Novel naphthyridinone derivatives having inhibitory activity against dinucleotide pyrophosphatase-phosphodiesterase, and use thereof

Abstract

To provide a compound having inhibitory activity against ENPP1.SOLUTION: To provide a new naphthyridinone derivative compound having inhibitory activity against ENPP1 and represented by the formula. (R1:H, C1-C13 alkyl, C3 - C10 cyclyl. R2:Z-R3 - (R4) m. Z is a bond, O, CO, COO or the like; R3:C3-C10 cyclyl, C3 - C10 heterocyclyl, etc. R4:H, hydroxy, halogen, etc. m:1-4. ) SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound selected from novel naphthyridinone derivative compounds having ectonucleotide pyrophosphatase-phosphodiesterase (ENPP) inhibitory activity, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, a method for producing the compound, and a pharmaceutical composition containing the compound for preventing, alleviating, or treating cancer. [Background technology]

[0002] Cancer is a group of diseases associated with uncontrolled cell proliferation, which can invade or spread to other parts of the body, reducing quality of life and ultimately leading to death. While genetic aberrations are the direct cause of uncontrolled cancer cell proliferation, failure of immune surveillance and / or the absence of an appropriate immune counterattack against cancer cells can also contribute to cancer cell proliferation, leading to the formation of a primary tumor with a tumor microenvironment (TME) that suppresses anti-cancer immune responses. Subsequently, cancer cells progress through a locally advanced cancer stage and eventually develop into metastatic cancer, which invades other organs, reducing the cure rate and survival rate of cancer patients. Therapeutic agents for treating these deadly diseases have evolved into two major categories: first, those that directly target cancer cells themselves; and second, those that target components of the tumor microenvironment (TME) to prevent further cancer cell proliferation or survival.

[0003] Cancer immunotherapy is a therapeutic approach that targets immune factors present in the TME to induce immune cells to attack tumor cells. In some cases, cancer immunotherapy aims to promote tumor cell recognition through the release of tumor-associated antigens in the TME (e.g., cancer vaccines). In other cases, cancer immunotherapy aims to promote attack against tumor cells by modulating the activity of innate and / or adaptive immune cells (e.g., immune checkpoint blockade). In other cases, cancer immunotherapy aims to induce tumor killing by engineering patient-derived lymphocytes ex vivo to express chimeric antigen receptors, which recognize antigens on the tumor surface and enhance lymphocyte activity (e.g., chimeric antigen receptor T-cell therapy (CAR-T cell therapy)).

[0004] Microbial infections can cause a variety of diseases worldwide. Pathogenic microorganisms are diverse and include viruses, bacteria, fungi, and protozoa. In some cases, therapeutic agents are chemicals that directly prevent microbial growth. In other cases, therapeutic agents are therapeutic substances that enhance or stimulate host immune function against pathogenic microorganisms.

[0005] The tumor microenvironment (TME) is composed not only of malignant tumor cells but also of various types of immune cells (e.g., macrophages, lymphocytes, NK cells, and dendritic cells) and non-immune cells (e.g., cancer-associated fibroblasts, pericytes, endothelial cells, and adipocytes). Meanwhile, the presence of tumor-infiltrating lymphocytes has been reported to respond to many pipeline immunotherapies in different types of cancer and to lead to positive clinical outcomes. The modulation or upregulation of other types of immune cells besides lymphocytes, particularly innate immune cells, has been reported in preclinical studies to modulate the responsiveness of tumors to anticancer therapies. The innate immune system is one of the two major components of the host immune defense system in vertebrates. The primary functions of innate immunity are 1) identifying and eliminating foreign substances (e.g., bacteria and viruses) in body tissues, 2) recruiting immune cells to specific sites by producing cytokines and promoting adaptive immune responses, and 3) activating the complement cascade. Innate immunity is activated by recognizing molecular patterns derived from microbial pathogens (pathogen-associated molecular patterns, or PAMPs) or remnants of destroyed cells (damage-associated molecular patterns, or DAMPs).

[0006] Pattern recognition receptors (PRRs) are a group of different types of receptors primarily expressed by innate immune cells. They can recognize specific PAMPs or DAMPs depending on their ligand specificity. Cytoplasmic DNA is a type of molecular pattern recognized by cytoplasmic DNA sensors (a type of PRR) to trigger innate immune responses. One such cytoplasmic DNA sensor, the cGAS-STING pathway (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes), is involved in 1) the recognition of cytoplasmic DNA resulting from microbial infection or DNA damage, and 2) the production of chemical factors, primarily type 1 interferons (IFNs), via activation of the IRE3 transcription factor.

[0007] In transformed cancer cells, type 1 IFNs produced in the TME promote the recruitment and activation of inflammatory cells, including NK cells, at the tumor site, both inducing tumor cell killing and the production of chemoattractants that promote adaptive immune responses.

[0008] Systemic administration of type 1 IFN has demonstrated proven efficacy in cancer settings, with systemic injection of IFN-β resulting in tumor regression and improved survival in preclinical mouse models. However, systemic administration of type 1 IFN has the drawback of requiring high doses to reach a therapeutically effective dose for therapeutic efficacy. In this case, drug resistance issues have been reported.

[0009] Recent reports have published clinical results of exogenous STING agonists (modified cyclic dinucleotides), which showed lower than expected disease control rates despite a clear increase in inflammatory cytokine production.

[0010] Therefore, research into new therapeutic methods that can activate the cGAS-STING pathway is needed. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] China published patent CN110575458A [Patent Document 2] International Publication WO2019 / 233300A1 [Patent Document 3] International Publication WO2018 / 119325A1 [Patent Document 4] International Publication WO2018 / 119328A1 [Patent Document 5] International Publication WO2019 / 046778A1 [Patent Document 6] International Publication WO2019 / 177971A1 [Patent Document 7] Japan Publication JP2020-15670 [Patent Document 8] International Publication WO2019 / 051269A1 [Patent Document 9] U.S. Publication US2020 / 0039979A1 [Patent Document 10] International Publication WO2019 / 023635A1 [Patent Document 11] International Publication WO2019 / 051269A1 Summary of the Invention [Problem to be solved by the invention]

[0012] To solve the above problems, the present invention aims to provide a method for increasing the activity of the cGAS-STING pathway.

[0013] Therefore, one aspect of the present invention is to provide novel naphthyridinone derivative compounds that have inhibitory activity against ENPP1 and that enhance and / or regulate the production of type 1 interferons (IFNs) in the body.

[0014] Another object of the present invention is to provide a pharmaceutical composition useful for treating, preventing, and alleviating cancer diseases, which contains a novel naphthyridinone derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0015] Another object of the present invention is to provide a method for preventing, alleviating, or treating cancer, which comprises administering a novel naphthyridinone derivative compound or a pharmaceutical composition containing the compound to a patient or subject in need thereof.

[0016] Another object of the present invention is to provide a method for preventing, alleviating or treating an infectious disease, which comprises administering a novel naphthyridinone derivative compound or a pharmaceutical composition containing the compound to a patient or subject in need thereof.

[0017] Another object of the present invention is to provide a method for preventing, alleviating, or treating periodontal disease, which comprises administering a novel naphthyridinone derivative compound or a pharmaceutical composition containing the compound to a patient or subject in need thereof.

[0018] Another object of the present invention is to provide a method for preventing, alleviating, or treating pathological mineralization of soft tissue, comprising administering a novel naphthyridinone derivative compound or a pharmaceutical composition containing said compound to a patient or subject in need thereof.

[0019] Another object of the present invention is to provide a novel naphthyridinone derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or an isomer thereof as an active ingredient, which embodies the following mechanism: In one aspect, the method includes priming a cancer cell with an agent that induces ICD (immunogenic cell death) before stimulating the cGAS-STING pathway. In yet another aspect, the method includes blocking the degradation of endogenous STING ligands before priming a cancer cell with an agent that induces ICD. In another aspect, the method includes using an inhibitor of 2'3'-cGAMP-degrading polypeptides together with an agent that induces ICD for cancer treatment. In one aspect, the present invention provides a method for designing inhibitors of 2'3'-cGAMP-degrading polypeptides and a detailed analytical method for evaluating the enzymatic activity of cGAMP-degrading polypeptides. [Means for solving the problem]

[0020] In order to solve the above problems, the present invention provides a compound selected from naphthyridinone derivative compounds represented by the following chemical formula 1, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof:

[0021] [ka]

[0022] In the above Chemical Formula 1,

[0023] R1 is hydrogen; C1-C 13 Alkyl group; or C3-C 10 cyclyl group;

[0024] R2 is -Z-R3-(R4) m in,

[0025] The Z may be present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C n H n+2 -, -O(Cn H n+2 ) - , -(OC2H4) n -, -(C2H4O) n -, -(C n H n+2 )O-, -(C n H n+2 )CO-, -(C n H n+2 )O(C m H m+2 )-, -NR6(C n H n+2 )-, -(NR6C2H4) n -, -(C2H4NR6) n - or -(C n H n+2 )NR6-;

[0026] n is an integer from 0 to 8,

[0027] The R3 is C3-C 10 Cyclyl group, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl group, or C3-C 10 Heteroaryl groups,

[0028] R4 is hydrogen; a hydroxy group; a halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C1-C6 alkenyl group; C6-C 10 Aryl group; C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; C3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl; tert-butyloxycarbonyl group (Boc); amino group (-NR5R6); -(C m H m+2 )NR5R6; nitro group (-N(O)2); amide group (-(C=O)NR5R6); ester group (-C(O)OR6); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-NHS(O)2R6); urea group; sulfamoyl group (-NHS(O)2NHR6); sulfonamide group; sulfamoyl alkyl group (-(Cm H m+2 )NHS(O)2NHR6); sulfamoyl alkyl group (-(C m H m+2 )NR5S(O)2NHR6); a sulfide group (-SR6); a sulfone group (-S(O)2R6); or a phosphiryl group (-P(O)R5R6); or, connected to the same carbon as connected to R3, to form a 3- to 7-membered saturated ring; or, connected to the same carbon as connected to R3, to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S; or, connected to the carbon adjacent to connected to R3, to form a 3- to 7-membered saturated ring; or, connected to the carbon adjacent to connected to R3, to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S;

[0029] m is an integer from 1 to 4,

[0030] The C1-C6 alkyl group, C1-C 13 Alkyl group or C3-C 10 Cyclyl groups are hydrogen; hydroxyl groups; halogen groups; C1-C 13 Alkyl group; C1-C6 alkoxy group; Amino group (-NR5R6); Nitro group (-N(O)2); Amide group (-(C=O)NR5R6); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Urea group (-NR5(C=O)NR6-); Sulfonamide group (-NHS(O)2-); Sulfide group (-S-); Sulfone group (-S(O)2-); Phosphylyl group (-P(O)R5R6); C6-C 10 Aryl group; C3-C 10 Heteroaryl groups; and C3-C 10 one or more substituents selected from the group consisting of heterocyclyl groups;

[0031] Said C6-C 10 Aryl groups, C3-C 10 Heteroaryl group or C3-C 10A heterocyclyl group is a group selected from the group consisting of hydrogen, hydroxy, halogen, carbonyl (-(C=O)R5R6), halogen, or C3-C 10 The heterocyclyl group is substituted or unsubstituted C1-C3 alkyl group; halogen or C3-C 10 Heterocyclyl groups with substituted or unsubstituted C1-C3 alkoxy groups; C6-C 10 Phenoxy; Amino group (-NR5R6); Nitro group (-N(O)2); Amide group (-(C=O)NR5R6); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Urea group (-NR5(C=O)NR6-); Sulfonamide group (-NHS(O)2-); Sulfide group (-S-); Sulfone group (-S(O)2-); Phosphylyl group (-P(O)R5R6); C6-C 10 Aryl group; C3-C 10 containing one or more substituents selected from the group consisting of heteroaryl groups and C3-C10 heterocyclyl groups;

[0032] R5 and R6 are each independently hydrogen; a C1-C6 alkyl group; a C1-C6 alkenyl group; a C1-C6 alkynyl group; a C6-C 10 Aryl group; C3-C 10 Heteroaryl group; C3-C 10 or R5, together with the nitrogen or carbon atom connected to R6, can optionally contain at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, and SO2, and can be selected from the group consisting of hydrogen, C1-C 13 Alkyl groups, C6-C 10 Aryl groups, C3-C 10 forming a 3- to 7-membered saturated ring which may be optionally substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group;

[0033] Said C3-C 10 Heteroaryl groups and C3-C 10 Heterocyclyl groups contain one or more heteroatoms selected from the group consisting of N, O, and S. [Effects of the Invention]

[0034] The compounds according to the present invention have excellent ability to inhibit the activity of ENPP1, and therefore can be used for the treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth.

[0035] The compound according to the present invention, its pharmaceutically acceptable salt, or hydrate, and a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient can effectively suppress ENPP1, activate the STING pathway, and be useful for preventing or treating cancer and preventing cancer metastasis.

[0036] Cancer diseases that may be treated, prevented, or alleviated by treatment with the compounds of the present invention include stomach cancer, lung cancer, liver cancer, colon cancer, small intestine 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, myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, or fibroadenoma, etc.

[0037] In particular, the compounds according to the present invention are effective in preventing, alleviating or treating diseases in which ENPP1 is involved. DETAILED DESCRIPTION OF THE INVENTION

[0038] definition

[0039] Unless otherwise specified, all numbers, values, and / or expressions expressing ingredients, reaction conditions, and ingredient contents used herein are approximations that reflect various uncertainties in measurement that may arise in obtaining such values, even though these numbers may vary substantially, and should be understood in all cases to be modified by the term "about." Also, when ranges of numerical values ​​are disclosed herein, such ranges are continuous and include all values ​​from the minimum value to the maximum value, inclusive, unless otherwise indicated. Furthermore, when such ranges refer to integers, they include all integers from the minimum value to the maximum value, inclusive, unless otherwise indicated.

[0040] When a range is recited herein for a variable, the variable may be understood to include all values ​​within the recited range, including each of the recited endpoints of the range. For example, the range "5 to 10" may be understood to include not only the values ​​5, 6, 7, 8, 9, and 10, but also any subranges such as 6 to 10, 7 to 10, 6 to 9, and 7 to 9, as well as any value between each integer within the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9. Also, for example, the range "10% to 30%" may be understood to include values ​​such as 10%, 11%, 12%, 13%, etc., and all integers up to and including 30%, as well as any subranges such as 10% to 15%, 12% to 18%, 20% to 30%, and any value between each integer within the recited range, such as 10.5%, 15.5%, 25.5%, etc.

[0041] As used herein, the terms "individual," "subject," and "patient" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. None of the terms require or are limited to situations characterized by the supervision (e.g., full-time or intermittent) of a health care professional (e.g., a physician, registered nurse, licensed practical nurse, physician assistant, handyman, or hospice worker).

[0042] "Treatment" refers to an attempt to prevent the development or alteration of a disease lesion. Therefore, "treatment" refers to both therapeutic and prophylactic treatments. The need for treatment includes not only conditions where the disease already exists, but also conditions where the disease must be prevented. In tumor treatment, a therapeutic agent may directly reduce the pathology of tumor cells or make tumor cells more susceptible to treatment with other therapeutic agents, such as radiation and / or chemotherapy and / or immunotherapy. As used herein, the term "alleviation" or "treated" refers to a sign approaching a normalized value measured by a standard statistical test. Here, a sign approaching a normalized value may be, for example, a value that shows less than a 50% difference, preferably less than a 25% difference, more preferably less than a 10% difference, and even more preferably no significant difference from the normalized value, compared to a value obtained from a healthy patient or individual.

[0043] "Treatment of cancer" means any one or more of the following effects: 1) inhibition of tumor growth, including i) slowing or ii) complete cessation of growth; 2) reduction in tumor cell count; 3) maintenance of tumor size; 4) reduction in tumor size; 5) inhibition of tumor cell infiltration into peripheral organs, including i) reduction, ii) slowing, or iii) complete prevention; 6) inhibition of metastasis, including i) reduction, ii) slowing, or iii) complete prevention; 7) enhancement of the anti-tumor immune response, which may result in i) maintenance of tumor size, ii) reduction in tumor size, iii) slowing of tumor growth, or iv) reduction, slowing, or prevention of invasion.

[0044] As used herein, an "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein to alleviate to some extent the symptoms of the disease or condition being treated (e.g., cancer or inflammatory disease, periodontal disease, or soft tissue calcification). In some embodiments, the result is 1) a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or 2) any other favorable alteration of a biological system in a clinical setting. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.

[0045] In some embodiments, an "effective amount" refers to the amount of a disclosed compound in monotherapy or combination therapy, i.e., an amount that, when administered in one or more doses, is 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), or about 90% or more (90% inhibition), when compared to ENPP1 activity in an individual not treated with the compound, or when compared to ENPP1 activity in an individual before and after treatment with the compound.

[0046] In some embodiments, a "therapeutically effective amount" refers to an amount of a disclosed compound, i.e., an amount administered in one or more doses, in monotherapy or combination therapy, that is effective to reduce a subject's tumor burden by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more, compared to the tumor burden in a subject not treated with the compound, or compared to the tumor burden in a subject before and after treatment with the compound. As used herein, the term "tumor burden" refers to the total mass of tumor tissue in a subject with cancer.

[0047] In some embodiments, a "therapeutically effective amount" is an amount of a disclosed compound, i.e., an amount that, when administered in one or more doses, is effective in monotherapy or combination therapy to reduce the amount of radiation therapy required to observe tumor shrinkage in a subject by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more compared to the amount of radiation therapy required to observe tumor shrinkage in a subject not treated with the compound.

[0048] The present invention will now be described in detail.

[0049] The present inventors have continued their research to solve the above problems, and as a result, have developed a compound for inhibiting ENPP1, a composition for inhibiting ENPP1, and a method for inhibiting ENPP1. In one aspect, the present inventors have developed a novel naphthyridinone derivative compound for inhibiting ENPP1, its pharmaceutically acceptable salt, hydrate, and stereoisomer, or a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. In one embodiment, the method comprises treating a sample with a cell-permeable ENPP1 inhibitor to inhibit cGAMP hydrolysis by ENPP1. In one embodiment, the method comprises administering a therapeutically effective amount of the cell-permeable ENPP1 inhibitor to a patient or subject to treat cancer. The compound, composition containing the same, or the compound and composition according to one aspect of the present invention can be used for various applications or diseases requiring ENPP1 inhibition.

[0050] cGAS-STING pathway, immunogenic cell killing, and production of type 1 IFNs

[0051] Cytoplasmic double-stranded DNA can enter the cell from the outside through microbial infection or vesicular transfer from nearby dead cells. Cytoplasmic DNA can also arise from damaged genomic or mitochondrial DNA inside the cell. Once present, cytoplasmic DNA can be detected by various DNA sensors, including RNA polymerase III, DDX41, DAI, IFI6, cGAS, LEEFIP1, DHX9, DHX36, Ku70, and AIM2.

[0052] cGAS (cyclic GMP-AMP synthase) is a dimeric cytoplasmic protein that contains two DNA-binding domains and a nucleotidyltransferase domain (which converts ATP and GTP into the cyclic dinucleotide 2'3-cGAMP with 2'5' and 3',5' phosphodiester bonds). cGAMP acts as a second messenger, binding to STING with high affinity (Kd ~ 4 nM) and inducing type 1 IFN expression.

[0053] STING (also known as TMEM173, MITA, and MPYS) is an endoplasmic reticulum (ER)-anchored protein containing four transmembrane domains at its N-terminus and a dimerization domain at its C-terminus. Upon cGAMP binding, STING tetramerizes and translocates from the ER to the ER-Golgi intermediate compartment. In the Golgi, STING recruits and activates tank-binding kinase 1 (TBK1). Activated TBK1 phosphorylates the C-terminal domain of STING, leading to the recruitment and activation of interferon regulator factor 3 (IRF3). Activated IRF3 then translocates to the nucleus and increases the expression of immune-stimulated genes (ISGs) and type 1 IFNs. Following activation, STING terminates cGAS-STING pathway activation by being delivered to endolysosomes for degradation.

[0054] Immunogenic Cell Killing (ICD)

[0055] ICD (immunogenic cell death) is a type of cell death that triggers the activation of a regulated immune response. This cell death is characterized by apoptotic morphology and maintains the integrity of biological membranes. Furthermore, ICD is characterized by the secretion of DAMPs (e.g., calreticulin, high mobility group box 1 (HMGB1), ATP, and Hsp70 / 90 proteins) as well as the exposure of polypeptides formed by cell-specific or mutated proteins. These exposed polypeptides (acting as antigens) are recognized by dendritic cells (DCs) and subsequently prime effector T lymphocytes for the activation of adaptive immune responses.

[0056] ICD can also be further classified by different types of ICD-inducing agents, such as 1) radiation (e.g., UV radiation or gamma radiation), 2) small chemotherapeutic molecules (e.g., doxorubicin or paclitaxel), and 3) biologics (e.g., polypeptides, oligosaccharides, lipids, or nucleic acids).

[0057] radiation therapy

[0058] Radiation therapy is well known and is used to treat patients suffering from a variety of diseases. Radiation therapy is typically used to kill or inhibit the growth of undesirable tissue (e.g., cancerous tissue). Determined amounts of high-energy electromagnetic radiation and / or high-energy particles are aimed at directly damaging undesirable tissue or lesions in the path of the radiation, while minimizing unintended damage to desirable or healthy tissue.

[0059] Previous research has shown that the impact on normal tissues is greater with fraction size than with the dose itself. Therefore, a 1.8-2.0-Gy fractionated dose is considered the standard for conventional radiation therapy, resulting in a longer treatment time. In fact, a small dose per fraction induces tumor activity through mitotic death of cancer cells while simultaneously allowing for recovery from sublethal damage to normal tissues after administration. Stereotactic body radiation therapy (SBRT) is an improved form of radiation therapy that uses sophisticated image guidance to accurately determine the three-dimensional location of tumors and deliver radiation more precisely to cancer cells. In addition to direct cytotoxicity, SBRT can have a substantial effect on tumor cell killing at high doses accompanied by microvascular damage, adding a new mechanism for radiation-induced damage. However, recent reports have shown that high doses of radiation can induce the expression of nuclease enzymes, weakening the effect of radiation on STING-mediated innate immune activation.

[0060] pathogen

[0061] As described above, intracellular entry of pathogen-derived nucleic acids activates the cGAS-STING pathway, increasing the immune response to the pathogen. In some cases, the pathogen is a virus, such as 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 herpesvirus (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 examples, 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 Neisseria gonorrhoeae.

[0062] Phosphodiesterases

[0063] Phosphodiesterases (PDEs) include cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and many other less well-known small molecule phosphodiesterases. An exemplary group of PDE enzymes is the important enzyme that hydrolyzes the cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) to their inactive 5'-monophosphates.

[0064] Cyclic nucleotide phosphodiesterases comprise a group of enzymes that cleave the phosphodiester bond of the cyclic nucleotide second messenger molecules cAMP and cGMP, regulating the localization, duration, and amplification of cyclic nucleotide signals within subcellular domains.

[0065] Ecto-nucleotide pyrophosphatases / phosphodiesterases

[0066] The phosphodiesterase class also includes ectonucleotide pyrophosphatases / phosphodiesterases. Ectonucleotide pyrophosphatases / phosphodiesterases (ENPPs) or nucleotide pyrophosphatases / phosphodiesterases (NPPs) are a group of ectonucleotidase enzymes that hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to generate nucleotide 5'-monophosphates (or phospholipids and phosphocholines). 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 ectonucleotidases that have similar protein structures and are found on the surface of cells.

[0067] Each ENPP enzyme has a modular structure containing a catalytic domain of approximately 400 amino acids. This catalytic domain is not related to phospholipases, nuclease hydrolases, or ectonucleotide triphosphate diphosphohydrolases, even if they exhibit overlapping activities. ENPP1 and 3 possess an N-terminal transmembrane domain and a C-terminal nuclease-like domain and are predicted to be type 2 single-spanning transmembrane proteins with their catalytic domains directed to the extracellular space. ENPP2, which lacks an N- or C-terminal transmembrane domain, possesses an N-terminal signal peptide and is predicted to be secreted extracellularly. ENPP4, 5, 6, and 7, which contain a predicted N-terminal signal peptide and a C-terminal transmembrane domain, are predicted to be type 1 single-spanning transmembrane proteins with their catalytic domains directed to the extracellular space.

[0068] ENPP1, 2, and 3 are known to use nucleotides and their derivatives as substrates to produce nucleoside monophosphates (ENPP1, 2, and 3) or nucleoside diphosphates (ENPP1 and 2). Only ENPP2 is known to use lysophospholipids. ENPP6 and 7 are known to use choline phosphate esters as substrates to produce choline phosphate. ENPP4 and 5 have no known substrates.

[0069] ENPP1, also known as NPP1 or PC-1, is a type 2 transmembrane glycoprotein expressed in many tissues (pancreas, kidney, bladder, and liver). ENPP1 is important for purinergic signaling, which plays an important role in regulating cardiovascular, neuronal, immune, and hematologic functions in mammals. ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP, generating inorganic pyrophosphate (PPi). Generally, inorganic pyrophosphate regulates bone and cartilage mineralization, and the generation of PPi by ENPP1 allows ENPP1 to serve as a central regulator of bone and cartilage development. In contrast to the inhibitory effects of excess ENPP1-generated PPi in joint tissues, the formation of calcium phosphate from ENPP1-generated PPi is essential for bone mineralization. ENPP1 has broad specificity and hydrolyzes a variety of substrates, including phosphodiester bonds and pyrophosphate bonds in nucleotide and nucleotide sugars.

[0070] Recently, ENPP1 has been shown to play an important role in immunological responses to various external signals that activate the cGAS-STING pathway. Exploratory studies of the enzymatic activity that degrades the cGAMP molecule revealed that ENPP1 functions as the primary hydrolase of cGAMP. Consistent with these findings, it has been reported that the half-life of cGAMP is highly dependent on ENPP1, demonstrating a significantly longer half-life of cGAMP in ENPP1 knockout mice.

[0071] A bisphosphothionate analog of cGAMP that is resistant to ENPP1 hydrolysis has been shown to activate STING 10-fold more effectively than cGAMP, suggesting that delaying or reducing cGAMP hydrolysis by inhibiting ENPP1 significantly increases STING activation. ENPP1 inhibition has been reported to attenuate pseudorabies virus infection and reduce Mycobacterium tuberculosis infection by inducing sustained cGAMP and activating the STING pathway.

[0072] Therefore, one aspect of the present invention provides an inhibitor of ENPP1, a cGAMP-degrading polypeptide.

[0073] In one aspect, the ENPP1 inhibitor is a reversible inhibitor.

[0074] In one aspect, the ENPP1 inhibitor is a competitive inhibitor.

[0075] In another aspect, the ENPP1 inhibitor is an allosteric inhibitor.

[0076] In another aspect, the ENPP1 inhibitor is an irreversible inhibitor.

[0077] In one aspect, the ENPP1 inhibitor binds to a PDE (phosphodiesterase) catalytic domain to which AMP or GMP is bound.

[0078] In one aspect, the inhibitor of ENPP1 binds to the PDE catalytic domain but binds weakly when AMP is bound.

[0079] 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.

[0080] How to inhibit ENPP1

[0081] As mentioned above, the present invention includes the following: 1) an ENPP1 inhibitor; 2) a method for inhibiting the ENPP1 enzyme with the ENPP1 inhibitor; 3) a method for inhibiting the hydrolase activity of ENPP1 against cGAMP; 4) a method for enhancing the signal output of STING pathway activation; and 5) a method for suppressing tumor growth in an appropriate mouse tumor model in a monotherapy or combination therapy setting.

[0082] In some embodiments, inhibiting ENPP1 means that ENPP1 activity is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more, compared to a control group not treated with the compound. In some embodiments, inhibiting ENPP1 means that ENPP1 activity is reduced by 2-fold or more, e.g., 3-fold or more, 5-fold or more, 10-fold or more, 100-fold or more, or 1000-fold or more, compared to a control group not treated with the compound.

[0083] In some embodiments, the cell-permeable ENPP1 inhibitor is an inhibitor as described herein, ie, any one of a naphthyridinone derivative compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0084] [C1] TIFF2026004378000002.tif2223

[0085] In some embodiments, the permeable ENPP1 inhibitor is any one of the following compounds:

[0086] Compound No. 1: tert-butyl(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)carbamate;

[0087] Compound No. 2: tert-butyl (3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0088] Compound No. 3: tert-butyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0089] Compound No. 4: tert-butyl(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0090] Compound No. 5: tert-butyl (4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0091] Compound No. 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0092] Compound No. 7: 5-(3-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0093] Compound No. 8: 5-(5-(amino-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0094] Compound No. 9: 5-(3-(aminomethyl)-4-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0095] Compound No. 10: 5-(4-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0096] Compound No. 11: 5-(4-(aminomethyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0097] Compound No. 12: 5-(4-(aminomethyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0098] Compound No. 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0099] Compound No. 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0100] Compound No. 15: (R)-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0101] Compound No. 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0102] Compound No. 17: (R)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0103] Compound No. 18: (S)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0104] Compound No. 19: (R)-5-(4-(1-(cyclopropylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0105] Compound No. 20: 5-(4-((ethylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0106] Compound No. 21: 5-(2-fluoro-4-((isopropylamine)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0107] Compound No. 22: 5-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0108] Compound No. 23: 5-(3-fluoro-4-((methylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0109] Compound No. 24: 5-(4-((ethylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0110] Compound No. 25: 5-(4-((cyclopropylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0111] Compound No. 26: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0112] Compound No. 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0113] Compound No. 28: 5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0114] Compound No. 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride;

[0115] Compound No. 30: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamoyl)carbamate;

[0116] Compound No. 31: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0117] Compound No. 32: tert-butyl (N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0118] Compound No. 33: tert-butyl (N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0119] Compound No. 34: tert-butyl (N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0120] Compound No. 35: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide;

[0121] Compound No. 36: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide hydrochloride;

[0122] Compound No. 37: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0123] Compound No. 38: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0124] Compound No. 39: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide;

[0125] Compound No. 40: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0126] Compound No. 41: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0127] Compound No. 42: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0128] Compound No. 43: N-(2,3-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0129] Compound No. 44: N-(3,5-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0130] Compound No. 45: N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0131] Compound No. 46: (R)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0132] Compound No. 47: (S)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0133] Compound No. 48: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0134] Compound No. 49: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0135] Compound No. 50: N-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0136] Compound No. 51: N-ethyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0137] Compound No. 52: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride;

[0138] Compound No. 53: N-ethyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0139] Compound No. 54: N-cyclopropyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0140] Compound No. 55: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride;

[0141] Compound No. 56: N-ethyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0142] Compound No. 57: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-isopropyl)sulfamide hydrochloride;

[0143] Compound No. 58: N-cyclopropyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0144] Compound No. 59: (R)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0145] Compound No. 60: (R)-(N-cyclopropyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0146] Compound No. 61: (S)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0147] Compound No. 62: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0148] Compound No. 63: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0149] Compound No. 64: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindolin-2-yl)sulfamide hydrochloride;

[0150] Compound No. 65: 7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)dihydroisoquinoline-2(1H)-sulfamide hydrochloride;

[0151] Compound No. 66: 6-fluoro-7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride;

[0152] Compound No. 67: N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0153] Compound No. 68: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide;

[0154] Compound No. 69: 4-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide;

[0155] Compound No. 70: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide;

[0156] Compound No. 71: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)cyclopropanesulfonamide;

[0157] Compound No. 72: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

[0158] Compound No. 73: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate;

[0159] Compound No. 74: ethyl hydrogen(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

[0160] Compound No. 75: (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonic acid;

[0161] Compound No. 76: 5-((3-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0162] Compound No. 77: 5-((3-aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0163] Compound No. 78: 5-((3-aminomethyl)-4-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0164] Compound No. 79: 5-((5-(2-aminoethyl)-2-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0165] Compound No. 80: 5-((3-(2-methylphenylethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0166] Compound No. 81: 5-((4-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0167] Compound No. 82: 5-((4-(aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0168] Compound No. 83: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0169] Compound No. 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0170] Compound No. 85: 5-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0171] Compound No. 86: 5-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0172] Compound No. 87: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0173] Compound No. 88: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride;

[0174] Compound No. 89: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0175] Compound No. 90: N-(2-fluoro-5((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0176] Compound No. 91: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0177] Compound No. 92: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0178] Compound No. 93: N-methyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0179] Compound No. 94: N-ethyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0180] Compound No. 95: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0181] Compound No. 96: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)-N-methylsulfamide dihydrochloride;

[0182] Compound No. 97: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride;

[0183] Compound No. 98: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0184] Compound No. 99: N-cyclopropyl-N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0185] Compound No. 100: N-(3-chloro-4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0186] Compound No. 101: 5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)isoindolin-2-yl)sulfamide dihydrochloride;

[0187] Compound No. 102: 7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0188] Compound No. 103: (8-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-1,3,4,5-tetrahydro-2(1H)-benzo[c]azepin-2-yl)sulfamide dihydrochloride;

[0189] Compound No. 104: (6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0190] Compound No. 105: 6-fluoro-7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0191] Compound No. 106: (7-fluoro-6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0192] Compound No. 107: N-(5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-2,3-dihydro-1H-inden-2-yl)sulfamide dihydrochloride;

[0193] Compound No. 108: (7-(methyl(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0194] Compound No. 109: tert-butyl (1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)carbamate;

[0195] Compound No. 110: tert-butyl ((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate;

[0196] Compound No. 111: tert-butyl(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)carbamate;

[0197] Compound No. 112: tert-butyl ((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate;

[0198] Compound No. 113: 5-(4-aminopiperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0199] Compound No. 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0200] Compound No. 115: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0201] Compound No. 116: 5-(1,4-diazepan-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0202] Compound No. 117: 5-(2,8-diazaspiro[4,5]decan-8-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0203] Compound No. 118: 5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride;

[0204] Compound No. 119: tert-butyl (N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamoyl)carbamate;

[0205] Compound No. 120: tert-butyl (N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;

[0206] Compound No. 121: tert-butyl (N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate;

[0207] Compound No. 122: tert-butyl (N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;

[0208] Compound No. 123: N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamide;

[0209] Compound No. 124: N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide;

[0210] Compound No. 125: N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamide;

[0211] Compound No. 126: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide;

[0212] Compound No. 127: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide;

[0213] Compound No. 128: N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide;

[0214] Compound No. 129: tert-butyl(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0215] Compound No. 130: tert-butyl(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0216] Compound No. 131: 5-(3-(aminophenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0217] Compound No. 132: 5-(3-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0218] Compound No. 133: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0219] Compound No. 134: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0220] Compound No. 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0221] Compound No. 136: tert-butyl (N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0222] Compound No. 137: tert-butyl (N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0223] Compound No. 138: tert-butyl ((7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-diisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0224] Compound No. 139: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)phenyl)sulfamide;

[0225] Compound No. 140: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0226] Compound No. 141: N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0227] Compound No. 142: N-(2-fluoro-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0228] Compound No. 143: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindoline-2-sulfamide hydrochloride

[0229] Compound No. 144: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride;

[0230] Compound No. 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide hydrochloride;

[0231] Compound No. 146: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide;

[0232] Compound No. 147: 4-methyl-N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide; and

[0233] Compound No. 148: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide.

[0234] In some embodiments, compounds of the invention have an ENPP1 inhibition profile that reflects activity against additional enzymes, hi some embodiments, compounds of the invention specifically inhibit ENPP1 without unintended inhibition of one or more other enzymes.

[0235] In some embodiments, compounds of the invention inhibit ENPP1 as determined by inhibition assays, e.g., assays that determine the activity of an enzyme in a cell-free or cell-based system after treatment with a compound of the invention compared to a control, by measuring IC or EC, respectively. In some embodiments, compounds of the invention have an IC (or EC) 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.

[0236] Assay procedures that can be used to determine the activity of ENPP1 can include many, but are not limited to, the following: cell-free assay systems, such as avidity assays, assays using purified enzymes, cellular assays in which the phenotype of cells is measured, such as gene expression assays, and in vivo assays associated with specific animals.

[0237] In some 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 a compound of the present invention to reduce cancer cell proliferation. In some embodiments, the method can be performed in conjunction with chemotherapy. Any available cancer cells can be used.

[0238] Treatment method

[0239] As mentioned above, the present invention includes a method for inhibiting ENPP1 activity toward cGAMP, thereby increasing cGAMP levels and / or modulating downstream factors of the STING pathway. Recent reports have shown that ENPP1 inhibition can modulate STING activity in vivo and thus may be used in the treatment of various diseases, such as cancer immunotherapy or the treatment of infectious diseases. As described above, the method of the present invention is a method for increasing STING-mediated responses in a subject and modulating an immune response.

[0240] In some embodiments, the STING-mediated response includes increasing interferon (e.g., type 1 interferon, type 3 interferon) production in the subject. Interferons (IFNs) are a group of signaling proteins produced and released by host cells in response to the presence of one or more pathogens to enhance the defense of surrounding cells against the pathogen(s). IFNs also have a variety of other functions: 1) activating immune cells, such as NK cells and macrophages; and 2) increasing host defense by upregulating antigen presentation through increased expression of major histocompatibility complex (MHC) antigens. IFNs are generally classified into three classes: type 1 IFNs, type 2 IFNs, and type 3 IFNs. Mammalian type 1 IFNs 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 1 IFNs bind to a unique cell surface receptor complex known as the IFN-α / β receptor (IFNAR), which consists of the IFNAR1 and IFNAR2 chains.

[0241] Interferons have been investigated as cancer therapeutics due to their antitumor activity, which exhibits two distinct effects: tumor-intrinsic and / or immunomodulatory. IFNs regulate the expression of numerous genes that directly affect tumor cell growth, proliferation, differentiation, survival, migration, and other specialized functions. In some cases, in vitro treatment with type 1 IFNs has a direct antiproliferative effect due to the IFN-induced prolongation of all stages of the cell cycle. In some cases, CRKL, one of the CRK proteins activated by type 1 IFNs, interacts with the tumor-suppressor small G-protein RAP1A and inhibits RAS family GTPases, resulting in cancer cell growth arrest. IFNs are known to regulate two major apoptotic responses: the extrinsic (death receptor-mediated pathway) and the intrinsic (mitochondrial) pathway. In response to type 1 IFNs, upregulation of sensor protein activation (e.g., DR receptors) occurs, which induces apoptosis in tumor cells.

[0242] IFNs exert an external effect on tumors through the regulation of processes such as angiogenesis, osteoclastogenesis, and immunity. Both endogenous and exogenous type 1 IFNs play a major role in anti-cancer immune activity. For example, they suppress the activity of α / β T cells, γ / δ T cells, NK cells, and dendritic cells, as well as immune-suppressive cells, such as regulatory T cells, bone marrow-derived suppressor cells, and tumor-associated macrophages. Furthermore, type 1 IFNs act directly on tumor cells to improve antigen expression and upregulate numerous immune-interacting molecules, such as stress ligands recognized by major histocompatibility complex class 1 (MHC I) and gonad-encoded immune receptors.

[0243] One aspect of the method includes administering a therapeutically effective amount of an ENPP1 inhibitor to a subject with cancer to treat the subject. In one embodiment, the subject may be diagnosed with or suspected of having cancer. Any suitable ENPP1 inhibitor may be administered to the subject. In one embodiment, the cancer is any one selected from adrenal, 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 cancers. In one embodiment, the cancer is lymphoma.

[0244] In one embodiment, the effective amount of the compound may be in the range of about 10 ng to about 100 mg, e.g., 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, or about 50 mg to about 100 mg. The amount may be a single dose or a total daily amount. The total daily amount may range from 10 ng to 100 mg, from 100 mg to about 500 mg, or from 500 mg to about 1000 mg.

[0245] In one embodiment, a single dose of the compound is administered. In another embodiment, multiple doses are administered. When the multiple doses are administered over a period of time, the compound may be administered twice daily (bid), daily (qd), every other day (qod), every third day, three times per week (tiw), or twice per week (biw).

[0246] Combination therapy

[0247] The ENPP1 inhibitor compound of the present invention can be administered to a subject alone or in combination with an additional active agent or therapy, such as radiation therapy. The terms "agent," "compound," and "drug" are used interchangeably herein. In one embodiment, the method of the present invention further includes administering to the subject an additional agent, such as a small molecule, a chemotherapy agent, an antibody, an antibody-drug combination, an aptamer, a protein, an immune checkpoint inhibitor, or radiation therapy, in parallel, sequentially, or in combination.

[0248] "Co-administration" or "in combination with" includes administering two or more therapeutic agents simultaneously, concurrently, or sequentially, without specific time limitations. In some embodiments, each agent or formulation is present in a cell or subject's body at the same time and exerts a simultaneous biological or therapeutic effect. In some embodiments, each therapeutic agent is in the same composition or unit dosage form. In some embodiments, each therapeutic agent is in a separate composition or unit dosage form. In some embodiments, the first formulation may 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), concomitantly with, or subsequent 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 after) the administration of the second therapeutic agent.

[0249] "Concomitant administration" of a known therapeutic agent or additional therapy with a composition comprising a disclosed compound of the present invention means administering the compound and the second agent or additional therapy such that both the known formulation and the composition of the disclosed compound have a therapeutic effect. Such concomitant administration can include simultaneous or prior administration of the drug in conjunction with administration of the compound of the present invention. While the routes of administration of the two formulations can vary, representative administration routes are described in detail below. One of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence, and dosages of the drug or therapy and the disclosed compound.

[0250] For the treatment of cancer, the ENPP1 inhibitor compounds may be administered in combination with chemotherapeutic agents selected from the group consisting of alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, taxanes, nucleoside analogs, anthracyclines, thymidylate-targeted drugs, cell death regulators, cell cycle regulator inhibitors, colony-stimulating factor-1 receptor inhibitors, CD47 inhibitors, and others.

[0251] Combination with immunotherapy

[0252] For the treatment of cancer, the ENPP1 inhibitor compound may be administered in combination with an immunotherapeutic agent. An immunotherapeutic agent is any suitable agent used in cancer treatment by inducing, enhancing, or suppressing an immune response. In some embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. Any immune checkpoint inhibitor may be used, including, but not limited to, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, scheduled death 1 (PD-1) inhibitors, and scheduled death ligand 1 (PD-L1) inhibitors. Exemplary immune checkpoint inhibitors may include, but are not limited to, ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, etc. In some embodiments, the immunotherapeutic agent is an immune cell therapy. Any suitable cell therapy may be used, including, but not limited to, chimeric antigen receptor T cell therapy, chimeric antigen receptor NK cell therapy, and other cell therapies.

[0253] For the treatment of cancer, the ENPP1 inhibitor compound can be administered in combination with a suitable cancer vaccine therapy, such as a dendritic cell vaccine formulation that promotes Th1 / Th17 immunity. In some cases, the ENPP1 inhibitor compound is suitable for use as an adjuvant therapeutic agent in combination with Th17-inducing vaccination.

[0254] Combination with radiation therapy

[0255] In cancer treatment methods, the ENPP1 inhibitor compound may be administered in conjunction with radiation therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after radiation therapy. The combination of radiation therapy and administration of a compound of the present invention can provide a synergistic therapeutic effect. When an individual is treated with radiation (RT) at a dose and / or frequency tailored to the individual during radiation therapy (RT), cGAMP production can be induced. The induced cGAMP level can be increased, for example, compared to the level achieved with RT alone, by the ENPP1 inhibitor compound preventing the degradation of cGAMP, thereby improving the therapeutic efficacy in the subject. Thus, details of the methods of the present invention include administering a reduced dose and / or frequency / therapy of radiation therapy compared to the dose and / or frequency / reduction of the therapeutic effect of radiation therapy alone. In some embodiments, radiation therapy is administered in combination with a compound of the present invention at a dose and / or frequency effective to reduce the risk of radiation damage to the subject, e.g., effective to reduce the risk of radiation damage expected to occur at a therapeutically effective dose.

[0256] In one embodiment, the method includes administering an ENPP1 inhibitor to a subject before administering radiation therapy. In another embodiment, the method includes administering an ENPP1 inhibitor to a subject after exposing the subject to radiation therapy. In another embodiment, the method includes sequentially administering radiation therapy, a subsequent ENPP1 inhibitor, and a subsequent immune checkpoint inhibitor to a subject in need thereof.

[0257] Combination with anti-cancer vaccines

[0258] In the case of cancer treatment methods, the ENPP1 inhibitor compound may be administered together with an anti-cancer vaccine therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after the administration of an anti-cancer vaccine therapy.

[0259] Combination with CAR-T

[0260] In the case of cancer treatment methods, the ENPP1 inhibitor compound may be administered together with CAR-T cell therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after the administration of CAR-T cell therapy.

[0261] Monotherapy

[0262] Myocardial regeneration promotion therapy

[0263] In the case of myocardial regeneration therapy, in one aspect, the method includes administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a lesion due to myocardial infarction to treat the subject.

[0264] Hypophosphatemia Treatment

[0265] In one aspect, a method for treating hypophosphatemia includes administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a lesion caused by hereditary hypophosphatemia to treat the subject.

[0266] Pharmaceutical Composition

[0267] Pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers, or diluents, are readily available to one of ordinary skill in the art. Pharmaceutically acceptable auxiliary substances, such as pH adjusting agents, buffering agents, tonicity adjusting agents, stabilizers, wetting agents, and the like, are readily available to one of ordinary skill in the art.

[0268] In some embodiments, the compounds of the present invention are formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers, ranging in strength from 5 mM to 1000 mM. In some embodiments, the aqueous buffer contains an agent that provides an isotonic solution. Such agents include, but are not limited to, sodium chloride, sugars such as mannitol, dextrose, and sucrose. In some embodiments, the aqueous buffer further contains a non-ionic surfactant such as polysorbate 20 or 80. Optionally, the formulation can further contain a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In other embodiments, the dosage form is stored at about 4°C. The formulation can also be lyophilized, and these typically contain a cryoprotectant such as sucrose, trehalose, lactose, maltose, or mannitol. The lyophilized formulation can be stored at room temperature for extended periods of time.

[0269] As used herein, pharmaceutical compositions may comprise or consist essentially of the compounds disclosed herein, or pharmaceutically acceptable salts, isomers, or tautomers thereof. Furthermore, pharmaceutical compositions are provided that may comprise or consist essentially of one or more additional active agents of interest. Any convenient active agent may be used in the present method together with the compounds of the present invention. In one embodiment, the compounds of the present invention and immune checkpoint inhibitors, as well as the additional therapeutic agents described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. In other embodiments, the compounds of the present invention and chemotherapeutic agents (particularly chemotherapeutic agents capable of inducing cGAMP production in vivo), and the additional therapeutic agents described herein for combination therapy may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The compounds of the present invention and the second active agent (if present) may be administered by the same or different routes of administration. Therapeutic agents may be administered by any suitable means, including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, or intratumoral injection into the affected organ.

[0270] The compounds of the present invention can be administered in unit dosage form and can be prepared by any method well known in the art. Such methods include combining the compounds of the present invention with a pharmaceutically acceptable carrier or diluent, which constitutes one or more accessory ingredients. The pharmaceutically acceptable carrier is selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in that it is compatible with the other ingredients of the formulation and is not harmful to the subject or patient. The carrier may be solid or liquid, and the type is selected based on the type of administration commonly used.

[0271] Examples of suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powders. Examples of suitable liquid carriers include solutions and / or suspensions reconstituted from water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, such as esters, emulsions, syrups or elixirs, suspensions, and non-effervescent granules. Such liquid carriers may contain, for example, compatible solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0272] Various aspects of the present invention will now be described.

[0273] One aspect of the present invention provides a compound selected from naphthyridinone derivative compounds represented by the following chemical formula 1, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof:

[0274] [C1] TIFF2026004378000003.tif2223

[0275] R1 is hydrogen; C1-C 13 Alkyl group; or C3-C 10 cyclyl group;

[0276] R2 is -Z-R3-(R4) m in,

[0277] The Z may be present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C n H n+2 -, -O(C n H n+2 )-, -(OC2H4) n -, -(C2H4O) n -, -(C n H n+2 )O-, -(C n H n+2 )CO-, -(C n H n+2 )O(C m H m+2 )-, -NR6(C n H n+2 )-, -(NR6C2H4) n -, -(C2H4NR6) n - or -(C n H n+2 )NR6-;

[0278] n is an integer from 0 to 8,

[0279] The R3 is C3-C 10 Cyclyl group, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl group, or C3-C 10 Heteroaryl groups,

[0280] R4 is hydrogen; a hydroxy group; a halogen group; C1-C 13 Alkyl group;C1-C6 alkoxy group;C1-C6 alkenyl group;C6-C10 aryl group;C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; C3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl; tert-butyloxycarbonyl group (Boc); amino group (-NR5R6); -(C m H m+2)NR5R6; nitro group (-N(O)2); amide group (-(C=O)NR5R6); ester group (-C(O)OR6); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-NHS(O)2R6); urea group; sulfamoyl group (-NHS(O)2NHR6); sulfonamide group; sulfamoyl alkyl group (-(C m H m+2 )NHS(O)2NHR6); sulfamoyl alkyl group (-(C m H m+2 )NR5S(O)2NHR6); a sulfide group (-SR6); a sulfone group (-S(O)2R6); or a phosphiryl group (-P(O)R5R6); or, connected to the same carbon as connected to R3, to form a 3- to 7-membered saturated ring; or, connected to the same carbon as connected to R3, to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S; or, connected to the carbon adjacent to connected to R3, to form a 3- to 7-membered saturated ring; or, connected to the carbon adjacent to connected to R3, to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S;

[0281] m is an integer from 1 to 4,

[0282] The C1-C6 alkyl group, C1-C 13 Alkyl group or C3-C 10 Cyclyl groups are hydrogen; hydroxyl groups; halogen groups; C1-C 13 Alkyl group; C1-C6 alkoxy group; Amino group (-NR5R6); Nitro group (-N(O)2); Amide group (-(C=O)NR5R6); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Urea group (-NR5(C=O)NR6-); Sulfonamide group (-NHS(O)2-); Sulfide group (-S-); Sulfone group (-S(O)2-); Phosphylyl group (-P(O)R5R6); C6-C 10 Aryl group; C3-C 10 Heteroaryl groups; and C3-C 10heterocyclyl groups,

[0283] Said C6-C 10 Aryl groups, C3-C 10 Heteroaryl group or C3-C 10 A heterocyclyl group is a group selected from the group consisting of hydrogen, hydroxy, halogen, carbonyl (-(C=O)R5R6), halogen, or C3-C 10 The heterocyclyl group is substituted or unsubstituted C1-C3 alkyl group; halogen or C3-C 10 Heterocyclyl groups with substituted or unsubstituted C1-C3 alkoxy groups; C6-C 10 Phenoxy; Amino group (-NR5R6); Nitro group (-N(O)2); Amide group (-(C=O)NR5R6); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Urea group (-NR5(C=O)NR6-); Sulfonamide group (-NHS(O)2-); Sulfide group (-S-); Sulfone group (-S(O)2-); Phosphylyl group (-P(O)R5R6); C6-C 10 Aryl group; C3-C 10 Heteroaryl groups and C3-C 10 heterocyclyl groups,

[0284] R5 and R6 are each independently hydrogen; a C1-C6 alkyl group; a C1-C6 alkenyl group; a C1-C6 alkynyl group; a C6-C 10 Aryl group; C3-C 10 Heteroaryl group; C3-C 10 or R5, together with the nitrogen or carbon atom connected to R6, can optionally contain at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, and SO2, and can be selected from the group consisting of hydrogen, C1-C 13 Alkyl groups, C6-C 10 Aryl groups, C3-C 10 forming a 3- to 7-membered saturated ring which may be optionally substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group;

[0285] Said C3-C 10 The heteroaryl and C3-C10 heterocyclyl groups contain one or more heteroatoms selected from the group consisting of N, O, and S.

[0286] In the definitions of substituents of this invention, the term "alkyl" refers to an aliphatic hydrocarbon radical. Alkyl can be a "saturated alkyl" that does not contain an alkenyl or alkynyl moiety, or an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety. "Alkenyl" refers to a group that contains at least one carbon-carbon double bond, and "alkynyl" refers to a group that contains at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, can be cyclic, branched, or linear, respectively.

[0287] The term "aryl," alone or in combination with other radicals, refers to a carbocyclic aromatic monocyclic group containing six carbon atoms, which may be further fused to a second five- or six-membered carbocyclic group, which may be aromatic, saturated, or unsaturated. Examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like. An aryl may be linked to another group at any suitable position on the aromatic ring.

[0288] The term "alkoxy" refers to an alkyl group linked to another group through an oxygen atom (i.e., -O-alkyl). An alkoxy group can be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6)alkoxy groups, such as -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, and 3-O-methyl-1-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, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

[0289] The term "phenoxy" refers to a phenyl group linked to another group through an oxygen atom (i.e., -O-aryl). The phenoxy group can be unsubstituted or substituted with one or more halogens, alkyl groups, aryl groups, and heteroaryl groups, but is not limited to these.

[0290] The term "amine group" means an alkyl group linked to another group through a nitrogen atom (i.e., -NH- or -N-alkyl). Amine groups can be unsubstituted or substituted with one or more suitable substituents.Examples of amine groups include (C1-C6) amino groups, such as -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-t-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, - Including, but not limited to, 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, and -N,N-dihexyl.

[0291] The term "halogen group" means fluorine, chlorine, bromine or iodine.

[0292] The term "heterocyclyl group," unless otherwise specified, refers to a heteroaromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S. Preferably, the heterocyclyl group may include, but is not limited to, pyrrolidine, furan, morpholine, piperazine, and piperidine groups, and more preferably, pyrrolidine, piperidine, piperazine, and morpholine groups.

[0293] The term "heteroaryl group," unless otherwise specified, refers to a heteroaromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S. Preferably, the heteroaryl group may include, but is not limited to, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, imidazole, triazole, indole, oxadiazole, thiadiazole, quinoline, isoquinoline, isoxazole, oxazole, thiazole, and pyrrole.

[0294] In one aspect of the invention, R1 is hydrogen; or a C1-C5 alkyl group; and R3 is a C5-C7 heterocyclyl group, a C6-C8 aryl group, or a C5-C 10 The present invention provides a compound selected from naphthyridinone derivative compounds represented by Chemical Formula 1, which are heteroaryl groups, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.

[0295] In one aspect of the invention, R1 is hydrogen; or a C1-C3 alkyl group; and R3 is 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 piperidine; Provided is a compound selected from naphthyridinone derivative compounds represented by Chemical Formula 1, which is rolidin; 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 furin; substituted or unsubstituted cyclopropane; or substituted or unsubstituted cyclobutane; and pharmaceutically acceptable salts, hydrates, and stereoisomers thereof.

[0296] In one aspect of the present invention, there is provided a compound selected from naphthyridinone derivative compounds represented by Chemical Formula 1, wherein R1 is hydrogen; or a C1-C3 alkyl group; and R3 is substituted or unsubstituted benzene; or a substituted or unsubstituted piperidine; and pharmaceutically acceptable salts, hydrates, and stereoisomers thereof.

[0297] In one aspect of the present invention, R2 is The present invention provides a compound selected from naphthyridinone derivative compounds represented by Chemical Formula 1, which is TIFF2026004378000004.tif50170, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.

[0298] In one aspect of the present invention, R4 is selected from the group consisting of halogen, methyl, ethyl, -NH2, -CH2NH2, -CHCH3NH2, -CH(CH3)2NH2, -CHCH3NHCH3, -CH2NHCH2CH3, -tert-butyloxycarbonyl (Boc) group, The present invention provides a compound selected from naphthyridinone derivative compounds represented by Chemical Formula 1, which is TIFF2026004378000005.tif46170, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.

[0299] In one aspect of the present invention, there is provided a compound selected from naphthyridinone derivative compounds represented by Chemical Formula 1, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, wherein the compound is any one selected from the group consisting of Compound Nos. 1 to 148 below:

[0300] Selected compounds:

[0301] Compound No. 1: tert-butyl(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)carbamate;

[0302] Compound No. 2: tert-butyl (3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0303] Compound No. 3: tert-butyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0304] Compound No. 4: tert-butyl(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0305] Compound No. 5: tert-butyl (4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0306] Compound No. 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0307] Compound No. 7: 5-(3-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0308] Compound No. 8: 5-(5-(amino-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0309] Compound No. 9: 5-(3-(aminomethyl)-4-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0310] Compound No. 10: 5-(4-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0311] Compound No. 11: 5-(4-(aminomethyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0312] Compound No. 12: 5-(4-(aminomethyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0313] Compound No. 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0314] Compound No. 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0315] Compound No. 15: (R)-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0316] Compound No. 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0317] Compound No. 17: (R)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0318] Compound No. 18: (S)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0319] Compound No. 19: (R)-5-(4-(1-(cyclopropylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0320] Compound No. 20: 5-(4-((ethylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0321] Compound No. 21: 5-(2-fluoro-4-((isopropylamine)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0322] Compound No. 22: 5-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0323] Compound No. 23: 5-(3-fluoro-4-((methylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0324] Compound No. 24: 5-(4-((ethylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0325] Compound No. 25: 5-(4-((cyclopropylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0326] Compound No. 26: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0327] Compound No. 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0328] Compound No. 28: 5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0329] Compound No. 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride;

[0330] Compound No. 30: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamoyl)carbamate;

[0331] Compound No. 31: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0332] Compound No. 32: tert-butyl (N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0333] Compound No. 33: tert-butyl (N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0334] Compound No. 34: tert-butyl (N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0335] Compound No. 35: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide;

[0336] Compound No. 36: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide hydrochloride;

[0337] Compound No. 37: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0338] Compound No. 38: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0339] Compound No. 39: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide;

[0340] Compound No. 40: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0341] Compound No. 41: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0342] Compound No. 42: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0343] Compound No. 43: N-(2,3-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0344] Compound No. 44: N-(3,5-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0345] Compound No. 45: N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0346] Compound No. 46: (R)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0347] Compound No. 47: (S)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0348] Compound No. 48: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0349] Compound No. 49: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0350] Compound No. 50: N-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0351] Compound No. 51: N-ethyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0352] Compound No. 52: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride;

[0353] Compound No. 53: N-ethyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0354] Compound No. 54: N-cyclopropyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0355] Compound No. 55: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride;

[0356] Compound No. 56: N-ethyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0357] Compound No. 57: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-isopropyl)sulfamide hydrochloride;

[0358] Compound No. 58: N-cyclopropyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride;

[0359] Compound No. 59: (R)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0360] Compound No. 60: (R)-(N-cyclopropyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0361] Compound No. 61: (S)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0362] Compound No. 62: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0363] Compound No. 63: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride;

[0364] Compound No. 64: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindolin-2-yl)sulfamide hydrochloride;

[0365] Compound No. 65: 7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)dihydroisoquinoline-2(1H)-sulfamide hydrochloride;

[0366] Compound No. 66: 6-fluoro-7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride;

[0367] Compound No. 67: N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0368] Compound No. 68: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide;

[0369] Compound No. 69: 4-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide;

[0370] Compound No. 70: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide;

[0371] Compound No. 71: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)cyclopropanesulfonamide;

[0372] Compound No. 72: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

[0373] Compound No. 73: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate;

[0374] Compound No. 74: ethyl hydrogen(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

[0375] Compound No. 75: (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonic acid;

[0376] Compound No. 76: 5-((3-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0377] Compound No. 77: 5-((3-aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0378] Compound No. 78: 5-((3-aminomethyl)-4-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0379] Compound No. 79: 5-((5-(2-aminoethyl)-2-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0380] Compound No. 80: 5-((3-(2-methylphenylethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0381] Compound No. 81: 5-((4-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0382] Compound No. 82: 5-((4-(aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0383] Compound No. 83: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0384] Compound No. 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0385] Compound No. 85: 5-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0386] Compound No. 86: 5-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0387] Compound No. 87: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride;

[0388] Compound No. 88: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride;

[0389] Compound No. 89: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0390] Compound No. 90: N-(2-fluoro-5((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0391] Compound No. 91: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0392] Compound No. 92: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0393] Compound No. 93: N-methyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0394] Compound No. 94: N-ethyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0395] Compound No. 95: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride;

[0396] Compound No. 96: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)-N-methylsulfamide dihydrochloride;

[0397] Compound No. 97: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride;

[0398] Compound No. 98: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0399] Compound No. 99: N-cyclopropyl-N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0400] Compound No. 100: N-(3-chloro-4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride;

[0401] Compound No. 101: 5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)isoindolin-2-yl)sulfamide dihydrochloride;

[0402] Compound No. 102: 7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0403] Compound No. 103: (8-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-1,3,4,5-tetrahydro-2(1H)-benzo[c]azepin-2-yl)sulfamide dihydrochloride;

[0404] Compound No. 104: (6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0405] Compound No. 105: 6-fluoro-7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0406] Compound No. 106: (7-fluoro-6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0407] Compound No. 107: N-(5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-2,3-dihydro-1H-inden-2-yl)sulfamide dihydrochloride;

[0408] Compound No. 108: (7-(methyl(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride;

[0409] Compound No. 109: tert-butyl (1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)carbamate;

[0410] Compound No. 110: tert-butyl ((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate;

[0411] Compound No. 111: tert-butyl(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)carbamate;

[0412] Compound No. 112: tert-butyl ((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate;

[0413] Compound No. 113: 5-(4-aminopiperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0414] Compound No. 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0415] Compound No. 115: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0416] Compound No. 116: 5-(1,4-diazepan-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0417] Compound No. 117: 5-(2,8-diazaspiro[4,5]decan-8-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

[0418] Compound No. 118: 5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride;

[0419] Compound No. 119: tert-butyl (N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamoyl)carbamate;

[0420] Compound No. 120: tert-butyl (N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;

[0421] Compound No. 121: tert-butyl (N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate;

[0422] Compound No. 122: tert-butyl (N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;

[0423] Compound No. 123: N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamide;

[0424] Compound No. 124: N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide;

[0425] Compound No. 125: N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamide;

[0426] Compound No. 126: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide;

[0427] Compound No. 127: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide;

[0428] Compound No. 128: N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide;

[0429] Compound No. 129: tert-butyl(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0430] Compound No. 130: tert-butyl(4-(7-oxo-5, 6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate;

[0431] Compound No. 131: 5-(3-(aminophenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0432] Compound No. 132: 5-(3-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0433] Compound No. 133: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0434] Compound No. 134: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0435] Compound No. 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride;

[0436] Compound No. 136: tert-butyl (N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0437] Compound No. 137: tert-butyl (N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate;

[0438] Compound No. 138: tert-butyl ((7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-diisoquinolin-2(1H)-yl)sulfonyl)carbamate;

[0439] Compound No. 139: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)phenyl)sulfamide;

[0440] Compound No. 140: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0441] Compound No. 141: N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0442] Compound No. 142: N-(2-fluoro-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide;

[0443] Compound No. 143: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindoline-2-sulfamide hydrochloride

[0444] Compound No. 144: (7-(7-oxo-5, 6,7,8-tetrahydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride;

[0445] Compound No. 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide hydrochloride;

[0446] Compound No. 146: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide;

[0447] Compound No. 147: 4-methyl-N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide; and

[0448] Compound No. 148: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide.

[0449] 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 or organic acid, and preferred salts include at least one selected from the group consisting of 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.

[0450] 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 refer to a compound formed by combining the compound of Chemical Formula 1 with water molecules.

[0451] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, which comprises a compound according to one aspect of the present invention as an active ingredient.

[0452] Another aspect of the present invention provides an ENPP1 inhibitor comprising a compound according to one aspect of the present invention as an active ingredient.

[0453] Another aspect of the present invention provides a STING pathway activator comprising a compound according to one aspect of the present invention as an active ingredient.

[0454] In another aspect of the present invention, there is provided a pharmaceutical composition for preventing, alleviating or treating cancer, wherein the cancer is a cancer associated with the inhibition of ENPP1.

[0455] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, comprising, as an active ingredient, a compound selected from the compound of Chemical Formula 1 according to the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof.

[0456] The pharmaceutical composition of the present invention has an excellent ability to inhibit the activity of ENPP1.

[0457] Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treating, preventing, and alleviating cancer diseases caused by abnormal cell growth. Cancer diseases that can be prevented, treated, or alleviated by treatment with the pharmaceutical composition of the present invention may include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine 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, fibroadenoma, etc.

[0458] Another aspect of the present invention provides an ENPP1 inhibitor comprising any one of the above compounds as an active ingredient.

[0459] Another aspect of the present invention provides a STING pathway activator comprising any one of the above compounds as an active ingredient.

[0460] The pharmaceutical composition may be applied to experimental animals such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, but is not limited thereto, and is preferably applied to primates including humans, and more preferably to humans.

[0461] As used herein, "treatment" may be used in a sense that includes alleviation or improvement of symptoms, reduction in the extent of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of the disease state, partial or complete recovery, prolongation of survival, other beneficial therapeutic results, and the like.

[0462] In addition, in this specification, the treatment of cancer means the treatment of all cancer cells, and cancer also includes the angiogenesis of endothelial cells and their mitosis (solid tumors, tumor metastases and positive tumors). For example, cancer may include, but is not limited to, 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 carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, bile duct cancer, kidney cancer, bone and marrow disease, lymphoid disease, Hodgkin's disease, hair cell carcinoma, oral cavity cancer, pharyngeal (mouth) 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.

[0463] Depending on the mode and method of use of the pharmaceutical composition of the present invention, the content of the compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or hydrate, which is the active ingredient, may be appropriately adjusted according to the selection of a person skilled in the art.

[0464] For example, the pharmaceutical composition may contain the compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or hydrate in an amount of 0.1% to 10% by weight, more preferably 0.5% to 5% by weight, based on the total weight of the entire composition.

[0465] The compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or hydrate may be contained alone in the pharmaceutical composition, or may be contained together with other pharmaceutically acceptable carriers, excipients, diluents, or accessory ingredients.

[0466] Examples of the pharmaceutically acceptable carrier, excipient, or diluent include one or more selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline, but are not limited thereto, and all common carriers, excipients, and diluents can be used. In addition, the pharmaceutical composition may further contain a conventional filler, extender, binder, disintegrant, anti-agglomerating agent, lubricant, humectant, pH adjuster, nutrient, vitamin, electrolyte, alginic acid and its salts, pectinic acid and its salts, protective colloid, glycerin, flavoring, emulsifier, preservative, etc.

[0467] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of other anticancer agents when administered in combination with the other anticancer agents for treating cancer or tumors.

[0468] Specifically, the pharmaceutical composition may further contain one or more other anticancer agents or other therapeutic agents known to be effective in the treatment or prevention of cancer in addition to the active ingredient, and may be used as a combination therapy administered simultaneously or at different times. Examples of other anticancer agents or other therapeutic agents that may be administered in the combination therapy include, but are not limited to, one or more compounds selected from the group consisting of Gleevec (Gleevec®, imatinib), Sutent (Sutent®, sunitinib), Herceptin (Herceptin®, trastuzumab), Velcade (Velcade®, bortezomib), dexamethasone, Nexavar (Nexavar®, sorafenib), aromatase inhibitors, and kinase inhibitors.

[0469] The pharmaceutical composition may be administered orally or parenterally, and may be administered via a variety of routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular. The dosage form of the composition may vary depending on the intended use, and may be formulated using methods well known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a mammal. Solid formulations for oral administration generally include tablets, lozenges, soft or hard capsules, pills, powders, and granules. These formulations may be formulated with one or more excipients, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Oral liquid preparations include suspensions, solutions, emulsions, and syrups, and in addition to the frequently used simple diluents water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. Forms for parenteral administration may be in the form of creams, lotions, ointments, plasters, liquids and solutions, aerosols, fluid extracts, elixirs, infusions, sachets, patches, or injections, and injectable dosage forms, they may preferably be in the form of an isotonic aqueous solution or suspension.

[0470] The pharmaceutical composition may further contain auxiliary agents such as a sterilizing agent, a preservative, a stabilizer, a hydrating agent or an emulsifying agent, a salt for adjusting osmotic pressure and / or a buffer, and other therapeutically useful substances, and may be formulated by a conventional mixing, granulating or coating method, or may be formulated by any other suitable method known in the art.

[0471] The dosage of the pharmaceutical composition can be determined taking into consideration the administration method, the recipient's age and sex, the severity and condition of the patient, the absorption rate of the active ingredient in the body, the inactivation rate, and concomitant drugs, and can be administered once or in divided doses. The active ingredient of the pharmaceutical composition can be administered to mammals, including humans, preferably in an amount of 0.001 mg / kg to 100 mg / kg of body weight, preferably 0.01 mg / kg to 35 mg / kg of body weight per day, once or in divided doses per day via oral or parenteral routes.

[0472] Yet another embodiment of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof:

[0473] Preferably, the method of treatment may further comprise the step of identifying a patient in need of prevention or treatment of cancer before the administering step.

[0474] The "therapeutically effective amount" of the present invention means the amount of an active ingredient in a mammal that is effective in preventing or treating cancer. The therapeutically effective amount can be adjusted depending on 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 age, body weight, general health condition, sex and diet of the patient, the administration time, the administration route, the blood clearance rate of the composition, the treatment period, and concurrently used drugs. Preferably, as described above, the therapeutically effective amount is 0.001 mg / kg to 100 mg / kg of body weight, preferably 0.01 mg / kg to 35 mg / kg of body weight per day, administered orally or parenterally once a day or in divided doses.

[0475] The present invention also relates to a method for producing a compound selected from the naphthyridinone derivative compound represented by the above Chemical Formula 1, its pharmaceutically acceptable salt, its hydrate and its stereoisomer.

[0476] Meanwhile, the present invention is characterized by a method for preparing the compound represented by Chemical Formula 1. The preparation method according to the present invention will be specifically described as follows.

[0477] In one embodiment, the compound of the present invention represented by Chemical Formula 1 may be prepared by one or more of the following Preparation Methods 1 to 4.

[0478] Manufacturing Method 1

[0479] The naphthyridinone derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by a preparation method according to the following Reaction Scheme 1.

[0480] [Reaction Scheme 1]

[0481] TIFF2026004378000006.tif124102

[0482] Manufacturing Method 2

[0483] The naphthyridinone derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by a preparation method according to the following Reaction Scheme 2.

[0484] [Reaction Scheme 2]

[0485] TIFF2026004378000007.tif126111

[0486] Manufacturing method 3

[0487] The naphthyridinone derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by the preparation method shown in Reaction Scheme 3 below.

[0488] [Reaction Scheme 3]

[0489] TIFF2026004378000008.tif128103

[0490] Manufacturing method 4

[0491] The naphthyridinone derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by a preparation method according to the following Reaction Scheme 4.

[0492] [Reaction Scheme 4]

[0493] TIFF2026004378000009.tif124104 [Example]

[0494] The present invention will be described in detail below with reference to Synthesis Examples, Preparation Examples, Examples, Experimental Examples, and Formulation Examples, however, the following Preparation Examples, Examples, Experimental Examples, and Formulation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0495] [Manufacturing Example 1]

[0496] Preparation Example 1 involves steps for producing Product 3, Product 4, Product 7, or Product 8.

[0497] Manufacturing Example 1:

[0498] [Reaction Scheme 1]

[0499] TIFF2026004378000010.tif121101

[0500] Step 1: In a round-bottom flask, 1 (1.0 equiv.), palladium(II) acetate (0.050 equiv.), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv.), 2 (1.3 equiv.), and potassium carbonate (3.0 equiv.) were dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) and refluxed under nitrogen for 16 h. After the reaction was completed, the mixture was filtered through Celite, poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (1:20 MeOH:CHCl) to give 3 (40%-60% yield).

[0501] Examples of the present invention prepared according to step 1 above are as follows:

[0502] [Example 1]: tert-butyl (3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)carbamate

[0503] TIFF2026004378000011.tif2427

[0504] 1 H NMR (400MHz, MeOD-d4) δ8.57(d, J=4.9Hz, 1H), 7.99(d, J=9.8Hz, 1H), 7.59(s, 1H), 7.54(d, J=8.3Hz, 1H) , 7.45(t, J=7.9Hz, 1H), 7.25(d, J=4.9Hz, 1H), 7.11(d, J=7.6Hz, 1H), 6.65(d, J=9.7Hz, 1H), 1.52(s, 9H).

[0505] [Example 2]: tert-butyl (3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[0506] TIFF2026004378000012.tif2230

[0507] 1H NMR (400MHz, MeOD-d4) δ8.58 (d, J=49Hz, 1H), 7.96 (d, J=9.7Hz, 1H), 7.53 (t, J=7.6Hz, 1H), 7.45 (d, J=7. 7Hz, 1H), 7.38(d, J=9.8Hz, 2H), 7.24(d, J=5.0Hz, 1H), 6.63(d, J=9.8Hz, 1H), 4.33(s, 2H), 1.45(s, 9H).

[0508] [Example 3]: tert-butyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[0509] TIFF2026004378000013.tif3025

[0510] 1 H NMR (400MHz, MeOD-d4) δ8.57 (d, J=4.9Hz, 1H), 7.96 (d, J=9.7Hz, 1H), 7.50-7.44 (m, 4H), 7.24 (d, J=4.9Hz, 1H), 6.64 (d, J=9.8Hz, 1H), 4.34 (s, 2H), 1.47 (s, 9H).

[0511] [Example 4]: tert-butyl (2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[0512] TIFF2026004378000014.tif3023

[0513] 1 H NMR (400MHz, DMSO-d6) δ8.55 (d, J=4.9Hz, 1H), 7.76 (d, J=9.8Hz, 1H), 7.53-7.44 (m, 2H), 7.40- 7.29(m, 2H), 7.21(d, J=5.0Hz, 1H), 6.56(d, J=9.8Hz, 1H), 4.26(d, J=6.1Hz, 2H), 1.41(s, 9H).

[0514] [Example 5]: tert-butyl (4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[0515] TIFF2026004378000015.tif3124

[0516] 1 H NMR (400MHz, DMSO-d6) δ8.67(d, J=4.9Hz, 1H), 7.76(d, J=9.8Hz, 1H), 7.49(t, J=6.3Hz, 1H), 7.47-7.39 (m, 4H), 7.27(d, J=4.9Hz, 1H), 6.68(d, J=9.8Hz, 1H), 4.23(d, J=6.2Hz, 2H), 3.73(s, 3H), 1.41(s, 9H).

[0517] Step 2: Place 3 (1.0 equiv.) in a round-bottom flask and dissolve in dichloromethane (0.040 M). Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 4 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 4 (60%-80% yield).

[0518] Example 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0519] TIFF2026004378000016.tif2227

[0520] 1 H NMR (400MHz, MeOD-d4) δ8.63(d, J=4.9Hz, 1H), 7.89(d, J=9.8Hz, 1H), 7.76(t, J=7.9Hz, 1H), 7.64(d, J= 7.6Hz, 1H), 7.56(d, J=8.3Hz, 1H), 7.49(d, J=2.1Hz, 1H), 7.27(d, J=4.9Hz, 1H), 6.67(d, J=9.8Hz, 1H).

[0521] [Example 7]: 5-(3-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0522] TIFF2026004378000017.tif2430

[0523] 1 H NMR (400MHz, MeOD-d4) δ8.66 (d, J=5.1Hz, 1H), 8.01 (d, J=9.7Hz, 1H), 7.72-7 .65(m, 2H), 7.64-7.58(m, 2H), 7.35(d, J=5.2Hz, 1H), 6.74(d, J=9.5Hz, 1H).

[0524] Example 8: 5-(5-(amino-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0525] TIFF2026004378000018.tif2828

[0526] 1 H NMR (400MHz, DMSO-d6) δ12.37(s, 1H), 8.62(d, J=4.9Hz, 1H), 7.54(dd, J=9.8, 2.6Hz, 1H), 7.48(d , J=9.2Hz, 1H), 7.30(d, J=3.7Hz, 1H), 7.23(d, J=4.9Hz, 1H), 6.59(d, J=9.8Hz, 1H), 5.33(s, 4H).

[0527] [Example 9]: 5-(3-(aminomethyl)-4-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0528] TIFF2026004378000019.tif2526

[0529] 1H NMR (400MHz, DMSO-d6) δ12.32(s, 1H), 8.59(d, J=4.9Hz, 4H), 7.87(d, J=9.8Hz, 1H), 7.78(dd, J=7.0, 1.9Hz, 1 H), 7.64-7.55(m, 1H), 7.56-7.46(m, 1H), 7.23(d, J=4.9Hz, 1H), 6.58(d, J=9.8Hz, 1H), 4.16(d, J=5.6Hz, 2H).

[0530] [Example 10]: 5-(4-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0531] TIFF2026004378000020.tif2724

[0532] 1 H NMR (400MHz, MeOD-d4) δ8.63(d, J=5.0Hz, 1H), 7.93(d, J=9.7Hz, 1H), 7.67(d, J=8.0H z, 2H), 7.63-7.59(m, 2H), 7.29(d, J=5.0Hz, 1H), 6.70(d, J=9.7Hz, 1H), 4.25(s, 2H).

[0533] [Example 11]: 5-(4-(aminomethyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0534] JPEG2026004378000021.jpg3126

[0535] 1 H NMR (400MHz, DMSO-d6) δ12.37(s, 1H), 8.61(d, J=4.9Hz, 3H), 7.65(d, J=10.4Hz, 1H), 7.61-7.51(m, 2H), 7.45(dd, J=9.7, 2.7Hz, 1H), 7.22(d, J=4.9Hz, 1H), 6.61(d, J=9.8Hz, 1H), 4.16(q, J=5.6Hz, 2H)

[0536] [Example 12]: 5-(4-(aminomethyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0537] TIFF2026004378000022.tif2622

[0538] 1 H NMR (400MHz, MeOD-d4) δ8.65(d, J=5.1Hz, 1H), 7.94(d, J=9.7Hz, 1H), 7.72(t, J=7.7H z, 1H), 7.50-7.41(m, 2H), 7.32(d, J=5.0Hz, 1H), 6.74(d, J=9.7Hz, 1H), 4.32(s, 2H).

[0539] [Example 13]: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0540] TIFF2026004378000023.tif2821

[0541] 1 H NMR (400MHz, DMSO-d6) δ12.41(s, 1H), 8.64(d, J=4.9Hz, 4H), 7.67-7.57(m, 1H), 7.50(d, J=1.9Hz, 1 H), 7.43(dd, J=8.1, 4.6Hz, 1H), 7.26(d, J=4.9Hz, 1H), 6.63(d, J=9.8Hz, 1H), 4.22(d, J=5.6Hz, 2H).

[0542] [Example 14]: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0543] TIFF2026004378000024.tif2719

[0544] 1H NMR (400MHz, DMSO-d6) δ12.27(s, 1H), 8.55(d, J=5.0Hz, 1H), 7.78(d, J=9.8Hz, 1H), 7.56(d, J=8.2Hz, 2H), 7.4 6(d, J=8.2Hz, 2H), 7.20(d, J=5.0Hz, 2H), 6.56(d, J=9.8Hz, 1H), 4.53(d, J=6.7Hz, 1H), 1.46(d, J=6.9Hz, 3H).

[0545] [Example 15]: (R)-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0546] TIFF2026004378000025.tif3125

[0547] LC-MS(ESI) calculation for C 16 H 15 NO [M+H] + 265.12, found m / z 266.17

[0548] [Example 16]: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0549] TIFF2026004378000026.tif2821

[0550] 1 H NMR (400MHz, DMSO-d6) δ12.27(s, 1H), 8.69(s, 3H), 8.57(d, J=5.0Hz, 1H), 7.75(d, J=8.3Hz, 2H), 7. 70(d, J=9.8Hz, 1H), 7.59(d, J=8.3Hz, 2H), 7.21(d, J=5.0Hz, 1H), 6.59(d, J=9.8Hz, 1H), 1.70(s, 6H)

[0551] [Example 17]: (R)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0552] TIFF2026004378000027.tif3019

[0553] LC-MS(ESI) calculation for C 17 H 17 NO [M+H] + 279.14, found m / z 280.19

[0554] [Example 18]: (S)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0555] TIFF2026004378000028.tif3019

[0556] LC-MS(ESI) calculation for C 17 H 17 NO [M+H] + 279.14, found m / z 280.29

[0557] [Example 19]: (R)-5-(4-(1-(cyclopropylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0558] TIFF2026004378000029.tif3522

[0559] LC-MS(ESI) calculation for C 19 H 19 N 3O [M+H] + 305.15, found m / z 306.25

[0560] [Example 20]: 5-(4-((ethylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0561] TIFF2026004378000030.tif3021

[0562] 1 H NMR (400MHz, DMSO-d6) δ12.37(s, 1H), 9.21(s, 2H), 8.62(d, J=4.9Hz, 1H), 7.68(d, J=10.5Hz, 1H), 7.59(d, J=7.2Hz, 2H), 7.48(dd, J=9.8, 2.7Hz, 1H), 7.23(d, J=4.9Hz, 1H), 6.61(dd, J=9.8, 1.9Hz, 1H), 4.26(t, J=5.5Hz, 2H), 3.01(dd, J=12.2, 7.2Hz, 2H), 1.26(t, J=7.2Hz, 3H)

[0563] [Example 21]: 5-(2-fluoro-4-((isopropylamine)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0564] TIFF2026004378000031.tif3423

[0565] LC-MS(ESI) calculation for C 17 H 18 FN3O [M+H] + 311.14, found m / z 312.03

[0566] [Example 22]: 5-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0567] TIFF2026004378000032.tif3221

[0568] 1 H NMR (400MHz, DMSO-d6) δ12.37(s, 1H), 9.52(s, 2H), 8.62(d, J=4.9Hz, 1H), 7.70(d, J=10.3Hz, 1H), 7.59(d, J=4.4Hz, 2H), 7.46(dd, J=9.7, 2.6Hz, 1H), 7.23(d, J=4.9Hz, 1H), 6.61(d, J=9.7Hz, 1H), 4.36(s, 2H), 0.93(s, 2H), 0.79(t, J=6.6Hz, 2H)

[0569] [Example 23]: 5-(3-fluoro-4-((methylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0570] TIFF2026004378000033.tif2919

[0571] 1 H NMR (400MHz, DMSO-d6) δ12.34(s, 1H), 9.30(s, 3H), 8.59(d, J=4.9Hz, 1H), 7.86-7.80(m, 1H), 7.78-7.69(d , 1H), 7.55(d, J=10.6Hz, 1H), 7.48-7.43(dd, 1H), 7.24(d, J=4.9Hz, 1H), 4.28(t, J=5.7Hz, 2H), 2.50(s, 3H)

[0572] [Example 24]: 5-(4-((ethylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0573] TIFF2026004378000034.tif2922

[0574] 1 H NMR (400MHz, DMSO-d6) δ12.34(s, 1H), 9.13(s, 2H), 8.60(d, J=4.9Hz, 1H), 7.83(t, J=7.8Hz, 1H), 7.72(d, J=9.8Hz, 1H), 7.55(d, J=11.9 Hz, 1H), 7.48-7.43(dd, 1H), 7.23(d, J=4.9Hz, 1H), 6.61(dd, J=9.8, 1.7Hz, 1H), 4.28(s, 2H), 3.06(q, J=7.0Hz, 2H), 1.34-1.19(t, 3H).

[0575] [Example 25]: 5-(4-((cyclopropylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0576] TIFF2026004378000035.tif3227

[0577] 1 H NMR (400MHz, DMSO-d6) δ12.34(s, 1H), 9.48(s, 2H), 8.59(d, J=4.9Hz, 1H), 7.84(t, J=7.8Hz, 1H), 7.71(d, J=9.8Hz, 1H), 7.54(d, J=10.5Hz, 1H), 7.49-7.40(m, 1H), 7.23(d, J=4.9Hz, 1H), 6.61(dd, J=9.8, 1.9Hz, 1H), 4.37(s, 2H), 2.77(s, 1H), 0.88(d, J=15.4Hz, 2H), 0.79(q, J=6.7Hz, 2H).

[0578] [Example 26]: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0579] TIFF2026004378000036.tif2824

[0580] 1 H NMR (400MHz, DMSO-d6) δ12.31(s, 1H), 9.96(s, 2H), 8.58(d, J=4.9Hz, 1H), 7.74(d, J=9.8Hz, 1H), 7.61(d, J=7 .9Hz, 1H), 7.56(s, 1H), 7.50(d, J=7.8Hz, 1H), 7.20(d, J=4.9Hz, 1H), 6.57(dd, J=9.8, 1.6Hz, 1H), 4.60(s, 4H)

[0581] [Example 27]: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0582] TIFF2026004378000037.tif2522

[0583] 1H NMR (400MHz, DMSO-d6) δ12.30(s, 1H), 9.60(s, 2H), 8.57(d, J=4.9Hz, 1H), 7.76(d, J=9.8Hz, 1H), 7.41(d, J=6 .1Hz, 3H), 7.18(d, J=4.9Hz, 1H), 6.57(d, J=9.8Hz, 1H), 4.34(brs, 2H), 3.41(brs, 2H), 3.11(t, J=6.1Hz, 2H)

[0584] [Example 28]: 5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0585] TIFF2026004378000038.tif2622

[0586] LC-MS(ESI) calculation for C 17 H 14 FN3O [M+H] + 295.11, found m / z 296.11

[0587] [Example 29]: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride

[0588] TIFF2026004378000039.tif2822

[0589] 1 H NMR (400MHz, DMSO-d6) δ8.72(d, J=4.9Hz, 1H), 7.75-7.65(m, 3H), 7.59(d, J=7.9Hz, 2 H), 7.29(d, J=4.9Hz, 1H), 6.75(d, J=9.8Hz, 1H), 4.17(d, J=5.6Hz, 2H), 3.76(s, 3H).

[0590] Preparation of sulfamide 6: A round-bottom flask was charged with a solution of tert-butanol (1.0 equiv.) dissolved in anhydrous dichloromethane (1.4 M), and 5 (1.0 equiv.) was slowly added dropwise. N,N-dimethylpyridin-4-amine (2.0 equiv.) was then added. The solution was stirred at room temperature for 1 hour. After the reaction was completed, it was washed several times with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting colorless powder 6 (80% yield) was used as the reactant without further purification.

[0591] Step 3: A round-bottom flask was charged with a solution of triethylamine (2.5 equiv.) in dichloromethane (0.1 M). Then, 4 (1.0 equiv.) and 6 (1.1 equiv.) were added and stirred at room temperature for 1 day. After completion of the reaction, the mixture was concentrated under reduced pressure and dried. The resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH2Cl2) to give 7 (30%-60% yield).

[0592] [Example 30]: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamoyl)carbamate

[0593] TIFF2026004378000040.tif2230

[0594] 1 H NMR (400MHz, MeOD-d4) δ8.57(d, J=4.9Hz, 1H), 8.00(d, J=9.8Hz, 1H), 7.48(t, J=7.7Hz, 1H), 7.36( d, J=8.5Hz, 2H), 7.26(d, J=4.9Hz, 1H), 7.19(d, J=7.6Hz, 1H), 6.65(d, J=9.8Hz, 1H), 1.35(s, 9H).

[0595] [Example 31]: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[0596] TIFF2026004378000041.tif2433

[0597] 1 H NMR (400MHz, MeOD-d4) δ8.58(d, J=4.9Hz, 1H), 8.01(d, J=9.8Hz, 1H), 7.54(d, J=4.7Hz, 2H), 7.51( s, 1H), 7.44-7.38(m, 1H), 7.27(d, J=4.9Hz, 1H), 6.65(d, J=9.8Hz, 1H), 4.30(s, 2H), 1.39(s, 9H).

[0598] [Example 32]: tert-butyl (N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[0599] TIFF2026004378000042.tif2828

[0600] 1 H NMR (400MHz, DMSO-d6) δ12.23(s, 1H), 8.54(d, J=4.9Hz, 1H), 7.76(d, J=9.8Hz, 1H), 7.51(d, J=8.0Hz, 2H) , 7.45(d, J=7.8Hz, 2H), 7.18(d, J=4.9Hz, 1H), 6.54(d, J=9.8Hz, 1H), 4.09(d, J=6.1Hz, 3H), 1.37(s, 9H).

[0601] [Example 33]: tert-butyl (N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[0602] TIFF2026004378000043.tif2828

[0603] 1H NMR (400MHz, MeOD-d4) δ8.59(d, J=5.0Hz, 1H), 7.96(d, J=9.8Hz, 1H), 7.69(t, J= 7.7Hz, 1H), 7.31-7.23(m, 3H), 6.66(d, J=9.8Hz, 1H), 4.34(s, 2H), 1.44(s, 9H).

[0604] [Example 34]: tert-butyl (N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[0605] TIFF2026004378000044.tif3028

[0606] 1 H NMR (400MHz, DMSO-d6) δ8.68(d, J=4.9Hz, 1H), 7.76(d, J=9.8Hz, 1H), 7.52(d, J=8.0Hz, 2H), 7.45(d, J=8 .2Hz, 2H), 7.25(d, J=4.9Hz, 1H), 6.68(d, J=9.8Hz, 1H), 4.19(d, J=6.1Hz, 2H), 3.73(s, 3H), 1.38(s, 9H).

[0607] Step 4: Place 7 (1.0 equiv.) in a round-bottom flask and add dichloromethane (0.04 M) to dissolve. Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 16 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 8 (40%-80% yield).

[0608] [Example 35]: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide hydrochloride

[0609] TIFF2026004378000045.tif2430

[0610] 1H NMR (400MHz, MeOD-d4) δ8.60(d, J=5.0Hz, 1H), 8.04(d, J=9.8Hz, 1H), 7.52-7.47(m, 1H) , 7.39-7.34(m, 2H), 7.31(d, J=5.1Hz, 1H), 7.18(d, J=7.7Hz, 1H), 6.69(d, J=9.8Hz, 1H).

[0611] [Example 36]: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide hydrochloride

[0612] TIFF2026004378000046.tif2527

[0613] 1 H NMR (400MHz, DMSO-d6) δ12.29(s, 1H), 9.47(s, 2H), 8.57(d, J=4.9Hz, 1H), 7.80(d, J=9.8Hz, 1H), 7 .58(dd, J=7.8, 2.1Hz, 1H), 7.42(dd, J=10.5, 8.5Hz, 3H), 7.28-7.21(m, 6H), 6.56(d, J=9.8Hz, 2H).

[0614] [Example 37]: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0615] TIFF2026004378000047.tif2735

[0616] 1 H NMR (400MHz, MeOD-d4) δ8.64(d, J=5.2Hz, 1H), 8.07(d, J=9.7Hz, 1H), 7.57(q, J=3.9, 2. 9Hz, 3H), 7.47-7.40(m, 1H), 7.37(d, J=5.1Hz, 1H), 6.75(d, J=9.7Hz, 1H), 4.32(s, 2H).

[0617] [Example 38]: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0618] TIFF2026004378000048.tif3439

[0619] 1 H NMR (400MHz, DMSO-d6) δ12.29(s, 1H), 8.57(d, J=4.9Hz, 1H), 7.81(d, J=9.8Hz, 1H), 7.66-7.56(m, 1 H), 7.49-7.43(m, 1H), 7.43-7.32(m, 1H), 7.20(d, J=4.9Hz, 2H), 6.55(d, J=9.8Hz, 1H), 4.22(s, 2H).

[0620] [Example 39]: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide

[0621] TIFF2026004378000049.tif2822

[0622] 1 H NMR (400MHz, Acetone-d6) δ8.45 (d, J=5.0Hz, 1H), 8.01 (d, J=9.8Hz, 1H), 7.26 -7.22(m, 2H), 7.14(d, J=5.0Hz, 1H), 6.86-6.81(m, 2H), 6.55(d, J=9.8Hz, 1H).

[0623] [Example 40]: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0624] TIFF2026004378000050.tif2825

[0625] 1H NMR (400MHz, MeOD-d4) δ8.61(d, J=5.1Hz, 1H), 8.03(d, J=9.8Hz, 1H), 7.62(d, J=7.8Hz , 2H), 7.50(d, J=8.4Hz, 2H), 7.33(d, J=5.1Hz, 1H), 6.72(d, J=9.7Hz, 1H), 4.32(s, 2H).

[0626] [Example 41]: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0627] TIFF2026004378000051.tif2825

[0628] 1 H NMR (400MHz, MeOD-d4) δ8.62(d, J=4.8Hz, 1H), 8.01(d, J=10.3Hz, 1H), 7.73(t, J=7.7Hz, 1H), 7.35-7.28(m, 3H), 6.73(d, J=10.3Hz, 1H), 4.38(s, 2H).

[0629] [Example 42]: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0630] TIFF2026004378000052.tif3428

[0631] 1 H NMR (400MHz, DMSO-d6) δ12.32(s, 1H), 8.59(d, J=4.9Hz, 1H), 7.45(ddd, J=23.0, 16.6, 8.7H z, 5H), 7.30(s, 1H), 7.22(d, J=4.7Hz, 1H), 6.74(s, 2H), 6.58(d, J=9.6Hz, 1H), 4.21(s, 2H).

[0632] [Example 43]: N-(2,3-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0633] TIFF2026004378000053.tif3324

[0634] 1 H NMR (400MHz, DMSO-d6) δ12.36(s, 1H), 8.62(d, J=4.9Hz, 1H), 7.57(dd, J=9.8, 2.7Hz, 1H), 7.49(t, J=7. 2Hz, 1H), 7.31(t, J=6.7Hz, 2H), 7.26(d, J=4.9Hz, 1H), 6.76(s, 1H), 6.59(d, J=9.8Hz, 1H), 4.26(s, 2H).

[0635] [Example 44]: N-(3,5-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0636] TIFF2026004378000054.tif3324

[0637] 1 H NMR (400MHz, DMSO-d6) δ12.39(s, 1H), 8.63(d, J=4.9Hz, 1H), 7.45(d, J=9.8Hz, 1H), 7.35(d, J=8.6Hz, 2H) , 7.29(d, J=4.9Hz, 1H), 7.10(d, J=50.9Hz, 1H), 6.77(s, 1H), 6.60(d, J=9.8Hz, 1H), 4.22(d, J=6.2Hz, 2H).

[0638] [Example 45]: N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0639] TIFF2026004378000055.tif3728

[0640] 1H NMR (400MHz, DMSO-d6) δ12.30(s, 3H), 8.57(t, J=5.4Hz, 11H), 7.71(dd, J=9.0, 3.2Hz, 10H), 7.59(d, J=8.2Hz, 7H), 7.21(d, J=4.9Hz, 4H), 6.60(d, J=9.8Hz, 3H), 4.57-4.42(m, 3H), 1.58(d, J=6.8Hz, 9H).

[0641] [Example 46]: (R)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0642] TIFF2026004378000056.tif3027

[0643] 1 H NMR (400MHz, DMSO-d6) δ12.26 (brs, 1H), 8.55 (d, J=4.9Hz, 1H), 7.78 (d, J=9.8Hz, 1H), 7.56 (d, J=8.2Hz, 2H), 7. 46(d, J=8.2Hz, 2H), 7.19(t, J=10.8Hz, 2H), 6.56(d, J=9.8Hz, 2H), 4.53(d, J=5.9Hz, 1H), 1.46(d, J=6.9Hz, 3H).

[0644] [Example 47]: (S)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0645] TIFF2026004378000057.tif3331

[0646] 1H NMR (400MHz, DMSO-d6) δ12.26(brs, 1H), 8.55(d, J=5.0Hz, 1H), 7.78(d, J=9.8Hz, 1H), 7.56(d, J=8.2Hz, 2H), 7.46(d, J =8.2Hz, 2H), 7.21(d, J=5.0Hz, 1H), 6.56(d, J=9.8Hz, 1H), 6.06(brs, 4H), 4.53(q, J=6.8Hz, 1H), 1.46(d, J=6.9Hz, 3H).

[0647] [Example 48]: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0648] TIFF2026004378000058.tif2927

[0649] LC-MS(ESI) calculation for C 16 H 15 FN4O3S [M+H] + 362.08, found m / z 363.53

[0650] [Example 49]: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0651] TIFF2026004378000059.tif3028

[0652] LC-MS(ESI) calculation for C 16 H 15 FN4O3S [M+H] + 362.08, found m / z 363.53

[0653] [Example 50]: N-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0654] TIFF2026004378000060.tif3424

[0655] 1 H NMR (400MHz, DMSO-d6) δ12.27(s, 1H), 8.56(d, J=4.9Hz, 1H), 7.78(d, J=9.8Hz, 1H), 7.53(q, J=8 .4Hz, 4H), 7.22(d, J=4.9Hz, 1H), 6.96(s, 2H), 6.57(d, J=9.8Hz, 1H), 4.19(s, 2H), 2.60(s, 3H).

[0656] [Example 51]: N-ethyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0657] TIFF2026004378000061.tif3627

[0658] 1 H NMR (400MHz, DMSO-d6) δ12.27(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.77(d, J=9.8Hz, 1H), 7.57(d, J=8.2Hz, 2H), 7.49(d, J=8.2 Hz, 2H), 7.22(d, J=5.0Hz, 1H), 6.91(s, 2H), 6.57(d, J=9.8Hz, 1H), 4.33(s, 2H), 3.25-3.10(m, 2H), 1.07(t, J=7.1Hz, 3H).

[0659] [Example 52]: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride

[0660] TIFF2026004378000062.tif3424

[0661] 1H NMR (400MHz, DMSO-d6) δ12.30(s, 1H), 8.57(d, J=4.9Hz, 1H), 7.79(d, J=9.8Hz, 1H), 7.62(t, J=7.8Hz, 1H), 7.40 (dd, J=23.8, 9.8Hz, 2H), 7.24(d, J=4.9Hz, 1H), 6.99(s, 2H), 6.58(d, J=10.0Hz, 1H), 4.24(s, 2H), 2.65(s, 3H).

[0662] [Example 53]: N-ethyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0663] TIFF2026004378000063.tif3424

[0664] 1 H NMR (400MHz, DMSO-d6) δ12.29(s, 1H), 8.57(d, 1H), 7.77(d, 1H), 7.66(d, 1H), 7.38(dd, J=17.7, 9.3Hz, 2H), 7.31(s , 1H), 7.18(s, 1H) 7.05(s, 1H), 6.95(S, 1H) 6.58(d, J=10.1Hz, 1H), 4.37(s, 2H), 1.25(m, 2H), 1.09(t, J=7.0Hz, 3H)

[0665] [Example 54]: N-cyclopropyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0666] TIFF2026004378000064.tif3828

[0667] LC-MS(ESI) calculation for C 18 H 17 FN4O3S [M+H] + 389.26, found m / z 389.3

[0668] [Example 55]: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride

[0669] TIFF2026004378000065.tif3025

[0670] 1 H NMR (400MHz, DMSO-d6) δ12.33(s, 1H), 8.60(d, J=4.9Hz, 1H), 7.55(dd, J=9.8, 2.7Hz, 1H), 7.50(t, J=7.9Hz, 1H), 7.40(t, J=7.7Hz, 2H), 7.32(d, J=6.2Hz, 2H), 7.24(d, J=4.8Hz, 1H), 7.00(s, 2H), 6.57(d, J=9.2Hz, 1H), 4.22(s, 2H), 2.64(s, 3H).

[0671] [Example 56]: N-ethyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0672] TIFF2026004378000066.tif3626

[0673] 1 H NMR (400MHz, DMSO-d6) δ12.32(s, 1H), 8.59(d, J=4.9Hz, 1H), 7.53(dd, J=9.7, 2.8Hz, 1H), 7.45(dt, J=15.6, 7.2 Hz, 3H), 7.24(d, J=4.9Hz, 1H), 6.58(d, J=9.8Hz, 1H), 4.36(s, 2H), 3.16(q, J=7.2Hz, 2H), 1.09(t, J=7.1Hz, 3H).

[0674] [Example 57]: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-isopropyl)sulfamide hydrochloride

[0675] TIFF2026004378000067.tif3629

[0676] LC-MS(ESI) calculation for C 18 H 19 FN4O3S [M+H] + 391.25, found m / z 391.2

[0677] [Example 58]: N-cyclopropyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride

[0678] TIFF2026004378000068.tif3626

[0679] 1 H NMR (400MHz, DMSO-d6) δ12.32(s, 1H), 8.59(d, J=4.9Hz, 1H), 7.52(dd, J=9.7, 2.8Hz, 1H), 7.45(t, J=7.7Hz, 2H), 7.37(s, 1H), 7 .34(d, J=5.7Hz, 2H), 7.23(d, J=4.9Hz, 1H), 7.21(s, 1H), 7.08(s, 1H), 6.58(d, J=9.8Hz, 1H), 4.39(s, 2H), 0.64(d, J=5.1Hz, 4H)

[0680] [Example 59]: (R)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0681] TIFF2026004378000069.tif2928

[0682] 1H NMR (400MHz, DMSO-d6) δ12.28(s, 1H), 8.56(d, J=4.9Hz, 1H), 7.78(d, J=9.8Hz, 1H), 7.59(d, J=8.2Hz, 2H), 7.51(d, J=8.2Hz) , 2H), 7.22(d, J=4.9Hz, 1H), 6.89(s, 1H), 6.57(d, J=9.8Hz, 1H), 5.11(q, J=7.1Hz, 1H), 2.52(s, 3H), 1.56(d, J=7.0Hz, 3H).

[0683] [Example 60]: (R)-(N-cyclopropyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0684] TIFF2026004378000070.tif3226

[0685] 1 H NMR (400MHz, MeOD-d4) δ8.71(d, J=5.4Hz, 1H), 8.16(d, J=9.6Hz, 1H), 7.72(d, J=8.1Hz, 2H), 7.56(d, J=8.3Hz, 2H), 7.51(d, J=5.4Hz, 1H), 6.90(d, J=9. 6Hz, 1H), 5.26(q, J=7.1Hz, 1H), 2.46-2.37(m, 1H), 1.85(d, J=7.1Hz, 3H), 0 .94-0.82(m, 1H), 0.76-0.70(m, 1H), 0.60-0.48(m, 1H), 0.33-0.28(m, 1H).

[0686] [Example 61]: (S)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0687] TIFF2026004378000071.tif3131

[0688] 1H NMR (400MHz, MeOD-d4) δ8.69(d, J=5.3Hz, 1H), 8.14(d, J=9.6Hz, 1H), 7.71(d, J=8.1Hz, 2H), 7.58(d, J=8.2Hz) , 2H), 7.46(d, J=5.3Hz, 1H), 6.85(d, J=9.6Hz, 1H), 5.31(q, J=7.3Hz, 1H), 2.67(s, 3H), 1.69(d, J=7.0Hz, 3H).

[0689] [Example 62]: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0690] TIFF2026004378000072.tif3231

[0691] LC-MS(ESI) calculation for C 17 H 17 FN4O3S [M+H] + 376.10, found m / z 377.25

[0692] [Example 63]: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0693] TIFF2026004378000073.tif3027

[0694] LC-MS(ESI) calculation for C 17 H 17 FN4O3S [M+H] + 376.10, found m / z 377.28

[0695] [Example 64]: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindolin-2-yl)sulfamide hydrochloride

[0696] TIFF2026004378000074.tif3127

[0697] 1 H NMR (400MHz, DMSO-d6) δ12.28(s, 1H), 8.56(d, J=4.9Hz, 1H), 7.77(d, J=9.8Hz, 1H), 7.53(d, J=7.9Hz, 1H), 7.4 8(s, 1H), 7.42(d, J=7.7Hz, 1H), 7.20(d, J=5.0Hz, 1H), 6.99(s, 2H), 6.56(dd, J=9.8, 1.9Hz, 1H), 4.60(s, 4H).

[0698] [Example 65]: 7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)dihydroisoquinoline-2(1H)-sulfamide hydrochloride

[0699] TIFF2026004378000075.tif3028

[0700] 1 H NMR (400MHz, DMSO-d6) δ12.26(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.81(d, J=9.8Hz, 1H), 7.37(d, J=7.8Hz, 1H), 7.34-7.27(m, 2H), 7.20(d, J=5.0Hz, 1H), 6.97(s, 2H), 6.56(d, J=9.8Hz, 1H), 4.30(s, 2H), 3.33(t, J=5.9Hz, 2H), 3.01(t, J=5.6Hz, 2H).

[0701] [Example 66]: 6-fluoro-7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride

[0702] TIFF2026004378000076.tif2928

[0703] 1H NMR (400MHz, DMSO-d6) δ10.24(brs, 1H), 8.64(s, 1H), 8.16(d, J=6.5Hz, 1H), 7.47-7.23(m, 3H), 7.10(d, J=51.1Hz, 1H), 6.82(s, 1H), 6.57(brs, 2H), 6.37(d, J=6.2Hz, 1H), 4.00(s, 2H), 3.12(d, J=7.2Hz, 2H), 2.82(t, J=7.4Hz, 2H).

[0704] [Example 67]: N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0705] TIFF2026004378000077.tif3025

[0706] 1 H NMR (400MHz, DMSO-d6) δ8.68 (d, J=4.9Hz, 1H), 7.76 (d, J=9.8Hz, 1H), 7.55 (d, J=8.0Hz, 2H), 7 .46(d, J=7.9Hz, 2H), 7.27(d, J=4.9Hz, 1H), 6.70(d, J=9.8Hz, 1H), 4.18(s, 2H), 3.73(s, 3H).

[0707] [Reaction Scheme 1-1]

[0708] TIFF2026004378000078.tif35104

[0709] In a round-bottom flask, 4 (1.0 equiv.) and RSO2Cl (1.1 equiv.) were dissolved in dichloromethane (0.08 M), followed by the addition of triethylamine (4.5 equiv.) and stirring at room temperature for 16 hours. After the reaction was completed, the mixture was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (1:20 MeOH:CHCl l2 ) to give 9 (30%-50% yield).

[0710] [Example 68]: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide

[0711] TIFF2026004378000079.tif2821

[0712] 1 H NMR (400MHz, MeOD-d4) δ8.58 (d, J=5.0Hz, 1H), 7.95 (d, J=9.8Hz, 1H), 7.60 (d, J=8.0Hz, 2H), 7 .50(d, J=8.1Hz, 2H), 7.25(d, J=5.0Hz, 1H), 6.64(d, J=9.8Hz, 1H), 4.37(s, 2H), 2.94(s, 3H).

[0713] [Example 69]: 4-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide

[0714] TIFF2026004378000080.tif2821

[0715] 1 H NMR (400MHz, MeOD-d4) δ8.56(d, J=4.9Hz, 1H), 7.90(d, J=9.7Hz, 1H), 7.74(d, J=8.2Hz, 2H), 7.43(d, J= 8.0Hz, 2H), 7.40-7.34(m, 4H), 7.20(d, J=5.0Hz, 1H), 6.64(d, J=9.8Hz, 1H), 4.17(s, 2H), 2.41(s, 3H).

[0716] [Example 70]: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide

[0717] TIFF2026004378000081.tif2928

[0718] 1H NMR (400MHz, DMSO-d6) δ8.54(d, J=5.0Hz, 1H), 7.91(d, J=5.0Hz, 1H), 7.70(d, J=9.8Hz, 1H), 7.57(dd, J=3.8, 1.3Hz, 1H), 7.48-7.38(m, 4H), 7.16(dd, J=8.1, 4.8Hz, 2H), 6.58(d, J=9.8Hz, 1H), 4.18(s, 2H).

[0719] [Example 71]: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)cyclopropanesulfonamide

[0720] TIFF2026004378000082.tif2825

[0721] 1 H NMR (400MHz, MeOD-d4) δ8.57 (d, J=5.0Hz, 1H), 7.95 (d, J=9.8Hz, 1H), 7.61 (d, J=8.0Hz, 2H), 7.49 (d, J=8.1Hz, 2H), 7.25(d, J=5.0Hz, 1H), 6.64(d, J=9.8Hz, 1H), 4.40(s, 2H), 2.57-2.48(m, 1H), 1.10-1.04(m, 2H), 1.01-0.96(m, 2H).

[0722] [Reaction Scheme 1-2]

[0723] TIFF2026004378000083.tif3696

[0724] In a round-bottom flask, 4 (1.0 equiv.) was dissolved in acetonitrile (0.08 M), and then bromotrimethylsilane (5.0 equiv.) was added at 0 °C and stirred at room temperature for 2 h. The reaction was quenched with methanol, and the residue obtained after filtration under reduced pressure was purified by preparative HPLC to give 10 (14%-20% yield).

[0725] [Example 72]: Diethyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate

[0726] TIFF2026004378000084.tif2925

[0727] 1 H NMR (400MHz, DMSO-d6) δ12.26(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.75(d, J=9.8Hz, 1H), 7.53(d, J=8.2Hz, 2H), 7.47(d, J=8.2Hz, 2H), 7.1 9(d, J=4.9Hz, 1H), 6.56(d, J=9.8Hz, 1H), 5.66-5.46(m, 1H), 4.07(dd, J=12.1, 7.3Hz, 2H), 3.97-3.88(m, 3H), 1.20(t, J=7.1Hz, 6H).

[0728] [Example 73]: diethyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate

[0729] TIFF2026004378000085.tif3023

[0730] 1 H NMR (400MHz, DMSO-d6) δ12.26(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.75(d, J=9.8Hz, 1H), 7.47(s, 4H), 7.21(d, J=4.9Hz, 1 H), 6.57(dd, J=9.8, 2.0Hz, 1H), 4.00(dd, J=8.1, 7.1Hz, 4H), 3.39(s, 1H), 3.33-3.31(m, 1H), 1.21(t, J=7.0Hz, 6H).

[0731] [Example 74]: Ethyl hydrogen (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate

[0732] TIFF2026004378000086.tif3024

[0733] 1H NMR (400MHz, DMSO-d6) δ12.25(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.76(d, J=9.8Hz, 1H), 7.55-7.39(m, 4H), 7.2 0(d, J=4.9Hz, 1H), 6.57(d, J=9.8Hz, 1H), 4.04-3.81(m, 2H), 3.19(d, J=21.6Hz, 2H), 1.20(t, J=7.1Hz, 4H).

[0734] [Example 75]: (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonic acid

[0735] TIFF2026004378000087.tif3023

[0736] 1 H NMR (400MHz, DMSO-d6) δ12.26(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.78(d, J=9.8Hz, 1H), 7.45(d, J= 6.1Hz, 4H), 7.19(d, J=4.9Hz, 1H), 6.57(d, J=9.8Hz, 1H), 3.51(s, 1H), 3.08(d, J=21.6Hz, 2H).

[0737] [Manufacturing Example 2]

[0738] Preparation Example 2 involves steps for producing Product 3, Product 4, Product 7, or Product 8.

[0739] Manufacturing Example 2:

[0740] [Reaction Scheme 2]

[0741] TIFF2026004378000088.tif125106

[0742] Step 1: In a round-bottom flask, 1 (1.0 equiv.), palladium(II) acetate (0.050 equiv.), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv.), 2 (1.3 equiv.), and potassium carbonate (3.0 equiv.) were dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) and refluxed under nitrogen for 16 h. After the reaction was completed, the mixture was filtered through Celite, poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (1:20 MeOH:CHCl) to give 3 (40%-60% yield).

[0743] Step 2: Place 3 (1.0 equiv.) in a round-bottom flask and dissolve in dichloromethane (0.040 M). Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 4 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 4 (60%-80% yield).

[0744] Examples of the present invention prepared according to step 2 above are as follows:

[0745] [Example 76]: 5-((3-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0746] TIFF2026004378000089.tif2623

[0747] 1 H NMR (400MHz, DMSO-d6) δ10.99(s, 1H), 8.94(d, J=8.7Hz, 1H), 8.25(d, J=7.1Hz, 1H), 7.56(t, J=7.9Hz, 1H), 7 .34(d, J=8.3Hz, 3H), 7.25(d, J=7.4Hz, 1H), 7.17-7.07(m, 1H), 6.94(d, J=7.9Hz, 1H), 6.78(d, J=7.1Hz, 1H).

[0748] [Example 77]: 5-((3-aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0749] TIFF2026004378000090.tif2826

[0750] 1 H NMR (400MHz, DMSO-d6) δ10.32(s, 1H), 8.72(s, 1H), 8.45(s, 3H), 8.18(d, J=6.7Hz, 1H ), 7.64-7.46(m, 2H), 7.45-7.30(m, 2H), 6.81(d, J=6.7Hz, 2H), 4.08(d, J=5.7Hz, 2H).

[0751] [Example 78]: 5-((3-aminomethyl)-4-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0752] TIFF2026004378000091.tif2626

[0753] 1 H NMR (400MHz, DMSO-d6) δ10.00(s, 1H), 8.63(s, 1H), 8.13(d, J=6.5Hz, 1H), 7.46(d, J=8.3Hz, 2H) , 7.33(d, J=8.3Hz, 2H), 7.13(s, 1H), 6.68(s, 2H), 6.63(d, J=6.5Hz, 1H), 4.11(d, J=3.9Hz, 2H).

[0754] [Example 79]: 5-((5-(2-aminoethyl)-2-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0755] TIFF2026004378000092.tif3027

[0756] LC-MS(ESI) calculation for C 16 H 15FN4O [M+H] + 298.12, found m / z 299.24

[0757] [Example 80]: 5-((3-(2-methylphenylethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0758] TIFF2026004378000093.tif3023

[0759] 1 H NMR (400MHz, DMSO-d6) δ10.66(s, 1H), 9.05(s, 2H), 8.85(s, 1H), 8.19(d, J=6.8Hz, 1H), 7.50(t, J=7.7Hz, 1H), 7.32(d, J=12.0Hz) , 2H), 7.27(d, J=7.5Hz, 1H), 6.89(s, 1H), 6.75(d, J=7.0Hz, 1H), 3.16(d, J=3.9Hz, 2H), 3.06-2.97(m, 2H), 2.57(t, J=5.4Hz, 3H).

[0760] [Example 81]: 5-((4-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0761] TIFF2026004378000094.tif2734

[0762] 1 H NMR (400MHz, DMSO-d6) δ10.60(s, 1H), 8.79(s, 1H), 8.19(d, J=6.9Hz, 1H), 7.39(d, J =8.5Hz, 2H), 7.28(d, J=7.9Hz, 2H), 6.90(s, 1H), 6.65(d, J=7.0Hz, 1H), 4.04(s, 4H)

[0763] [Example 82]: 5-((4-(aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0764] TIFF2026004378000095.tif2932

[0765] 1 H NMR (400MHz, DMSO-d6) δ10.67(s, 1H), 8.85(s, 1H), 8.49(s, 3H), 8.23(d, J=6.9Hz, 1H), 7.64(d, J=8.4Hz, 2H), 7.46(d, J=8.3Hz, 2H), 6.88(s, 1H), 6.66(d, J=6.9Hz, 1H), 4.07(d, J=5.7Hz, 2H).

[0766] [Example 83]: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0767] TIFF2026004378000096.tif3230

[0768] 1 H NMR (400MHz, DMSO-d6) δ9.50(s, 2H), 8.73(s, 1H), 8.21(d, J=6.6Hz, 1H), 7.68(d, J=8.3Hz, 2H), 7.45(d, J=8.3Hz) , 2H), 6.81(s, 1H), 6.70(d, J=6.7Hz, 1H), 4.25(s, 2H), 2.68(s, 1H), 0.92(t, J=7.8Hz, 2H), 0.76(t, J=7.8Hz, 2H).

[0769] [Example 84]: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0770] TIFF2026004378000097.tif2932

[0771] 1H NMR (400MHz, DMSO-d6) δ10.58(s, 1H), 10.04(s, 2H), 8.81(s, 1H), 8.20(d, J=6.7Hz, 1H), 7.54(d, J =8.1Hz, 1H), 7.45(s, 1H), 7.39(d, J=8.3Hz, 1H), 6.86(s, 1H), 6.69(d, J=6.9Hz, 1H), 4.54(s, 4H).

[0772] [Example 85]: 5-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0773] TIFF2026004378000098.tif2628

[0774] 1 H NMR (400MHz, DMSO-d6) δ10.56(s, 1H), 9.58(s, 2H), 8.80(s, 1H), 8.20(d, J=6.9Hz, 1H), 7.37(d, J=8.2Hz, 1H), 7 .29(d, J=8.8Hz, 2H), 6.86(s, 1H), 6.67(d, J=6.9Hz, 1H), 4.30(s, 2H), 3.39-3.35(m, 2H), 3.06(t, J=6.1Hz, 2H).

[0775] [Example 86]: 5-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0776] TIFF2026004378000099.tif2528

[0777] 1 H NMR (400MHz, DMSO-d6) δ10.09(s, 1H), 9.53(s, 2H), 8.70(s, 1H), 8.20(d, J=6.2Hz, 1H), 7.48-7. 24(m, 2H), 6.79(s, 1H), 6.29(d, J=4.3Hz, 1H), 4.31(s, 2H), 3.57(m, 2H), 3.02(t, J=6.2Hz, 2H).

[0778] [Example 87]: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride

[0779] TIFF2026004378000100.tif3027

[0780] 1 H NMR (400MHz, DMSO-d6) δ10.44(s, 1H), 9.28(s, 2H), 8.78(s, 1H), 8.17(d, J=6.7Hz, 1H), 7.45(s, 1H), 7.39(d, J=8.1Hz, 1H) , 7.31(d, J=8.0Hz, 1H), 6.83(s, 1H), 6.73(d, J=6.8Hz, 1H), 4.34(s, 2H), 3.37(s, 2H), 3.03(d, J=10.1Hz, 2H), 1.90(s, 2H).

[0781] Step 3: A round-bottom flask was charged with a solution of triethylamine (2.5 equiv.) in dichloromethane (0.1 M). Then, 4 (1.0 equiv.) and 6 (1.1 equiv.) were added and stirred at room temperature for 1 day. After completion of the reaction, the mixture was concentrated under reduced pressure and dried. The resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH2Cl2) to give 7 (30%-60% yield).

[0782] Step 4: Place 7 (1.0 equiv.) in a round-bottom flask and add dichloromethane (0.04 M) to dissolve. Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 16 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 8 (40%-80% yield).

[0783] Examples of the present invention prepared according to step 4 above are as follows:

[0784] [Example 88]: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride

[0785] TIFF2026004378000101.tif3028

[0786] 1 H NMR (400MHz, DMSO-d6) δ10.58(s, 1H), 9.82(s, 1H), 8.77(s, 1H), 8.20(d, J=6.9Hz, 1H), 7.42(t, J=8.0Hz, 1H) , 7.22(s, 1H), 7.20(s, 1H), 7.13(d, J=8.1Hz, 1H), 7.01(d, J=7.8Hz, 1H), 6.90(s, 1H), 6.69(d, J=7.0Hz, 1H).

[0787] [Example 89]: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride

[0788] TIFF2026004378000102.tif3632

[0789] 1 H NMR (400MHz, DMSO-d6) δ10.46(s, 1H), 8.76(s, 1H), 8.17(d, J=6.8Hz, 1H), 7.48(t, J=7.7Hz, 1H), 7.40(s, 1H) , 7.33(d, J=7.5Hz, 1H), 7.29(d, J=7.5Hz, 1H), 7.19(s, 1H), 6.86(s, 1H), 6.70(d, J=6.9Hz, 2H), 4.14(s, 2H).

[0790] [Example 90]: N-(2-fluoro-5((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride

[0791] TIFF2026004378000103.tif3836

[0792] 1 H NMR (400MHz, DMSO-d6) δ9.32(s, 1H), 8.40(s, 1H), 8.06(d, 2H), 8.06(d, 1H), 7 .45(d, 1H), 7.26(m, 2H), 7.15(dd, 1H), 6.72(s, 2H), 6.60(d, 1H), 4.15(d, 2H).

[0793] [Example 91]: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride

[0794] TIFF2026004378000104.tif3335

[0795] 1 H NMR (400MHz, DMSO-d6) δ10.41(s, 1H), 8.70(s, 1H), 8.16(d, J=6.9Hz, 1H), 7.52(d, J=6.9Hz, 1H), 7.34(d, J=7.5Hz, 2H), 7.21(s, 1H), 6.86(s, 1H), 6.73(s, 1H), 6.63(d, J=6.9Hz, 1H), 4.17(s, 2H).

[0796] [Example 92]: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride

[0797] TIFF2026004378000105.tif3228

[0798] 1 H NMR (400MHz, DMSO-d6) δ10.71(s, 1H), 8.85(s, 1H), 8.17(d, J=6.8Hz, 1H), 7.47(t, J=7.6Hz, 1H), 7.28(d, J=14.4Hz, 3H), 6.93(s, 1H), 6.73(d, J=7.0Hz, 1H), 6.58(s, 2H), 3.19-3.10(m, 2H), 2.85(t, J=7.2Hz, 2H).

[0799] [Example 93]: N-methyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride

[0800] TIFF2026004378000106.tif4133

[0801] 1 H NMR (400MHz, DMSO-d6) δ10.58(s, 1H), 8.78(d, J=6.7Hz, 1H), 8.15(d, J=7.0Hz, 1H), 7.47(t, J=7.7Hz, 1H), 7.34-7.20(m , 3H), 6.89(s, 1H), 6.74(s, 1H), 6.70(d, J=7.0Hz, 1H), 3.19(dd, J=12.6, 4.7Hz, 2H), 2.90(t, J=7.4Hz, 2H), 2.68(s, 3H).

[0802] [Example 94]: N-ethyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride

[0803] TIFF2026004378000107.tif3531

[0804] 1 H NMR (400MHz, DMSO-d6) δ10.46(s, 1H), 8.74(s, 1H), 8.23-8.14(m, 1H), 7.46(t, J=7.7Hz, 1H), 7.29(s, 1H), 7.25(d, J=7.6Hz, 2H), 7.01-6.8 5(m, 1H), 6.73(s, 1H), 6.69(d, J=6.9Hz, 1H), 3.33-3.21(m, 2H), 3.11(q, J=7.1Hz, 2H), 2.89(dd, J=10.1, 5.1Hz, 2H), 1.06(t, J=7.1Hz, 3H).

[0805] [Example 95]: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride

[0806] TIFF2026004378000108.tif3635

[0807] 1 H NMR (400MHz, MeOD-d4) δ8.69(d, J=9.3Hz, 1H), 8.18(d, J=7.2Hz, 1H), 7.44(d, J=7.5Hz, 1H), 7.42-7.38(m, 1H), 7.36-7.29(m, 1H), 7.04(d, J=9.4Hz, 1H), 6.68(dd, J=7.1, 1.6Hz, 1H), 3.32-3.28(m, 2H), 2.93(t, J=6.8Hz, 2H).

[0808] [Example 96]: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)-N-methylsulfamide dihydrochloride

[0809] TIFF2026004378000109.tif3430

[0810] LC-MS(ESI) calculation for C 17 H 18 FN5O3S [M+H] + 399.11, found m / z 392.35

[0811] [Example 97]: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride

[0812] TIFF2026004378000110.tif3235

[0813] 1 H NMR (400MHz, DMSO-d6) δ9.55(s, 1H), 9.03(s, 1H), 8.38(s, 1H), 8.01(s, 1H), 7.34(s, 1H), 7.22(d, 3H), 7.11(d, 2H), 6.48(d, 1H).

[0814] [Example 98]: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride

[0815] TIFF2026004378000111.tif3043

[0816] 1 H NMR (400MHz, DMSO-d6) δ10.00(s, 1H), 8.63(s, 1H), 8.13(d, J=6.5Hz, 1H), 7.46(d, J=8.3Hz, 2H) , 7.33(d, J=8.3Hz, 2H), 7.13(s, 1H), 6.68(s, 2H), 6.63(d, J=6.5Hz, 1H), 4.11(d, J=3.9Hz, 2H).

[0817] [Example 99]: N-cyclopropyl-N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride

[0818] TIFF2026004378000112.tif3438

[0819] 1 H NMR (400MHz, DMSO-d6) δ10.50(s, 1H), 8.76(d, J=9.1Hz, 1H), 8.18(d, J=6.6Hz, 1H), 7.48(d, J=8.3Hz, 2H), 7.36(d, J=8.3Hz, 2H), 7.15(d , J=51.0Hz, 1H), 7.01(s, 2H), 6.88(d, J=8.7Hz, 1H), 6.66(d, J=6.9Hz, 1H), 4.32(s, 2H), 2.41-2.21(m, 1H), 0.58(dd, J=6.6, 5.1Hz, 4H).

[0820] [Example 100]: N-(3-chloro-4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride

[0821] TIFF2026004378000113.tif3036

[0822] 1 H NMR (400MHz, DMSO-d6) δ10.30(s, 1H), 8.80(d, J=9.1Hz, 1H), 8.17(d, J=6.5Hz, 1H), 7.69(s, 1H), 7.49(s, 2H), 7.4 4(s, 1H), 7.31-7.27(m, 1H), 7.18(s, 1H), 6.86(d, J=9.3Hz, 1H), 6.74(s, 1H), 6.10(d, J=6.7Hz, 1H), 4.17(s, 2H).

[0823] [Example 101]: 5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)isoindolin-2-yl)sulfamide dihydrochloride

[0824] TIFF2026004378000114.tif3535

[0825] 1 H NMR (400MHz, DMSO-d6) δ8.64(s, 1H), 8.15(d, J=5.6Hz, 1H), 7.46(d, J=7.9Hz, 1H), 7 .36(s, 1H), 7.30(d, J=8.2Hz, 1H), 6.99(s, 1H), 6.65(d, J=6.7Hz, 1H), 4.54(s, 4H).

[0826] [Example 102]: 7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride

[0827] TIFF2026004378000115.tif4135

[0828] 1H NMR (400MHz, DMSO-d6) δ10.70(s, 1H), 8.83(d, J=8.1Hz, 1H), 8.17(d, J=7.0Hz, 1H), 7.34(d, J=7.9Hz, 1H), 7.23(d, J=8.1Hz) , 2H), 6.99(s, 2H), 6.92(d, J=8.0Hz, 1H), 6.67(d, J=7.1Hz, 1H), 4.25(s, 2H), 3.31(t, J=5.8Hz, 2H), 2.96(t, J=5.8Hz, 2H).

[0829] [Example 103]: (8-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-1,3,4,5-tetrahydro-2(1H)-benzo[c]azepin-2-yl)sulfamide dihydrochloride

[0830] TIFF2026004378000116.tif3633

[0831] 1 H NMR (400MHz, DMSO-d6) δ10.58(s, 1H), 8.79(d, J=8.7Hz, 1H), 8.17(d, J=7.0Hz, 1H), 7.33(d, J=8.0Hz, 1H), 7.22(dd, J=11.8 , 3.8Hz, 2H), 6.89(s, 1H), 6.79(s, 1H), 6.69(d, J=7.0Hz, 1H), 4.32(s, 2H), 3.50(s, 2H), 2.99(d, J=9.9Hz, 2H), 1.82(s, 2H).

[0832] [Example 104]: (6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride

[0833] TIFF2026004378000117.tif3439

[0834] 1H NMR (400MHz, DMSO-d6) δ10.47(s, 1H), 8.77(s, 1H), 8.16(d, J=6.9Hz, 1H), 7.37(d, J=25.5Hz, 1H), 7.29(d, J=17.5Hz, 1H), 7.1 4-(t, J=17.2Hz, 2H), 6.97(s, 1H), 6.83(s, 1H), 6.67(d, J=6.9Hz, 1H), 4.25(s, 2H), 3.32-3.28(m, 2H), 2.96(t, J=5.5Hz, 2H).

[0835] [Example 105]: 6-fluoro-7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride

[0836] TIFF2026004378000118.tif4036

[0837] LC-MS(ESI) calculation for C 17 H 16 FN5O3S [M+H] + 389.10, found m / z 390.23

[0838] [Example 106]: (7-fluoro-6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride

[0839] TIFF2026004378000119.tif3944

[0840] 1H NMR (400MHz, DMSO-d6) δ10.39(s, 1H), 8.76(d, J=6.4Hz, 1H), 8.19(d, J=6.9Hz, 1H), 7.37(d, J=11.0Hz, 1H), 7.31(d, J=7.8 Hz, 1H), 7.00(s, 1H), 6.90(s, 1H), 6.36(dd, J=6.7, 2.1Hz, 1H), 4.27(s, 2H), 3.30(t, J=5.8Hz, 2H), 2.94(d, J=5.1Hz, 2H).

[0841] [Example 107]: N-(5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-2,3-dihydro-1H-inden-2-yl)sulfamide dihydrochloride

[0842] TIFF2026004378000120.tif4145

[0843] 1 H NMR (400MHz, DMSO-d6) δ10.46(s, 1H), 8.75(s, 1H), 8.15(d, J=6.9Hz, 1H), 7.35(d, J=7.9Hz, 1H), 7.23(s, 1H), 7.16(d, J=7.7 Hz, 1H), 6.98(s, 1H), 6.89(s, 1H), 6.61(d, J=6.9Hz, 2H), 4.23-4.04(m, 1H), 3.23(dd, J=15.8, 6.9Hz, 2H), 3.03-2.80(m, 2H).

[0844] [Example 108]: (7-(methyl(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride

[0845] TIFF2026004378000121.tif4236

[0846] 1H NMR (400MHz, DMSO-d6) δ8.42(d, J=5.9Hz, 1H), 7.37(d, J=9.8Hz, 1H), 7.18(d, J=8.3Hz, 1H), 7.09(s, 1H), 7.02(d, J=6.2 Hz, 1H), 6.97(d, J=7.6Hz, 1H), 6.92(s, 2H), 6.42(d, J=9.0Hz, 1H), 4.15(s, 3H), 3.49(s, 3H), 3.27(s, 2H), 2.90(s, 2H).

[0847] [Manufacturing Example 3]

[0848] Preparation Example 3 involves steps for producing Product 3, Product 4, Product 7, or Product 8.

[0849] Manufacturing Example 3:

[0850] [Reaction Scheme 3]

[0851] TIFF2026004378000122.tif125101

[0852] Step 1: In a round-bottom flask, 1 (1.0 equiv.), 2 (1.3 equiv.), and N,N-diisopropylethylamine (3.0 equiv.) were dissolved in n-butanol (0.1 M) and refluxed for 16 h. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain 3. The mixture was then poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (1:10 MeOH:CH2Cl2) to obtain 3 (40%-60% yield).

[0853] [Example 109]: tert-butyl (1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)carbamate

[0854] TIFF2026004378000123.tif3024

[0855] 1H NMR (400MHz, DMSO-d6) δ11.90(s, 1H), 8.26(d, J=5.5Hz, 1H), 7.79(d, J=9.7Hz, 1H), 6.96(d, J=7.6Hz, 1H), 6.75(d, J =5.6Hz, 1H), 6.46(d, J=9.7Hz, 1H), 2.89(t, J=11.8Hz, 2H), 1.88(d, J=13.9Hz, 2H), 1.70-1.54(m, 3H), 1.40(s, 9H).

[0856] [Example 110]: tert-butyl ((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate

[0857] TIFF2026004378000124.tif3227

[0858] 1 H NMR (400MHz, MeOD-d6) δ8.29(d, J=5.6Hz, 1H), 8.02(dd, J=9.8, 1.2Hz, 1H), 6.82(d, J=5.7Hz, 1H), 6.57(d, J=9.7Hz, 1H), 3.57(d, J=1 2.5Hz, 2H), 3.04(d, J=6.6Hz, 2H), 2.91(t, J=12.1Hz, 2H), 1.87(d, J=15.7Hz, 2H), 1.77-1.63(m, 1H), 1.55-1.47(m, 2H), 1.45(s, 9H).

[0859] [Example 111]: tert-butyl (2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)carbamate

[0860] TIFF2026004378000125.tif3532

[0861] 1H NMR (400MHz, DMSO-d6) δ11.87(s, 1H), 8.25(d, J=5.5Hz, 1H), 7.81(d, J=9.7Hz, 1H), 6.81(t, J=5.4Hz, 1H), 6.74(d, J=5.6Hz, 1H), 6.4 4(d, J=9.7Hz, 1H), 3.41(d, J=12.2Hz, 2H), 3.00(q, J=6.6Hz, 2H), 2.80(t, J=11.8Hz, 2H), 1.79(d, J=12.2Hz, 2H), 1.53-1.33(m, 14H).

[0862] [Example 112]: tert-butyl ((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate

[0863] TIFF2026004378000126.tif3728

[0864] 1 H NMR (400MHz, DMSO-d6) δ8.39(d, J=5.5Hz, 1H), 7.84(d, J=9.8Hz, 1H), 6.92(t, J=5.8Hz, 1H), 6.85(d, J=5.6Hz, 1H), 6.59(d, J=9.7Hz, 1H), 3.64 (s, 3H), 3.42(d, J=11.3Hz, 2H), 2.91(t, J=6.3Hz, 2H), 2.82(t, J=11.9Hz, 2H), 1.76(d, J=12.8Hz, 2H), 1.64-1.51(m, 1H), 1.44-1.34(m, 11H).

[0865] Step 2: Place 3 (1.0 equiv.) in a round-bottom flask and add dichloromethane (0.04 M) to dissolve. Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 4 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 4 (60%-80% yield).

[0866] [Example 113]: 5-(4-aminopiperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0867] TIFF2026004378000127.tif3030

[0868] 1 H NMR (400MHz, DMSO-d6) δ8.30(d, J=6.0Hz, 1H), 8.17(s, 3H), 7.91(s, 1H), 6.87(d, J=6.0Hz, 1H) , 6.58(s, 1H), 3.69-3.58(m, 4H), 3.15-2.97(m, 2H), 2.06(d, J=12.1Hz, 2H), 1.84-1.69(m, 2H).

[0869] [Example 114]: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0870] TIFF2026004378000128.tif3329

[0871] 1 H NMR (400MHz, MeOD-d4) δ8.27-8.22(m, 2H), 7.04(d, J=7.0Hz, 1H), 6.86(d, J=9.4Hz, 1H), 4.10(d, J=13.1Hz, 2H), 3.41(t, J=12.7Hz, 2H), 2.96(d, J=6.9Hz, 2H), 2.13-2.05(m, 1H), 2.06-1.97(m, 2H), 1.67-1.54(m, 2H).

[0872] [Example 115]: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0873] TIFF2026004378000129.tif3029

[0874] 1H NMR (400MHz, MeOD-d4) δ8.22(dd, J=8.2, 5.6Hz, 2H), 7.01(d, J=7.0Hz, 1H), 6.83(d, J=9.5Hz, 1H), 4.06(d, J=13.1Hz, 2H), 3.38(t , J=13.3Hz, 2H), 3.04(t, J=7.9Hz, 2H), 1.97(d, J=13.0Hz, 2H), 1.89-1.78(m, 1H), 1.71(dt, J=9.9, 7.1Hz, 2H), 1.62-1.47(m, 2H).

[0875] [Example 116]: 5-(1,4-diazepan-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0876] TIFF2026004378000130.tif2725

[0877] 1 H NMR (400MHz, DMSO-d6) δ9.45(s, 2H), 8.26(d, J=6.9Hz, 2H), 6.90(d, J=7.0Hz, 1H ), 6.71(s, 1H), 4.03(s, 2H), 3.88(s, 2H), 3.42(s, 2H), 3.21(s, 2H), 2.21(s, 2H).

[0878] [Example 117]: 5-(2,8-diazaspiro[4,5]decan-8-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[0879] TIFF2026004378000131.tif3523

[0880] 1 H NMR (400MHz, MeOD-d4) δ8.29(d, J=9.5Hz, 1H), 8.24(d, J=7.2Hz, 1H), 7.07(d, J=7.2Hz, 1H), 6.89(d, J=9. 5Hz, 1H), 3.88-3.73(m, 4H), 3.47(t, J=7.4Hz, 2H), 3.26(s, 2H), 2.11(t, J=7.5Hz, 2H), 2.02-1.89(m, 4H).

[0881] [Example 118]: 5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride

[0882] TIFF2026004378000132.tif3530

[0883] 1 H NMR (400MHz, MeOD-d4) δ8.20(d, J=6.9Hz, 1H), 7.98(d, J=9.9Hz, 1H), 7.12(d, J=6.9Hz, 1H), 6.70(d, J=9.9Hz, 1H), 4.01(d, J=13 .1Hz, 2H), 3.76(s, 3H), 3.42-3.34(m, 2H), 2.96(d, J=6.8Hz, 2H), 2.12-2.04(m, 1H), 2.01(d, J=13.0Hz, 2H), 1.67-1.51(m, 2H).

[0884] Preparation of sulfamide 6: A round-bottom flask was charged with a solution of tert-butanol (1.0 equiv.) in anhydrous dichloromethane (1.4 M), and 5 (1.0 equiv.) was slowly added dropwise. N,N-dimethylpyridin-4-amine (2.0 equiv.) was then added. The solution was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was washed with water several times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting colorless powder 6 (80% yield) was used as the reactant without further purification.

[0885] Step 3: A round-bottom flask was charged with a solution of 4 (1.0 equiv.) and triethylamine (2.5 equiv.) dissolved in dichloromethane (0.1 M). 6 (1.1 equiv.) was then added and stirred at room temperature for 1 day. After completion of the reaction, the mixture was concentrated under reduced pressure and dried. The resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH2Cl2) to give 7 (30%-60% yield).

[0886] [Example 119]: tert-butyl (N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamoyl)carbamate

[0887] TIFF2026004378000133.tif3028

[0888] 1 H NMR (400MHz, MeOD-d4) δ8.30(d, J=5.6Hz, 1H), 8.03(d, J=9.7Hz, 1H), 6.84(d, J=5.6Hz, 1H), 6.59(d, J=9.7 Hz, 1H), 3.57-3.41(m, 3H), 3.03(t, J=11.7Hz, 2H), 2.13(d, J=13.2Hz, 2H), 1.92-1.76(m, 2H), 1.48(s, 9H).

[0889] [Example 120]: tert-butyl (N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate

[0890] TIFF2026004378000134.tif3030

[0891] 1 H NMR (400MHz, DMSO-d6) δ11.88(s, 1H), 8.25(d, J=5.5Hz, 1H), 7.81(d, J=9.7Hz, 1H), 6.75(d, J=5.6Hz, 1H), 6.44 (d, J=9.7Hz, 1H), 3.41-3.37(m, 4H), 2.87-2.70(m, 4H), 1.81(d, J=12.8Hz, 2H), 1.68-1.58(m, 1H), 1.37(s, 9H).

[0892] [Example 121]: tert-butyl (N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate

[0893] TIFF2026004378000135.tif3033

[0894] 1 H NMR (400MHz, MeOD-d4) δ8.29(d, J=5.6Hz, 1H), 8.02(d, J=9.7Hz, 1H), 6.82(d, J=5.7Hz, 1H), 6.57(d, J=9.7Hz, 1H), 3.61-3.51(m, 2H), 3.09 (t, J=7.0Hz, 2H), 2.94(t, J=12.0Hz, 2H), 1.91(d, J=8.0Hz, 2H), 1.73-1.65(m, 1H), 1.60(q, J=6.9Hz, 2H), 1.56-1.50(m, 2H), 1.48(s, 9H).

[0895] [Example 122]: tert-butyl (N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate

[0896] TIFF2026004378000136.tif3130

[0897] 1 H NMR (400MHz, MeOD-d4) δ8.44(d, J=5.7Hz, 1H), 8.04(d, J=9.7Hz, 1H), 6.92(d, J=5.8Hz, 1H), 6.68(d, J=9.7Hz, 1H), 3.82(s, 3H), 3.60-3.54(m, 2H), 3.02(d, J=6.7Hz, 2H), 2.95(t, J=12.0Hz, 2H), 1.98(d, J=13.0Hz, 2H), 1.87-1.76(m, 1H), 1.62-1.48(m, 11H).

[0898] Step 4: Place 7 (1.0 equiv.) in a round-bottom flask and add dichloromethane (0.04 M) to dissolve. Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 16 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 8 (40%-80% yield).

[0899] [Example 123]: N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamide

[0900] TIFF2026004378000137.tif3024

[0901] 1 H NMR (400MHz, MeOD-d4) δ8.29(d, J=9.4Hz, 1H), 8.20(d, J=7.3Hz, 1H), 7.07(d, J=7.3Hz, 1H), 6.91( d, J=9.3Hz, 1H), 4.12(d, J=13.7Hz, 2H), 3.72-3.54(m, 3H), 2.31-2.19(m, 2H), 1.91-1.74(m, 2H).

[0902] [Example 124]: N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide

[0903] TIFF2026004378000138.tif3028

[0904] 1 H NMR (400MHz, MeOD-d4) δ8.21(dd, J=13.9, 8.1Hz, 2H), 6.99(d, J=7.0Hz, 1H), 6.82(d, J=9.4Hz, 1H), 4.05(d , J=13.1Hz, 2H), 3.38(d, J=13.4Hz, 2H), 3.02(d, J=6.3Hz, 2H), 2.08-1.90(m, 3H), 1.53(q, J=12.3Hz, 2H).

[0905] [Example 125]: N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamide

[0906] TIFF2026004378000139.tif3030

[0907] 1 H NMR (400MHz, DMSO-d6) δ8.27(d, J=6.3Hz, 1H), 8.01(s, 1H), 6.90(d, J=6.4Hz, 1H), 6.70-6.40(m, 4H), 3.78-3.69(m, 2H), 3. 15-3.08(m, 2H), 2.96(t, J=7.2Hz, 2H), 1.83(d, J=12.3Hz, 2H), 1.76-1.64(m, 1H), 1.50(q, J=7.0Hz, 2H), 1.45-1.32(m, 2H).

[0908] [Example 126]: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide

[0909] TIFF2026004378000140.tif4435

[0910] 1 H NMR (400MHz, Methanol-d4) δ8.28(d, J=9.5Hz, 1H), 8.20(d, J=7.2Hz, 1H), 7.04(d, J=7.2 Hz, 1H), 6.87(d, J=9.5Hz, 1H), 3.88-3.71(m, 4H), 3.41-3.37(m, 3H), 2.01-1.82(m, 7H).

[0911] [Example 127]: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide

[0912] TIFF2026004378000141.tif3530

[0913] 1H NMR (400MHz, DMSO-d6) δ8.33(d, J=8.0Hz, 1H), 8.21(d, J=7.2Hz, 1H), 6.91(d, J=7.3Hz, 1H), 6.93-6.76 (m, 3H), 6.72(d, J=9.6Hz, 1H), 3.93(s, 2H), 3.54(s, 2H), 3.33(s, 2H), 3.30-3.26(m, 2H), 2.04(s, 2H).

[0914] [Example 128]: N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide

[0915] TIFF2026004378000142.tif3027

[0916] 1 H NMR (400MHz, MeOD-d4) δ8.13 (d, J=7.2Hz, 1H), 7.98 (d, J=9.9Hz, 1H), 7.10 (d, J=7.1Hz, 1H), 6.68 (d, J=9.9Hz, 1H), 4.0 2(d, J=13.3Hz, 2H), 3.75(s, 3H), 3.40(d, J=12.8Hz, 2H), 3.02(d, J=6.3Hz, 2H), 2.08-1.92(m, 3H), 1.62-1.43(m, 2H).

[0917] [Manufacturing Example 4]

[0918] Preparation Example 4 involves steps for producing Product 3, Product 4, Product 7, or Product 8.

[0919] Manufacturing Example 4:

[0920] [Reaction Scheme 4]

[0921] TIFF2026004378000143.tif119103

[0922] Step 1: In a round-bottom flask, 1 (1.0 equiv.), palladium(II) acetate (0.050 equiv.), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv.), 2 (1.3 equiv.), and potassium carbonate (3.0 equiv.) were dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) and refluxed under nitrogen for 16 h. After the reaction was completed, the mixture was filtered through Celite, poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (1:20 MeOH:CHCl) to give 3 (40%-60% yield).

[0923] [Example 129]: tert-butyl (3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[0924] TIFF2026004378000144.tif2736

[0925] 1 H NMR (400MHz, MeOD-d4) δ8.15(d, J=5.2Hz, 1H), 7.45(t, J=7.6Hz, 1H), 7.36(d, J=7.8Hz, 1H), 7.32-7.24 (m, 2H), 6.99(d, J=5.1Hz, 1H), 4.29(s, 2H), 2.94(t, J=7.6Hz, 2H), 2.54(t, J=7.6Hz, 2H), 1.45(s, 9H).

[0926] Step 2: Place 3 (1.0 equiv.) in a round-bottom flask and dissolve in dichloromethane (0.040 M). Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 4 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 4 (60%-80% yield).

[0927] [Example 130]: tert-butyl (4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[0928] TIFF2026004378000145.tif3428

[0929] 1 H NMR (400MHz, DMSO-d6) δ10.48(s, 1H), 8.14(d, J=5.2Hz, 1H), 7.45(t, J=6.4Hz, 1H), 7.36(d, J=3.9Hz, 4H) , 6.93(d, J=5.2Hz, 1H), 4.18(d, J=6.2Hz, 2H), 2.84(t, J=7.6Hz, 2H), 2.42(t, J=7.5Hz, 2H), 1.40(s, 9H).

[0930] [Example 131]: 5-(3-(aminophenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[0931] TIFF2026004378000146.tif2930

[0932] 1 H NMR (400MHz, MeOD-d4) δ8.29(d, J=6.0Hz, 1H), 7.75(t, J=7.9Hz, 1H), 7.64-7.53(m, 3H), 7.31(d, J=6.0Hz, 1H), 3.06(dd, J=8.5, 6.6Hz, 2H), 2.68(dd, J=8.5, 6.6Hz, 2H).

[0933] [Example 132]: 5-(3-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[0934] TIFF2026004378000147.tif2632

[0935] 1H NMR (400MHz, MeOD-d4) δ8.25(d, J=5.8Hz, 1H), 7.68-7.60(m, 2H), 7.58(s, 1H), 7.56-7.52 (m, 1H), 7.25(d, J=5.8Hz, 1H), 4.23(s, 2H), 3.05(t, J=7.6Hz, 2H), 2.65(t, J=7.6Hz, 2H).

[0936] [Example 133]: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[0937] TIFF2026004378000148.tif2826

[0938] 1 H NMR (400MHz, MeOD-d4) δ8.17(d, J=5.2Hz, 1H), 7.57(d, J=8.0Hz, 2H), 7.48(d, J=8.1Hz , 2H), 6.98(d, J=5.2Hz, 1H), 4.15(s, 2H), 2.93(t, J=7.6Hz, 2H), 2.55(t, J=7.6Hz, 2H).

[0939] [Example 134]: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[0940] TIFF2026004378000149.tif3426

[0941] 1 H NMR (400MHz, MeOD-d4) δ8.27(d, J=6.0Hz, 1H), 7.73(d, J=8.6Hz, 2H), 7.62(d, J=8.6Hz, 2H), 7.32 (d, J=6.0Hz, 1H), 3.08 (dd, J=8.5, 6.6Hz, 2H), 2.68 (dd, J=8.5, 6.6Hz, 2H), 1.80 (s, 6H).

[0942] [Example 135]: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[0943] TIFF2026004378000150.tif3228

[0944] 1 H NMR (400MHz, DMSO-d6) δ10.65(s, 1H), 9.68(s, 2H), 8.19(d, J=5.2Hz, 1H), 7.39-7.28(m, 3H), 6.96(d, J=5 .3Hz, 1H), 4.30(s, 2H), 3.38(s, 2H), 3.08(t, J=6.1Hz, 2H), 2.86(t, J=7.5Hz, 2H), 2.45(t, J=7.5Hz, 2H).

[0945] Preparation of sulfamide 6: A round-bottom flask was charged with a solution of tert-butanol (1.0 equiv.) in anhydrous dichloromethane (1.4 M), and 5 (1.0 equiv.) was slowly added dropwise. N,N-dimethylpyridin-4-amine (2.0 equiv.) was then added. The solution was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was washed with water several times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting colorless powder 6 (80% yield) was used as the reactant without further purification.

[0946] Step 3: A round-bottom flask was charged with a solution of triethylamine (2.5 equiv.) in dichloromethane (0.1 M). Then, 4 (1.0 equiv.) and 6 (1.1 equiv.) were added and stirred at room temperature for 1 day. After completion of the reaction, the mixture was concentrated under reduced pressure and dried. The resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH2Cl2) to give 7 (30%-60% yield).

[0947] [Example 136]: tert-butyl (N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[0948] TIFF2026004378000151.tif3042

[0949] 1 H NMR (400MHz, MeOD-d4) δ8.15(d, J=5.2Hz, 1H), 7.48-7.42(m, 3H), 7.31-7.27(m, 1H), 7.02 (d, J=5.2Hz, 1H), 4.17(s, 2H), 2.97(t, J=7.5Hz, 2H), 2.55(t, J=7.5Hz, 2H), 1.41(s, 9H).

[0950] [Example 137]: tert-butyl (N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[0951] TIFF2026004378000152.tif3435

[0952] 1 H NMR (400MHz, MeOD-d4) δ8.15 (d, J=5.2Hz, 1H), 7.51 (d, J=8.1Hz, 2H), 7.36 (d, J=8.1Hz, 2H), 6 .99(d, J=5.1Hz, 1H), 4.21(s, 2H), 2.96(t, J=7.5Hz, 2H), 2.54(t, J=7.5Hz, 2H), 1.45(s, 9H).

[0953] [Example 138]: tert-butyl ((7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-diisoquinolin-2(1H)-yl)sulfonyl)carbamate

[0954] TIFF2026004378000153.tif3840

[0955] 1H NMR (400MHz, DMSO-d6) δ11.15(s, 1H), 10.52(s, 1H), 8.15(d, J=5.1Hz, 1H), 7.31-7.26(m, 2H), 7.23(d, J=7.7Hz, 1H), 6.92(d, J= 5.2Hz, 1H), 4.53(s, 2H), 3.57(t, J=5.9Hz, 2H), 2.94(t, J=5.8Hz, 2H), 2.85(d, J=7.9Hz, 2H), 2.43(t, J=7.5Hz, 2H), 1.33(s, 9H).

[0956] Step 4: Place 7 (1.0 equiv.) in a round-bottom flask and add dichloromethane (0.04 M) to dissolve. Then, add hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) and stir at room temperature for 16 hours. After the reaction was completed, concentrate under reduced pressure. The resulting residue was washed with diethyl ether, filtered, and dried to give 8 (40%-80% yield).

[0957] [Example 139]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)phenyl)sulfamide

[0958] TIFF2026004378000154.tif3441

[0959] 1 H NMR (400MHz, MeOD-d4) δ8.23(d, J=6.0Hz, 1H), 7.48(t, J=7.9Hz, 1H), 7.36-7.30(m, 3H ), 7.15 (dt, J=7.9, 1.2Hz, 1H), 3.11 (t, J=8.4, 6.6Hz, 2H), 2.66 (dd, J=8.4, 6.6Hz, 2H).

[0960] [Example 140]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0961] TIFF2026004378000155.tif3040

[0962] 1 H NMR (400MHz, MeOD-d4) δ8.27(d, J=6.2Hz, 1H), 7.60-7.53(m, 3H), 7.41(d, J=6.3Hz, 2H), 4.31(s, 2H), 3.14(t, J=7.5Hz, 2H), 2.70(t, J=7.5Hz, 2H).

[0963] [Example 141]: N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0964] TIFF2026004378000156.tif3532

[0965] 1 H NMR (400MHz, DMSO-d6) δ10.48(s, 1H), 8.14(d, J=5.1Hz, 1H), 7.46(d, J=8.0Hz, 2H), 7.37(d, J =8.0Hz, 2H), 6.93(d, J=5.2Hz, 1H), 4.13(s, 2H), 2.84(t, J=7.6Hz, 2H), 2.42(t, J=7.6Hz, 2H).

[0966] [Example 142]: N-(2-fluoro-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[0967] TIFF2026004378000157.tif3028

[0968] 1 H NMR (400MHz, MeOD-d4) δ8.26(d, J=6.1Hz, 1H), 7.73(t, J=7.7Hz, 1H), 7.35(d, J=6.1Hz, 1H ), 7.32-7.25(m, 2H), 4.36(s, 2H), 3.10(dd, J=8.4, 6.6Hz, 2H), 2.68(t, J=8.4, 6.6Hz, 2H).

[0969] [Example 143]: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindoline-2-sulfamide hydrochloride

[0970] TIFF2026004378000158.tif3730

[0971] LC-MS(ESI) calculation for C 16 H 16 N4O3S [M+H] + 344.09, found m / z 345.35

[0972] [Example 144]: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride

[0973] TIFF2026004378000159.tif4543

[0974] 1 H NMR (400MHz, DMSO-d6) δ10.92(s, 1H), 9.26(s, 1H), 7.85(s, 1H), 7.31-7.21(m, 1H), 7.08(d, J=17.5Hz, 2H), 6 .96(d, J=7.4Hz, 2H), 6.61(d, J=6.8Hz, 1H), 4.22(s, 2H), 3.29(s, 1H), 2.93(brs, 4H), 2.67(t, J=7.4Hz, 2H).

[0975] [Example 145]: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide hydrochloride

[0976] TIFF2026004378000160.tif3834

[0977] 1H NMR (400MHz, DMSO-d6) δ10.61(s, 1H), 8.17(d, J=5.2Hz, 1H), 7.30(d, J=8.2Hz, 12H), 7.24(d, J=7.2Hz, 2H), 6.99(d, J=5 .2Hz, 2H), 4.27-4.22(m, 2H), 3.31(t, J=5.9Hz, 2H), 2.97(t, J=5.8Hz, 2H), 2.88(t, J=7.5Hz, 2H), 2.44(t, J=7.5Hz, 2H).

[0978] [Reaction Scheme 4-1]

[0979] TIFF2026004378000161.tif3191

[0980] In a round-bottom flask, 4 (1.0 equiv.) and RSO2Cl (1.1 equiv.) were dissolved in dichloromethane (0.08 M), followed by the addition of triethylamine (4.5 equiv.) and stirring at room temperature for 16 h. After the reaction was completed, the mixture was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (1:20 MeOH:CH2Cl2) to give 9 (30%-50% yield).

[0981] [Example 146]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide

[0982] TIFF2026004378000162.tif2735

[0983] 1 H NMR (400MHz, MeOD-d4) δ8.16(d, J=5.1Hz, 1H), 7.52-7.45(m, 2H), 7.42(s, 1H), 7.33(d, J=6.9Hz, 1 H), 7.00(d, J=5.2Hz, 1H), 4.33(s, 2H), 2.95(t, J=7.6Hz, 2H), 2.91(s, 3H), 2.55(t, J=7.6Hz, 2H).

[0984] [Example 147]: 4-methyl-N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide

[0985] TIFF2026004378000163.tif2634

[0986] 1 H NMR (400MHz, MeOD-d4) δ8.15(d, J=5.2Hz, 1H), 7.71(d, J=8.2Hz, 2H), 7.39(t, J=7.6Hz, 1H), 7.32(d, J=7.8Hz, 3H), 7.25(d , J=7.6Hz, 1H), 7.17(s, 1H), 6.90(d, J=5.2Hz, 1H), 4.15(s, 2H), 2.86(t, J=7.5Hz, 2H), 2.53(t, J=7.5Hz, 2H), 2.39(s, 3H).

[0987] [Example 148]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide

[0988] TIFF2026004378000164.tif3043

[0989] 1 H NMR (400MHz, MeOD-d4) δ8.15(d, J=5.2Hz, 1H), 7.73(dd, J=5.0, 1.3Hz, 1H), 7.56(dd, J=3.8, 1.3Hz, 1H), 7.42(t, J=7.9Hz, 1H), 7.35(d, J=7 .9Hz, 1H), 7.30-7.24(m, 2H), 7.10(dd, J=5.0, 3.7Hz, 1H), 6.95(d, J=5.3Hz, 1H), 4.23(s, 2H), 2.90(t, J=7.6Hz, 2H), 2.54(t, J=7.6Hz, 2H).

[0990] [Experimental Example]

[0991] The following experiments were carried out using Examples 1-148 prepared as above.

[0992] Experimental example 1: ENPP1 enzyme assay with cGAMP substrate

[0993] ENPP1 hydrolyzes nucleotides or nucleotide derivatives to produce nucleoside 5'-monophosphate and pyrophosphate. ENPP1 also hydrolyzes 2'3'-cGAMP to produce 5'-adenosine monophosphate (AMP) and 5'-guanosine monophosphate (GMP). The AMP produced in the reaction is measured using the AMP-Glo® kit (Promega). The AMP-Glo® kit consists of two reagents. The first reagent terminates the AMP-producing enzyme reaction, removes ATP, and converts the produced AMP to ADP. The second reagent converts ADP to ATP, which is used to generate luminescence in a luciferase reaction. The measured amount of luminescence is proportional to the amount of AMP produced by ENPP1.

[0994] The final reaction mixture for the assay system contained 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM CaCl2, 1 μM ZnCl2, 5% glycerol, and 1% DMSO. Serially diluted ENPP1 inhibitors (generally ranging from 10 μM to 0.5 nM) were incubated with human recombinant ENPP1 enzyme (R&D Systems) at 3 ng / reaction for 5-10 minutes at room temperature. The reaction was initiated by adding cGAMP (at a final concentration of 5 μM) and incubated at 37°C for 90 minutes. At the end of the reaction, 10 μl of AMP-Glo ​​1 Reagent was added to terminate the reaction, followed by incubation at room temperature for 1 hour. Following incubation, 20 μl of AMP detection solution (a 1:100 mixture of AMP-Glo ​​2 Reagent and Kinase-Glo) was added and incubated at room temperature for 1 hour. Luminescence signals were measured using a Victor® plate reader (Perkin Elmer). A maximum activity control (enzyme and substrate in the presence of 1% DMSO; MAX) and a minimum activity control (substrate and 1% DMSO; MIN) were simultaneously evaluated. Serially diluted reference ENPP1 inhibitors were also tested in each experiment. IC50 values ​​for compound concentration versus % residual activity were determined by fitting the inhibition curves using the 3-parameter method in GraphPad Prism® software. Serially diluted samples of a single compound were tested more than once, and the average IC50 value for each compound was calculated.

[0995] The experimental results are shown in Tables 1 and 2 below.

[0996] [Table 1] TIFF2026004378000166.tif228153 TIFF2026004378000167.tif189153

[0997] [Table 2]

[0998] [Experimental Example 2]

[0999] Experiments were carried out using the examples prepared as above.

[1000] Experimental example 2: HCT116-dual cell Luciferase assay

[1001] HCT116-Dual® cells express a gene encoding secreted luciferase under the control of the interferon-stimulated gene 54 (ISG54) promoter, along with five interferon-stimulated response elements. The HCT116-Dual® cell line is used to measure and monitor the activity of interferon regulatory factor 3 (IRF3), which induces the formation of type I interferons and is involved in subsequent signal transduction. Lucia secreted into the culture medium is used to generate luminescence in the luciferase reaction.

[1002] HCT116-Dual® cells were cultured in a 96-well plate at 2 × 10 in DMEM medium containing 10% FBS and 25 mM HEPES (pH 7.2-7.5). 4 Cells were cultured for 1 day at 93.4 μL / well. 3.3 μL of ENPP1 inhibitor (typically 10 μM) was added, followed by 3.3 μL of cGAMP (10 μM) to bring the final volume to 100 μL. (The final DMSO concentration was 0.1%). The ENPP1 inhibitor and cGAMP-treated cells were cultured at 37°C for 48 hours, and luciferase activity was measured in 50 μL of Quanti-Luc reaction mixture added to 20 μL of cell culture medium. The compound-induced increase in interferon regulatory factor 3 (IRF3) levels relative to cGAMP was determined as a fold increase.

[1003] The experimental results are shown in Tables 3 and 4 below.

[1004] [Table 3]

[1005] [Table 4]

[1006] [Formulation Examples] Meanwhile, the novel compound represented by Chemical Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following are examples of some formulation methods containing the compound represented by Chemical Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[1007] Formulation Example 1: Tablets (direct compression)

[1008] 5.0 mg of the active ingredient was sieved, mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate, and compressed to form tablets.

[1009] Formulation Example 2: Tablets (wet granulation)

[1010] 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 an appropriate amount of this solution was added and then pulverized. After drying, the pulverized material was sieved and then mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The pulverized material was compressed into tablets.

[1011] Formulation Example 3: Powder and capsules

[1012] 5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate, and the mixture was filled into No. 5 hard gelatin capsules using suitable equipment.

[1013] Formulation Example 4: Injection

[1014] An injection was prepared by adding 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na2HPO4·12H2O, and 2974 mg of distilled water.

[1015] Although the embodiments of the present invention have been described above, those skilled in the art will understand that the present invention can be embodied in other specific forms without changing the technical concept or essential features of the present invention. Therefore, it should be understood that the embodiments described above are illustrative in all respects and are not limiting.

Claims

1. A compound selected from naphthyridinone derivative compounds represented by the following chemical formula 1, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof: [Chemical formula 1] In the above Chemical Formula 1, R 1 is hydrogen; C 1 -C 13 an alkyl group; or C 3 -C 10 a cyclyl group; R 2 is -Z-R 3 - (R 4 ) m in, The Z may or may not be present. When Z is present, Z is -O-, -CO-, -COO-, -C n H n+2 -, -O(C n H n+2 ) -, -(OC 2 H 4 ) n -, -(C 2 H 4 O) n -, -(C n H n+2 ) O-, -(C n H n+2 )CO-, -(C n H n+2 ) O(C m H m+2 ) -, -NR 6 (C n H n+2 ) -, -(NR 6 C 2 H 4 ) n -, -(C 2 H 4 NR 6 ) n -, or - (C n H n+2 ) NR 6 -;in, n is an integer from 0 to 8, The R 3 is C 3 -C 10 Cyclyl group, C 3 -C 10 Heterocyclyl group, C 6 -C 10 an aryl group, or C 3 -C 10 Heteroaryl groups, The R 4 represents hydrogen; a hydroxy group; a halogen group; C 1 -C 13 Alkyl group; C 1 -C 6 Alkoxy group; C 1 -C 6 Alkenyl group; C 6 -C 10 Aryl group; C 3 -C 10 Cyclyl group; C 3 -C 10 Heteroaryl group; C 3 -C 10 Heterocyclyl group; —C(O)—(C 1 -C 13 alkyl); tert-butyloxycarbonyl group (Boc); amino group (—NR 5 R 6 );-(C m H m+2 ) NR 5 R 6 ; nitro group (-N(O) 2 ); an amide group (—(C═O)NR 5 R 6 ); an ester group (—C(O)OR 6 ); carboxylic acid group (—C(O)OH); nitrile group (—CN); sulfonamide group (—NHS(O) 2 R 6 ); urea group; sulfamoyl group (—NHS(O) 2 NHR 6 ); sulfonamide group; sulfamoyl alkyl group (-(C m H m+2 ) NHS (O) 2 NHR 6 ); sulfamoyl alkyl group (-(C m H m+2 ) NR 5 S (O) 2 NHR 6 ); sulfide group (—SR 6 ); sulfonic acid group (—S(O) 2 R 6 ); or a phosphiryl group (—P(O)R 5 R 6 ) or R 3 to the same carbon atom as that to which R is attached, forming a 3- to 7-membered saturated ring; or 3 and R are bonded to the same carbon atom as R to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S; or 3 and the carbon atom adjacent to the carbon atom connected to R to form a 3- to 7-membered saturated ring; or 3 and the adjacent carbon atom to form a 3- to 7-membered heterocyclic saturated ring containing one or more heteroatoms selected from N, O, and S; m is an integer from 1 to 4, Said C 1 -C 6 Alkyl group, C 1 -C 13 Alkyl group or C 3 -C 10 The cyclyl group may be selected from the group consisting of hydrogen, hydroxyl, halogen, and C. 1 -C 13 Alkyl group; C 1 -C 6 Alkoxy group; amino group (—NR 5 R 6 ), nitro group (—N(O) 2 ); an amide group (—(C═O)NR 5 R 6 ), carboxylic acid group (—C(O)OH); nitrile group (—CN); urea group (—NR 5 (C=O)NR 6 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfone group (-S(O) 2 -); phosphiryl group (-P(O)R 5 R 6 ); C 6 -C 10 Aryl group; C 3 -C 10 heteroaryl groups; and C 3 -C 10 heterocyclyl groups, Said C 6 -C 10 Aryl group, C 3 -C 10 Heteroaryl group or C 3 -C 10 Heterocyclyl groups include hydrogen; hydroxy groups; halogen groups; carbonyl groups (-(C=O)R 5 R 6 ); halogen or C 3 -C 10 The heterocyclyl group may have a substituted or unsubstituted C 1 -C 3 Alkyl group; halogen or C 3 -C 10 The heterocyclyl group may have a substituted or unsubstituted C 1 -C 3 Alkoxy group; C 6 -C 10 Phenoxy; amino group (-NR 5 R 6 ), nitro group (—N(O) 2 ); an amide group (—(C═O)NR 5 R 6 ), carboxylic acid group (—C(O)OH); nitrile group (—CN); urea group (—NR 5 (C=O)NR 6 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfone group (-S(O) 2 -); phosphiryl group (-P(O)R 5 R 6 ); C 6 -C 10 Aryl group; C 3 -C 10 Heteroaryl groups and C 3 -C 10 heterocyclyl groups, The R 5 and R 6 are each independently hydrogen; C 1 -C 6 Alkyl group; C 1 -C 6 Alkenyl group; C 1 -C 6 Alkynyl group; C 6 -C 10 Aryl group; C 3 -C 10 Heteroaryl group; C 3 -C 10 a heterocyclyl group; or R 5 is R 6 and a nitrogen or carbon atom linked to N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O) 2 - and SO 2 and optionally contain at least one of hydrogen, C 1 -C 13 Alkyl group, C 6 -C 10 Aryl group, C 3 -C 10 forming a 3- to 7-membered saturated ring which may be optionally substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group; Said C 3 -C 10 Heteroaryl groups and C 3 -C 10 The heterocyclyl group contains one or more heteroatoms selected from the group consisting of N, O, and S.

2. R 1 is hydrogen; or C 1 -C 5 an alkyl group; R 3 is C 5 -C 7 Heterocyclyl group, C 6 -C 8 an aryl group, or C 5 -C 10 A compound selected from the group consisting of naphthyridinone derivative compounds represented by Chemical Formula 1 according to claim 1, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof, wherein the heteroaryl group is a heteroaryl group.

3. R 1 is hydrogen; or C 1 -C 3 an alkyl group; R 3 is 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; or 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 furine; substituted or unsubstituted cyclopropane; or substituted or unsubstituted cyclobutane;

4. R 1 is hydrogen; or C 1 -C 3 an alkyl group; R 3 is substituted or unsubstituted benzene; or substituted or unsubstituted piperidine; A compound selected from naphthyridinone derivative compounds represented by chemical formula 1 according to claim 1, their pharmaceutically acceptable salts, their hydrates and their stereoisomers.

5. The R 2 teeth, 2. A compound selected from the group consisting of naphthyridinone derivative compounds represented by Chemical Formula 1 according to claim 1, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof.

6. The R 4 is a halogen, a methyl group, an ethyl group, -NH 2 , -CH 2 NH 2 , -CHCH 3 NH 2 , -CH(CH 3 ) 2 NH 2 , -CHCH 3 NHCH 3 , -CH 2 NHCH 2 CH 3 , -tert-butyloxycarbonyl group (Boc), 6. A compound selected from the group consisting of naphthyridinone derivative compounds represented by Chemical Formula 1 according to claim 5, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof.

7. The compound is any one selected from the group consisting of the naphthyridinone derivative compounds represented by Chemical Formula 1 according to claim 1, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, wherein the compound is any one selected from the group consisting of Compound Nos. 1 to 148: Compound No. 1: tert-butyl(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)carbamate; Compound No. 2: tert-butyl(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound No. 3: tert-butyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound No. 4: tert-butyl(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound No. 5: tert-butyl(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound No. 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 7: 5-(3-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 8: 5-(5-(amino-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 9: 5-(3-(aminomethyl)-4-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 10: 5-(4-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 11: 5-(4-(aminomethyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 12: 5-(4-(aminomethyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 15: (R)-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 17: (R)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 18: (S)-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 19: (R)-5-(4-(1-(cyclopropylaminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 20: 5-(4-((ethylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 21: 5-(2-fluoro-4-((isopropylamine)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 22: 5-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 23: 5-(3-fluoro-4-((methylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 24: 5-(4-((ethylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 25: 5-(4-((cyclopropylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 26: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 28: 5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 30: tert-butyl(N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamoyl)carbamate; Compound No. 31: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound No. 32: tert-butyl (N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound No. 33: tert-butyl(N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound No. 34: tert-butyl (N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound No. 35: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide; Compound No. 36: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide hydrochloride; Compound No. 37: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 38: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 39: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide; Compound No. 40: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 41: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 42: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 43: N-(2,3-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 44: N-(3,5-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 45: N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 46: (R)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 47: (S)-(N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 48: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 49: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 50: N-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 51: N-ethyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 52: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride; Compound No. 53: N-ethyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 54: N-cyclopropyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 55: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride; Compound No. 56: N-ethyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 57: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-isopropyl)sulfamide hydrochloride; Compound No. 58: N-cyclopropyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound No. 59: (R)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 60: (R)-(N-cyclopropyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 61: (S)-(N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 62: (R)-(N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 63: (R)-(N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound No. 64: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindolin-2-yl)sulfamide hydrochloride; Compound No. 65: 7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)dihydroisoquinoline-2(1H)-sulfamide hydrochloride; Compound No. 66: 6-fluoro-7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride; Compound No. 67: N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 68: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide; Compound No. 69: 4-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide; Compound No. 70: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide; Compound No. 71: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)cyclopropanesulfonamide; Compound No. 72: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate; Compound No. 73: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate; Compound No. 74: ethyl hydrogen(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate; Compound No. 75: (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonic acid; Compound No. 76: 5-((3-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 77: 5-((3-aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 78: 5-((3-aminomethyl)-4-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 79: 5-((5-(2-aminoethyl)-2-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 80: 5-((3-(2-methylphenylethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 81: 5-((4-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 82: 5-((4-(aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 83: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 85: 5-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 86: 5-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 87: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound No. 88: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride; Compound No. 89: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound No. 90: N-(2-fluoro-5((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound No. 91: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound No. 92: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound No. 93: N-methyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound No. 94: N-ethyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound No. 95: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound No. 96: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)-N-methylsulfamide dihydrochloride; Compound No. 97: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride; Compound No. 98: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound No. 99: N-cyclopropyl-N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound No. 100: N-(3-chloro-4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound No. 101: 5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)isoindolin-2-yl)sulfamide dihydrochloride; Compound No. 102: 7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound No. 103: (8-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-1,3,4,5-tetrahydro-2(1H)-benzo[c]azepin-2-yl)sulfamide dihydrochloride; Compound No. 104: (6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound No. 105: 6-fluoro-7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound No. 106: (7-fluoro-6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound No. 107: N-(5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-2,3-dihydro-1H-inden-2-yl)sulfamide dihydrochloride; Compound No. 108: (7-(methyl(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound No. 109: tert-butyl(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)carbamate; Compound No. 110: tert-butyl((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate; Compound No. 111: tert-butyl(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)carbamate; Compound No. 112: tert-butyl((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate; Compound No. 113: 5-(4-aminopiperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 115: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 116: 5-(1,4-diazepan-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 117: 5-(2,8-diazaspiro[4,5]decan-8-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 118: 5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 119: tert-butyl (N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamoyl)carbamate; Compound No. 120: tert-butyl (N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate; Compound No. 121: tert-butyl(N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate; Compound No. 122: tert-butyl (N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate; Compound No. 123: N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamide; Compound No. 124: N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide; Compound No. 125: N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamide; Compound No. 126: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide; Compound No. 127: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide; Compound No. 128: N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide; Compound No. 129: tert-butyl(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound No. 130: tert-butyl(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound No. 131: 5-(3-(aminophenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 132: 5-(3-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 133: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 134: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound No. 136: tert-butyl (N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound No. 137: tert-butyl (N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound No. 138: tert-butyl ((7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-diisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound No. 139: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)phenyl)sulfamide; Compound No. 140: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 141: N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 142: N-(2-fluoro-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound No. 143: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindoline-2-sulfamide hydrochloride; Compound No. 144: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride; Compound No. 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide hydrochloride; Compound No. 146: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide; Compound No. 147: 4-methyl-N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide; and Compound No. 148: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide.

8. The pharmaceutically acceptable salt is a salt of an inorganic or organic acid selected from the group consisting of 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. The naphthyridinone derivative compound represented by Chemical Formula 1 according to claim 1, its pharmaceutically acceptable salt, its hydrate, and its stereoisomer.

9. A pharmaceutical composition for preventing, alleviating, or preventing cancer metastasis, enhancing the efficacy of anticancer vaccines, enhancing the efficacy of neoadjuvant anticancer therapy, treating infectious diseases, enhancing the anticancer effect of CAR-T, promoting myocardial regeneration, strengthening cardiac function, or treating hypophosphatemia, comprising the compound according to any one of claims 1 to 8 as an active ingredient.

10. An ENPP1 inhibitor comprising the compound according to any one of claims 1 to 8 as an active ingredient.

11. A STING pathway activator comprising a compound according to any one of claims 1 to 8 as an active ingredient.

12. The pharmaceutical composition for preventing, alleviating or treating cancer according to claim 9, wherein the cancer is a cancer associated with the suppression of ENPP1.

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