentyl, -NH-3-methyl-2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-tert-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl- N-butyl, -N-methyl-N-isobutyl, -N-methyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl-N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N,N-dihexyl, but are not limited to these.

[0351] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0352] Unless otherwise specified, the term "heterocyclic group" refers to a heteroaromatic compound containing one or more heteroatoms selected from N, O and S. Preferably, the heterocyclic group may include pyrrolidinyl, furanyl, morpholinyl, piperazinyl and piperidinyl, more preferably, may include pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, but is not limited thereto.

[0353] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic compound containing one or more heteroatoms selected from N, O and S. Preferably, the heteroaryl may include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl, pyrrolyl, but is not limited thereto.

[0354] One aspect of the present invention provides a compound selected from the group consisting of a phthalazine derivative compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, wherein the Y 1 and Y 2 are each independently hydrogen; or C 1 -C 13 Alkyl; R 1 or R 2 are independently hydrogen; hydroxyl; C 1 -C 13 Alkyl; or C 1 -C 6 Alkoxy; R 3 is hydrogen; C 1 -C 13 Alkyl; or C 6 -C 10 Aryl; R 4 C 1 -C 13 Alkyl; C 6 -C 10 Aryl; C 3 -C 10 Cyclic group; C 3 -C 10 Heteroaryl; C 3 -C 10 a heterocyclic group; an amino group; a nitro group; an amide group; a carboxylic acid group; a nitrile group; a urea group; a sulfonamide group; a thioether group; a sulfone group; or a phosphine group.

[0355] One aspect of the present invention provides a compound selected from the group consisting of a phthalazine derivative compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, wherein Y 1 and Y 2 Each is hydrogen, R 1 or R 2 are each independently hydrogen; C 1 -C 4 Alkyl; or C 1 -C 4 Alkoxy; R 3 is hydrogen; C 1 -C 4 Alkyl; or C 6 -C 10Aryl; R 4 is substituted or unsubstituted C 1 -C 6 alkyl; substituted or unsubstituted benzene; substituted or unsubstituted hexane; substituted or unsubstituted furan; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted naphthalene; substituted or unsubstituted anthracene; substituted or unsubstituted phenanthrene; substituted or unsubstituted pyridazine; substituted or unsubstituted piperidine; substituted or unsubstituted morpholine; substituted or unsubstituted pyrrolidine; substituted or unsubstituted pyrazine; substituted or unsubstituted imidazole; substituted or unsubstituted pyrazole; substituted or unsubstituted quinoline; substituted or unsubstituted pyrimidine; substituted or unsubstituted pyrrole; substituted or unsubstituted indole; substituted or unsubstituted purine; substituted or unsubstituted cyclopropane; or substituted or unsubstituted cyclobutane.

[0356] One aspect of the present invention provides a compound selected from the group consisting of a phthalazine derivative compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, wherein Y 1 and Y 2 Each is hydrogen, R 1 or R 2 are each independently hydrogen; or methoxy; R 3 is hydrogen; C 1 -C 4 Alkyl; phenyl; or benzyl; R 4 is substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,

[0357]

[0358] One aspect of the present invention provides a compound selected from the group consisting of a phthalazine derivative compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, wherein the compound is selected from any one of the following Compound No. 1 to Compound No. 203.

[0359] Compound No. 1: 4-phenylphthalazin-1(2H)-one;

[0360] Compound No. 2: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate;

[0361] Compound No. 3: tert-butyl (3(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate;

[0362] Compound No. 4: tert-butyl (3(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate;

[0363] Compound No. 5: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)carbamate;

[0364] Compound No. 6: tert-butyl 3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0365] Compound No. 7: tert-butyl (3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0366] Compound No. 8: tert-butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0367] Compound No. 9: tert-butyl (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0368] Compound No. 10: tert-butyl (4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0369] Compound No. 11: tert-butyl 4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0370] Compound No. 12: tert-butyl (4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0371] Compound No. 13: tert-butyl (4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0372] Compound No. 14: tert-butyl (4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0373] Compound No. 15: tert-butyl (4-(7z-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0374] Compound No. 16: tert-butyl 4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0375] Compound No. 17: tert-butyl 4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate;

[0376] Compound No. 18: tert-butyl (4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0377] Compound No. 19: tert-butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0378] Compound No. 20: tert-butyl (4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0379] Compound No. 21: tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate;

[0380] Compound No. 22: (R)-tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate;

[0381] Compound No. 23: tert-butyl (2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)carbamate;

[0382] Compound No. 24: tert-butyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzylcarbamate;

[0383] Compound No. 25: tert-butyl methyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate;

[0384] Compound No. 26: tert-butyl 6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0385] Compound No. 27: tert-butyl 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0386] Compound No. 28: tert-butyl 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0387] Compound No. 29: tert-butyl 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;

[0388] Compound No. 30: 4-(3-aminophenyl)phthalazin-1(2H)-one hydrochloride;

[0389] Compound No. 31: 4-(3-aminophenyl)-2-methylphthalazin-1(2H)-one hydrochloride;

[0390] Compound No. 32: 4-(3-aminophenyl)-2-benzylphthalazin-1(2H)-one hydrochloride;

[0391] Compound No. 33: 4-(3-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0392] Compound No. 34: 4-(3-(aminomethyl)phenyl)-2-methylphthalazin-1-(2H)-one hydrochloride;

[0393] Compound No. 35: 4-(3-(aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride;

[0394] Compound No. 36: 4-(4-(aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0395] Compound No. 37: 4-(4-aminomethyl)phenyl)-2-methylphthalazin-1(2H)-one hydrochloride;

[0396] Compound No. 38: 4-(4-(aminomethyl)phenyl)-2-ethylphthalazin-1(2H)-one hydrochloride;

[0397] Compound No. 39: 4-(4-(aminomethyl)phenyl)-2-isopropylphthalazin-1-(2H)-one hydrochloride;

[0398] Compound No. 40: 4-(4-aminomethyl)phenyl)-2-phenylphthalazin-1(2H)-one hydrochloride;

[0399] Compound No. 41: 4-(4-aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride;

[0400] Compound No. 42: 4-(4-(aminomethyl)phenyl)-2-(4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride;

[0401] Compound No. 43: 4-(4-(aminomethyl)phenyl)-6-methoxyphthalazin-1(2H)-one hydrochloride;

[0402] Compound No. 44: (4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride;

[0403] Compound No. 45: (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride;

[0404] Compound No. 46: 4-(4-(aminomethyl)phenyl)-7-methoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0405] Compound No. 47: 4-(4-(Aminomethyl)-phenyl)-7-methoxyphthalazin-1(2H)-one hydrochloride;

[0406] Compound No. 48: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0407] Compound No. 49: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0408] Compound No. 50: 4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0409] Compound No. 51: (R)-4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0410] Compound No. 52: 4-(4-(2-aminopropan-2-yl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0411] Compound No. 53: 4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0412] Compound No. 54: 4-(4-((methylamino)methyl)phenyl)phthalazin-1(2H)-one hydrochloride;

[0413] Compound No. 55: 4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0414] Compound No. 56: 2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0415] Compound No. 57: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0416] Compound No. 58: 6,7-dimethoxy-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride;

[0417] Compound No. 59: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroquinolin-7-yl)phthalazin-1(2H)-one;

[0418] Compound No. 60: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate;

[0419] Compound No. 61: tert-butyl (N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate;

[0420] Compound No. 62: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate;

[0421] Compound No. 63: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0422] Compound No. 64: tert-butyl N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0423] Compound No. 65: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0424] Compound No. 66: tert-butyl (N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0425] Compound No. 67: tert-butyl (N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0426] Compound No. 68: tert-butyl N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0427] Compound No. 69: tert-butyl (N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0428] Compound No. 70: tert-butyl (N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0429] Compound No. 71: tert-butyl (N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0430] Compound No. 72: tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0431] Compound No. 73: tert-butyl N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0432] Compound No. 74: tert-butyl N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate;

[0433] Compound No. 75: tert-butyl (N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0434] Compound No. 76: tert-butyl (N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0435] Compound No. 77: tert-butyl (N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0436] Compound No. 78: tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0437] Compound No. 79: (R)-tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0438] Compound No. 80: tert-butyl (N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamoyl)carbamate;

[0439] Compound No. 81: tert-butyl N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamoylcarbamate;

[0440] Compound No. 82: tert-butyl (N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate;

[0441] Compound No. 83: tert-butyl ((6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0442] Compound No. 84: tert-butyl ((6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0443] Compound No. 85: tert-butyl ((6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0444] Compound No. 86: tert-butyl ((6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0445] Compound No. 87: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0446] Compound No. 88: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride;

[0447] Compound No. 89: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride;

[0448] Compound No. 90: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0449] Compound No. 91: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0450] Compound No. 92: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0451] Compound No. 93: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0452] Compound No. 94: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate;

[0453] Compound No. 95: N-(3-(3-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0454] Compound No. 96: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0455] Compound No. 97: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0456] Compound No. 98: N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0457] Compound No. 99: N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate;

[0458] Compound No. 100: N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0459] Compound No. 101: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0460] Compound No. 102: N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0461] Compound No. 103: N-(4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0462] Compound No. 104: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0463] Compound No. 105: N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0464] Compound No. 106: N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0465] Compound No. 107: N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0466] Compound No. 108: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride;

[0467] Compound No. 109: N-(3-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide;

[0468] Compound No. 110: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide;

[0469] Compound No. 111: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)sulfonamide hydrochloride;

[0470] Compound No. 112: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)sulfonamide hydrochloride;

[0471] Compound No. 113: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)-N-methylsulfonamide hydrochloride;

[0472] Compound No. 114: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)-N-methylsulfonamide hydrochloride;

[0473] Compound No. 115: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)sulfonamide hydrochloride;

[0474] Compound No. 116: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)sulfonamide hydrochloride;

[0475] Compound No. 117: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)-N-methylsulfonamide hydrochloride;

[0476] Compound No. 118: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride;

[0477] Compound No. 119: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride;

[0478] Compound No. 120: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride;

[0479] Compound No. 121: 7-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide hydrochloride;

[0480] Compound No. 122: 7-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0481] Compound No. 123: N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride;

[0482] Compound No. 124: (R)-N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride;

[0483] Compound No. 125: N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfonamide hydrochloride;

[0484] Compound No. 126: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride;

[0485] Compound No. 127: N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide;

[0486] Compound No. 128: 6-(4-oxo-3,4-dihydrophthalazin-1-yl-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0487] Compound No. 129: 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0488] Compound No. 130: 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0489] Compound No. 131: 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride;

[0490] Compound No. 132: tert-butyl ((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate;

[0491] Compound No. 133: tert-butyl ((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate;

[0492] Compound No. 134: 4-(4-(aminomethyl)piperidin-1-yl)phthalazin-1(2H)-one hydrochloride;

[0493] Compound No. 135: 4-(4-(aminomethyl)piperidin-1-yl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0494] Compound No. 136: tert-butyl N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate;

[0495] Compound No. 137: tert-butyl N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate;

[0496] Compound No. 138: N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride;

[0497] Compound No. 139: N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride;

[0498] Compound No. 140: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride;

[0499] Compound No. 141: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride;

[0500] Compound No. 142: N-(2-(1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)ethyl)sulfonamide trifluoroacetate;

[0501] Compound No. 143: 4-Benzylphthalazin-1(2H)-one;

[0502] Compound No. 144: 4-benzyl-6,7-dimethoxyphthalazin-1(2H)-one;

[0503] Compound No. 145: tert-butyl (3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0504] Compound No. 146: tert-butyl (3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0505] Compound No. 147: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0506] Compound No. 148: tert-butyl (4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0507] Compound No. 149: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0508] Compound No. 150: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate;

[0509] Compound No. 151: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate;

[0510] Compound No. 152: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate;

[0511] Compound No. 153: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate;

[0512] Compound No. 154: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate;

[0513] Compound No. 155: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate;

[0514] Compound No. 156: 4-(3-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0515] Compound No. 157: 4-(3-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0516] Compound No. 158: 4-(4-aminobenzyl)-phthalazin-1(2H)-one hydrochloride;

[0517] Compound No. 159: 4-(4-aminobenzyl)-2-methylphthalazin-1(2H)-one hydrochloride;

[0518] Compound No. 160: 4-(4-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0519] Compound No. 161: 4-(4-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0520] Compound No. 162: 4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride;

[0521] Compound No. 163: 6,7-dimethoxy-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride;

[0522] Compound No. 164: 6,7-dimethoxy-2-methyl-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride;

[0523] Compound No. 165: 4-(Indolin-5-ylmethyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride;

[0524] Compound No. 166: 4-(Indolin-5-ylmethyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride;

[0525] Compound No. 167: tert-butyl (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0526] Compound No. 168: tert-butyl (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0527] Compound No. 169: tert-butyl (N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0528] Compound No. 170: tert-butyl (N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0529] Compound No. 171: tert-butyl (N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0530] Compound No. 172: tert-butyl (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate;

[0531] Compound No. 173: tert-butyl N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoylcarbamate;

[0532] Compound No. 174: tert-butyl N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate;

[0533] Compound No. 175: tert-butyl N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate;

[0534] Compound No. 176: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate;

[0535] Compound No. 177: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate;

[0536] Compound No. 178: (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0537] Compound No. 179: (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0538] Compound No. 180: N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0539] Compound No. 181: N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0540] Compound No. 182: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0541] Compound No. 183: (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0542] Compound No. 184: N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0543] Compound No. 185: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride;

[0544] Compound No. 186: N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride;

[0545] Compound No. 187: 5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride;

[0546] Compound No. 188: 5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride;

[0547] Compound No. 189: N-(3-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0548] Compound No. 190: N-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0549] Compound No. 191: N-(3-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0550] Compound No. 192: N-(2-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride;

[0551] Compound No. 193: 4-(3-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one;

[0552] Compound No. 194: 4-(4-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one;

[0553] Compound No. 195: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)methanesulfonamide;

[0554] Compound No. 196: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)cyclopropanesulfonamide;

[0555] Compound No. 197: 4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)benzenesulfonamide;

[0556] Compound No. 198: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)thiophene-2-sulfonamide;

[0557] Compound No. 199: (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide;

[0558] Compound No. 200: N-methyl-1-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanesulfonamide;

[0559] Compound No. 201: 2-methyl-4-(4-((morpholinesulfonyl)methyl)phenyl)phthalazin-1(2H)-one;

[0560] Compound No. 202: 2-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethane-1-sulfonamide; and

[0561] Compound No. 203: 4-(4-(Aminomethyl)-3-(trifluoromethyl)phenyl-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride.

[0562] The compound of Chemical Formula 1 according to the present invention can be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, and a preferred salt can be a salt of one or more inorganic acids or organic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

[0563] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may include a hydrate and a solvate. The hydrate may be formed by combining the compound of Chemical Formula 1 with water molecules.

[0564] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, comprising the compound of one aspect of the present invention as an effective ingredient.

[0565] Another aspect of the present invention provides an ENPP1 inhibitor comprising the compound according to one aspect of the present invention as an active ingredient.

[0566] Another aspect of the present invention provides a STING pathway activator comprising the compound according to one aspect of the present invention as an active ingredient.

[0567] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, wherein the cancer is associated with the inhibition of ENPP1.

[0568] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, the pharmaceutical composition comprising a compound selected from the compound of Chemical Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof as an active ingredient.

[0569] The pharmaceutical composition according to the present invention has excellent ability to inhibit ENPP1 activity.

[0570] Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treating, preventing and alleviating cancer caused by abnormal cell growth.Cancers that can be prevented, treated or alleviated by using the pharmaceutical composition of the present invention can include gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestinal cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma and myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis or fibroadenoma, etc.

[0571] Another aspect of the present invention provides an ENPP1 inhibitor comprising any one of the above compounds as an active ingredient.

[0572] Another aspect of the present invention provides a STING pathway activator comprising any one of the above compounds as an active ingredient.

[0573] The pharmaceutical composition can be applied to experimental animals such as mice, rabbits, rats, guinea pigs or hamsters, or primates including humans, but is not limited thereto. It can be preferably applied to primates including humans, and more preferably applied to humans.

[0574] In this specification, "treatment" can be used to include alleviating or improving symptoms, reducing the scope of the disease, delaying or alleviating the progression of the disease, improving, alleviating or stabilizing the disease state, partial or complete recovery, prolonging survival and other beneficial treatment results.

[0575] In addition, in this specification, the treatment of cancer refers to the treatment of all cancer cells, and cancer also includes angiogenesis of endothelial cells and its mitosis (solid tumors, tumor metastasis and benign tumors). For example, cancer can include breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated cancer, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and bile duct cancer, kidney cancer, bone marrow disease, lymphatic disease, Hodgkin's disease, hairy cell cancer, oral cancer, pharyngeal (oral) cancer, lip cancer, tongue cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma or pyogenic granuloma, but is not limited to this.

[0576] According to the use form and method of the pharmaceutical composition of the present invention, the content of the compound represented by the chemical formula 1 as an active ingredient, or a pharmaceutically acceptable salt or hydrate thereof can be appropriately adjusted and used according to the choice of those skilled in the art.

[0577] As an example, the pharmaceutical composition may contain 0.1-10 wt % of the compound represented by the chemical formula 1, a pharmaceutically acceptable salt or a hydrate thereof, relative to the total weight of the entire composition, and more preferably may contain 0.5-5 wt % of the compound represented by the chemical formula 1, a pharmaceutically acceptable salt or a hydrate thereof.

[0578] The compound represented by the Chemical Formula 1, a pharmaceutically acceptable salt or a hydrate thereof may be contained in the pharmaceutical composition alone, or may be contained in the pharmaceutical composition together with other pharmaceutically acceptable carriers, excipients, diluents or auxiliary ingredients.

[0579] Examples of the pharmaceutically acceptable carrier, excipient or diluent can include one or more selected from lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin and physiological saline, but are not limited thereto, and any conventional carrier, excipient or diluent can be used. In addition, the pharmaceutical composition may further contain conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, wetting agents, pH regulators, nutrients, vitamins, electrolytes, alginic acid and its salts, pectinic acid and its salts, protective colloids, glycerin, flavors, emulsifiers or preservatives, etc.

[0580] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be administered in combination with other anticancer agents for treating cancer or tumors, thereby enhancing the therapeutic effect of the anticancer agents.

[0581] Specifically, the pharmaceutical composition may contain, in addition to the active ingredient, one or more other anticancer agents or other therapeutic agents known to be effective in treating or preventing cancer, and may be used in combination therapy applied simultaneously or at different times. Other anticancer agents or other therapeutic agents that can be used in the combination therapy may include, for example, Gleevec ( Imatinib), Sutent sunitinib), Herceptin Trastuzumab), Velcade Bortezomib), dexamethasone, Nexavar Sorafenib), aromatase inhibitors or kinase inhibitors, but not limited thereto.

[0582] The method of application of the pharmaceutical composition can be oral or parenteral, as an example, can be applied by various routes including oral, percutaneous, subcutaneous, intravenous or intramuscular. In addition, the dosage form of the composition can be different according to the method of use, and can be prepared using methods known in the art of the present invention to provide a quick, continuous or delayed release of active ingredients after being applied to mammals. Usually, solid preparations for oral administration include tablets (TABLETS), lozenges, soft capsules or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS) and granules (GRANULES) etc., and these preparations can be prepared by mixing more than one excipient, and the excipient, for example, includes starch, calcium carbonate (calciumcarbonate), sucrose (sucrose), lactose (lactose) or gelatin etc. In addition, in addition to simple excipients, lubricants, such as magnesium stearate, talcum powder etc. can also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to water and liquid paraffin as commonly used simple diluents, various excipients may also be included, such as wetting agents, sweeteners, fragrances, preservatives, etc. Dosage forms for non-oral administration include creams, lotions, ointments, plasters, liquids and solutions, aerosols, fluid extracts, elixirs, infusions, sachets, patches, or injections. In the case of a dosage form for injection, it is preferably in the form of an isotonic aqueous solution or suspension.

[0583] The pharmaceutical composition may also contain sterilizers, preservatives, stabilizers, wettable powders or emulsifiers, auxiliary agents such as salts and / or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation or coating methods. In addition, it may also be formulated using appropriate methods known in the art.

[0584] In addition, the dosage of the pharmaceutical composition can be determined according to the method of administration, the age, sex, severity of the patient's disease, state, absorption rate and inactivation rate of the active ingredient in the body and the co-administered drug, and can be administered once or in multiple doses. Preferably, the active ingredient of the pharmaceutical composition can be administered to mammals including humans once or in multiple doses per day at a dose of 0.001-100 mg / kg body weight, preferably 0.01-35 mg / kg body weight, via oral or parenteral routes.

[0585] Another specific embodiment of the present invention provides a method for treating cancer, comprising the step of administering a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof in a therapeutically effective amount.

[0586] Preferably, the treatment method may further include the step of identifying a patient in need of prevention or treatment of the cancer before the administering step.

[0587] The "therapeutically effective amount" of the present invention refers to the amount of the active ingredient that is effective for preventing or treating cancer in mammals. The therapeutically effective amount can be adjusted according to various factors including the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form, the patient's age, weight, general health status, gender and diet, administration time, administration route, blood clearance rate of the composition, treatment time and concomitantly used drugs, but preferably, as described above, it can be administered once or multiple times a day at a dose of 0.001-100 mg / kg body weight, preferably 0.01-35 mg / kg body weight, via oral or parenteral routes.

[0588] In addition, the present invention relates to a method for preparing a 7-amino-3,4-dihydropyrimidopyrimidin-2-one derivative compound represented by the Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof.

[0589] In addition, the present invention is characterized by a method for preparing the compound represented by the chemical formula 1. The preparation method according to the present invention is described in detail below.

[0590] In a specific embodiment, the compound represented by Chemical Formula 1 of the present invention can be prepared by any one or more of the following Preparation Methods 1 to 4.

[0591] Preparation method 1

[0592] The phthalazine derivative compound of Chemical Formula 1 according to one aspect of the present invention may be prepared by a preparation method according to the following Reaction Formula 1-1 to Reaction Formula 1-3.

[0593] [Reaction formula 1-1]

[0594]

[0595] [Reaction 1-2]

[0596]

[0597] [Reaction 1-3]

[0598]

[0599] Preparation method 2

[0600] The phthalazine derivative compound of Chemical Formula 1 according to one aspect of the present invention may be prepared by a preparation method according to the following Reaction Formula 2.

[0601] [Reaction 2]

[0602]

[0603] Preparation method 3

[0604] The phthalazine derivative compound of Chemical Formula 1 according to one aspect of the present invention may be prepared by a preparation method according to the following Reaction Formula 3-1 to Reaction Formula 3-2.

[0605] [Reaction formula 3-1]

[0606]

[0607] [Reaction formula 3-2]

[0608] DETAILED DESCRIPTION

[0609] Hereinafter, the present invention will be described in detail by synthesis examples, preparation examples, embodiments, experimental examples and formulation examples. However, the following preparation examples, embodiments, experimental examples and formulation examples are only used to illustrate the present invention, and the content of the present invention is not limited to the following specific embodiments.

[0610] [Preparation Example 1]

[0611] Preparation Example 1 is subjected to the process of preparing product 4 (Preparation Example 1-1) or product 6 (Preparation Example 1-2). Then, the phthalazine derivative is prepared by using the product 4 or product 6 as reactant 7 in Preparation Example 1-3.

[0612] Preparation Example 1-1: Preparation of reactant 4

[0613] [Reaction formula 1-1]

[0614]

[0615] Step 1: In a round bottom flask, reactant 1 (1.0 eq.) and hydrazine hydrate (1.7 eq.) were added to ethanol and refluxed for 2 hours. The reactant was cooled to room temperature and filtered to obtain solid 2 (yield 71-94%).

[0616] Examples of reactant 1 used in step 1 are as follows.

[0617] Reactant 1-1: 2,3-dihydrophthalazine-1,4-dione

[0618]

[0619] 1 H NMR (400MHz, DMSO) δ11.51(s,2H),8.15-7.95(m,2H),7.92-7.79(m,2H).

[0620] Reactant 1-2: 6,7-dimethoxy-2,3-dihydrophthalazine-1,4-dione

[0621]

[0622] 1 H NMR (400MHz, DMSO) δ11.25(br s,2H),7.42(s,2H),3.93(s,6H).

[0623] Reactant 1-3: 6-methoxy-2,3-dihydrophthalazine-1,4-dione

[0624]

[0625] 1 H NMR (400MHz, DMSO) δ11.44 (s, 2H), 8.00 (d, J = 9.2Hz, 1H), 7.60-7.20 (m, 2H), 3.92 (s, 3H).

[0626] Step 2-1: In a round-bottom flask, the reactant 2 (1.0 equivalent) obtained in the step 1 and anhydrous pyridine (5.0 equivalent) were dissolved in anhydrous acetonitrile (0.61M) under nitrogen, and the temperature was then lowered to 0°C and stirred for 10 minutes. Trifluoromethanesulfonic anhydride (1.05 equivalent) was added at 0°C, and the temperature was then raised to room temperature and stirred for 6 hours. The mixture was poured into ethyl acetate and washed with a 5% aqueous hydrochloric acid solution, and the aqueous solution layer was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then recrystallized from ethyl acetate to obtain 3 (yield 67-79%).

[0627] Reactant 3-1: 4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0628]

[0629] 1 H NMR (400 MHz, DMSO) δ 12.91 (s, 1H), 8.36-8.29 (m, 1H), 8.12 (td, J = 7.6, 1.4 Hz, 1H), 8.05 (td, J = 7.6, 1.3 Hz, 1H), 7.88 (apparent d, J = 7.7 Hz 1H).

[0630] Reactant 3-2: 6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0631]

[0632] 1 H NMR (400MHz, DMSO) δ12.82(s,1H),7.82(d,J=8.8Hz,1H),7.70(d,J=2.6Hz,1H),7.67(dd,J=8.8,2.7Hz,1H),3.99(s,3H).

[0633] Reactant 3-3: 7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate

[0634]

[0635] 1 H NMR (400MHz, DMSO) δ12.80(s,1H),8.24(d,J=8.9Hz,1H),7.61(dd,J=8.8,2.6Hz,1H),7.13(d,J=2.5Hz,1H),3.97(s,3H).

[0636] Reactant 3-4: 6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl trifluoromethanesulfonate

[0637]

[0638] 1 H NMR (400MHz, DMSO) δ12.77(s,1H),7.67(s,1H),7.13(s,1H),4.00(s,3H),3.99(s,3H).

[0639] Step 2-2: In a round-bottom flask, the reactant 3 (1.0 equivalent) obtained in step 2-1 was dissolved in anhydrous acetonitrile (0.2 M), and K 2 CO 3 (3.0 eq.) and alkyl halide (3.0 eq.) were added and stirred at 80° C. for 4 hours. After washing with ethyl acetate and filtering with celite to remove the solid, the compound was purified by column chromatography (yield 60-87%).

[0640] Reactant 3-5: 3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0641]

[0642] 1 H NMR (400MHz, DMSO) δ8.36 (dt, J=8.0, 1.1Hz, 1H), 8.16-8.02 (m, 2H), 7.90 (d, J=7.8Hz, 1H), 3.69 (s, 3H).

[0643] Reactant 3-6: 3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0644]

[0645] 1 H NMR (400 MHz, CDCl 3 )δ8.47(dt,J=6.9,1.7Hz,1H),7.96-7.80(m,3H),7.25(dd,J=5.2,2.8Hz,1H),4.24(q,J=7.2Hz,2H),1.41(td,J=7.2Hz,3H).

[0646] Reactant 3-7: 3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0647]

[0648] 1 H NMR (400 MHz, CDCl 3 )δ8.46(dd,J=7.8,1.5Hz,1H),8.04(dd,J=7.8,1.4Hz,1H),7.80(dtd,J=15.0 ,7.6,1.5Hz,2H),5.18(p,J=6.2Hz,1H),1.43-1.41(m,3H),1.41-1.39(m,3H).

[0649] Reactant 3-8: 3-Benzyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0650]

[0651] 1 H NMR (600 MHz, CDCl 3 )δ8.48-8.44(m,1H),7.94-7.84(m,2H),7.83(dd,J=8.0,1.3Hz,1H),7.49-7.45(m,2H),7.44-7.26(m,3H),5.31(s,2H).

[0652] Reactant 3-9: 6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0653]

[0654] 1 H NMR (600MHz, DMSO) δ7.67 (s, 1H), 7.13 (s, 1H), 3.99 (d, J = 7.4Hz, 6H), 3.68 (s, 3H).

[0655] Preparation Example 1-2: Preparation of reactant 6

[0656] [Reaction 1-2]

[0657]

[0658] Step 1: In a round bottom flask, 1 (1.0 eq.) and arylhydrazine (3.0 eq.) were added to 10% aqueous HCl and refluxed for 10 h. The reaction was cooled to room temperature and 1 M Na 2 CO 3 The solid was removed by adding 2N HCl aqueous solution to the filtrate again and filtering to obtain solid 5 (yield 65%).

[0659] Reactant 5-1: 2-phenyl-2,3-dihydrophthalazine-1,4-dione

[0660]

[0661] 1 H NMR (400MHz, DMSO) δ11.83(s,br,1H),8.30(dd,J=7.5,1.6Hz,1H),8.06-7.89(m,3H),7.66-7.61(m,2H),7.49(dd,J=8.6,7.1Hz,2H),7.40-7.34(m,1H).

[0662] Step 2: In a round-bottom flask, the reactant 5 (1.0 equivalent) prepared in step 1 and anhydrous pyridine (5.0 equivalent) were dissolved in anhydrous acetonitrile (0.61 M) under nitrogen, and the temperature was then reduced to 0°C and stirred for 10 minutes. Trifluoromethanesulfonic anhydride (1.05 equivalent) was added at 0°C, and the temperature was then raised to room temperature and stirred for 6 hours. The mixture was poured into ethyl acetate and washed with 5% aqueous hydrochloric acid, and the aqueous layer was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the compound was purified by column chromatography to obtain 6 (yield was 77%).

[0663] Reactant 6-1: 4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl-trifluoromethanesulfonate

[0664]

[0665] 1 H NMR (600 MHz, CDCl 3 )δ8.55(d,J=7.7Hz,1H),8.02-7.93(m,2H),7.91(d,J=7.8Hz,1H),7.69(d,J=7.9Hz,2H),7.50(t,J=7.8Hz,2H),7.40(t,J=7.5Hz,1H).

[0666] Preparation Example 1-3

[0667] 4 prepared in the preparation example 1-1 or 6 prepared in the preparation example 1-2 is used as reactant 7, and is prepared according to the reaction formula 1-3 shown below.

[0668] [Reaction 1-3]

[0669]

[0670] Step 1 (representative synthesis method A): In reaction formula 1-3, 7 (1.0 equivalent), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.1 equivalent), 8 (1.05 equivalent) and tripotassium phosphate (1.5 equivalent) were dissolved in 1,4-dioxane (0.3M) in a round-bottom flask and refluxed for 4 hours under nitrogen. After the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. For the obtained residue, 9 was obtained by column chromatography (EtOAc: Hexane = 1:1) (yield 40-80%).

[0671] Step 1 (representative synthesis method B): In reaction formula 1-3, 7 (1.0 equivalent), tetrakis(triphenylphosphine)palladium(0) (0.06 equivalent), 8 (1.25 equivalent) and potassium carbonate (3.75 equivalent) were dissolved in 1,4-dioxane (0.09 M) and water (0.9 M) in a round-bottom flask and refluxed for 4 hours under nitrogen. After the reaction was completed, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. For the obtained residue, 9 was obtained by column chromatography (EtOAc: hexane = 1: 1) (yield of 40-80%).

[0672] The embodiments of the present invention prepared according to Preparation Example 1 as described above are as follows:

[0673] [Example 1]: 4-phenylphthalazin-1(2H)-one

[0674]

[0675] 1 H NMR (400MHz, DMSO): δ12.87(s,1H),8.39-8.32(m,1H),7.91(td,J=6.0,5.2,3.2Hz,2H),7.71-7.67(m,1H),7.62-7.54(m,5H).

[0676] [Example 2]: tert-Butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

[0677]

[0678] 1H NMR(400MHz,DMSO)δ12.83(s,1H),9.55(s,1H),8.99-8.16(m,1H),7.94-7.86(m,2H),7.71(d, J=9.2Hz,2H),7.58(d,J=7.2Hz,1H),7.42(t,J=7.9Hz,1H),7.17(d,J=7.7Hz,1H),1.47(s,9H).

[0679] [Example 3]: tert-Butyl (3(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

[0680]

[0681] 1 H NMR (400MHz, DMSO) δ9.55(s,1H),8.61-8.20(m,1H),8.00-7.82(m,2H),7.73(s,1H),7.69(dd,J=6.1,3.0H z,1H),7.58(d,J=8.4Hz,1H),7.43(t,J=7.9Hz,1H),7.17(dt,J=7.6,1.3Hz,1H),3.78(s,3H),1.47(s,9H).

[0682] [Example 4]: tert-Butyl (3(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

[0683]

[0684] 1 H NMR(400MHz,DMSO)δ9.55(s,1H),8.45-8.26(m,1H),7.99-7.88(m,2H),7.79-7.67(m, 2H),7.60(dd,1H),7.48-7.21(m,7H),7.18(d,J=7.3Hz,1H),5.39(s,2H),1.47(s,9H).

[0685] [Example 5]: tert-Butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)carbamate

[0686]

[0687] 1H NMR(400MHz,DMSO)δ12.85(s,1H),8.38-8.31(m,1H),7.93-7.85(m,2H),7.72-7.67( m,1H),7.53-7.43(m,4H),7.40(d,J=7.5Hz,1H),4.22(d,J=6.2Hz,2H),1.38(s,9H).

[0688] [Example 6]: tert-Butyl 3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate

[0689]

[0690] 1 H NMR (400MHz, MeOD) δ8.50-8.44(m,1H),7.94-7.84(m,2H),7.81(d,J=7.0Hz,1H),7.58-7.45(m,4H),4.35(s,2H),3.90(s,3H),1.46(s,9H).

[0691] [Example 7]: tert-Butyl (3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0692]

[0693] 1 H NMR (400MHz, CDCl3δ8.53(d,J=7.1Hz,1H),7.90-7.61(m,3H),7.58-7.37(m,7H),7.37-7.28(m,3H),5.47(s,2H),4.42(d,J=5.6Hz,2H),1.46(s,9H).

[0694] [Example 8]: tert-Butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0695]

[0696] 1 H NMR(400MHz,MeOD)δ8.44(dd,J=6.3,2.9Hz,1H),7.95-7.84(m,2H),7.80(d,J=3.3Hz,1H),7 .70(d,J=7.3Hz,1H),7.47(d,J=8.1Hz,2H),7.26(d,J=7.7Hz,1H),4.35(s,2H),1.48(s,9H).

[0697] [Example 9]: tert-Butyl (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0698]

[0699] 1 H NMR (400MHz, DMSO) δ8.40-8.33(m,1H),7.94-7.86(m,2H),7.69(s,1H),7.55(d,J=7.9Hz, 2H),7.49(s,1H),7.41(d,J=7.8Hz,2H),4.23(d,J=6.2Hz,2H),3.78(s,3H),1.42(s,9H).

[0700] [Example 10]: tert-Butyl (4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0701]

[0702] 1 H NMR(400MHz,MeOD)δ8.50-8.40(m,1H),7.91-7.85(m,2H),7.82-7.77(m,1H),7.58(d,J= 7.9Hz,2H),7.48(d,J=7.9Hz,2H),4.37-4.32(m,4H),1.48(s,9H),1.44(t,J=7.2Hz,3H).

[0703] [Example 11]: tert-Butyl 4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate

[0704]

[0705] 1 H NMR (400MHz, CDCl3) δ10.53-10.43(m,1H),9.79-9.65(m,3H),9.55(d,J=8.2Hz,2H),9.42(d,J=7. 9Hz,2H),7.44(dt,J=13.3,6.8Hz,1H),6.39(d,J=6.1Hz,2H),3.45(s,9H),3.40(d,J=6.6Hz,6H).

[0706] [Example 12]: tert-Butyl (4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0707]

[0708] 1 H NMR (400MHz, MeOD) δ8.53 (dd, J=6.1, 3.3Hz, 1H), 7.93 (dt, J=7.2, 3.6Hz, 2H), 7.85 (dd, J=6.2, 3.4Hz,1H),7.71-7.61(m,4H),7.49(ddd,J=22.9,15.2,7.4Hz,5H),4.34(s,2H),1.47(s,9H).

[0709] [Example 13]: tert-Butyl (4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0710]

[0711] 1 H NMR (400MHz, MeOD) δ8.49-8.42(m,1H),7.91-7.84(m,2H),7.81(d,J=6.0Hz,1H),7.56(d,J =7.9Hz,2H),7.49-7.40(m,4H),7.36-7.24(m,3H),5.46(s,2H),4.34(s,2H),1.48(s,9H).

[0712] [Example 14]: tert-Butyl (4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0713]

[0714] 1 H NMR (400MHz, DMSO) δ8.38 (dd, J=5.9, 3.2Hz, 1H), 7.91 (dd, J=6.0, 3.3Hz, 2H), 7.75-7.67 (m, 1H), 7.55 (d,J=8.1Hz,2H),7.49(s,1H),7.42(t,J=9.3Hz,5H),7.16(t,J=8.9Hz,2H),5.36(s,2H),1.41(s,9H).

[0715] [Example 15]: tert-Butyl (4-(7z-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0716]

[0717] 1H NMR (400MHz, DMSO): δ12.70(s,1H),8.27(d,J=8.8Hz,1H),7.58(d,J=8.0Hz,2H),7.52-7.44(m,2 H),7.40(d,J=7.9Hz,2H),7.03(d,J=2.5Hz,1H),4.23(d,J=6.1Hz,2H),3.82(s,3H),1.41(s,9H).

[0718] [Example 16]: tert-Butyl 4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate

[0719]

[0720] 1 H NMR(400MHz,MeOD)δ8.36(d,J=8.9Hz,1H),7.58(d,J=8.1Hz,2H),7.50-7.42(m, 3H),7.10(d,J=2.5Hz,1H),4.35(s,2H),3.86(s,3H),3.84(s,3H),1.48(s,9H).

[0721] [Example 17]: tert-Butyl 4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate

[0722]

[0723] 1 H NMR (400MHz, MeOD) δ7.84(d,J=2.8Hz,1H),7.72(d,J=9.0Hz,1H),7.59-7.50(m,2H),7.50-7.36(m,3H),4.34(s,2H),3.99(s,3H),1.48(s,9H).

[0724] [Example 18]: tert-Butyl (4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0725]

[0726] 1H NMR(400MHz,DMSO)δ7.74(d,J=2.8Hz,1H),7.63(d,J=9.0Hz,1H),7.55-7.43(m,4H), 7.40(d,J=8.2Hz,2H),4.23(d,J=6.1Hz,2H),3.96(s,3H),3.77(s,3H),1.41(s,9H).

[0727] [Example 19]: tert-Butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0728]

[0729] 1 H NMR (400 MHz, CDCl 3 ): δ9.92(s,1H),7.88(d,J=2.8Hz,1H),7.67(d,J=9.0Hz,1H),7.54(d,J=8.1Hz,2H),7.44(d,J=7.9 Hz,2H),7.33(dd,J=8.9,2.8Hz,1H),4.93(s,1H),4.42(d,J=5.9Hz,2H),3.99(s,3H),1.49(s,9H).

[0730] [Example 20]: tert-Butyl (4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0731]

[0732] 1 H NMR(400MHz,MeOD)δ7.82(s,1H),7.59(d,J=7.9Hz,2H),7.48(d,J=7.9Hz,2H), 7.11(s,1H),4.35(s,2H),4.03(s,3H),3.88(s,3H),3.83(s,3H),1.48(s,9H).

[0733] [Example 21]: tert-Butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate

[0734]

[0735] 1H NMR(400MHz,DMSO)δ12.83(s,1H),8.33(s,1H),8.08-7.79(m,2H),7.69(s,1H),7 .54(d,J=8.2Hz,2H),7.46(d,J=8.0Hz,2H),1.39(s,9H),1.23(s,3H),0.85(m,1H)

[0736] [Example 22]: (R)-tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate

[0737]

[0738] 1 H NMR(400MHz,MeOD)δ8.44(dd,J=6.3,3.1Hz,1H),7.93-7.84(m,2H),7.84-7.77(m,2 H),7.56(d,J=8.2Hz,2H),7.50(d,J=8.1Hz,2H),1.47(d,J=7.1Hz,3H),1.45(s,9H).

[0739] [Example 23]: tert-Butyl (2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)carbamate

[0740]

[0741] 1 H NMR (400MHz, MeOD) δ8.44(dd,J=6.3,3.2Hz,1H),7.89(dd,J=5.9,3.4Hz,2H),7.86-7.80(m,1H),7.57(q,J=8.2Hz,4H),1.65(s,6H),1.42(s,9H).

[0742] [Example 24]: tert-Butyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzylcarbamate

[0743]

[0744] 1 H NMR (DMSO, 600MHz) δ12.93 (s, 1H), 8.37-8.34 (m, 1H), 7.94-7.89 (m, 4H), 7.68-7.62 (m, 3H), 4.42 (d, J = 6Hz, 2H), 1.43 (s, 9H).

[0745] [Example 25]: tert-Butyl methyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate

[0746]

[0747] 1 H NMR (400MHz, CDCl3) δ10.27(s,1H),8.56-8.50(m,1H),7.85-7.74(m,3H),7.56(d,J =7.8Hz,2H),7.39(d,J=7.3Hz,2H),4.53(s,2H),2.88(d,J=14.3Hz,3H),1.51(s,9H)

[0748] [Example 26]: tert-Butyl 6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0749]

[0750] 1 H NMR(400MHz, CDCl3)δ9.94(s,1H),8.59-8.46(m,1H),7.90-7.69(m,3H),7.44-7.34(m,2 H),7.28(s,1H),4.67(s,2H),3.71(t,J=5.8Hz,2H),2.92(t,J=5.9Hz,2H),1.52(s,9H).

[0751] [Example 27]: tert-Butyl 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0752]

[0753] 1 H NMR (400MHz, DMSO) δ8.42-8.33(m,1H),7.90(d,J=9.2Hz,2H),7.72(s,1H),7.38(d ,J=12.1Hz,3H),4.60(s,2H),3.78(s,3H),3.61(t,2H),2.87(t,2H),1.45(s,9H).

[0754] [Example 28]: 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[0755]

[0756] 1 H NMR (400MHz, DMSO) δ12.69(s,1H),7.70(s,1H),7.48-7.40(m,2H),7.34(d,J=7.9Hz,1H),7.09(s,1H ),4.60(s,2H),3.97(s,3H),3.79(s,3H),3.61(t,J=6.0Hz,2H),2.88(t,J=5.9Hz,2H),1.45(s,9H).

[0757] [Example 29]: 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[0758]

[0759] 1 H NMR (400MHz, DMSO) δ7.71 (s, 1H), 7.45 (d, J = 9.5Hz, 2H), 7.36 (s, 1H), 7.07 (s, 1H), 4.60 (s,2H),3.97(s,3H),3.80(s,3H),3.76(s,3H),3.61(t,2H),2.88(t,2H),1.45(s,9H).

[0760] Step 2: In reaction formula 1-3, 9 (1.0 equivalent) was added to a round-bottom flask, and dichloromethane (0.04 M) was added for dissolution. Then, a hydrochloride solution (4.0 M, 0.2 M in 1,4-dioxane) was added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 10 (yield of 50-90%).

[0761] [Example 30]: 4-(3-aminophenyl)phthalazin-1(2H)-one hydrochloride

[0762]

[0763] 1 H NMR (400MHz, DMSO) δ12.80 (s, 1H), 8.33 (m, J = 7.2Hz, 1H), 7.90 (m, J = 5.7Hz, 2H), 7.73 (d, J = 7.2Hz, 1H), 7.31 (m, 1H), 6.91 (m, 3H).

[0764] [Example 31]: 4-(3-aminophenyl)-2-methylphthalazin-1(2H)-one hydrochloride

[0765]

[0766] 1 H NMR (400MHz, DMSO) δ8.41-8.31(m,1H),7.98-7.80(m,2H),7.79-7.68(m,1H),7.37(s,1H),7.06(s,3H),3.78(s,3H).

[0767] [Example 32]: 4-(3-aminophenyl)-2-benzylphthalazin-1(2H)-one hydrochloride

[0768]

[0769] 1 H NMR (400MHz, DMSO) δ8.42-8.35(m,1H),8.00-7.88(m,2H),7.84-7.72(m,1H),7.40-7.18(m,6H),6.92(s,3H),5.38(s,2H).

[0770] [Example 33]: 4-(3-(Aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0771]

[0772] 1 H NMR (400MHz, DMSO) δ12.92 (s, 1H), 8.45-8.31 (m, 4H), 7.96-7.86 (m, 2H), 7.79-7.69 (m, 2H), 7.69-7.58 (m, 3H), 4.14 (q, J = 5.8Hz, 2H).

[0773] [Example 34]: 4-(3-(Aminomethyl)phenyl)-2-methylphthalazin-1-(2H)-one hydrochloride

[0774]

[0775] 1 H NMR (400MHz, MeOD) δ8.52-8.46(m,1H),7.97-7.86(m,2H),7.80(d,J=7.1Hz,1H),7.75-7.62(m,4H),4.24(s,2H),3.91(s,3H).

[0776] [Example 35]: 4-(3-(Aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride

[0777]

[0778] 1 H NMR(400MHz,MeOD)δ8.51-8.38(m,1H),7.94-7.84(m,2H),7.83-7.74(m,1H),7.73 -7.59(m,4H),7.42(d,J=6.8Hz,2H),7.36-7.19(m,3H),5.47(s,2H),4.24(s,2H).

[0779] [Example 36]: 4-(4-(Aminomethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0780]

[0781] 1 H NMR (400MHz, DMSO) δ12.91(s,1H),8.42-8.20(m,4H),7.98-7.90(m,2H),7.71-7.62(m,5H),4.20-4.12(m,2H).

[0782] [Example 37]: 4-(4-aminomethyl)phenyl)-2-methylphthalazin-1(2H)-one hydrochloride

[0783]

[0784] 1 H NMR(400MHz,DMSO)δ8.39(dd,J=6.1,3.3Hz,1H),8.23(s,3H),7.92(dt,J=7.2,3 .6Hz,2H),7.66(qd,J=7.2,6.1,3.0Hz,5H),4.15(s,2H),3.78(d,J=3.1Hz,3H).

[0785] [Example 38]: 4-(4-(Aminomethyl)phenyl)-2-ethylphthalazin-1(2H)-one hydrochloride

[0786]

[0787] 1H NMR(400MHz,MeOD)δ8.50-8.45(m,1H),7.94-7.85(m,2H),7.78-7.70(m,3H),7 .65(d,J=7.9Hz,2H),4.34(q,J=7.2Hz,2H),4.24(s,2H),1.44(t,J=7.2Hz,3H).

[0788] [Example 39]: 4-(4-(Aminomethyl)phenyl)-2-isopropylphthalazin-1-(2H)-one hydrochloride

[0789]

[0790] 1 H NMR (400MHz, MeOD) δ8.40-8.34(m,1H),7.83-7.74(m,2H),7.71-7.67(m,1H),7.64(d,J=8. 2Hz, 2H), 7.56 (d, J = 8.2Hz, 2H), 5.34 (p, J = 6.6Hz, 1H), 4.15 (s, 2H), 1.34 (d, J = 6.6Hz, 6H).

[0791] [Example 40]: 4-(4-aminomethyl)phenyl)-2-phenylphthalazin-1(2H)-one hydrochloride

[0792]

[0793] 1 H NMR(400MHz,MeOD)δ8.59-8.51(m,1H),7.94(td,J=7.1,6.3,3.4Hz,2H),7.84-7.79(m,1H),7.77(d ,J=8.0Hz,2H),7.70-7.63(m,4H),7.53(dd,J=8.6,6.9Hz,2H),7.44(t,J=7.3Hz,1H),4.23(s,2H).

[0794] [Example 41]: 4-(4-aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride

[0795]

[0796] 1H NMR(400MHz,MeOD)δ8.52-8.44(m,1H),7.93-7.85(m,2H),7.78-7.73(m,1H),7.70(d,J=8.3H z,2H),7.63(d,J=8.1Hz,2H),7.44-7.39(m,2H),7.35-7.25(m,3H),5.47(s,2H),4.22(s,2H).

[0797] [Example 42]: 4-(4-(Aminomethyl)phenyl)-2-(4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride

[0798]

[0799] 1 H NMR (400MHz, DMSO) δ8.43-8.37(m,1H),8.25-8.00(m,2H),7.94(dd,J=6.0,3.2Hz,2H ),7.71-7.60(m,5H),7.43(dd,J=8.6,5.6Hz,2H),7.17(t,J=8.9Hz,2H),4.14(s,2H).

[0800] [Example 43]: 4-(4-(Aminomethyl)phenyl)-6-methoxyphthalazin-1(2H)-one hydrochloride

[0801]

[0802] 1 H NMR (400MHz, DMSO) δ12.74(s,1H),8.29(d,J=8.8Hz,1H),7.66(d,J=8.3Hz,2H),7.60(d,J =8.0Hz,2H),7.50(dd,J=8.9,2.4Hz,1H),7.00(d,J=2.5Hz,1H),4.06(s,2H),3.83(s,3H).

[0803] [Example 44]: (4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride

[0804]

[0805] 1H NMR(400MHz,MeOD)δ8.39(d,J=8.9Hz,1H),7.75-7.68(m,2H),7.67-7.62(m,2H), 7.50-7.46(m,1H),7.07(d,J=2.5Hz,1H),4.21(s,2H),3.86(s,3H),3.85(s,3H).

[0806] [Example 45]: (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride

[0807]

[0808] 1 H NMR(400MHz,MeOD)δ7.87(d,J=2.8Hz,1H),7.72-7.61(m,2H),7.48-7.40(m, 2H),7.27(d,J=8.4Hz,1H),6.83(d,J=8.5Hz,1H),4.24(s,2H),4.01(s,3H).

[0809] [Example 46]: 4-(4-(Aminomethyl)phenyl)-7-methoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0810]

[0811] 1 H NMR (400MHz, DMSO) δ8.19 (s, 2H), 7.76 (d, J=2.7Hz, 1H), 7.64 (s, 4H), 7.58 (d, J= 9.0Hz,1H),7.49(dd,J=9.0,2.7Hz,1H),4.14(s,2H),3.97(s,3H),3.78(s,3H).

[0812] [Example 47]: 4-(4-(Aminomethyl)-phenyl)-7-methoxyphthalazin-1(2H)-one hydrochloride

[0813]

[0814] 1 H NMR(400MHz,DMSO)δ12.82(s,1H),8.34(br s,3H),7.74(d,J=2.7Hz,1H),7.68-7.62(m,4H),7.57(d,J=9.0Hz,1H),7.49(dd,J=9.0,2.7Hz,1H),),4.14(s,2H),3.96(s,3H).

[0815] [Example 48]: 4-(4-(Aminomethyl)phenyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[0816]

[0817] 1 H NMR (400MHz, DMSO) δ12.76(s,1H),8.27(s,3H),7.77-7.68(m,3H),7.63(d,J=8.1Hz,2H),7.03(s,1H),4.15(s,2H),3.97(s,3H),3.79(s,3H).

[0818] [Example 49]: 4-(4-(Aminomethyl)phenyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[0819]

[0820] 1 H NMR (400MHz, MeOD) δ7.86 (s, 1H), 7.79-7.71 (m, 2H), 7.67 (d, J = 8.2Hz, 2H), 7.07 (s, 1H), 4.25 (s, 3H), 4.05 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H).

[0821] [Example 50]: 4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0822]

[0823] 1 H NMR (400MHz, MeOD) δ8.52-8.39(m,1H),7.94-7.84(m,2H),7.78-7.69(m,3H),7.69-7.60(m,2H),4.60(q,J=6.9Hz,1H),1.72(d,J=6.9Hz,3H).

[0824] [Example 51]: (R)-4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0825]

[0826] 1H NMR(400MHz,MeOD)δ8.49-8.42(m,1H),7.94-7.85(m,2H),7.77-7.73(m,1H),7.72( d,J=8.2Hz,2H),7.65(d,J=8.3Hz,2H),4.59(q,J=6.8Hz,1H),1.72(d,J=6.8Hz,3H).

[0827] [Example 52]: 4-(4-(2-aminopropane-2-yl)phenyl)phthalazin-1(2H)-one hydrochloride

[0828]

[0829] 1 H NMR (400MHz, MeOD) δ8.48-8.44(m,1H),7.93-7.88(m,2H),7.77-7.68(m,5H),1.83(s,6H).

[0830] [Example 53]: 4-(4-(Aminomethyl)-3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0831]

[0832] 1 H NMR(DMSO,600MHz)δ13.00(s,1H),8.50(br s,3H),8.38-8.36(m,1H),8.08-8.06(m,1H),8.02(d,J=2Hz,1H),7.97-7.91(m,3H),7.61-7.59(m,1H),4.30(s,2H).

[0833] [Example 54]: 4-(4-((methylamino)methyl)phenyl)phthalazin-1(2H)-one hydrochloride

[0834]

[0835] 1 H NMR (400MHz, MeOD) δ8.49-8.41(m,1H),7.91(dt,J=6.1,3.5Hz,2H),7.82-7.65(m,5H),4.32(s,2H),2.80(s,3H).

[0836] [Example 55]: 4-(1,2,3,4-Tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0837]

[0838] 1 H NMR (400MHz, DMSO) δ12.88(s,1H),9.57(s,2H),8.38-8.31(m,1H),7.96-7.84(m,2H),7.70-7.62( m,1H),7.47(d,J=7.0Hz,2H),7.40(d,J=8.5Hz,1H),3.42(t,J=6.2Hz,2H),3.10(t,J=6.3Hz,2H).

[0839] [Example 56]: 2-Methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0840]

[0841] 1 H NMR (400MHz, CDCl3) δ10.37 (s, 1H), 8.54 (dd, J = 7.2, 1.9Hz, 1H), 7.85-7.72 (m, 2H), 7.70-7.66 (m, 1H),7.55-7.40(m,2H),7.31(d,J=8.0Hz,1H),4.49(s,2H),3.92(s,3H),3.57(t,2H),3.32(t,2H).

[0842] [Example 57]: 6,7-Dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0843]

[0844] 1 H NMR (400MHz, DMSO) δ12.75(s,1H),9.14(s,2H),7.71(s,1H),7.58-7.48(m,2H),7.40(d,J=7.9Hz,1H), 7.04(s,1H),4.37(s,2H),3.97(s,3H),3.79(s,3H),3.49-3.40(t,J=6.0Hz,2H),3.11(t,J=6.1Hz,2H).

[0845] [Example 58]: 6,7-Dimethoxy-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride

[0846]

[0847] 1 H NMR (400MHz, DMSO) δ9.05 (s, 1H), 7.74 (s, 1H), 7.61-7.47 (m, 2H), 7.41 (d, J = 7.3Hz, 1H), 7 .04(s,1H),4.37(s,2H),3.99(s,3H),3.81(s,3H),3.78(s,3H),3.43(t,2H),3.11(t,2H).

[0848] [Example 59]: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroquinolin-7-yl)phthalazin-1(2H)-one

[0849]

[0850] 1 H NMR (400MHz, DMSO) δ12.77(s,1H),9.32(s,2H),7.72(s,1H),7.65(d,J=1.24Hz,1H),7.53(s,1H),7.41(d ,J=8.0Hz,1H),7.06(s,1H),4.38(s,2H),3.98(s,3H),3.82(s,3H),3.44-3.45(m,2H),3.09-3.13(m,2H)

[0851] Step 3: Under nitrogen, 10 (1.0 equivalent) of the reaction formula 1-3 is added to a round-bottom flask, and dichloromethane (0.2M) is added at 0°C. A solution of tert-butyl alcohol (1.0 equivalent) dissolved in dichloromethane (0.2M) is slowly added dropwise to the solution. The solution is stirred at room temperature for 30 minutes. After that, a solution of 11 (1.0 equivalent) and triethylamine (2.5 equivalents) dissolved in dichloromethane (0.1M) is slowly added dropwise at 0°C, and stirred at room temperature for one day. After the reaction is completed, it is concentrated under reduced pressure and dried, and then the obtained residue is extracted with ethyl acetate and water. For the obtained residue, 12 (yield is 20-40%) is obtained by column chromatography (DCM: MeOH = 40: 1).

[0852] [Example 60]: tert-Butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate

[0853]

[0854] 1H NMR(400MHz, CDCl3)δ10.73(s,1H),8.52-8.46(m,1H),8.40(s,1H),7.87-7.6 5(m,2H),7.62(s,2H),7.56-7.41(m,2H),7.33(d,J=7.6Hz,1H),1.44(s,9H).

[0855] [Example 61]: tert-Butyl (N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate

[0856]

[0857] 1 H NMR (400MHz, DMSO) δ8.37(d,J=7.4Hz,1H),7.96-7.81(m,2H),7.70(d,J=7.2Hz,1H),7.51-7.3 6(m,1H),7.36(s,1H),7.30(d,J=9.2Hz,1H),7.21(d,J=7.5Hz,1H),6.69(s,2H),1.29(s,9H).

[0858] [Example 62]: tert-Butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate

[0859]

[0860] 1 H NMR (400MHz, DMSO) δ8.43-8.32(m,1H),8.13(d,J=6.9Hz,2H),7.99-7.83(m,2H),7.73(d,J=6.6Hz,1H),7.44 (t,J=7.8Hz,1H),7.40-7.25(m,5H),7.22(d,J=7.1Hz,1H),6.71(d,J=6.8Hz,2H),5.38(s,2H),1.26(s,9H).

[0861] [Example 63]: tert-Butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0862]

[0863] 1H NMR (400MHz, MeOD) δ8.49-8.43(m,1H),7.95-7.87(m,2H),7.87-7.83(m,1H),7.63(d,J=1.6Hz,1H),7.59-7.52(m,3H),4.34(s,2H),1.41(s,9H).

[0864] [Example 64]: tert-Butyl N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate

[0865]

[0866] 1 H NMR(400MHz,MeOD)δ8.46(dd,J=6.1,3.2Hz,1H),7.93-7.85(m,2H),7.85-7.78(m,1H), 7.66(s,1H),7.57(s,1H),7.53(d,J=5.6Hz,2H),4.26(s,2H),3.90(s,3H),1.33(s,9H).

[0867] [Example 65]: tert-Butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0868]

[0869] 1 H NMR(400MHz,MeOD)δ8.44(dd,J=6.1,3.1Hz,1H),7.85(ddq,J=13.6,6.4,3.4Hz,3H),7.62(s,1H),7.59-7.47(m,3H ),7.43(d,J=7.2Hz,2H),7.32(t,J=7.3Hz,2H),7.25(dd,J=8.4,6.1Hz,1H),5.45(s,2H),4.32(s,2H),1.37(s,9H).

[0870] [Example 66]: tert-Butyl (N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0871]

[0872] 1H NMR (400MHz, MeOD) δ8.51-8.41(m,1H),7.91-7.82(m,2H),7.82-7.77(m,1H),7.57(d,J=0.8Hz,4H),4.31(s,2H),3.89(s,3H),1.45(d,J=1.6Hz,9H).

[0873] [Example 67]: tert-Butyl (N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0874]

[0875] 1 H NMR (400MHz, MeOD) δ8.49-8.43(m,1H),7.92-7.84(m,2H),7.83-7.78(m,1H),7.58(d,J=2.0Hz,4H),4.38-4.31(m,4H),1.47-1.41(m,12H).

[0876] [Example 68]: tert-Butyl N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate

[0877]

[0878] 1 H NMR(400MHz,MeOD)δ8.52-8.43(m,1H),7.94-7.85(m,2H),7.86-7.81(m,1H),7 .62(s,4H),5.51-5.39(m,1H),4.35(s,2H),1.46(d,J=6.6Hz,6H),1.29(s,9H).

[0879] [Example 69]: tert-Butyl (N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0880]

[0881] 1H NMR (400MHz, MeOD) δ8.57-8.50(m,1H),7.97-7.90(m,2H),7.89-7.83(m,1H),7.66(dd,J=13. 5,7.7Hz,4H),7.54(dd,J=23.6,7.9Hz,4H),7.43(t,J=7.5Hz,1H),4.31(s,2H),1.41(s,9H).

[0882] [Example 70]: tert-Butyl (N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0883]

[0884] 1 H NMR(400MHz,MeOD)δ8.55-8.38(m,1H),7.93-7.84(m,2H),7.84-7.78(m,1H),7.56(s, 4H),7.42(d,J=6.9Hz,2H),7.36-7.24(m,3H),5.46(s,2H),4.30(s,2H),1.42(s,9H).

[0885] [Example 71]: tert-Butyl (N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0886]

[0887] 1 H NMR (400MHz, DMSO) δ10.88(s,1H),8.39(dd,J=6.1,3.1Hz,1H),7.94-7.89(m,2H),7.73-7.68(m,1H),7.5 8-7.48(m,4H),7.43(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.36(s,2H),4.20(s,2H),1.38(s,9H).

[0888] [Example 72]: tert-Butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0889]

[0890] 1H NMR (400MHz, MeOD) δ8.36 (d, J = 8.9 Hz, 1H), 7.63-7.51 (m, 4H), 7.46 (dd, J = 8. 9, 2.5Hz, 1H), 7.13 (d, J = 2.5Hz, 1H), 4.33 (s, 2H), 3.85 (s, 3H), 1.46 (s, 9H).

[0891] [Example 73]: tert-Butyl N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate

[0892]

[0893] 1 H NMR(400MHz,MeOD)δ8.37(d,J=8.9Hz,1H),7.62-7.55(m,4H),7.46(dd,J=9.0,2.5 Hz,1H),7.13(d,J=2.5Hz,1H),4.29(s,2H),3.86(s,3H),3.85(s,3H),1.46(s,9H).

[0894] [Example 74]: tert-Butyl N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate

[0895]

[0896] 1 H NMR(400MHz,MeOD)δ7.86(d,J=2.7Hz,1H),7.74(d,J=9.0Hz,1H),7.61-7.53 (m,4H),7.45(dd,J=9.0,2.8Hz,1H),4.31(s,2H),4.00(s,3H),1.46(s,9H).

[0897] [Example 75]: tert-Butyl (N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0898]

[0899] 1H NMR(400MHz,MeOD)δ7.86(d,J=2.7Hz,1H),7.73(d,J=9.0Hz,1H),7.56(s,4H),7 .42(dd,J=9.0,2.7Hz,1H),4.32(s,2H),4.00(s,3H),3.88(s,3H),1.46(s,9H).

[0900] [Example 76]: tert-Butyl (N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0901]

[0902] 1 H NMR(400MHz,DMSO)δ12.70(s,1H),10.89(s,1H),8.25(br m,1H),7.70(s,1H),7.60(d,J=7.9Hz,2H),7.50(d,J=7.9Hz,2H),7.07(s,1H),4.23(d,J=6.2Hz,2H),3.97(s,3H),3.79(s,3H),1.40(s,9H).

[0903] [Example 77]: tert-Butyl (N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0904]

[0905] 1 H NMR (400MHz, MeOD) δ7.79(s,1H),7.64-7.54(m,4H),7.09(d,J=3.1Hz,1H),4.34(s,2H),4.02(s,3H),3.87(s,3H),3.83(s,3H),1.48(s,9H).

[0906] [Example 78]: tert-Butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate

[0907]

[0908] 1H NMR(400MHz,MeOD)δ8.54-8.33(m,1H),7.94-7.86(m,2H),7.85-7.73(m,1H),7.56(d, J=8.4Hz,2H),7.50(d,J=8.2Hz,2H),1.47(d,J=7.1Hz,3H),1.45(s,9H),1.29(m,1H).

[0909] [Example 79]: (R)-tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate

[0910]

[0911] 1 H NMR (400MHz, MeOD) δ8.49-8.40(m,1H),7.93-7.85(m,2H),7.84-7.79(m,1H),7.56(s,4H),4.64(q,J=6.9Hz,1H),1.55(d,J=7.0Hz,3H),1.40(s,9H).

[0912] [Example 80]: tert-Butyl (N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamoyl)carbamate

[0913]

[0914] 1 H NMR(400MHz,MeOD)δ8.53(d,J=7.7Hz,2H),7.94-7.83(m,2H),7.76(d,J=8.2H z,1H),7.58(d,J=8.1Hz,1H),7.00(d,J=7.7Hz,2H),1.49(s,6H),1.36(s,9H).

[0915] [Example 81]: tert-Butyl N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamoylcarbamate

[0916]

[0917] 1H NMR(DMSO,600MHz)δ12.95(s,1H),11.07(s,1H),8.47(s,1H),8.37-8.34(m, 1H),7.95-7.90(m,5H),7.65-7.63(m,1H),4.42(d,J=6Hz,2H),1.43(s,9H).

[0918] [Example 82]: tert-Butyl (N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate

[0919]

[0920] 1 H NMR(400MHz,MeOD)δ8.51-8.45(m,1H),7.96-7.90(m,2H),7.87-7.80(m,1H),7.6 4(d,J=8.1Hz,2H),7.59(d,J=8.0Hz,2H),4.57(s,2H),2.90(s,3H),1.55(s,9H).

[0921] [Example 83]: Tert-butyl ((6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0922]

[0923] 1 H NMR (400MHz, DMSO) δ12.83(s,1H),11.15(s,1H),8.40-8.29(m,1H),7.98-7.82(m,2H),7.72-7.63(m ,1H),7.38(q,J=8.0Hz,3H),4.56(s,2H),3.57(t,J=5.8Hz,2H),2.96(t,J=5.9Hz,2H),1.35(s,9H).

[0924] [Example 84]: tert-Butyl ((6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0925]

[0926] 1H NMR (400MHz, DMSO) δ11.17(s,1H),8.63-8.27(m,1H),8.18-7.81(m,2H),7.81-7.52(m,1H),7.41(q ,J=8.1Hz,3H),4.57(s,2H),3.79(s,3H),3.58(t,J=5.2Hz,2H),2.98(t,J=5.2Hz,2H),1.37(s,9H).

[0927] [Example 85]: tert-Butyl ((6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0928]

[0929] 1 H NMR (400MHz, DMSO) δ12.68(s,1H),7.69(s,1H),7.50-7.38(m,2H),7.34(d,J=7.5Hz,1H),7.07(s,1H ),4.49(s,2H),3.97(s,3H),3.79(s,3H),3.51(t,J=6.0Hz,2H),2.95(t,J=6.1Hz,2H),1.33(s,9H).

[0930] [Example 86]: tert-Butyl ((6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0931]

[0932] 1 H NMR (400MHz, MeOD) δ7.75(d,J=1.6Hz,1H),7.42(d,J=9.5Hz,2H),7.31(d,J=7.6Hz,1H),7.07(s,1H),4.65(s,1H),4.45(s,1 H), 4.00 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.69 (t, J = 5.9Hz, 1H), 3.53 (t, J = 5.9Hz, 1H), 3.04 (t, J = 5.8Hz, 2H), 1.43 (s, 9H).

[0933] Step 4: In the reaction formula 1-3, 12 (1.0 equivalent) was added to a round-bottom flask, and dichloromethane (0.04 M) was added for dissolution. Then, a hydrochloride solution (4.0 M, 0.1 M in 1,4-dioxane) was added and stirred at room temperature for 24 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 13 (yield of 20-40%).

[0934] [Example 87]: N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride

[0935]

[0936] 1 H NMR(400MHz,DMSO)δ12.85(s,1H),9.71(s,1H),8.50-8.23(m,1H),7.94-7.83(m,2H),7.71(d, J=9.1Hz,1H),7.45(t,J=7.7Hz,1H),7.38(s,1H),7.31(d,J=8.1Hz,1H),7.18(d,J=8.7Hz,3H).

[0937] [Example 88]: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride

[0938]

[0939] 1 H NMR(400MHz,MeOD)δ8.48-8.41(m,1H),7.92-7.78(m,3H),7.52-7.46(m,2H) ,7.39(ddd,J=8.3,2.1,1.0Hz,1H),7.30(dt,J=7.9,1.4Hz,1H),3.90(s,3H).

[0940] [Example 89]: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride

[0941]

[0942] 1H NMR (400MHz, DMSO) δ9.72 (s, 1H), 8.43-8.35 (m, 1H), 7.92 (dd, J = 6.0, 3.2Hz, 2H), 7.78- 7.68(m,1H),7.46(t,J=8.0Hz,1H),7.41-7.24(m,7H),7.23-7.11(m,3H),5.39(s,2H).

[0943] [Example 90]: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0944]

[0945] 1 H NMR(400MHz,MeOD)δ8.49(d,J=9.1Hz,1H),7.91(dd,J=7.1,2.4Hz,2H),7.86(s,1H),7 .69-7.53(m,4H),7.46(d,J=6.9Hz,2H),7.39-7.25(m,3H),5.50(s,2H),4.34(s,2H).

[0946] [Example 91]: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide

[0947]

[0948] 1 H NMR (400MHz, DMSO) δ12.64 (s, 1H), 8.31 (dd, J = 7.8, 1.7Hz, 1H), 7.93-7.74 (m, 3H),7.29-7.16(m,2H),6.72-6.62(m,2H),5.42(s,2H),4.09(t,J=5.3Hz,1H).

[0949] [Example 92]: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide

[0950]

[0951] 1 H NMR(400MHz,DMSO)δ8.41-8.32(m,1H),7.95-7.85(m,2H),7.74(s,1H),7.50 (d,J=8.3Hz,2H),7.30(d,J=8.2Hz,2H),7.17(s,2H),3.77(d,J=6.1Hz,3H).

[0952] [Example 93]: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide

[0953]

[0954] 1 H NMR (400MHz, MeOD) δ8.46-8.39(m,1H),7.92-7.83(m,3H),7.57(t,J=7.3Hz,1H),7.42(t,J=6.1Hz,3H),7.35-7.18(m,7H),6.85-6.81(m,2H).

[0955] [Example 94]: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate

[0956]

[0957] 1 H NMR(400MHz,MeOD)δ8.49-8.43(m,1H),7.93-7.84(m,2H),7.84-7.79(m,1H), 7.67(s,1H),7.63-7.57(m,1H),7.57-7.50(m,2H),4.34(s,2H),3.91(s,3H).

[0958] [Example 95]: N-(3-(3-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0959]

[0960] 1 H NMR (400 MHz, (CD 3 ) 2 CO)δ8.46-8.37(m,1H),7.94-7.84(m,2H),7.84-7.76(m,1H),7.73-7.63(m,1H),7.63-7.46(m,3H),4.38(d,J=2.6Hz,2H).

[0961] [Example 96]: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0962]

[0963] 1H NMR(400MHz,DMSO)δ12.84(s,1H),8.43-8.29(m,1H),8.01-7.84(m,2H),7.71-7.66( m,1H),7.59-7.50(m,4H),7.18(t,J=6.8Hz,1H),6.69(s,2H),4.19(d,J=6.3Hz,2H).

[0964] [Example 97]: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0965]

[0966] 1 H NMR (400MHz, MeOD) δ8.51-8.38(m,1H),7.88(td,J=7.2,6.4,3.5Hz,2H),7.83-7.76(m,1H),7.59(s,4H),4.33(s,2H),3.89(s,3H).

[0967] [Example 98]: N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0968]

[0969] 1 H NMR (400MHz, MeOD) δ8.49-8.42(m,1H),7.92-7.84(m,2H),7.84-7.76(m,1H),7.60(s,4H),4.38-4.30(m,4H),1.44(t,J=7.1Hz,3H).

[0970] [Example 99]: N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate

[0971]

[0972] 1 H NMR (400MHz, MeOD) δ8.48-8.43(m,1H),7.90-7.85(m,2H),7.85-7.80(m,1H),7.60(s,4H),5.44(p,J=6.6Hz,1H),4.33(s,2H),1.45(d,J=6.7Hz,6H).

[0973] [Example 100]: N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0974]

[0975] 1 H NMR(400MHz,MeOD)δ8.57-8.49(m,1H),7.94(t,J=4.9Hz,2H),7.86(s,1H),7.66(dd,J=11.8, 7.9Hz, 4H), 7.60 (d, J = 7.5Hz, 2H), 7.53 (t, J = 7.6Hz, 2H), 7.43 (t, J = 7.2Hz, 1H), 4.33 (s, 2H).

[0976] [Example 101]: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0977]

[0978] 1 H NMR(400MHz,MeOD)δ8.54-8.32(m,1H),7.92-7.84(m,2H),7.83-7.78(m,1H),7 .58(s,4H),7.43(d,J=7.5Hz,2H),7.35-7.24(m,3H),5.46(s,2H),4.32(s,2H).

[0979] [Example 102]: N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0980]

[0981] 1 H NMR(400MHz,MeOD)δ8.48-8.43(m,1H),7.90-7.86(m,2H),7.83-7.77(m,1H),7.58( s,4H),7.48(dd,J=8.7,5.5Hz,2H),7.05(t,J=8.8Hz,2H),5.44(s,2H),4.32(s,2H).

[0982] [Example 103]: N-(4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0983]

[0984] 1 H NMR(400MHz,MeOD)δ11.70(s,1H),8.34(d,J=8.8Hz,1H),7.68-7.53(m,5H),7.44(dd,J=8.8,2 .4Hz,1H),7.14(d,J=2.4Hz,1H),6.27(s,1H),6.04(s,1H),4.38(d,J=6.3Hz,2H),3.88(s,3H).

[0985] [Example 104]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0986]

[0987] 1 H NMR(400MHz,DMSO)δ12.84(s,1H),8.43-8.29(m,1H),8.01-7.84(m,2H),7.71-7.66( m,1H),7.59-7.50(m,4H),7.18(t,J=6.8Hz,1H),6.69(s,2H),4.19(d,J=6.3Hz,2H).

[0988] [Example 105]: N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0989]

[0990] 1 H NMR (400MHz, MeOD) δ8.37(d,J=8.9Hz,1H),7.60(s,4H),7.46(dd,J=8.9,2.5Hz,1H),7.11(d,J=2.5Hz,1H),4.33(s,2H),3.86(s,3H),3.84(s,3H).

[0991] [Example 106]: N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0992]

[0993] 1H NMR (400MHz, MeOD) δ7.86(d,J=2.8Hz,1H),7.73(d,J=8.9Hz,1H),7.63-7.50(m,4H),7.45(dd,J=9.0,2.8Hz,1H),4.32(s,2H),4.00(s,3H).

[0994] [Example 107]: N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0995]

[0996] 1 H NMR (400MHz, DMSO) δ7.74(d,J=2.7Hz,1H),7.62(d,J=8.9Hz,1H),7.53(s,4H),7.47(dd,J=8.9, 2.8Hz,1H),7.16(t,J=6.5Hz,1H),6.67(s,2H),4.18(d,J=6.4Hz,2H),3.95(s,3H),3.77(s,3H).

[0997] [Example 108]: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride

[0998]

[0999] 1 H NMR (400MHz, MeOD) δ7.82(s,1H),7.60(s,4H),7.10(s,1H),4.32(s,2H),4.02(s,3H),3.87(s,3H),3.82(s,3H).

[1000] [Example 109]: N-(3-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide

[1001]

[1002] 1 H NMR(400MHz,DMSO)δ12.74(s,1H),7.71(s,1H),7.66(s,1H),7.49-7.53(m,3H),7.22 (brs,1H),7.10(s,1H),6.68(s,2H),4.19(d,J=6.08Hz,2H),3.98(s,3H),3.83(s,3H)

[1003] [Example 110]: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide

[1004]

[1005] 1 H NMR (400MHz, DMSO) δ7.73 (s, 1H), 7.66 (s, 1H), 7.50-7.53 (m, 3H), 7.22 (t, J = 6.32Hz, 1H) ,7.07(s,1H),6.67(s,2H),4.20(d,J=6.32Hz,2H),3.98(s,3H),3.81(s,3H),3.78(s,3H)

[1006] [Example 111]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)sulfonamide hydrochloride

[1007]

[1008] LC / MS[M+H] + 409.07

[1009] [Example 112]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)sulfonamide hydrochloride

[1010]

[1011] LCMS [M+H] + 409.16

[1012] [Example 113]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)-N-methylsulfonamide hydrochloride

[1013]

[1014] LCMS [M+H] + 423.10

[1015] [Example 114]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)-N-methylsulfonamide hydrochloride

[1016]

[1017] LCMS [M+H]+ 423.29

[1018] [Example 115]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)sulfonamide hydrochloride

[1019]

[1020] LCMS [M+H] + 427.17

[1021] [Example 116]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)sulfonamide hydrochloride

[1022]

[1023] LCMS [M+H] + 459.20

[1024] [Example 117]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)-N-methylsulfonamide hydrochloride

[1025]

[1026] LCMS [M+H] + 441.29

[1027] [Example 118]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride

[1028]

[1029] LCMS [M+H] + 458.33

[1030] [Example 119]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride

[1031]

[1032] LCMS [M+H] + 459.1

[1033] [Example 120]: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride

[1034]

[1035] LCMS [M+H] + 473.10

[1036] [Example 121]: 7-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide hydrochloride

[1037]

[1038] [Example 122]: 7-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1039]

[1040] 1 H NMR (400MHz, DMSO) δ12.71(s,1H),7.70(s,1H),7.45(d,J=8.60Hz,1H),7.34(d,J=7.92Hz,1H),7.20(s,1 H),7.07(s,3H),6.97(s,1H),4.31(s,2H),3.98(s,3H),3.81(s,3H),3.07-3.11(m,2H),3.01-3.05(m,2H)

[1041] [Example 123]: N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride

[1042]

[1043] 1 H NMR(400MHz,MeOD)δ8.47-8.42(m,1H),7.89(dd,J=6.0,3.4Hz,2H),7.84-7.7 8(m,1H),7.58(d,J=3.5Hz,4H),4.66(q,J=6.8Hz,1H),1.57(d,J=6.9Hz,3H).

[1044] [Example 124]: (R)-N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride

[1045]

[1046] 1 H NMR(400MHz,MeOD)δ8.44(dq,J=7.4,3.8Hz,1H),7.89(dt,J=7.2,3.7Hz,2H),7.81(d t,J=5.9,3.6Hz,1H),7.73-7.48(m,4H),4.66(q,J=6.9Hz,1H),1.57(d,J=7.0Hz,3H).

[1047] [Example 125]: N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfonamide hydrochloride

[1048]

[1049] 1 H NMR (400MHz, MeOD) δ8.47-8.43(m,1H),7.92-7.87(m,2H),7.82(s,1H),7.61(d,J=1.3Hz,4H),1.60(s,6H).

[1050] [Example 126]: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride

[1051]

[1052] 1 H NMR (DMSO, 600MHz) δ12.94 (s, 1H), 8.36-8.35 (m, 1H), 7.99-7.89 (m, 5H), 7.65 (d, J = 8Hz, 1H), 7.34 (t, J = 6Hz, 1H), 6.80 (s, 2H), 4.37 (d, J = 7Hz, 2H).

[1053] [Example 127]: N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide

[1054]

[1055] 1 H NMR (400MHz, MeOD) δ8.50-8.38(m,1H),7.95-7.85(m,2H),7.84-7.75(m,1H),7.59(q,J=7.9Hz,4H),4.31(s,2H),2.71(s,3H).

[1056] [Example 128]: 6-(4-oxo-3,4-dihydrophthalazin-1-yl-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[1057]

[1058] 1H NMR (400MHz, DMSO) δ12.83 (s, 1H), 8.37-8.30 (m, 1H), 7.90 (m, J = 6.4, 5.4, 3.5Hz, 2H), 7. 76-7.65(m,1H),7.37(d,J=12.0Hz,3H),6.96(s,2H),4.30(s,2H),3.00(t,J=5.8Hz,2H).

[1059] [Example 129]: 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[1060]

[1061] 1 H NMR(400MHz,MeOD)δ8.49-8.42(m,1H),7.93-7.84(m,2H),7.83-7.76(m,1H),7.43(d,J=5.7Hz, 2H),7.33(d,J=8.5Hz,1H),4.42(s,2H),3.89(s,3H),3.57-3.38(t,2H),3.08(t,J=5.9Hz,2H).

[1062] [Example 130]: 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[1063]

[1064] 1 H NMR(400MHz,MeOD)δ7.83(s,1H),7.44(d,J=7.1Hz,2H),7.35-7.23(d,J=7.9Hz,1H),7.14 (s,1H),4.41(s,2H),4.03(s,3H),3.84(s,3H),3.50-3.45(t,2H),3.08(t,J=6.0Hz,2H).

[1065] [Example 131]: 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride

[1066]

[1067] 1 H NMR (400MHz, MeOD) δ7.83(s,1H),7.44(s,2H),7.33(d,J=9.2Hz,1H),7.12(d,J=3.7Hz,1H),4.46( s,1H),4.42(s,1H),4.03(s,3H),3.88(s,3H),3.84(s,3H),3.54(t,1H),3.49(t,1H),3.09(t,2H).

[1068] [Preparation Example 2]

[1069] The product 2 in Preparation Example 1 was used as a reactant to prepare a phthalazine derivative through the following reaction formula 2.

[1070] [Reaction 2]

[1071]

[1072] Step 1: In a round-bottom flask, 2 was added to phosphorus oxychloride (0.67 M) and stirred at 110°C for 1 hour. After the reaction was completed, the reactant was cooled to room temperature and slowly added to ice water, and then stirred for 10 minutes. The reactant was filtered, and the solid was washed with distilled water and then dried under reduced pressure to obtain 16. An example of 16 is as follows.

[1073] Reactant 16-1: 1,4-dichlorophthalazine

[1074]

[1075] 1 H NMR (400MHz, DMSO) δ8.43-8.35(m,2H),8.32-8.25(m,2H).

[1076] Reactant 16-2: 1,4-dichloro-6,7-dimethoxyphthalazine

[1077]

[1078] 1 H NMR (DMSO, 600MHz) δ7.53 (s, 2H), 4.08 (s, 6H).

[1079] Step 2: In a round-bottom flask, 16 (1.0 eq.) was dissolved in N,N-dimethylformamide (0.25 M), and then amine (1.5 eq. mmol) and potassium carbonate (4.0 eq.) were added, and then stirred at 80 °C for 14 h under nitrogen. After the reaction was completed, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (5% MeOH / CH 2 Cl 2 )Separate 17. An example of 17 is as follows.

[1080] Reactant 17-1: N-(2-(1-(4-chlorophthalazin-1-yl)piperidin-4-yl)ethyl)sulfonamide

[1081]

[1082] 1 H NMR (400MHz, DMSO) δ8.24-8.16(m,1H),8.14-8.02(m,3H),6.52-6.44(m,3H),3.87-3. 78(m,2H),3.05-2.92(m,4H),1.88-1.78(m,2H),1.73-1.60(m,1H),1.58-1.39(m,4H).

[1083] Reactant 17-2: tert-butyl ((1-(4-chlorophthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[1084]

[1085] 1 H NMR (DMSO, 600MHz) δ8.20-8.18(m,1H),8.11-8.09(m,1H),8.08-8.05(m,2H),6.95(t,J=6Hz,1H),3.82(d,J=12Hz,2H ),2.97(t,J=12Hz,2H),2.93(t,J=6Hz,2H),1.79(d,J=12Hz,2H),1.67-1.63(m,1H),1.47-1.42(m,2H),1.39(s,9H).

[1086] Reactant 17-3: tert-butyl ((1-(4-chloro-6,7-dimethoxyphthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[1087]

[1088] 1H NMR (DMSO, 600MHz) δ7.39 (s, 1H), 7.25 (s, 1H), 6.92 (t, J = 6Hz, 1H), 4.01 (s, 3H), 4.01 (s, 3H), 3.75 (d, J =12Hz,2H),2.94-2.90(m,4H),1.79(d,J=13Hz,2H),1.66-1.63(m,1H),1.47-1.43(m,2H),1.39(s,9H).

[1089] Step 3: In a round-bottom flask, 17 (N-(2-(1-(4-chlorophthalazin-1-yl)piperidin-4-yl)ethyl)sulfonamide) was dissolved in acetic acid (0.1 M) and refluxed at 120°C for 10 hours. The reactant was concentrated, diluted with ethyl acetate, and neutralized with sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was solidified in diethyl ether to obtain 18.

[1090] [Example 132]: tert-Butyl ((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[1091]

[1092] 1 H NMR (DMSO, 600MHz) δ12.08 (s, 1H), 8.23-8.21 (m, 1H), 7.93-7.87 (m, 2H), 7.84-7.81 (m, 1H), 6.92 (t, J = 6Hz, 1H), 3.41 ( d,J=12Hz,2H),2.91(t,J=6Hz,2H),2.67(t,J=12Hz,2H),1.75(d,J=12Hz,2H),1.57-1.51(m,1H),1.41-1.35(m,11H).

[1093] [Example 133]: tert-Butyl ((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate

[1094]

[1095] 1H NMR (DMSO, 600MHz) δ11.96 (s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 6.92 (t, J = 6Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.41 (d, J = 12 Hz,2H),2.91(t,J=6Hz,2H),2.67-2.63(m,2H),1.75(d,J=12Hz,2H),1.58-1.51(m,1H),1.38(s,9H),1.37--1.35(m,2H).

[1096] [Example 134]: 4-(4-(Aminomethyl)piperidin-1-yl)phthalazin-1(2H)-one hydrochloride

[1097]

[1098] 1 H NMR (DMSO, MHz) δ12.13 (s, 1H), 8.24-8.22 (m, 1H), 7.97-7.81 (m, 6H), 3.46 (d, J = 12Hz, 2H), 2.8 2-2.78(m,2H),2.73-2.69(m,2H),1.86(d,J=13Hz,2H),1.78-1.75(m,1H),1.50-1.44(m,2H).

[1099] [Example 135]: 4-(4-(Aminomethyl)piperidin-1-yl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[1100]

[1101] 1 H NMR(DMSO,600MHz)δ12.00(s,1H),7.79(br s,3H),7.58(s,1H),7.16(s,1H),3.94(s,3H),3.93(s,3H),3.46(d,J=12Hz,2H),2.82-2.8 0(m,2H),2.69(t,J=12Hz,2H),1.85(d,J=13Hz,2H),1.79-1.72(m,1H),1.51-1.45(m,2H).

[1102] [Example 136]: tert-Butyl N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate

[1103]

[1104] 1 H NMR(DMSO,600MHz)δ12.08(s,1H),10.82(s,1H),8.23-8.21(m,1H),7.93-7.86(m,2H),7.84-7.81(m,1H),7.70(br s,1H),3.41(d,J=13Hz,2H),2.86(s,2H),2.67(t,J=12Hz,2H),1.83(d,J=13Hz,2H),1.65-1.63(m,1H),1.43-1.35(m,11H).

[1105] [Example 137]: tert-Butyl N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate

[1106]

[1107] 1 H NMR(DMSO,600MHz)δ11.96(s,1H),10.81(s,1H),7.70(br s,1H),7.57(s,1H),7.16(s,1H),3.94(s,3H),3.92(s,3H),3.41(d,J=12Hz,2H),2.86(br s,2H),2.65(t,J=12Hz,2H),1.83(d,J=13Hz,2H),1.68-1.60(m,1H),1.42(s,9H),1.40-1.36(m,2H).

[1108] [Example 138]: N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride

[1109]

[1110] 1 H NMR(DMSO,600MHz)δ12.07(s,1H),8.23-8.21(m,1H),7.93-7.88(m,2H),7.84-7.81(m,1H),6.59(t,J=6Hz,1H),6.49(s,2H ),3.42(d,J=12Hz,2H),2.85(t,J=6Hz,2H),2.71-2.67(m,2H),1.85(d,J=12Hz,2H),1.68-1.64(m,1H),1.44-1.37(m,2H).

[1111] [Example 139]: N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride

[1112]

[1113] 1 H NMR(DMSO,600MHz)δ11.96(s,1H),7.57(s,1H),7.17(s,1H),6.58(br s,1H),6.49(br s,2H),3.94(s,3H),3.93(s,3H),3.42(d,J=13Hz,2H),2.85(d,J=7Hz,2H),2 .69-2.65(m,2H),1.85(d,J=13Hz,2H),1.67-1.64(m,1H),1.43-1.37(m,2H).

[1114] [Example 140]: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride

[1115]

[1116] LCMS [M+H] + 406.13

[1117] [Example 141]: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride

[1118]

[1119] LCMS [M+H] + 406.12

[1120] [Example 142]: N-(2-(1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)ethyl)sulfonamide trifluoroacetate

[1121]

[1122] 1H NMR(600MHz,DMSO)δ12.08(s,1H),8.23-8.20(m,1H),7.94-7.87(m,2H),7.85-7.80(m,2H),7.17(s,1H),7.09(s,1H) ,7.00(s,1H),3.41(d,J=12.3Hz,2H),3.10(q,J=6.7Hz,2H),2.72-2.65(m,2H),1.81-1.76(m,2H),1.52-1.36(m,5H).

[1123] [Preparation Example 3]

[1124] Preparation Example 3 is a process for preparing product 23**. Then, the phthalazine derivative is prepared by using the product 22** or 23** as the reactant 24** in Preparation Example 3-2.

[1125] Preparation Example 3-1: Preparation of reactant 23**

[1126] [Reaction formula 3-1]

[1127]

[1128] Step 1: In a round-bottom flask, 19** (1.0 equivalent) was dissolved in 37% aqueous hydrochloric acid solution (0.37M), then 30% formaldehyde (1.25 equivalent) was added and stirred at 90°C for 10 hours. The reactant was cooled to room temperature and water was added and extracted with ethyl acetate. The organic layer was washed with 2.5M aqueous sodium hydroxide solution and brine (brine) aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. For the obtained residue, 20** (yield was 59-70%) was obtained by column chromatography (EtOAc: hexane = 4: 6).

[1129] Reactant 20**-1: 5,6-dimethoxyisobenzofuran-1(3H)-one

[1130]

[1131] 1 H NMR (400 MHz, CDCl 3 ): δ7.32(s,1H),6.90(s,1H),5.23(s,2H),3.98(s,3H),3.95(s,3H).

[1132] Step 2: In a round-bottom flask, 20** (1.0 eq.) and aromatic aldehyde (1.0 eq.) were dissolved in ethyl acetate, and then sodium methoxide solution (25% in methanol) (4.0 eq.) was slowly added at 0°C. The reactants were stirred at room temperature for 1 hour, at 80°C for 1 hour, and then concentrated under reduced pressure. Ice water was added to the residue, and the pH was adjusted to 2 to 3 with acetic acid. The reactants were filtered to obtain solid 21** (21-60%).

[1133] Reactant 21**-1: 3-Hydroxy-5,6-dimethoxy-2-phenyl-1H-inden-1-one

[1134]

[1135] 1 H NMR (400 MHz, CDCl 3 ): δ7.42(s,2H),7.38-7.28(m,3H),7.21-7.15(m,2H),4.21(s,1H),4.05(s,6H).

[1136] Reactant 21**-2: 2-(4-bromophenyl)-3-hydroxy-5,6-dimethoxy-1H-inden-1-one

[1137]

[1138] 1 H NMR (400 MHz, CDCl 3 ): δ7.48(d,J=8.5Hz,2H),7.41(s,2H),7.07(d,J=8.4Hz,2H),4.17(s,1H),4.05(s,6H).

[1139] Reactant 21**-3: 2-(3-bromophenyl)-3-hydroxy-5,6-dimethoxy-1H-inden-1-one

[1140]

[1141] 1 H NMR (400 MHz, CDCl 3 ): δ7.44(ddd,J=7.9,1.9,1.1Hz,1H),7.41(s,2H),7.32(t,J=1.9Hz,1H),7.23(t,J=7.9Hz,1H),7.17-7.13(m,1H),4.18(s,1H),4.06(s,6H).

[1142] Step 3-1: In a round-bottom flask, 21** (1.0 equivalent) was added to water (4.7 M) and hydrazine monohydrate (24.5 equivalents). The reactants were stirred at 100°C for 5 hours and then cooled to room temperature. The solid was filtered and washed with ethanol to obtain 22** (yield of 40-62%).

[1143] Step 3-2: According to Step 2-2 of Preparation Example 1-1, 23** was prepared from reactant 22**.

[1144] [Example 143]: 4-Benzylphthalazin-1(2H)-one

[1145]

[1146] 1 H NMR (400MHz, DMSO) δ12.60(s,1H),8.25(dd,J=7.8,1.0Hz,1H),7.93(d,J=7.6Hz,1H),7.88 -7.83(m,1H),7.80(t,J=7.5Hz,1H),7.33-7.25(m,4H),7.18(t,J=6.9Hz,1H),4.29(s,2H).

[1147] [Example 144]: 4-Benzyl-6,7-dimethoxyphthalazin-1(2H)-one

[1148]

[1149] 1 H NMR (400MHz, DMSO): δ12.41(s,1H),7.59(s,1H),7.37-7.25(m,5H),7.19(t,J=7.2Hz,1H),4.28(s,2H),3.90(s,3H),3.83(s,3H).

[1150] [Example 145]: tert-Butyl (3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[1151]

[1152] 1 H NMR (600 MHz, CDCl 3)δ10.10(s,1H),7.76(s,1H),7.51(s,1H),7.20(t,J=7.8Hz,1H),7.13-7.09(m,2H),6 .95(d,J=7.5Hz,1H),6.46(s,1H),4.23(s,2H),4.01(s,3H),3.88(s,3H),1.49(s,9H).

[1153] [Example 146]: tert-Butyl (3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[1154]

[1155] 1 H NMR (600MHz, DMSO) δ9.27(s,1H),7.59(s,1H),7.47(s,1H),7.28-7.24(m,2H),7.16(t,J=7.9H z,1H),6.97(d,J=7.6Hz,1H),4.22(s,2H),3.90(s,3H),3.84(s,3H),3.72(s,3H),1.43(s,9H).

[1156] [Example 147]: tert-Butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[1157]

[1158] 1 H NMR (600MHz, DMSO) δ12.51(s,1H),9.19(s,1H),8.20(dd,J=7.8,1.5Hz,1H),7.88-7.85(m,1H),7.84-7 .79(m,1H),7.78-7.74(m,1H),7.30(d,J=8.2Hz,2H),7.14(d,J=8.6Hz,2H),4.17(s,2H),1.41(s,9H).

[1159] [Example 148]: tert-Butyl (4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[1160]

[1161] 1H NMR(600MHz,DMSO)δ9.24(s,1H),8.32-8.20(m,1H),7.91-7.88(m,1H),7.85-7.79(m,2 H),7.34(d,J=8.2Hz,2H),7.20(d,J=8.6Hz,2H),4.22(s,2H),3.74(s,3H),1.44(s,9H).

[1162] [Example 149]: tert-Butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[1163]

[1164] 1 H NMR (600 MHz, CDCl 3 )δ9.75(s,1H),7.76(s,1H),7.30(d,J=8.0Hz,2H),7.20(d,J=8.5Hz,2H),7. 01(s,1H),6.42(s,1H),4.20(s,2H),4.01(s,3H),3.85(s,3H),1.50(s,9H).

[1165] [Example 150]: tert-Butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate

[1166]

[1167] 1 H NMR (600 MHz, CDCl 3 )δ7.77(s,1H),7.29(d,J=8.2Hz,2H),7.19(d,J=8.5Hz,2H),6.95(s,1H),6. 42(s,1H),4.19(s,2H),4.00(s,3H),3.87(s,3H),3.81(s,3H),1.49(s,9H).

[1168] [Example 151]: tert-Butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate

[1169]

[1170] 1H NMR (600MHz, DMSO) δ12.59(s,1H),8.25(dd,J=7.9,1.4Hz,1H),7.96(d,J=8.0Hz,1H),7.87(td,J=8.2,7.7,1.5Hz ,1H),7.81(t,J=7.6Hz,1H),7.27(d,J=8.5Hz,2H),7.18(d,J=8.4Hz,2H),4.28(s,2H),3.12(s,3H),1.36(s,9H).

[1171] [Example 152]: tert-Butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate

[1172]

[1173] 1 H NMR (600MHz, DMSO) δ12.41 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 8.5Hz, 2H), 7.27 (s, 1H), 7. 18(d,J=8.5Hz,2H),4.26(s,2H),3.90(s,3H),3.84(s,3H),3.12(s,3H),1.35(s,9H).

[1174] [Example 153]: tert-Butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate

[1175]

[1176] 1 H NMR (600MHz, DMSO) δ7.60(s,1H),7.32(d,J=8.3Hz,2H),7.25(s,1H),7.18(d,J=8.4H z,2H),4.27(s,2H),3.90(s,3H),3.82(s,3H),3.72(s,3H),3.11(s,3H),1.34(s,9H).

[1177] [Example 154]: (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylic acid tert-butyl ester

[1178]

[1179] 1H NMR (600 MHz, DMSO) δ 12.40 (s, 1H), 7.70-7.47 (m, 2H), 7.28 (s, 1H), 7.14 (apparent s, 2H), 4.19 (s, 2H), 3.90 (s, 3H), 3.87-3.81 (m, 5H), 2.99 (t, J = 8.6 Hz, 2H), 1.47 (s, 9H).

[1180] [Example 155]: (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylic acid tert-butyl ester

[1181]

[1182] 1 H NMR (600 MHz, DMSO) δ7.69-7.49 (m, 2H), 7.26 (s, 1H), 7.16 (apparent s, 2H), 4.20 (s, 2H), 3.90 (s, 3H), 3.87 (m, 5H), 3.72 (s, 3H), 2.99 (t, J = 8.7 Hz, 2H), 1.47 (s, 9H).

[1183] Preparation Example 3-2

[1184] The 22** or 23** prepared in the preparation example 3-1 is used as the reactant 24** and is prepared by the reaction formula 3-2 shown below.

[1185] [Reaction formula 3-2]

[1186]

[1187] Step 1: According to step 2 of Preparation Example 1-3, 25** was prepared from reactant 24**.

[1188] [Example 156]: 4-(3-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[1189]

[1190] 1 H NMR (600MHz, DMSO) δ12.48(s,1H),7.60(s,1H),7.45-7.34(m,2H),7.26(s,1H),7.17-7.04(m,2H),4.32(s,2H),3.91(s,3H),3.86(s,3H).

[1191] [Example 157]: 4-(3-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[1192]

[1193] 1 H NMR (600MHz, DMSO) δ7.61 (s, 1H), 7.37-7.29 (m, 3H), 7.25 (s, 1H), 7.06 (d, J = 29.7Hz, 2H), 4.32 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H).

[1194] [Example 158]: 4-(4-Aminobenzyl)-phthalazin-1(2H)-one hydrochloride

[1195]

[1196] 1 H NMR (600 MHz, DMSO) δ 12.59 (s, 1H), 9.59 (br s, 2H), 8.25 (dd, J = 7.8, 1.4 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.87 (td, J = 8.1, 7.6, 1.4 Hz, 1H), 7.82 (td, J = 7.5, 1.2 Hz, 1H), 7.37 (apparent br s, 2H), 7.18 (apparent br s, 2H), 4.31 (s, 2H).

[1197] [Example 159]: 4-(4-aminobenzyl)-2-methylphthalazin-1(2H)-one hydrochloride

[1198]

[1199] 1 H NMR (600 MHz, DMSO) δ9.49 (s, 2H), 8.29-8.27 (m, 1H), 7.92-7.89 (m, 1H), 7.86-7.80 (m, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.16 (apparent br s, 2H), 4.32 (s, 2H), 3.74 (s, 3H).

[1200] [Example 160]: 4-(4-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[1201]

[1202] 1H NMR (600MHz, DMSO) δ12.44(s,1H),10.02(br s,3H),7.59(s,1H),7.44(d,J=8.4Hz,2H),7.31-7.25(m,3H),4.32(s,2H),3.91(s,3H),3.86(s,3H).

[1203] [Example 161]: 4-(4-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[1204]

[1205] 1 H NMR (600 MHz, DMSO) δ 7.60 (s, 1H), 7.38 (apparent br s, 2H), 7.24 (s, 1H), 7.13 (apparent br s, 2H), 4.29 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H).

[1206] [Example 162]: 4-(4-(Methylamino)benzyl)phthalazin-1(2H)-one hydrochloride

[1207]

[1208] 1 H NMR (DMSO, 600 MHz) δ 12.57 (s, 1H), 8.25 (d, J = 8 Hz, 1H), 7.94 (d, J = 9 Hz, 1H), 7.86 (t, J = 7 Hz, 1H), 7.81 (t, J = 7 Hz, 1H), 7.26 (apparent br s, 2H), 6.98 (apparent br s, 2H), 4.24 (s, 2H), 2.76 (s, 3H).

[1209] [Example 163]: 6,7-Dimethoxy-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride

[1210]

[1211] 1 H NMR (DMSO, 600 MHz) δ 12.41 (s, 1H), 7.59 (s, 1H), 7.36 (apparent br s, 2H), 7.28 (s, 1H), 7.12 (apparent br s, 2H), 4.26 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.80 (s, 3H).

[1212] [Example 164]: 6,7-Dimethoxy-2-methyl-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride

[1213]

[1214] 1 H NMR (600 MHz, DMSO) δ 7.59 (s, 1H), 7.30 (apparent br s, 2H), 7.26 (s, 1H), 6.94 (apparent br s, 2H), 4.23 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.71 (s, 3H), 2.75 (s, 3H).

[1215] [Example 165]: 4-(Indolin-5-ylmethyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[1216]

[1217] 1 H NMR(DMSO,600MHz)δ12.42(s,1H),7.59(s,1H),7.35(br s,1H),7.33-7.29(m,2H),7.23(br s,1H),4.30(s,2H),3.91(s,3H),3.87(s,3H),3.64(t,J=8Hz,2H),3.10(t,J=8Hz,2H).

[1218] [Example 166]: 4-(Indolin-5-ylmethyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride

[1219]

[1220] 1 H NMR(DMSO,600MHz)δ7.60(s,1H),7.38-7.30(m,2H),7.27(s,1H),7.19(br s,1H),4.30(s,2H),3.91(s,3H),3.84(s,3H),3.72(s,3H),3.62(t,J=8Hz,2H),3.08(t,J=8Hz,2H).

[1221] Step 2: According to step 3 of Preparation Example 1-3, 26** was prepared from reactant 25**.

[1222] [Example 167]: tert-Butyl (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[1223]

[1224] 1 H NMR (600MHz, DMSO) δ12.42(s,1H),11.16(s,1H),10.20(s,1H),7.58(s,1H),7.25(t,J=7.8Hz,1H),7.23(s,1H) ,7.12(d,J=7.4Hz,1H),7.09(s,1H),7.04(d,J=8.1Hz,1H),4.22(s,2H),3.90(s,3H),3.84(s,3H),1.24(s,9H).

[1225] [Example 168]: tert-Butyl (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[1226]

[1227] 1 H NMR (600MHz, DMSO) δ11.16(s,1H),10.19(s,1H),7.59(s,1H),7.25(t,J=7.8Hz,1H),7.22(s,1H),7.15(d,J=7. 7Hz,1H),7.10(s,1H),7.04(d,J=8.1Hz,1H),4.23(s,2H),3.90(s,3H),3.83(s,3H),3.72(s,3H),1.23(s,9H).

[1228] [Example 169]: tert-Butyl (N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[1229]

[1230] 1H NMR (600MHz, DMSO) δ12.57 (s, 1H), 11.15 (s, 1H), 10.14 (s, 1H), 8.24 (dd, J = 7.8, 1.5Hz, 1H), 7.96-7.89 (m, 1H), 7. 86-7.83(m,1H),7.80(td,J=7.5,1.2Hz,1H),7.28-7.17(m,2H),7.06(d,J=8.1Hz,2H),4.23(s,2H),1.24(s,9H).

[1231] [Example 170]: tert-Butyl (N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[1232]

[1233] 1 H NMR (600MHz, DMSO) δ11.14 (s, 1H), 10.16 (s, 1H), 8.27 (dd, J = 7.6, 1.6Hz, 1H), 7.93-7.88 (m, 1H), 7.8 5-7.79(m,2H),7.27(d,J=8.0Hz,2H),7.06(d,J=8.2Hz,2H),4.25(s,2H),3.74(s,3H),1.23(s,9H).

[1234] [Example 171] Tert-butyl (N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[1235]

[1236] 1 H NMR (600MHz, DMSO) δ12.40(s,1H),11.11(s,1H),10.15(s,1H),7.57(s,1H),7.28(d,J=8.3Hz ,2H),7.23(s,1H),7.08(d,J=8.5Hz,2H),4.22(s,2H),3.89(s,3H),3.83(s,3H),1.21(s,9H).

[1237] [Example 172]: tert-Butyl (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate

[1238]

[1239] 1 H NMR (600MHz, DMSO) δ11.12(s,1H),10.18(s,1H),7.58(s,1H),7.30(d,J=8.1Hz,2H),7.21(s, 1H),7.08(d,J=8.4Hz,2H),4.23(s,2H),3.89(s,3H),3.81(s,3H),3.72(s,3H),1.19(s,9H).

[1240] [Example 173] Tert-butyl N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoylcarbamate

[1241]

[1242] 1 H NMR(DMSO,600MHz)δ12.61(s,1H),11.09(s,1H),8.26-8.25(m,1H),7.99-7.97(m,1H),7.90-7.87(m,1 H),7.83-7.81(m,1H),7.36(d,J=8Hz,2H),7.26(d,J=8Hz,2H),4.30(s,2H),3.27(s,3H),1.33(s,9H).

[1243] [Example 174]: tert-Butyl N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate

[1244]

[1245] 1 H NMR(DMSO,600MHz)δ12.43(s,1H),11.08(s,1H),7.59(s,1H),7.37(br s,2H),7.28(s,2H),7.26(s,1H),4.27(s,2H),3.90(s,3H),3.85(s,3H),3.28(s,3H),1.31(s,9H).

[1246] [Example 175]: tert-Butyl N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate

[1247]

[1248] 1 H NMR(DMSO,600MHz)δ11.07(s,1H),7.60(s,1H),7.40(d,J=8Hz,2H),7.27(d,J=8Hz,2H),7 .25(s,1H),4.29(s,2H),3.90(s,3H),3.83(s,3H),3.73(s,3H),3.28(s,3H),1.30(s,9H).

[1249] [Example 176]: tert-Butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate

[1250]

[1251] 1 H NMR (DMSO, 600MHz) δ12.41 (s, 1H), 11.48 (s, 1H), 7.57 (s, 1H), 7.27 (s, 1H), 7.23 (d, J = 8Hz, 1H), 7.18 (s, 1H), 7. 09(d,J=8Hz,1H),4.21(s,2H),4.10(t,J=8Hz,2H),3.89(s,3H),3.85(s,3H),3.02(t,J=8Hz,2H),1.11(s,9H).

[1252] [Example 177]: tert-Butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate

[1253]

[1254] 1 H NMR(DMSO,600MHz)δ11.48(s,1H),7.58(s,1H),7.27-7.23(m,2H),7.20-7.17(m 1H),7.09(d,J=8Hz,1H),4.22(s,2H),4.13-4.05(m,2H),3.90(s,3H),3.83(s,3H),3.72(s,3H),3.01(t,J=8Hz,2H),1.10(s,9H).

[1255] Step 3: According to step 4 of Preparation Example 1-3, 27** was prepared from reactant 26**.

[1256] [Example 178]: (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1257]

[1258] 1 H NMR (600MHz, DMSO) δ12.42(s,1H),9.45(s,1H),7.58(s,1H),7.25(s,1H),7.17(t,J=7.9Hz,1H),7.13(t,J=2.0Hz, 1H),7.06(s,2H),7.01(ddd,J=8.1,2.3,1.0Hz,1H),6.93(d,J=7.7Hz,1H),4.21(s,2H),3.90(s,3H),3.84(s,3H).

[1259] [Example 179]: (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1260]

[1261] 1 H NMR(600MHz,DMSO)δ9.44(s,1H),7.60(s,1H),7.23(s,1H),7.19―7.14(m,2H),7.06(s,2H),7 .02-6.99(m,1H),6.94(d,J=7.5Hz,1H),4.22(s,2H),3.91(s,3H),3.82(s,3H),3.73(s,3H).

[1262] [Example 180]: N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1263]

[1264] 1 H NMR(DMSO,600MHz)δ12.56(s,1H),9.39(s,1H),8.25-8.23(m,1H),7.94-7.93(m,1H),7.88-7. 85(m,1H),7.82-7.79(m,1H),7.21-7.20(m,2H),7.08-7.05(m,2H),7.01(s,2H),4.22(s,2H).

[1265] [Example 181]: N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1266]

[1267] 1 H NMR(DMSO,600MHz)δ9.39(s,1H),8.28-8.26(m,1H),7.93-7.92(m,1H),7.86-7.83(m,1H),7. 82-7.79(m,1H),7.24-7.22(m,2H),7.07-7.05(m,2H),7.01(s,2H),4.23(s,2H),3.75(s,3H).

[1268] [Example 182]: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1269]

[1270] 1 H NMR (600MHz, DMSO) δ12.38(s,1H),9.37(s,1H),7.58(s,1H),7.28(s,1H),7.23(d,J=8 .5Hz,2H),7.08(d,J=8.5Hz,2H),7.00(s,2H),4.20(s,2H),3.90(s,3H),3.85(s,3H).

[1271] [Example 183]: (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1272]

[1273] 1 H NMR (600MHz, DMSO) δ9.38 (s, 1H), 7.59 (s, 1H), 7.27-7.24 (m, 3H), 7.07 (d, J= 8.6Hz,2H),7.00(s,2H),4.21(s,2H),3.90(s,3H),3.83(s,3H),3.72(s,3H).

[1274] [Example 184]: N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1275]

[1276] 1 H NMR(DMSO,600MHz)δ12.60(s,1H),8.26-8.25(m,1H),8.00-7.99(m,1H),7.90-7.88(m,1H),7.8 3-7.81(m,1H),7.32(d,J=9Hz,2H),7.25(d,J=8Hz,2H),6.96(s,2H),4.28(s,2H),3.05(s,3H).

[1277] [Example 185]: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride

[1278]

[1279] 1 H NMR (DMSO, 600MHz) δ12.43 (s, 1H), 7.59 (s, 1H), 7.34 (d, J = 8Hz, 2H), 7.31 (s, 1H), 7.26 (d, J = 8Hz, 2H), 4.26 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.05 (s, 3H).

[1280] [Example 186]: N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride

[1281]

[1282] 1 H NMR (DMSO, 600MHz) δ7.60 (s, 1H), 7.36 (d, J = 8Hz, 2H), 7.29 (s, 1H), 7.26 (d, J = 9Hz, 2H),6.95(s,2H),4.28(s,2H),3.91(s,3H),3.85(s,3H),3.73(s,3H),3.04(s,3H).

[1283] [Example 187]: 5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride

[1284]

[1285] 1H NMR(DMSO,600MHz)δ12.40(s,1H),7.58(s,1H),7.30(s,1H),7.19(br s,2H),7.17-7.16(m,3H),4.20(s,2H),3.90(s,3H),3.87(s,3H),3.74(t,J=8Hz,2H),2.98(t,J=8Hz,2H).

[1286] [Example 188]: 5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride

[1287]

[1288] 1 H NMR(DMSO,600MHz)δ7.59(s,1H),7.28(s,1H),7.20-7.17(m,5H),4.21(s,2H), 3.90(s,3H),3.85(s,3H),3.75(d,J=8Hz,2H),3.72(s,3H),2.97(t,J=8Hz,2H).

[1289] [Example 189]: N-(3-Fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1290]

[1291] LCMS [M+H] + 349.33

[1292] [Example 190]: N-(2-Fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1293]

[1294] LCMS [M+H] + 349.21

[1295] [Example 191]: N-(3-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1296]

[1297] LCMS [M+H] + 399.23

[1298] [Example 192]: N-(2-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride

[1299]

[1300] LCMS [M+H] + 399.34

[1301] [Example 193]: 4-(3-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one

[1302]

[1303] 1 H NMR (400MHz, DMSO) δ12.44(s,1H),7.61(s,2H),7.42(d,J=7.9Hz,1H),7.38 -7.31(m,2H),7.27(t,J=7.7Hz,1H),4.32(s,2H),3.93(s,3H),3.90(s,3H).

[1304] [Example 194]: 4-(4-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one

[1305]

[1306] 1 H NMR (400MHz, DMSO) δ12.42(s,1H),7.59(s,1H),7.49(d,J=8.3Hz,2H),7.30(d,J=8.3Hz,2H),7.26(s,1H),4.27(s,2H),3.91(s,3H),3.86(s,3H).

[1307] [Preparation Example 4-1]

[1308]

[1309] In a round bottom flask, 28 (1.0 eq.) and RSO 2 Cl (1.1 equivalents) was dissolved in dichloromethane (0.08 M), and then triethylamine (4.5 equivalents) was added and stirred at room temperature for 16 hours. After the reaction was completed, water was added to the mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (1:20 MeOH:CH 2 Cl 2 ) to obtain 29 (yield 20-40%).

[1310] [Example 195]: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)methanesulfonamide

[1311]

[1312] 1 H NMR (400MHz, MeOD) δ8.47(s,1H),7.96-7.89(m,2H),7.82(s,1H),7.67-7.58(m,4H),4.40(s,2H),2.96(s,3H).

[1313] [Example 196]: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)cyclopropanesulfonamide

[1314]

[1315] 1 H NMR(400MHz,MeOD)δ8.52-8.44(m,1H),8.00-7.88(m,2H),7.85-7.78(m,1H),7. 62(s,4H),4.44(s,2H),2.57-2.48(m,1H),1.13-1.05(m,2H),1.05-0.94(m,2H).

[1316] [Example 197]: 4-Methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)benzenesulfonamide

[1317]

[1318] 1 H NMR(400MHz,MeOD)δ8.51-8.41(m,1H),7.96-7.89(m,2H),7.80-7.70(m,3H),7.51(d, J=7.9Hz,2H),7.43(d,J=8.5Hz,2H),7.39(d,J=7.8Hz,2H),4.20(s,2H),2.44(s,3H).

[1319] [Example 198]: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)thiophene-2-sulfonamide

[1320]

[1321] 1H NMR (400MHz, MeOD) δ8.47-8.41(m,1H),7.93-7.85(m,2H),7.80-7.71(m,2H),7.61(dd,J=3. 7,1.3Hz,1H),7.52(d,J=8.2Hz,2H),7.45(d,J=8.3Hz,2H),7.16-7.11(m,1H),4.26(s,2H).

[1322] [Preparation Example 4-2]

[1323]

[1324] Step 1-1: 4-Bromobenzyl bromide 30 (1.0 equivalent) and thiourea (1.0 equivalent) were added to ethanol (1.0 M) and refluxed. After removing ethanol under low pressure to obtain a solid or viscous oil, the next step was carried out without further purification.

[1325] Step 1-2: Slowly add a mixed solution of N-chlorosuccinimide (5.0 equivalents), 2M HCl (3.1M), and acetonitrile (0.63M) to the product obtained in step 1-1. The solution is kept at an internal temperature of 10°C to 20°C in a 10°C water bath. After the reaction is completed, diethyl ether is added, and the solution layer is separated by adding water. The organic layer is separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the product.

[1326] Step 1-3: (4-Bromophenyl)methanesulfonyl chloride (1.0 equivalent) was dissolved in tetrahydrofuran (0.1 M), and then a 25% ammonium hydroxide solution was added at 0° C. The reaction mixture was stirred for 1 hour at 5° C. The reaction mixture was condensed, and then the precipitate was washed with water and filtered to obtain the product in a yield of 64%.

[1327] Step 2-1: The product of step 1-3 (1.0 equivalent), B 2 pin 2 (1.2 equivalents) and potassium acetate (3.0 equivalents) were dissolved in anhydrous dioxane (0.15M). The mixture was stirred and bubbled with nitrogen for 20 minutes. Afterwards, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 equivalents) was added and a reflux condenser was installed. The reaction mixture was stirred at 65°C for 18 hours under nitrogen. Afterwards, the temperature of the solution was reduced to 23°C and condensed, and then separated by column chromatography to obtain the product in a yield of 74%.

[1328] Step 2-2: In a round-bottom flask, the product obtained in step 2-1 was dissolved in 1,4-dioxane (0.09 M) and water (0.9 M) with 7 (1.0 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.06 equiv.), 8 (1.25 equiv.) and potassium carbonate (3.75 equiv.) and refluxed under nitrogen for 4 hours. After the reaction was completed, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. For the obtained residue, 31 (yield was 70%) was obtained by column chromatography (EtOAc: hexane = 1: 1).

[1329] [Example 199]: (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide

[1330]

[1331] 1 H NMR (400MHz, CDCl3) δ8.55 (d, J = 7.6Hz, 1H), 7.85-7.67 (m, 3H), 7.64 (s, 4H), 4.53 (s, 2H), 4.44 (s, 2H), 3.93 (s, 3H).

[1332] [Preparation Example 4-3]

[1333]

[1334] Step 1-1: The product was obtained by the same method as Step 1-1 of [Preparation Example 4-2].

[1335] Step 1-2: The product was obtained by the same method as Step 1-2 of [Preparation Example 4-2].

[1336] Step 1-3: The product of step 1-2 (1.0 equivalent), tetrahydrofuran (0.19M) and tert-butanol (0.37M) were added to a 40% aqueous solution of methylamine (6.8 equivalents) and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the organic layer was separated with ethyl acetate. The separated organic layer was washed with brine and water, then dried with anhydrous sodium sulfate and concentrated under reduced pressure, and then the product was obtained without further purification (yield was 89%).

[1337] Step 2-1: The product was obtained by the same method as Step 2-1 of [Preparation Example 4-2] (yield: 89%).

[1338] Step 2-2: Product 32 was obtained by the same method as in Step 2-2 of [Preparation Example 4-2] (yield 15%).

[1339] [Example 200]: N-methyl-1-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanesulfonamide

[1340]

[1341] 1 H NMR (400MHz, CDCl3) δ8.55(d,J=7.7Hz,1H),7.83-7.68(m,3H),7.67-7.55(m,5H),4.36(s,2H),3.93(s,3H),2.82(d,J=5.2Hz,3H).

[1342] [Preparation Example 4-4]

[1343]

[1344] Step 1-1: The product was obtained by the same method as Step 1-1 of [Preparation Example 4-2].

[1345] Step 1-2: The product was obtained by the same method as Step 1-2 of [Preparation Example 4-2].

[1346] Step 1-3: Sodium carbonate (2.0 equivalents) was dissolved in acetonitrile (0.21 M), and then morpholine (2.0 equivalents) was added to the reaction mixture. After that, solid (4-bromophenyl)methanesulfonyl chloride (1.0 equivalents) was added and the flask was stirred for 2 hours under nitrogen. After the reaction was completed, the reaction mixture was diluted with distilled water, and the aqueous solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain a white solid without further purification (yield 96%).

[1347] Step 2-1: The product was obtained by the same method as Step 2-1 of [Preparation Example 4-2] (yield: 89%).

[1348] Step 2-2: Product 33 was obtained by the same method as in Step 2-2 of [Preparation Example 4-2] (yield: 65%).

[1349] [Example 201]: 2-Methyl-4-(4-((morpholinesulfonyl)methyl)phenyl)phthalazin-1(2H)-one

[1350]

[1351] 1H NMR (400MHz, DMSO) δ8.41-8.34(m,1H),7.95-7.85(m,2H),7.70-7.58(m,5H),4.57(s,2H),3.79(s,3H),3.66-3.59(m,4H),3.21-3.14(m,4H).

[1352] [Preparation Example 4-5]

[1353]

[1354] Step 1: Potassium thioacetate (1.1 eq) was dissolved in dimethylformamide (0.3 M) at 0°C, and then bromide 34 (1.0 eq) was slowly added. The mixture was stirred at 25°C for 2 hours. After the reaction was completed, the mixture was poured into ethyl acetate and washed with brine, and then the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the product was obtained without further purification and used in the next step reaction.

[1355] Step 2: N-chlorosuccinimide (4.0 equivalents) was added to a mixture of acetonitrile (0.2M) / 2M HCl (5 / 1 v / v) and cooled to 0°C. Thioacetate (1.0 equivalents) was then slowly added. The mixture was stirred for 1 hour. After the reaction was completed, diethyl ether was used for extraction and then washed with brine, and then the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (yield was 73%).

[1356] Step 3: (4-Bromophenyl)methanesulfonyl chloride (1.0 eq.) was dissolved in tetrahydrofuran (0.1 M) and 25% ammonium hydroxide solution was added at 0° C. The reaction mixture was stirred for 1 hour at 5° C. The reaction mixture was condensed and the precipitate was washed with water and filtered to obtain the product in 82% yield.

[1357] Step 4: The product was obtained by the same method as Step 2-1 of [Preparation Example 4-2] (yield: 74%).

[1358] Step 5: Product 35 was obtained by the same method as Step 2-2 of [Preparation Example 4-2] (yield 70%).

[1359] [Example 202]: 2-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethane-1-sulfonamide

[1360]

[1361] 1H NMR (400MHz, CDCl3) δ8.57-8.49(m,1H),7.84-7.64(m,3H),7.60-7.55(m,2H),7.4 1(d,J=8.1Hz,2H),4.57(s,2H),3.92(s,3H),3.50-3.42(m,2H),3.32-3.24(m,2H).

[1362] [Example 203]: 4-(4-(Aminomethyl)-3-(trifluoromethyl)phenyl-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride

[1363]

[1364] LCMS [M+H] + 380.2

[1365] [Experimental example]

[1366] The following experiments were conducted using Examples 1 to 203 prepared as described above as objects.

[1367] Experimental Example 1: Assay of ENPP1 enzyme using cGAMP substrate

[1368] ENPP1 hydrolyzes nucleotides or nucleotide derivatives to form nucleoside-5'-monophosphates and pyrophosphates. In addition, ENPP1 hydrolyzes 2'3'-cGAMP to form adenosine 5'-monophosphate (AMP) and guanosine 5'-monophosphate (GMP). The AMP formed by the above reaction is used The measurement was performed using a kit (Promega). The kit consists of two reagents. The first reagent terminates the enzyme reaction that forms AMP, removes ATP, and converts the formed AMP into ADP. The second is a second reagent that converts ADP into ATP, which is used to produce luminescence in the luciferase reaction. The amount of luminescence measured as described above is proportional to the amount of AMP formed by ENPP1.

[1369] The final reaction mixture of the evaluation system contained 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM CaCl 2 , 1μm ZnCl 2, 5% glycerol and 1% DMSO. Serial dilutions of ENPP1 inhibitors (usually in the range of 10μM to 0.5nM) were pre-stored for 5-10 minutes at 3ng / reaction and room temperature (RT) together with human recombinant ENPP1 enzyme (R&D systems). The above reaction was started by adding cGAMP (at a final concentration of 5μM) and reacted at 37°C for 90 minutes. At the end of the reaction, 10μl of AMP-Glo ​​first reagent was added to terminate the reaction, and then stored at room temperature for 1 hour. After the above storage, 20μl of AMP detection solution (a mixture of AMP-Glo ​​II reagent and Kinase-Glo in a ratio of 1:100) was added and stored at room temperature for 1 hour. The luminescent signal was used The measurements were performed using a plate reader (Perkin Elmer). Both the maximally active control (containing enzyme and substrate only in the presence of 1% DMSO; MAX) and the minimally active control (containing substrate and 1% DMSO; MIN) were evaluated simultaneously. In each experiment, serial dilutions of a benchmark ENPP1 inhibitor were tested together. IC50 values ​​of % residual activity relative to compound concentration were calculated using GraphPad The inhibition curves were fitted using the 3-parameter variable method of the software. Serial dilutions of a compound were tested more than twice, and the average IC50 value of each compound was calculated.

[1370] The experimental results are shown in Tables 1 and 2 below.

[1371] [Table 1]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378] [Table 2]

[1379]

[1380] [Preparation Example]

[1381] In addition, the novel compound represented by the chemical formula 1 according to the present invention can be formulated into various forms according to the purpose. Several formulation methods containing the compound represented by the chemical formula 1 of the present invention as an active ingredient are exemplified below, but the present invention is not limited thereto.

[1382] Preparation Example 1: Tablet (direct compression)

[1383] 5.0 mg of the active ingredient was sieved, then mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and compressed into tablets.

[1384] Preparation Example 2: Tablets (wet granulation)

[1385] 5.0 mg of the active ingredient was sieved and then mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of the solution was added and micronized. After drying, the microparticles were sieved and then mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The microparticles were compressed into tablets.

[1386] Preparation Example 3: Powder and Capsule

[1387] 5.0 mg of the active ingredient is sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone and 0.2 mg of magnesium stearate. The mixture is filled into hard size 5 gelatin capsules using a suitable device.

[1388] Preparation Example 4: Injection

[1389] Contains 100 mg of active ingredients and contains 180 mg of mannitol, 26 mg of Na 2 HPO 4 12H 2 O and 2974 mg of distilled water to prepare the injection.

[1390] The embodiments of the present invention are described above, but those skilled in the art to which the present invention belongs can understand that the present invention can be implemented by other specific embodiments without changing the technical concept or essential features of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all aspects and are not restrictive.

Claims

1. A compound selected from the group consisting of phthalazine derivative compounds represented by the following chemical formula 1 and pharmaceutically acceptable salts thereof: [Chemical formula 1] In the chemical formula 1, Y1 and Y2 are each hydrogen; R1 or R2 are each independently hydrogen; or methoxy; R3 is hydrogen; C1-C4 alkyl; phenyl; or benzyl; R4 is 2. The compound selected from the group consisting of the phthalazine derivative compounds represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof according to claim 1, characterized in that: The compound is any one selected from the following compound numbers 2 to 203: Compound No. 2: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate; Compound No. 3: tert-butyl (3(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate; Compound No. 4: tert-butyl (3(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate; Compound No. 5: tert-butyl (3-(4-oxo-3,4-dihydrophthalazin-1-yl)carbamate; Compound No. 6: tert-butyl 3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate; Compound No. 7: tert-butyl (3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 8: tert-butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 9: tert-butyl (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 10: tert-butyl (4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 11: tert-butyl 4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate; Compound No. 12: tert-butyl (4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 13: tert-butyl (4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 14: tert-butyl (4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 15: tert-butyl (4-(7z-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 16: tert-butyl 4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate; Compound No. 17: tert-butyl 4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzylcarbamate; Compound No. 18: tert-butyl (4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 19: tert-butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 20: tert-butyl (4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 21: tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate; Compound No. 22: (R)-tert-butyl (1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)carbamate; Compound No. 23: tert-butyl (2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)carbamate; Compound No. 24: tert-butyl 4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzylcarbamate; Compound No. 25: tert-butyl methyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)carbamate; Compound No. 26: tert-butyl 6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 27: tert-butyl 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 28: tert-butyl 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 29: tert-butyl 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; Compound No. 30: 4-(3-aminophenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 31: 4-(3-aminophenyl)-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 32: 4-(3-aminophenyl)-2-benzylphthalazin-1(2H)-one hydrochloride; Compound No. 34: 4-(3-(aminomethyl)phenyl)-2-methylphthalazin-1-(2H)-one hydrochloride; Compound No. 35: 4-(3-(aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride; Compound No. 37: 4-(4-aminomethyl)phenyl)-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 38: 4-(4-(aminomethyl)phenyl)-2-ethylphthalazin-1(2H)-one hydrochloride; Compound No. 39: 4-(4-(aminomethyl)phenyl)-2-isopropylphthalazin-1-(2H)-one hydrochloride; Compound No. 40: 4-(4-aminomethyl)phenyl)-2-phenylphthalazin-1(2H)-one hydrochloride; Compound No. 41: 4-(4-aminomethyl)phenyl)-2-benzylphthalazin-1(2H)-one hydrochloride; Compound No. 42: 4-(4-(aminomethyl)phenyl)-2-(4-fluorobenzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 43: 4-(4-(aminomethyl)phenyl)-6-methoxyphthalazin-1(2H)-one hydrochloride; Compound No. 44: (4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride; Compound No. 45: (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methylammonium chloride; Compound No. 46: 4-(4-(aminomethyl)phenyl)-7-methoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 47: 4-(4-(Aminomethyl)-phenyl)-7-methoxyphthalazin-1(2H)-one hydrochloride; Compound No. 48: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 49: 4-(4-(aminomethyl)phenyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 50: 4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 51: (R)-4-(4-(1-aminoethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 52: 4-(4-(2-aminopropan-2-yl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 53: 4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 54: 4-(4-((methylamino)methyl)phenyl)phthalazin-1(2H)-one hydrochloride; Compound No. 55: 4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 56: 2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 57: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 58: 6,7-dimethoxy-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 59: 6,7-dimethoxy-4-(1,2,3,4-tetrahydroquinolin-7-yl)phthalazin-1(2H)-one; Compound No. 60: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate; Compound No. 61: tert-butyl (N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate; Compound No. 62: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfamoyl)carbamate; Compound No. 63: tert-butyl (N-(3-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 64: tert-butyl N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate; Compound No. 65: tert-butyl (N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 66: tert-butyl (N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 67: tert-butyl (N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 68: tert-butyl N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate; Compound No. 69: tert-butyl (N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 70: tert-butyl (N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 71: tert-butyl (N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 72: tert-butyl (4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 73: tert-butyl N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate; Compound No. 74: tert-butyl N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoylcarbamate; Compound No. 75: tert-butyl (N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 76: tert-butyl (N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 77: tert-butyl (N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 78: tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate; Compound No. 79: (R)-tert-butyl (N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfamoyl)carbamate; Compound No. 80: tert-butyl (N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfamoyl)carbamate; Compound No. 81: tert-butyl N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfamoylcarbamate; Compound No. 82: tert-butyl (N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 83: tert-butyl ((6-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 84: tert-butyl ((6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 85: tert-butyl ((6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 86: tert-butyl ((6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 87: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide; Compound No. 88: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride; Compound No. 89: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide hydrochloride; Compound No. 90: N-(3-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 91: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide; Compound No. 92: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide; Compound No. 93: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide; Compound No. 94: N-(3-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate; Compound No. 95: N-(3-(3-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 96: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 97: N-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 98: N-(4-(3-ethyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 99: N-(4-(3-isopropyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide trifluoroacetate; Compound No. 100: N-(4-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 101: N-(4-(3-benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 102: N-(4-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 103: N-(4-(7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 104: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 105: N-(4-(7-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 106: N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 107: N-(4-(6-methoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 108: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide hydrochloride; Compound No. 109: N-(3-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide; Compound No. 110: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-benzyl)sulfonamide; Compound No. 111: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)sulfonamide hydrochloride; Compound No. 112: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)sulfonamide hydrochloride; Compound No. 113: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-fluorobenzyl)-N-methylsulfonamide hydrochloride; Compound No. 114: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-fluorobenzyl)-N-methylsulfonamide hydrochloride; Compound No. 115: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)sulfonamide hydrochloride; Compound No. 116: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)sulfonamide hydrochloride; Compound No. 117: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2,3-difluorobenzyl)-N-methylsulfonamide hydrochloride; Compound No. 118: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride; Compound No. 119: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride; Compound No. 120: N-(4-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)-N-methylsulfonamide hydrochloride; Compound No. 121: 7-(4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide hydrochloride; Compound No. 122: 7-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide; Compound No. 123: N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride; Compound No. 124: (R)-N-(1-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethyl)sulfonamide hydrochloride; Compound No. 125: N-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propan-2-yl)sulfonamide hydrochloride; Compound No. 126: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-2-(trifluoromethyl)benzyl)sulfonamide hydrochloride; Compound No. 127: N-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)sulfonamide; Compound No. 128: 6-(4-oxo-3,4-dihydrophthalazin-1-yl-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 129: 6-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 130: 6-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 131: 6-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride; Compound No. 132: tert-butyl ((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate; Compound No. 133: tert-butyl ((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)carbamate; Compound No. 134: 4-(4-(aminomethyl)piperidin-1-yl)phthalazin-1(2H)-one hydrochloride; Compound No. 135: 4-(4-(aminomethyl)piperidin-1-yl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 136: tert-butyl N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate; Compound No. 137: tert-butyl N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfamoylcarbamate; Compound No. 138: N-((1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride; Compound No. 139: N-((1-(6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)methyl)sulfonamide hydrochloride; Compound No. 140: N-(4-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride; Compound No. 141: N-(3-(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)-amino)phenyl)sulfonamide hydrochloride; Compound No. 142: N-(2-(1-(4-oxo-3,4-dihydrophthalazin-1-yl)piperidin-4-yl)ethyl)sulfonamide trifluoroacetate; Compound No. 144: 4-benzyl-6,7-dimethoxyphthalazin-1(2H)-one; Compound No. 145: tert-butyl (3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 146: tert-butyl (3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 147: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 148: tert-butyl (4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 149: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 150: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)carbamate; Compound No. 151: tert-butyl (4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate; Compound No. 152: tert-butyl (4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate; Compound No. 153: tert-butyl (4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)(methyl)carbamate; Compound No. 154: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate; Compound No. 155: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-carboxylate; Compound No. 156: 4-(3-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 157: 4-(3-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 158: 4-(4-aminobenzyl)-phthalazin-1(2H)-one hydrochloride; Compound No. 159: 4-(4-aminobenzyl)-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 160: 4-(4-aminobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 161: 4-(4-aminobenzyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 162: 4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 163: 6,7-dimethoxy-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 164: 6,7-dimethoxy-2-methyl-4-(4-(methylamino)benzyl)phthalazin-1(2H)-one hydrochloride; Compound No. 165: 4-(Indolin-5-ylmethyl)-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride; Compound No. 166: 4-(Indolin-5-ylmethyl)-6,7-dimethoxy-2-methylphthalazin-1(2H)-one hydrochloride; Compound No. 167: tert-butyl (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 168: tert-butyl (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 169: tert-butyl (N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 170: tert-butyl (N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 171: tert-butyl (N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 172: tert-butyl (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoyl)carbamate; Compound No. 173: tert-butyl N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfamoylcarbamate; Compound No. 174: tert-butyl N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate; Compound No. 175: tert-butyl N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfamoylcarbamate; Compound No. 176: tert-butyl (5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate; Compound No. 177: tert-butyl (5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indolin-1-yl)sulfonylcarbamate; Compound No. 178: (N-(3-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 179: (N-(3-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 180: N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 181: N-(4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 182: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 183: (N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 184: N-methyl-N-(4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 185: N-(4-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride; Compound No. 186: N-(4-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N-methylsulfonamide hydrochloride; Compound No. 187: 5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride; Compound No. 188: 5-((6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)indoline-1-sulfonamide hydrochloride; Compound No. 189: N-(3-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 190: N-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 191: N-(3-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 192: N-(2-(trifluoromethyl)-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)sulfonamide hydrochloride; Compound No. 193: 4-(3-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one; Compound No. 194: 4-(4-bromobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one; Compound No. 195: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)methanesulfonamide; Compound No. 196: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)cyclopropanesulfonamide; Compound No. 197: 4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)benzenesulfonamide; Compound No. 198: N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzyl)thiophene-2-sulfonamide; Compound No. 199: (4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)sulfonamide; Compound No. 200: N-methyl-1-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)methanesulfonamide; Compound No. 201: 2-methyl-4-(4-((morpholinesulfonyl)methyl)phenyl)phthalazin-1(2H)-one; Compound No. 202: 2-(4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethane-1-sulfonamide; and Compound No. 203: 4-(4-(Aminomethyl)-3-(trifluoromethyl)phenyl-6,7-dimethoxyphthalazin-1(2H)-one hydrochloride.

3. The compound selected from the group consisting of the phthalazine derivative compounds represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof according to claim 1, wherein: The pharmaceutically acceptable salt is a salt of an inorganic acid or an organic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

4. A pharmaceutical composition for preventing, alleviating or treating cancer, comprising the compound according to any one of claims 1 to 3 as an active ingredient. 5 . An ENPP1 inhibitor comprising the compound according to claim 1 as an active ingredient.

6. A STING pathway activator comprising the compound according to any one of claims 1 to 3 as an active ingredient.

7. The pharmaceutical composition for preventing, alleviating or treating cancer according to claim 4, wherein: The cancers are associated with the inhibition of ENPP1.

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