KR20220095154A - Novel naphthyridinone derivatives as a Ectonucleotide pyrophosphatase-phosphodiesterase inhibitors and use thereof - Google Patents

Abstract

The present invention relates to a novel naphthyridinone derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof, which are each relevant to a compound for inhibiting ENPP1, a composition for inhibiting ENPP1, and a method for inhibiting ENPP1.

Description

Novel naphthyridinone derivatives having inhibitory activity of ectonucleotide pyrophosphatase-phosphodiesterase and uses thereof

The present invention relates to a novel naphthyridinone derivative compound having ectonucleotide pyrophosphatase-phosphodiesterase (ENPP) inhibitory activity, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof. It relates to a selected compound, a method for preparing the compound, and a pharmaceutical composition for preventing, alleviating or treating cancer comprising the compound.

Cancer is a group of diseases related to uncontrolled cell proliferation that can invade or spread to other parts of the body, reducing quality of life and eventually leading to death. Although genetic aberrations are a direct cause of the uncontrolled proliferation of cancer cells, failure of immune surveillance and/or the absence of an adequate immune counterattack of the immune system against cancer cells are also causes of cancer cell proliferation, as well as anticancer immunity. A primary tumor having a tumor microenvironment (TME) with suppressed response is formed. Afterwards, cancer cells go through a locally advanced cancer stage and eventually develop into metastatic cancer that infiltrates other organs, thereby lowering the cure rate and survival rate of cancer patients. Therapeutic agents for treating such fatal diseases have been largely developed into two categories. The first is to directly target the cancer cell itself, and the second is to target the components of the tumor microenvironment (TME) to prevent further proliferation or survival of cancer cells.

Cancer immunotherapy is one of the therapeutic approaches that target immune factors present in the TME to induce immune cells to attack tumor cells. In some instances, cancer immunotherapy aims to promote recognition of tumor cells through the release of tumor-associated antigens in the TME (eg, Cancer vaccines). In other cases, cancer immunotherapy aims to promote attack on tumor cells by modulating the activity of innate and/or adaptive immune cells (eg, immune checkpoint blockade). In other cases, cancer immunotherapy aims to induce tumor death by in vitro manipulation of patient-derived lymphocytes to express chimeric antigen receptors, recognizing antigens on the tumor surface, and enhancing the activity of lymphocytes (e.g., chimeric Antigen Receptor T Cell Therapy (CAR-T Cell Therapy)).

Microbial infections can cause a variety of diseases worldwide. Pathogenic microorganisms are diverse and include viruses, bacteria, fungi and protozoa. In some cases, the therapeutic agent is a chemical that directly prevents microbial growth. In other instances, the therapeutic agents are therapeutic agents for enhancing or stimulating host immune function against pathogenic microorganisms.

The tumor microenvironment (TME) contains malignant tumor cells as well as various types of immune cells (e.g., macrophages, lymphocytes, NK cells, dendritic cells) and non-immune cells (e.g., cancer-associated fibroblasts). associated fibroblast), pericyte, endothelial cells, and adipocytes). On the other hand, it has been reported that the presence of tumor-infiltrating lymphocytes can lead to positive clinical outcomes in response to multiple pipelines of immunotherapy in different types of cancer. Modulation or elevation of immune cells other than lymphocytes, particularly innate immune cells, has been reported to modulate the responsiveness of anticancer therapies to tumors in preclinical studies. The innate immune system is one of the two major components of the host immune defense system in vertebrates. The main functions of innate immunity are 1) to identify and remove foreign substances (eg, bacteria, viruses) from body tissues, 2) to recruit immune cells to specific sites by producing cytokines and promoting adaptive immune responses, and 3 ) to activate the complement cascade. Such innate immunity is achieved by recognizing molecular patterns derived from microbial pathogens (pathogen-associated molecular pattern, PAMP) or residues of destroyed cells (damage-associated molecular pattern, DAMP). is activated

Pattern recognition receptors (PRRs) are several different types of receptors that are mainly expressed by innate immune cells and 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) and triggers an innate immune response. One of these cytoplasmic DNA sensors, the cGAS-STING pathway (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes) is 1) cytoplasmic DNA recognition generated by microbial infection or DNA damage itself, and 2) generation of chemical factors. , mainly involved in both type 1 interferons (IFNs) by activation of the IRE3 transcription factor.

Type 1 IFN produced by TME due to transformed cancer cells promotes recruitment and activation of inflammatory cells, including NK cells, at the tumor site, and induces both tumor cell death and production of chemoattractants that promote adaptive immune responses. do

Systemic administration of type 1 IFN showed demonstrated efficacy in cancer environments by showing tumor regression and improved survival rate by systemic injection of IFN-beta in a preclinical mouse model. However, systemic administration of type 1 IFN has a problem in that a high dose is required to reach a therapeutically effective amount to exhibit therapeutic efficacy. In this case, tolerability issues were reported.

A recently published report published the clinical results of an exogenous STING agonist (modified cyclic dinucleotide), and showed a lower-than-expected disease control rate despite an apparent increase in pro-inflammatory cytokine production.

Therefore, there is a need for research on a new treatment method that can activate the cGAS-STING pathway.

Chinese Patent Publication CN 110575458 A International Publication WO 2019/233300 A1 International Publication WO 2018/119325 A1 International Publication WO 2018/119328 A1 International Publication WO 2019/046778 A1 International Publication WO 2019/177971 A1 Japanese Publication JP 2020-15670 International Publication WO 2019/051269 A1 US Publication US 2020/0039979 A1 International Publication WO 2019/023635 A1 International Publication WO 2019/051269 A1

In order to solve the above problems, the present invention is to provide a method capable of increasing the activity of the cGAS-STING pathway.

Accordingly, one aspect of the present invention is to provide a novel naphthyridinone derivative compound having an inhibitory activity of ENPP1. In addition, one aspect of the present invention is to provide a novel naphthyridinone derivative compound that improves and/or modulates the production of type 1 interferon (IFNs) in the body.

In addition, another object of the present invention is a novel naphthyridinone derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof is useful for the treatment, prevention and alleviation of cancer diseases containing as an active ingredient. Its purpose is to provide a pharmaceutical composition.

Another object of the present invention is to provide a method for preventing, alleviating or treating cancer, comprising administering a novel naphthyridinone derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof do.

Another object of the present invention is to provide a method for preventing, alleviating or treating an infectious disease, comprising administering a novel naphthyridinone derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof want to

Another object of the present invention is to provide a method for preventing, alleviating or treating periodontal disease, comprising administering a novel naphthyridinone derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof want to

In addition, another object of the present invention is the pathological mineralization of soft tissue comprising administering a novel naphthyridinone derivative compound or a pharmaceutical composition comprising the compound to a patient or subject in need thereof ( To provide a method for preventing, alleviating or treating pathological mineralization.

In addition, another object of the present invention is to implement the following mechanism as an active ingredient of a novel naphthyridinone derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or an isomer thereof. In one aspect, the method comprises priming the cancer with an agent that induces ICD (immunogenic cell death) prior to stimulating the cGAS-STING pathway. In another aspect, the method comprises blocking degradation of an endogenous STING ligand prior to priming the cancer with an agent that induces ICD. In another aspect, the method comprises using an inhibitor of a 2'3'-cGAMP degrading polypeptide in combination with an agent that induces ICD for the treatment of cancer. In one aspect, the present invention provides a method for designing an inhibitor of a 2'3'-cGAMP-degrading polypeptide and a detailed assay method for evaluating the enzymatic activity of a cGAMP-degrading polypeptide.

In order to solve the above problems, the present invention provides a compound selected from a naphthyridinone derivative compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[Formula 1]

In Formula 1,

R ₁ is hydrogen; C ₁ -C ₁₃ alkyl group; or C ₃ -C ₁₀ cyclyl group; is,

R ₂ is -ZR ₃ -(R ₄ ) _m ,

Z is present or not, and 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 -, ; is

n is an integer from 0 to 8,

Wherein R ₃ is a C ₃ -C ₁₀ cyclyl group, a C ₃ -C ₁₀ heterocyclyl group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group,

wherein R ₄ is hydrogen; hydroxyl group; 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 ); amide group (-(C=O)NR ₅ R ₆ ); 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; sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₆ ); sulfamoylalkyl group (-(C _m H _m+2 )NR ₅ S(O) ₂ NHR ₆ ); sulfide group (-SR ₆ ); sulfone group (-S(O) ₂ R ₆ ); a phospyryl group (-P(O)R ₅ R ₆ ); connected to the same carbon as the carbon connected to R ₃ to form a 3 to 7 membered saturated ring; It is connected to the same carbon as the carbon connected to R ₃ to form a 3 to 7 membered hetero saturated ring containing one or more heteroatoms of N, O and S; It is connected to the carbon connected to R ₃ and the adjacent carbon to form a 3 to 7 membered saturated ring; or connected to the carbon connected to R ₃ and the adjacent carbon to form a 3 to 7 membered hetero saturated ring containing one or more heteroatoms of N, O and S;

m is an integer from 1 to 4,

The C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group, or C ₃ -C ₁₀ cyclyl group may include hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₅ R ₆ ); nitro group (-N(O) ₂ ); 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-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₅ R ₆ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it includes one or more substituents selected from the group consisting of C ₃ -C ₁₀ heterocyclyl group,

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ₅ R ₆ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; a C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₅ R ₆ ); nitro group (-N(O) ₂ ); 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-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₅ R ₆ ); C ₆ -C ₁₀ aryl group; Containing one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group,

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 heterocyclyl group; or R ₅ together with the nitrogen or carbon atom connected to R ₆ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of, hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group, and Forms a 3 to 7 membered saturated ring that may be optionally substituted with at least one of a cyano group,

The C ₃ -C ₁₀ heteroaryl group and the C ₃ -C ₁₀ heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

The compound according to the present invention has an excellent ability to inhibit the activity of ENPP1. Therefore, it can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth.

The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient effectively inhibits ENPP1 to activate the STING pathway, thereby preventing or treating cancer metastasis It can be useful for prevention.

Cancer diseases that can be treated, prevented and alleviated by treatment with the compound according to the present invention include gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, adenopathy, 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, and the like.

In particular, the compound according to the present invention is effective for preventing, alleviating or treating diseases involving ENPP 1.

Justice

Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term “about” in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.

In this specification, when a range is described for a variable, the variable will be understood to include all values within the stated range including the stated endpoints of the range. For example, a range of “5 to 10” includes the values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood to include any value between integers that are appropriate for the scope of the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also for example, ranges from "10% to 30%" include values of 10%, 11%, 12%, 13%, etc. and all integers up to and including 30%, as well as 10% to 15%, 12% to It will be understood to include any subranges such as 18%, 20% to 30%, etc., as well as any value between reasonable integers within the scope of the recited ranges, such as 10.5%, 15.5%, 25.5%, and the like.

As used herein, the terms “individual(s),” “subject(s),” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. Neither term requires, or is limited to, a situation characterized by the supervision (e.g., regular or intermittent) of a health care practitioner (e.g., physician, registered nurse, apprentice nurse, physician's assistant, handyman or hospice worker) doesn't happen

"Treatment" is an attempt made with the intention of preventing the development or alteration of a lesion of a disease. Accordingly, "treatment" refers to both therapeutic, therapeutic and prophylactic dimensions. Those that need to be treated include those already having the disease as well as those in which the disease is to be prevented. In the treatment of tumors, a therapeutic agent may mean either directly reducing the pathology of the tumor cells or making the tumor cells more susceptible to treatment by other therapeutic agents, for example radiation and/or chemotherapy and/or immunotherapy. . As used herein, the terms “relief” or “treated” refer to signs approaching normalized values measured by conventional statistical tests. A sign approaching a normalized value here is, for example, a value obtained from a healthy patient or individual, a value differing by less than 50% from the normalized value, preferably a value differing by less than 25%, more preferably It may be a value showing a difference of less than 10%, and more preferably a value not significantly different from a normalized value.

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

As used herein, “effective amount” or “therapeutically effective amount” refers to a compound disclosed herein that relieves to some extent the symptoms of a disease or condition to be treated (eg, cancer or inflammatory disease, periodontal disease, or soft tissue calcification). means a sufficient amount. In some embodiments, the result is 1) reduction and/or alleviation of the signs, symptoms or causes of a disease, or 2) any other desirable alteration of a biological system in a clinical setting. In some embodiments, an appropriate "effective" amount for any individual case is determined using techniques such as dose escalation studies.

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

In some embodiments, a "therapeutically effective amount" is an amount of a compound disclosed in monotherapy or combination therapy, i.e., when administered in one or more doses, compared to the tumor burden of a subject not treated with the compound, or to be treated with the compound. 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, when compared to the subject's tumor burden before or after , an amount effective to reduce by an amount greater than or equal to about 90%. As used herein, the term “tumor burden” is the total mass of tumor tissue carried by a subject with cancer.

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

Hereinafter, the present invention will be described in detail.

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

cGAS-STING pathway, immunogenic apoptosis, and production of type 1 IFNs

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

cGAS (cyclic-GMP-AMP synthase) is a cytoplasmic protein that exists as a dimer, and has two DNA binding domains and a nucleotidyltransferase domain (ATP and GTP to 2'5' and 3'5' phosphodiesters). converted to 2'3-cGAMP) of a cyclic dinucleotide with a bond. In addition, cGAMP acts as a secondary messenger and induces type 1 IFN expression by binding to STING with high affinity (Kd ~ 4 nM).

STING (also known as TMEM173, MITA, MPYS) is an endoplasmic reticulum (ER) anchor protein comprising four transmembrane domains at the N-terminus and a dimerization domain at the C-terminus. Upon cGAMP binding, STING forms a tetramer and translocates from the ER to the ER-Golgi intermediate compartment. In the Golgi apparatus, STING attracts and activates TBK1 (Tank binding kinase1), and activated TBK1 phosphorylates the C-terminal domain of STING, and STING recruits and activates IRF3 (interferon regulator factor 3). The activated IRF3 then migrates to the nucleus and increases the expression of immune-stimulated genes (ISG) and type 1 IFN. After activation, STING is sent to endolysosomes where it is degraded, thereby terminating cGAS-STING pathway activation.

Immunogenic cell death (ICD)

ICD (immunogenic cell death, immunogenic cell death) is a form of cell death, a cellular phenomenon that induces activation of a controlled immune response. The cell death is characterized by an apoptotic morphology and maintains the integrity of the biological membrane. ICD is also characterized by exposing polypeptides formed by native or mutated proteins to cells as well as secretion of DAMPs (eg, Calreticulin, high mobility group box1 (HMGB1), ATP and Hsp70/90 proteins). The exposed polypeptides (acting as antigens) are recognized by dendritic cells (DCs) and subsequently primed effector T-cell lymphocytes to activate an adaptive immune response.

ICD can also be further classified by different types of ICD inducers. ICD inducers such as 1) radiation (eg UV radiation or gamma radiation), 2) chemotherapy small molecules (eg doxorubicin or paclitaxel) and 3) biological agents (eg polypeptides, oligosaccharides, lipids or nucleic acids) have.

radiation therapy

Radiation therapy is well known and used for the treatment of patients suffering from a variety of ailments. Radiation therapy is typically used to inhibit the death or growth of undesirable tissue (eg, cancerous tissue). A determined amount of high-energy electromagnetic radiation and/or high-energy particles aims to minimize unintended damage to desirable or healthy tissue while directly damaging undesirable tissues or lesions in the path through which the radiation is passed.

According to the research results so far, since the effect on normal tissue is more affected by the fraction size than the dose, the 1.8-2.0-Gy fractional dose is considered the standard of the existing radiation therapy and the treatment time is longer. . Indeed, a small dose per fraction makes it possible to induce a tumor effect by mitotic death of cancer cells while at the same time restoring sublethal damage to normal tissues after administration. SBRT (stereotactic body radiation therapy) is an improved radiation therapy that uses sophisticated image guidance to pinpoint the three-dimensional location of a tumor so that radiation can be delivered more accurately to cancer cells. In addition to direct cytotoxicity, SBRT may have a substantial effect on tumor cell death at high doses accompanying microvascular damage, adding a novel mechanism of radiation-induced damage. However, a recent report reports that high-dose radiation induces the expression of nuclease enzymes, thereby attenuating the effect of radiation on STING-mediated innate immune activation.

pathogen

As described above, intracellular invasion of nucleic acids derived from pathogens activates the cGAS-STING pathway, thereby increasing the immune response to pathogens. In some cases, the pathogen is a virus, such as a DNA virus or 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 papilloma. virus (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 Ney Includes Seria Gonorjoeae.

Phosphodiesterases

Phosphodiesterases (PDEs) are cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxins, sphingomyelin phosphodiesterases, DNases, RNases, restriction endonucleases, and many less well known small molecule phosphodiesterases. An exemplary group of PDE enzymes are important for hydrolysis of the cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphate. is a group of enzymes.

Cyclic nucleotide phosphodiesterases contain a group of enzymes that cleave the phosphodiester bonds of the cyclic nucleotide secondary messenger molecules cAMP and cGMP. They regulate the localization, persistence and amplification of cyclic nucleotide signals within subcellular domains.

Ecto-nucleotide pyrophosphatases/phosphodiesterase

The class of phosphodiesterases also includes ecto-nucleotide rhophosphatases/phosphodiesterases. Ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) or nucleotide pyrophosphatase/phosphodiesterase (NPP) hydrolyzes the pyrophosphate and phosphodiester bonds of their substrates to produce nucleotide 5'-mono A family of enzymes in the ectonucleotidases that produce phosphates (or phospholipids and phosphocholines). In some embodiments, the ENPP enzyme family is an ecto-nucleotidase having a similar protein structure on the cell surface and includes 7 enzyme members (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP- 5, ENPP-6 and ENPP-7).

ENPP enzymes usually have a modular structure comprising a catalytic domain of 400 amino acids. Although this catalytic domain exhibits partially overlapping activities, it is not related to phospholipase, nudix hydrolase or ectonucleotide triphosphate diphosphohydrolase. ENPPs 1 and 3 have a transmembrane domain at the N-terminus and a nuclease-like domain at the C-terminus, and are predicted to be type 2 single-spanning transmembrane proteins whose catalytic domains are directed towards the extracellular space. ENPP 2, which lacks a transmembrane domain at either the N- or C-terminus, has a signal peptide at the N-terminus and is expected to be secreted extracellularly. ENPPs 4, 5, 6, 7 containing putative N-terminal signal peptides and C-terminal transmembrane domains are predicted to be type 1 single-spanning transmembrane proteins whose catalytic domains are also directed to the extracellular space.

ENPP1, 2 and 3 are known to generate nucleoside monophosphates (ENPP1,2,3) or nucleoside diphosphates (ENPP1,2) using nucleotides and their derivatives as substrates. Only ENPP2 is known to utilize lysophospholipids. ENPP6 and 7 are known to use choline phosphate esters as substrates and produce choline phosphates. For ENPP4 and 5 there is no known substrate.

ENPP1, also called NPP1 or PC-1, is a type 2 transmembrane glycoprotein and is expressed in many tissues (pancreas, kidney, bladder and liver). ENPP1 is important for purinergic signaling, which plays an important role in the regulation of cardiovascular, neuronal, immune and blood functions in mammals. ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP to produce inorganic pyrophosphate (PPi). In general, as inorganic pyrophosphate regulates bone and cartilage mineralization, the production of PPi by ENPP1 makes ENPP1 a central regulator of bone and cartilage development. In contrast to the inhibitory effect of excess PPi produced by ENPP1 in joint tissue, calcium phosphate formation from PPi produced by ENPP1 is essential for bone tissue mineralization. ENPP1 has broad specificity and hydrolyzes a variety of substrates, including phosphodiester linkages of nucleotides and nucleotide sugars and pyrophosphate linkages of nucleotides and nucleotide sugars.

Recently, ENPP1 was found to play an important role in the immunological response to various extrinsic signals that activate the cGAS-STING pathway. An exploratory study of enzymatic activity degrading cGAMP molecules revealed that ENPP1 functions as a major hydrolase of cGAMP. Consistent with these findings, it was reported that the half-life of cGAMP was highly dependent on ENPP1 by demonstrating a much longer cGAMP half-life in ENPP1 knockout mice.

The bisphosphothionate analog of cGAMP, which is resistant to ENPP1 hydrolysis, was shown to activate STING 10-fold more than cGAMP, suggesting that delay or reduction of cGAMP hydrolysis by inhibition of ENPP1 significantly reduced the activation of STING. imply that it will increase. It has been reported that inhibition of ENPP1 induces the presence of persistent cGAMP and activates the STING pathway, thereby attenuating Pseudorayvis virus infection and reducing Mycobacterium tuberculosis infection.

Accordingly, one aspect of the present invention provides an inhibitor of ENPP1, a cGAMP-degrading polypeptide.

In one aspect, the ENPP1 inhibitor is a reversible inhibitor.

In one aspect, the ENPP1 inhibitor is a competitive inhibitor.

In another aspect, the ENPP1 inhibitor is an allosteric inhibitor.

In another aspect, the ENPP1 inhibitor is an irreversible inhibitor.

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

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

In another aspect, the inhibitor of ENPP1 does not inhibit the ATP hydrolytic activity of the catalytic domain or weakly inhibits the ATP hydrolytic activity.

How to Inhibit ENPP1

As mentioned above, the present invention includes the following. 1) ENPP1 inhibitors; 2) a method of inhibiting the ENPP1 enzyme with the ENPP1 inhibitor; 3) a method of inhibiting the hydrolase activity of ENPP1 on cGAMP; 4) How to improve the signal output of STING path activation; 5) Methods of inhibiting tumor growth in appropriate mouse tumor models in a monotherapy or combination therapy setting.

In some embodiments, inhibition of ENPP1 indicates that the activity of ENPP1 is 10% or greater, such as 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater as compared to a control not treated with the compound. It means a reduction of more than 80%, more than 90%, more than 95%. In some embodiments, inhibition of ENPP1 indicates that the activity of ENPP1 is at least 2-fold, such as at least 3-fold, at least 5-fold, at least 10-fold, at least 100-fold, or 1000-fold as compared to a control not treated with the compound. means more than double

In some embodiments, the cell permeable ENPP1 inhibitor is an inhibitor mentioned herein. In some embodiments, the cell-penetrating ENPP1 inhibitor is an inhibitor according to any one of compounds selected from the naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[Formula 1]

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

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 number 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

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

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

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

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

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

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

Compound number 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 15: ( R )-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 17: ( R )-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

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

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

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

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

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

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

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

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

Compound No. 26: 5-(Asoindorin-5-yl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

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

Compound number 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1 H )-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 number 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)sulfa mide hydrochloride;

Compound No. 49: ( R )-( N- (1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfa mide 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 -Cyclophyllophil- 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 -Cyclophyllophil- 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)sulfa mide 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)sulfa mide hydrochloride;

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

Compound number 64: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindorin-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 (1 H )- 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 number 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 number 72: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

Compound number 73: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate;

Compound No. 74: Ethylhydrogen (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(1 H )-one dihydrochloride;

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

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

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

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

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

Compound No. 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1 H )-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 di hydrochloride;

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)isoindorin-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-dihydroisoquinoline-2(1 H )-yl)sulfamide dihydrochloride;

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

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

Compound No. 108: (7- (methyl (7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl) amino) -3,4-dihydroisoquinoline-2 (1 H )- 1) 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(1 H )-one hydrochloride;

Compound No. 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1 H )-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(1 H )-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(1 H )-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)sulfa Moyl) 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-4yl)piperidin-4-yl)sulfamide;

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

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

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

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

Compound No. 128: N -((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)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(1 H )-one hydrochloride;

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

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

Compound No. 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1 H )-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-diisoquinoline-2(1) H )-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 (1 H )-sulfamide hydrochloride;

Compound No. 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoguanoline-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.

In some embodiments, the compounds of the present invention have an ENPP1 inhibition profile that reflects activity on additional enzymes. In some embodiments, compounds of the invention specifically inhibit ENPP1 without unintended inhibition of one or more other enzymes.

In some embodiments, the compound of the present invention is used for determining the activity of an enzyme in a cell-free or cellular system after treatment with a compound of the present invention as compared to a control by an inhibition assay, e.g., by measuring an IC50 or EC50, respectively. Inhibits ENPP 1 as determined by the assay. In some embodiments, the compounds of the present invention are 10 uM or less, such as 3 uM or less, 1 uM 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, IC50 values (or EC50 values) of 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower.

The assay procedure that can be used to determine the activity of ENPP1 may include many of the following, but the assay procedure is not limited by the assay procedure below. cell-free assay systems, such as avidity assays, assays using purified enzymes, cell assays in which the phenotype of cells is determined, such as gene expression assays, and in vivo assays involving specific animals.

In some embodiments, the method of the present invention is a method of reducing cancer cell proliferation, the method comprising treating the cell with an effective amount of a compound of the present invention to reduce cancer cell proliferation. In some embodiments, the method may be performed in combination with chemotherapy. Any cancer cell can be used as long as there are available cancer cells.

treatment method

As mentioned above, the present invention includes methods for inhibiting ENPP1 activity for cGAMP, resulting in increased levels of cGAMP and/or modulation of sub-factors of the STING pathway. According to a recent report, ENPP1 inhibition can modulate STING activity in vivo, and thus can be used for the treatment of various diseases, for example, cancer immunotherapy or targeted treatment of infectious diseases. As described above, the method of the present invention is a method of increasing the STING-mediated response in a subject and regulating the immune response.

In some embodiments, the STING mediated response comprises increasing production of interferon (eg, type 1 interferon, type 3 interferon) in the subject. Interferons (IFNs) are a group of signal proteins produced and released by host cells in response to the presence of one or more pathogens to enhance the defenses of surrounding cells against one or more pathogens. IFNs also have a variety of other functions. 1) activate immune cells such as NK cells and macrophages; 2) Increases 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 INFs include IFN-α (alpha), IFN-β (beta), IFN-δ (delta), IFN-ε (epsilon), IFN-κ (kappa), IFN-τ (tau), IFN- ω (omega), and IFN-ζ (zeta). All type 1 IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR), which consists of IFNAR1 and IFNAR2 chains.

Interferons have been studied as cancer therapy because of their antitumor activity, which exhibits two different effects: tumor-intrinsic and/or immunomodulatory effects. IFN regulates the expression of many genes that directly affect tumor cell growth, proliferation, differentiation, survival, migration and other specialized functions. In some cases, in vitro treatment with type 1 IFN has a direct antiproliferative effect due to the prolongation of all phases of the cell cycle by IFN. In some cases, CRKL, one of the CRK proteins activated by type 1 IFN, interacts with the tumor suppressor gene, small G-protein RAP1A, to inhibit RAS family GTPase, resulting in growth arrest of cancer cells. IFNs are known to regulate two major apoptotic responses. The two apoptosis responses are extrinsic (apoptotic receptor-mediated pathway) and intrinsic (mitochondrial) pathways. In response to type 1 IFN, upregulation of sensor protein activation (eg, DR receptor) occurs, leading to apoptosis of tumor cells.

IFNs exert extrinsic effects 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 the activity of anticancer immunity. For example, enhancing the activity of α/β T cells, γ/δ T cells, NK cells and dendritic cells, as well as inhibiting the activity of immune-suppressive cells, such as regulatory T cells, bone marrow-derived Inhibits the conversion of suppressor cells and tumor-associated macrophages. Type 1 IFN also acts directly on tumor cells to improve antigen expression and is a stress ligand recognized by numerous immune-interacting molecules (e.g., major histocompatibility complex class 1 (MHC I) and germline-encoded immunoreceptors). ) is up-regulated.

One aspect of the method includes treating the subject having cancer by administering to the subject a therapeutically effective amount of an ENPP1 inhibitor. In one embodiment, the subject may be a subject diagnosed with or suspected of having cancer. Any suitable ENPP1 inhibitor may be used in the subject. In one embodiment, the cancer is adrenal, liver, kidney, bladder, breast, colon, stomach, ovary, cervix, uterus, esophagus, colorectal, prostate, pancreas, lung (small and non-small cell), thyroid, carcinoma, sarcoma , glioblastoma, melanoma, and any one cancer selected from various head and neck cancers. In one embodiment, the cancer is lymphoma.

In one embodiment, the effective amount of the compound ranges from about 10 ng to about 100 mg, e.g., from about 10 ng to about 50 ng, from about 50 ng to about 150 ng, from 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 ug, about 1 ug to about 10 ug, about 10 ug to about 50 ug, about 50 ug to about 150 ug, about 150 ug to about 250 ug, about 250 ug to about 500 ug, about 500 ug to about 750 ug, about 750 ug to about 1 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, about 50 mg to about 100 mg can be in the range of The amount may be a single dose or a total daily dose. The total daily amount may range from 10 ng to 100 mg, or from 100 mg to about 500 mg, or from 500 mg to about 1000 mg.

In one embodiment, a single dose of the compound is administered. In other embodiments, multiple doses are administered. When the multiple doses are administered over a period of time, the compound is administered twice daily (bid), daily (qd), every other day (qod), every 3 days, 3 times per week (tiw), or twice per week (biw). may be administered.

combination therapy

combination therapy

An ENPP1 inhibitor compound of the invention may be administered to a subject alone or in combination with an additional active agent or additional therapy, eg, radiation therapy. The terms "agent", "compound" and "drug" are used interchangeably herein. In one embodiment, the methods of the present invention administer to the subject an additional agent, e.g., a small molecule, a chemotherapeutic agent, an antibody, an antibody-drug conjugate, an aptamer, a protein, an immune checkpoint inhibitor, or radiotherapy in parallel or sequentially in combination. or administering.

"Co-administration" or "in combination with" includes the administration of two or more therapeutic agents simultaneously, concurrently, or sequentially, without any specific time limit. In some embodiments, agents or agents are present in the body of a cell or subject concurrently or simultaneously exert a biological or therapeutic effect. In some embodiments, the therapeutic agents are in the same composition or unit dosage form. In some embodiments, the therapeutic agents are separate compositions or unit dosage forms. In some embodiments, the first agent is administered prior to administration of the second therapeutic agent (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 after (eg 5 minutes, 15 weeks) 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, after 6 weeks, 8 weeks, 12 weeks).

"Concomitant administration" of additional therapy with a known therapeutic agent or composition comprising a disclosed compound of the present invention is the administration of a compound and a second agent or additional therapy such that both the known agent and the composition of the disclosed compound have a therapeutic effect. means to administer. Such concomitant administration may include simultaneous or previous administration of drugs in connection with administration of the compounds of the present invention. The routes of administration of the two agents may vary, and representative routes of administration are described in detail below. One of ordinary skill in the art will have no difficulty in determining the appropriate timing, sequence, and dosage for a drug or therapy and for a compound disclosed herein.

For the treatment of cancer, ENPP1 inhibitor compounds include alkylating agents, anti-metabolites, anti-tumor antibiotics, plant alkaloids, taxanes, nucleoside analogs, anthracyclines, thymidylate-targeting drugs, apoptosis modulators, cell cycle control inhibitors, colony stimulation. It may be administered in combination with a chemotherapeutic agent selected from the group consisting of factor-1 receptor inhibitors, CD47 inhibitors and others.

Combination with immunotherapeutic agents

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

For the treatment of cancer, the ENPP1 inhibitor compound may be administered in combination with a suitable cancer vaccine regimen, for example, a dendritic cell vaccine that promotes Th1/Th17 immunity. In some cases, the ENPP1 inhibitor compound is suitable for use as an adjuvant therapeutic in combination with Th-17-inducing vaccination.

Combination with radiation therapy

For cancer treatment methods, ENPP1 inhibitor compounds may be administered in combination with radiation therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after administration of radiation therapy. The combination of radiation therapy and administration of a compound of the invention may provide a synergistic therapeutic effect. When the subject is treated (RT) with radiation at an appropriate dosage and/or frequency during radiation therapy (RT), the production of cGAMP can be induced in the subject. Induced cGAMP levels can enhance therapeutic efficacy in a subject by an ENPP1 inhibitor compound preventing degradation of cGAMP, eg, enhancing as compared to levels achieved with RT alone. As such, the details of the methods of the present invention include administration of a reduced dosage and/or frequency/therapy of radiation therapy as compared to the dosage 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 invention at a dosage and/or frequency effective to reduce the risk of radiation damage to a subject, e.g., expected to occur under a therapeutically effective dosage. It is effective in reducing the risk of radiation damage.

In one embodiment, the method comprises administering to the subject an ENPP1 inhibitor prior to radiation therapy. In one embodiment, the method comprises administering an ENPP1 inhibitor to the subject after exposing the subject to radiation therapy. In another embodiment, the method comprises sequentially administering to a subject in need thereof radiation therapy, followed by an ENPP1 inhibitor, followed by an immune checkpoint inhibitor.

Combination with anticancer vaccine

In the case of a cancer treatment method, an ENPP1 inhibitor compound may be administered together with anticancer vaccine therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after administration of an anti-cancer vaccine therapy.

Combination with CAR-T

In the case of a cancer treatment method, an 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 administration of CAR-T cell therapy.

monotherapy

Myocardial regeneration promotion therapy

In the case of myocardial regeneration therapy, in one aspect, it comprises the step of administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a lesion due to myocardial infarction to treat the subject.

Hypophosphatemia treatment regimen

In the case of a method for treating hypophosphatemia, in one aspect, the method comprises administering to a subject having a lesion caused by a hypophosphatemic genetic disease, a therapeutically effective amount of an ENPP1 inhibitor to treat the subject.

pharmaceutical composition

Pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are readily available to those skilled in the art. Pharmaceutically acceptable auxiliary substances such as pH adjusting agents and buffers, isotonicity adjusting agents, stabilizing agents, wetting agents and the like are readily available to those skilled in the art.

In some embodiments, a compound of the invention is formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate and phosphate buffers of varying strengths from 5 mM to 1000 mM. In some embodiments, aqueous buffers include reagents that provide isotonic solutions. Such reagents include, but are not limited to, sodium chloride, sugars such as mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer further comprises a nonionic surfactant such as polysorbate 20 or 80. Optionally, the formulation may further comprise a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In another embodiment, the formulation is stored at about 4°C. The formulations may also be lyophilized, which generally contain a cryoprotectant such as sucrose, trehalose, lactose, maltose, mannitol and the like. Freeze-dried preparations can be stored for a long period of time even at room temperature.

In the present specification, a pharmaceutical composition may comprise or consist essentially of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a tautomer thereof, and additionally the pharmaceutical composition comprises one or more additional active agents of interest. It provides a pharmaceutical composition comprising or consisting essentially of. Any convenient active agent may be used in the present methods with the compounds of the present invention. In one embodiment, the compound of the invention and the checkpoint inhibitor, as well as the additional therapeutic agent as described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally or by other routes. In another embodiment, a compound of the present invention and a chemotherapeutic agent (particularly a chemotherapeutic agent capable of inducing cGAMP production in vivo), and an additional therapeutic agent described herein for combination therapy, are administered orally, subcutaneously, intramuscularly , intranasal, parenteral or other routes. The compound of the invention and the second active agent, if present, may be administered by the same route of administration or by different routes of administration. The therapeutic agent may be administered by any suitable means, including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, intratumoral injection into the organ affected.

The compounds of the present invention may be administered in unit dosage form and may be prepared by any method well known in the art. Such methods include the step of combining a compound of the present invention with a pharmaceutically acceptable carrier or diluent which constitutes one of one or more accessory ingredients. Pharmaceutically acceptable carriers are selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harming the subject or patient. This carrier may be solid or liquid, the type of which is generally selected according to the type of administration used.

Examples of suitable solid carriers include lactose, sucrose, gelatin, agar and bulk powder. Examples of suitable liquid carriers include water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents such as esters, emulsions, syrups or elixirs, suspensions and solutions reconstituted from non-foaming granules and/or including suspensions. Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening, thickening and melting agents.

Hereinafter, various aspects of the present invention will be described.

One aspect of the present invention provides a compound selected from a naphthyridinone derivative compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[Formula 1]

R ₁ is hydrogen; C ₁ -C ₁₃ alkyl group; or C ₃ -C ₁₀ cyclyl group; is,

R ₂ is -ZR ₃ -(R ₄ ) _m ,

Z is present or not, and 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 -, ; is

n is an integer from 0 to 8,

Wherein R ₃ is a C ₃ -C ₁₀ cyclyl group, a C ₃ -C ₁₀ heterocyclyl group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group,

wherein R ₄ is hydrogen; hydroxyl group; 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 ); amide group (-(C=O)NR ₅ R ₆ ); 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; sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₆ ); sulfamoylalkyl group (-(C _m H _m+2 )NR ₅ S(O) ₂ NHR ₆ ); sulfide group (-SR ₆ ); sulfone group (-S(O) ₂ R ₆ ); a phospyryl group (-P(O)R ₅ R ₆ ); connected to the same carbon as the carbon connected to R ₃ to form a 3 to 7 membered saturated ring; It is linked to the same carbon as the carbon linked to R ₃ to form a 3 to 7 membered hetero saturated ring containing one or more heteroatoms of N, O and S; It is connected to the carbon connected to R ₃ and the adjacent carbon to form a 3 to 7 membered saturated ring; or connected to the carbon connected to R ₃ and the adjacent carbon to form a 3 to 7 membered hetero saturated ring containing one or more heteroatoms of N, O and S;

m is an integer from 1 to 4,

The C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group, or C ₃ -C ₁₀ cyclyl group may include hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₅ R ₆ ); nitro group (-N(O) ₂ ); 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-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₅ R ₆ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it includes one or more substituents selected from the group consisting of C ₃ -C ₁₀ heterocyclyl group,

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ₅ R ₆ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; a C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₅ R ₆ ); nitro group (-N(O) ₂ ); 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-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₅ R ₆ ); C ₆ -C ₁₀ aryl group; Containing one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group,

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 heterocyclyl group; or R ₅ together with the nitrogen or carbon atom connected to R ₆ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of, hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group, and Forms a 3 to 7 membered saturated ring that may be optionally substituted with at least one of a cyano group,

The C ₃ -C ₁₀ heteroaryl group and the C ₃ -C ₁₀ heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

In the definition of a substituent in the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be "saturated alkyl" containing no alkenyl or alkynyl moieties, or "unsaturated alkyl" containing at least one alkenyl or alkynyl moiety. "Alkenyl" means a group comprising at least one carbon-carbon double bond, and "alkynyl" means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, may each be cyclic, branched or straight-chain.

The term 'aryl', alone or in combination with other radicals, refers to a carbocyclic containing 6 carbon atoms which may be further fused with a second 5 or 6 membered carbocyclic group which may be aromatic, saturated or unsaturated. aromatic monocyclic group. Examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, teprahyadronaphthyl, and the like. Aryl may be linked with other groups at appropriate positions on the aromatic ring.

The term 'alkoxy' refers to an alkyl group linked to another group through an oxygen atom (ie, -O-alkyl). Alkoxy groups may be unsubstituted or substituted with one or more suitable substituents. Examples of the alkoxy group include a (C1-C6)alkoxy group, 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, 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, -O-t-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

The term 'phenoxy' refers to a phenyl group linked to another group through an oxygen atom (ie, -O-aryl). The phenoxy group is unsubstituted or one or more halogen; an alkyl group; It may be substituted with an aryl group and a heteroaryl group, but is not limited thereto.

The term 'amine group' refers to an alkyl group linked to another group through a nitrogen atom (ie, -NH- or -N-alkyl). The amine group may be unsubstituted or substituted with one or more suitable substituents. Examples of the amine group 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, -N-propyl-N-iso Butyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N -Butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N -dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N,N-dihexyl.

The term 'halogen group' means fluorine, chlorine, bromine or iodine.

The term 'heterocycle group' refers to a heteroaromatic compound containing at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise specified. Preferably, the heterocyclyl group may include a pyrrolidine group, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mol It may include a porine group, but is not limited thereto.

The term 'heteroaryl group' refers to a heteroaromatic compound including at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise specified. Preferably, the heteroaryl group is a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, an isoquinoline group, It may include, but is not limited to, an isoxazole group, an oxazole group, a thiazole group, and a pyrrole group.

In one aspect of the present invention, R ₁ Is hydrogen; Or a C ₁ -C ₅ alkyl group; and R ₃ is a C ₅ -C ₇ heterocyclyl group, a C ₆ -C ₈ aryl group, or a C ₅ -C ₁₀ heteroaryl group, a naphthyridinone derivative compound represented by Formula 1 , a pharmaceutically acceptable salt thereof, a hydrate thereof and a stereoisomer thereof.

In one aspect of the present invention, R ₁ Is hydrogen; Or a C ₁ -C ₃ alkyl group; and 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 phenathrene; 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 purines; substituted or unsubstituted cyclopropane; or substituted or unsubstituted cyclobutane; a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

In one aspect of the present invention, R ₁ Is hydrogen; Or a C ₁ -C ₃ alkyl group; and R ₃ is substituted or unsubstituted benzene; or a substituted or unsubstituted piperidine; a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

또는

인, 화학식 1로 표시되는 나프티리딘온 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R ₂ is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Provided is a compound selected from phosphorus, a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

또는

인, 화학식 1로 표시되는 나프티리딘온 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R ₄ is halogen, methyl group, 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),

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Provided is a compound selected from phosphorus, a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

In one aspect of the present invention, the compound is a naphthyridinone derivative compound represented by Formula 1, characterized in that any one selected from the group consisting of the following compound numbers 1 to 148, a pharmaceutically acceptable salt thereof, Provided are compounds selected from hydrates thereof and stereoisomers thereof:

Selected compounds:

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 number 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

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

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

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

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

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

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

Compound number 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 15: ( R )-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 17: ( R )-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

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

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

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

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

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

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

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

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

Compound No. 26: 5-(Asoindorin-5-yl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

Compound number 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1 H )-one hydrochloride;

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

Compound number 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1 H )-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 number 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)sulfa mide hydrochloride;

Compound No. 49: ( R )-( N- (1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfa mide 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 -Cyclophyllophil- 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 -Cyclophyllophil- 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)sulfa mide 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)sulfa mide hydrochloride;

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

Compound number 64: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindorin-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 (1 H )- 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 number 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 number 72: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

Compound number 73: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate;

Compound No. 74: Ethylhydrogen (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(1 H )-one dihydrochloride;

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

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

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

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

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

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

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

Compound No. 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1 H )-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 di hydrochloride;

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)isoindorin-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-dihydroisoquinoline-2(1 H )-yl)sulfamide dihydrochloride;

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

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

Compound No. 108: (7- (methyl (7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl) amino) -3,4-dihydroisoquinoline-2 (1 H )- 1) 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(1 H )-one hydrochloride;

Compound No. 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1 H )-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(1 H )-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(1 H )-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)sulfa Moyl) 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-4yl)piperidin-4-yl)sulfamide;

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

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

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

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

Compound No. 128: N -((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)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(1 H )-one hydrochloride;

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

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

Compound No. 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1 H )-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-diisoquinoline-2(1) H )-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 (1 H )-sulfamide hydrochloride;

Compound No. 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoguanoline-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.

The compound of Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, and preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, and 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, It may be at least one selected from the group consisting of methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may include hydrates and solvates. The hydrate may mean formed by combining the compound of Formula 1 with a water molecule.

Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, wherein the compound according to one aspect of the present invention is included as an active ingredient.

Another aspect of the present invention provides an ENPP 1 inhibitor comprising the compound according to one aspect of the present invention as an active ingredient.

Another aspect of the present invention provides a STING pathway activator, in which the compound according to one aspect of the present invention is included as an active ingredient.

In another aspect of the present invention, the cancer is a cancer associated with inhibition of ENPP 1, it provides a pharmaceutical composition for preventing, alleviating or treating cancer.

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

The pharmaceutical composition according to the present invention has excellent ability to inhibit the activity of ENPP 1.

Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth. Cancer diseases that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition of the present invention are gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, 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, and the like.

Another aspect of the present invention provides an ENPP 1 inhibitor comprising any one of the compounds as an active ingredient.

Another aspect of the present invention provides a STING pathway activator, in which any one of the above compounds is included as an active ingredient.

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, preferably primates including humans, more preferably humans.

As used herein, 'treatment' refers to alleviation or amelioration of symptoms, reduction of the scope of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of disease state, partial or complete recovery, prolongation of survival and other beneficial therapeutic results, etc. may be used in the meaning of including all of them.

In addition, as used herein, the treatment of cancer refers to treatment of all cancer cells, and cancer includes angiogenesis of endothelial cells and mitosis (solid tumors, tumor metastases and benign tumors). For example, cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital organ cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacytoma, lung cancer, squamous cell carcinoma, large cell carcinoma, Small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, adenocarcinoma, adenocarcinoma, follicular adenocarcinoma, undifferentiated cancer, papillary cancer, seminomas, melanoma, sarcoma, bladder cancer, liver and bile duct cancer, kidney cancer, myeloid disease, lymphoid Disease, Hodgkin's disease, hair cell cancer, oral cancer, pharyngeal (oral) cancer, labial cancer, tongue cancer, small intestine cancer, colon-rectal cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma or sarcoidosis suppurativa may include, but is not limited thereto.

Depending on the mode and method of use of the pharmaceutical composition of the present invention, the content of the compound represented by Formula 1 as an active ingredient, a pharmaceutically acceptable salt thereof, or a hydrate thereof may be appropriately adjusted according to the selection of those skilled in the art.

For example, the pharmaceutical composition may contain the compound represented by Formula 1, a pharmaceutically acceptable salt, or hydrate thereof 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 composition. can be included as

The pharmaceutically acceptable salt or hydrate of the compound represented by Formula 1 may be included alone in the pharmaceutical composition, or may be included together with other pharmaceutically acceptable carriers, excipients, diluents or sub-components.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , dextrin, calcium carbonate, propylene glycol, liquid paraffin, and at least one selected from the group consisting of physiological saline, but is not limited thereto, and all common carriers, excipients or diluents may be used. In addition, the pharmaceutical composition may contain conventional fillers, bulking agents, binders, disintegrants, anti-aggregating agents, lubricants, wetting agents, pH adjusting agents, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective colors, glycerin , a fragrance, emulsifier or preservative may be further included.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be administered in combination with another anticancer agent for treating cancer or tumor, thereby enhancing the therapeutic effect of the anticancer agent.

Specifically, the pharmaceutical composition may be used as a combination therapy applied at the same time or at the same time by further including one or more other anticancer agents or other therapeutic agents known to be effective for the treatment or prevention of cancer in addition to the active ingredient. Other anticancer agents or other therapeutic agents that can be applied to the combination therapy include, for example, Gleevec®, imatinib), Sutent®, sunitinib), Herceptin® (Herceptin®, Trastuzumab), Velcade®, Bortezomib. ), dexamethasone, nexavar (Nexavar®, Sorafenib), and one or more compounds selected from the group consisting of aromatase inhibitors or kinase inhibitors, but is not limited thereto.

The method of administering the pharmaceutical composition may be oral or parenteral. For example, it may be administered through several routes including oral, transdermal, subcutaneous, intravenous or intramuscular. In addition, the formulation of the composition may vary depending on the method of use, and it is formulated using a method well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. can be In general, solid preparations for oral administration include tablets (TABLETS), pills, soft or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS), and granules (GRANULES), and such preparations include one or more An excipient, for example, may be prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions (SUSTESIONS), internal solutions, emulsions (EMULSIONS), and syrups (SYRUPS). Sweetening agents, flavoring agents, preservatives, and the like may be included. Forms for parenteral administration include creams, lotions, ointments, PLASTERS, LIQUIDS AND SOULTIONS, aerosols, FRUIDEXTRACTS, and elixirs. (ELIXIR), infusions (INFUSIONS), sachets (SACHET), patches (PATCH) or injections (INJECTIONS) may be in the form of, etc., and preferably in the form of an isotonic aqueous solution or suspension in the case of an injection formulation. .

The pharmaceutical composition may further contain adjuvants such as sterilizing agents, preservatives, stabilizers, wetting agents or emulsifying agents, salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, and conventional mixing, granulation Alternatively, it may be formulated according to a coating method, and in addition, it may be formulated using an appropriate method known in the art.

In addition, the dosage of the pharmaceutical composition can be determined in consideration of the administration method, the age, sex, severity, condition of the patient, the absorption of the active ingredient in the body, the inactivation rate, and the drug to be used in combination, once or several times. It can be administered in divided doses. As an active ingredient of the pharmaceutical composition, preferably in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, per day to mammals including humans, once a day or divided into oral or parenteral It may be administered by the oral route.

Another embodiment of the present invention provides a method for treating cancer, comprising administering a compound represented by the following formula (1), a pharmaceutically acceptable salt, or hydrate thereof in a therapeutically effective amount.

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

"Therapeutically effective amount" of the present invention means an amount of an active ingredient for a mammal that is effective for the prevention or treatment of cancer, and the therapeutically effective amount includes the type of disease, the severity of the disease, the active ingredient and other ingredients contained in the composition. It can be adjusted according to various factors including the type and content of the drug, the type of dosage form, and the patient's age, weight, general health, sex and diet, administration time, administration route and blood clearance of the composition, treatment period, and concurrently used drugs. However, preferably, as described above, in an amount of 0.001 to 100 mg/kg of body weight, preferably 0.01 to 35 mg/kg of body weight, per day, once a day or divided, administered by oral or parenteral route can do.

The present invention also relates to a method for preparing a compound selected from the naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

On the other hand, the present invention is characterized in that the method for preparing the compound represented by the formula (1). The manufacturing method according to the present invention will be described in detail as follows.

In one embodiment, the compound represented by Formula 1 of the present invention may be prepared by any one or more methods of Preparation Methods 1 to 4 below.

Manufacturing method 1

The naphthyridinone derivative compound of Formula 1 according to one aspect of the present invention may be prepared according to the preparation method according to Scheme 1 below.

[Scheme 1]

Manufacturing method 2

The naphthyridinone derivative compound of Formula 1 according to an aspect of the present invention may be prepared according to the preparation method according to Scheme 2 below.

[Scheme 2]

Manufacturing method 3

The naphthyridinone derivative compound of Formula 1 according to one aspect of the present invention may be prepared according to the preparation method according to Scheme 3 below.

[Scheme 3]

Manufacturing method 4

The naphthyridinone derivative compound of Formula 1 according to an aspect of the present invention may be prepared according to a preparation method according to Scheme 4 below.

[Scheme 4]

Hereinafter, the present invention will be described in detail by way of 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 by the following embodiments.

[Production Example 1]

Preparation Example 1 goes through a process of preparing product 3, product 4, product 7, or product 8.

Preparation Example 1:

[Scheme 1]

Step 1: In a round bottom flask 1 (1.0 equiv) with palladium(II) acetate (0.050 equiv), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv), 2 (1.3 equiv) and potassium carbonate (3.0 equiv) are dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) and refluxed under nitrogen for 16 hours. 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 obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 3 (40-60% yield).

Examples of the present invention prepared according to step 1 as described above are as follows.

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.57 (d, J = 4.9 Hz, 1H), 7.99 (d, J = 9.8 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.3) Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 4.9 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 9.7 Hz, 1H), 1.52 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.58 (d, J = 4.9 Hz, 1H), 7.96 (d, J = 9.7 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.45 ( d, J = 7.7 Hz, 1H), 7.38 (d, J = 9.8 Hz, 2H), 7.24 (d, J = 5.0 Hz, 1H), 6.63 (d, J = 9.8 Hz, 1H), 4.33 (s, 2H), 1.45 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.57 (d, J = 4.9 Hz, 1H), 7.96 (d, J = 9.7 Hz, 1H), 7.50 - 7.44 (m, 4H), 7.24 (d, J ) = 4.9 Hz, 1H), 6.64 (d, J = 9.8 Hz, 1H), 4.34 (s, 2H), 1.47 (s, 9H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.40 - 7.29 (m) , 2H), 7.21 (d, J = 5.0 Hz, 1H), 6.56 (d, J = 9.8 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 1.41 (s, 9H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.49 (t, J = 6.3 Hz, 1H), 7.47 - 7.39 (m, 4H), 7.27 (d, J = 4.9 Hz, 1H), 6.68 (d, J = 9.8 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 3.73 (s, 3H), 1.41 (s, 9H).

Step 2: Add 3 (1.0 equiv.) to a round-bottom flask and add dichloromethane (0.040 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) is added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (60-80% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.63 (d, J = 4.9 Hz, 1H), 7.89 (d, J = 9.8 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.64 ( d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 4.9 Hz, 1H), 6.67 (d, J = 9.8 Hz, 1H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.66 (d, J = 5.1 Hz, 1H), 8.01 (d, J = 9.7 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.64 - 7.58 (m , 2H), 7.35 (d, J = 5.2 Hz, 1H), 6.74 (d, J = 9.5 Hz, 1H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.62 (d, J = 4.9 Hz, 1H), 7.54 (dd, J = 9.8, 2.6 Hz, 1H), 7.48 (d, J ) = 9.2 Hz, 1H), 7.30 (d, J = 3.7 Hz, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.59 (d, J = 9.8 Hz, 1H), 5.33 (s, 4H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.59 (d, J = 4.9 Hz, 4H), 7.87 (d, J = 9.8 Hz, 1H), 7.78 (dd, J = 7.0) , 1.9 Hz, 1H), 7.64 - 7.55 (m, 1H), 7.56 - 7.46 (m, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.58 (d, J = 9.8 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.63 (d, J = 5.0 Hz, 1H), 7.93 (d, J = 9.7 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.63 - 7.59 (m, 2H), 7.29 (d, J = 5.0 Hz, 1H), 6.70 (d, J = 9.7 Hz, 1H), 4.25 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.61 (d, J = 4.9 Hz, 3H), 7.65 (d, J = 10.4 Hz, 1H), 7.61 - 7.51 (m, 2H) ), 7.45 (dd, J = 9.7, 2.7 Hz, 1H), 7.22 (d, J = 4.9 Hz, 1H), 6.61 (d, J = 9.8 Hz, 1H), 4.16 (q, J = 5.6 Hz, 2H) )

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.65 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 9.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.32 (d, J = 5.0 Hz, 1H), 6.74 (d, J = 9.7 Hz, 1H), 4.32 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.64 (d, J = 4.9 Hz, 4H), 7.67 - 7.57 (m, 1H), 7.50 (d, J = 1.9 Hz, 1H) ), 7.43 (dd, J = 8.1, 4.6 Hz, 1H), 7.26 (d, J = 4.9 Hz, 1H), 6.63 (d, J = 9.8 Hz, 1H), 4.22 (d, J = 5.6 Hz, 2H) ).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.55 (d, J = 5.0 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.56 (d, J = 8.2) Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 5.0 Hz, 2H), 6.56 (d, J = 9.8 Hz, 1H), 4.53 (d, J = 6.7 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H).

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

LC-MS (ESI) calcd for C ₁₆ H ₁₅ N ₃ O [M + H] ⁺ 265.12, found m/z 266.17

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.69 (s, 3H), 8.57 (d, J = 5.0 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 9.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 5.0 Hz, 1H), 6.59 (d, J = 9.8 Hz, 1H), 1.70 ( s, 6H)

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

LC-MS (ESI) calcd for C ₁₇ H ₁₇ N ₃ O [M + H] ⁺ 279.14, found m/z 280.19

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

LC-MS (ESI) calcd for C ₁₇ H ₁₇ N ₃ O [M + H] ⁺ 279.14, found m/z 280.29

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

LC-MS (ESI) calcd for C19H19N3O [M + H]+ 305.15, found m/z 306.25

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.21 (s, 2H), 8.62 (d, J = 4.9 Hz, 1H), 7.68 (d, J = 10.5 Hz, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.48 (dd, J = 9.8, 2.7 Hz, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.61 (dd, J = 9.8, 1.9 Hz, 1H) ), 4.26 (t, J = 5.5 Hz, 2H), 3.01 (dd, J = 12.2, 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H)

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

LC-MS (ESI) calcd for C ₁₇ H ₁₈ FN ₃ O [M + H] ⁺ 311.14, found m/z 312.03

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.52 (s, 2H), 8.62 (d, J = 4.9 Hz, 1H), 7.70 (d, J = 10.3 Hz, 1H), 7.59 (d, J = 4.4 Hz, 2H), 7.46 (dd, J = 9.7, 2.6 Hz, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.61 (d, J = 9.7 Hz, 1H), 4.36 (s, 2H), 0.93 (s, 2H), 0.79 (t, J = 6.6 Hz, 2H)

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.30 (s, 3H), 8.59 (d, J = 4.9 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.78 - 7.69 (d, 1H), 7.55 (d, J = 10.6 Hz, 1H), 7.48 - 7.43 (dd, 1H), 7.24 (d, J = 4.9 Hz, 1H), 4.28 (t, J = 5.7 Hz, 2H) , 2.50 (s, 3H)

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.13 (s, 2H), 8.60 (d, J = 4.9 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.55 (d, J = 11.9 Hz, 1H), 7.48 - 7.43 (dd, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.61 (dd, J ) = 9.8, 1.7 Hz, 1H), 4.28 (s, 2H), 3.06 (q, J = 7.0 Hz, 2H), 1.34 - 1.19 (t, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.48 (s, 2H), 8.59 (d, J = 4.9 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 9.8 Hz, 1H), 7.54 (d, J = 10.5 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.61 (dd, J ) = 9.8, 1.9 Hz, 1H), 4.37 (s, 2H), 2.77 (s, 1H), 0.88 (d, J = 15.4 Hz, 2H), 0.79 (q, J = 6.7 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.96 (s, 2H), 8.58 (d, J = 4.9 Hz, 1H), 7.74 (d, J = 9.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 4.9 Hz, 1H), 6.57 (dd, J = 9.8 , 1.6 Hz, 1H), 4.60 (s, 4H)

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.60 (s, 2H), 8.57 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.41 (d, J = 6.1 Hz, 3H), 7.18 (d, J = 4.9 Hz, 1H), 6.57 (d, J = 9.8 Hz, 1H), 4.34 (brs, 2H), 3.41 (brs, 2H), 3.11 (t, J = 6.1 Hz, 2H)

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

LC-MS (ESI) calcd for C17H14FN3O [M + H]+ 295.11, found m/z 296.11

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 4.9 Hz, 1H), 7.75 - 7.65 (m, 3H), 7.59 (d, J = 7.9 Hz, 2H), 7.29 (d, J ) = 4.9 Hz, 1H), 6.75 (d, J = 9.8 Hz, 1H), 4.17 (d, J = 5.6 Hz, 2H), 3.76 (s, 3H).

[Preparation of Sulfamide 6 ]: Put a solution of tert -butanol (1.0 equiv.) in anhydrous dichloromethane (1.4 M) in a round-bottom flask, and slowly add 5 (1.0 equiv.) drop by drop. Thereafter, N,N -dimethylpyridin-4-amine (2.0 equivalents) is added. The solution is stirred at room temperature for 1 hour. After the reaction is complete, it is washed several times with water. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained colorless powder 6 (80% yield) was used as a reactant without further purification.

Step 3: Put a solution of triethylamine (2.5 eq) in dichloromethane (0.1 M) in a round bottom flask. Then, 4 (1.0 equivalent) and 6 (1.1 equivalent) were added and stirred at room temperature for one day. When the reaction is completed, the mixture is concentrated under reduced pressure and dried, and the obtained residue is extracted using dichloromethane and water. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 7 (30-60% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.57 (d, J = 4.9 Hz, 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.36 ( d, J = 8.5 Hz, 2H), 7.26 (d, J = 4.9 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 9.8 Hz, 1H), 1.35 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.58 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 9.8 Hz, 1H), 7.54 (d, J = 4.7 Hz, 2H), 7.51 ( s, 1H), 7.44 - 7.38 (m, 1H), 7.27 (d, J = 4.9 Hz, 1H), 6.65 (d, J = 9.8 Hz, 1H), 4.30 (s, 2H), 1.39 (s, 9H) ).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.51 (d, J = 8.0) Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 4.9 Hz, 1H), 6.54 (d, J = 9.8 Hz, 1H), 4.09 (d, J = 6.1 Hz, 3H), 1.37 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.59 (d, J = 5.0 Hz, 1H), 7.96 (d, J = 9.8 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.31 - 7.23 (m, 3H), 6.66 (d, J = 9.8 Hz, 1H), 4.34 (s, 2H), 1.44 (s, 9H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.45 ( d, J = 8.2 Hz, 2H), 7.25 (d, J = 4.9 Hz, 1H), 6.68 (d, J = 9.8 Hz, 1H), 4.19 (d, J = 6.1 Hz, 2H), 3.73 (s, 3H), 1.38 (s, 9H).

Step 4: Put 7 (1.0 equivalent) in a round-bottom flask, add dichloromethane (0.04 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2M) was added and stirred at room temperature for 16 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 8 (40-80% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.60 (d, J = 5.0 Hz, 1H), 8.04 (d, J = 9.8 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.39 - 7.34 (m , 2H), 7.31 (d, J = 5.1 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 9.8 Hz, 1H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.47 (s, 2H), 8.57 (d, J = 4.9 Hz, 1H), 7.80 (d, J = 9.8 Hz, 1H), 7.58 (dd, J = 7.8, 2.1 Hz, 1H), 7.42 (dd, J = 10.5, 8.5 Hz, 3H), 7.28 - 7.21 (m, 6H), 6.56 (d, J = 9.8 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.64 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 9.7 Hz, 1H), 7.57 (q, J = 3.9, 2.9 Hz, 3H), 7.47 - 7.40 (m, 1H), 7.37 (d, J = 5.1 Hz, 1H), 6.75 (d, J = 9.7 Hz, 1H), 4.32 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 9.8 Hz, 1H), 7.66 - 7.56 (m, 1H) ), 7.49 - 7.43 (m, 1H), 7.43 - 7.32 (m, 1H), 7.20 (d, J = 4.9 Hz, 2H), 6.55 (d, J = 9.8 Hz, 1H), 4.22 (s, 2H) .

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

¹ H NMR (400 MHz, Acetone-d6) δ 8.45 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.8 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.14 (d, J ) = 5.0 Hz, 1H), 6.86 - 6.81 (m, 2H), 6.55 (d, J = 9.8 Hz, 1H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.61 (d, J = 5.1 Hz, 1H), 8.03 (d, J = 9.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.50 ( d, J = 8.4 Hz, 2H), 7.33 (d, J = 5.1 Hz, 1H), 6.72 (d, J = 9.7 Hz, 1H), 4.32 (s, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.62 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 10.3 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.35 - 7.28 (m, 3H), 6.73 (d, J = 10.3 Hz, 1H), 4.38 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 7.45 (ddd, J = 23.0, 16.6, 8.7 Hz, 5H), 7.30 (s) , 1H), 7.22 (d, J = 4.7 Hz, 1H), 6.74 (s, 2H), 6.58 (d, J = 9.6 Hz, 1H), 4.21 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.62 (d, J = 4.9 Hz, 1H), 7.57 (dd, J = 9.8, 2.7 Hz, 1H), 7.49 (t, J ) = 7.2 Hz, 1H), 7.31 (t, J = 6.7 Hz, 2H), 7.26 (d, J = 4.9 Hz, 1H), 6.76 (s, 1H), 6.59 (d, J = 9.8 Hz, 1H), 4.26 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.63 (d, J = 4.9 Hz, 1H), 7.45 (d, J = 9.8 Hz, 1H), 7.35 (d, J = 8.6) Hz, 2H), 7.29 (d, J = 4.9 Hz, 1H), 7.10 (d, J = 50.9 Hz, 1H), 6.77 (s, 1H), 6.60 (d, J = 9.8 Hz, 1H), 4.22 ( d, J = 6.2 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 3H), 8.57 (t, J = 5.4 Hz, 11H), 7.71 (dd, J = 9.0, 3.2 Hz, 10H), 7.59 (d, J ) = 8.2 Hz, 7H), 7.21 (d, J = 4.9 Hz, 4H), 6.60 (d, J = 9.8 Hz, 3H), 4.57 - 4.42 (m, 3H), 1.58 (d, J = 6.8 Hz, 9H) ).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.26 (brs, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.56 (d, J = 8.2) Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.19 (t, J = 10.8 Hz, 2H), 6.56 (d, J = 9.8 Hz, 2H), 4.53 (d, J = 5.9 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.26 (brs, 1H), 8.55 (d, J = 5.0 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.56 (d, J = 8.2) Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 5.0 Hz, 1H), 6.56 (d, J = 9.8 Hz, 1H), 6.06 (brs, 4H), 4.53 ( q, J = 6.8 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H).

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

LC-MS (ESI) calcd for C ₁₆ H ₁₅ FN ₄ O ₃ S [M + H] ⁺ 362.08, found m/z 363.53

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

LC-MS (ESI) calcd for C ₁₆ H ₁₅ FN ₄ O ₃ S [M + H] ⁺ 362.08, found m/z 363.53

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.53 (q, J = 8.4) Hz, 4H), 7.22 (d, J = 4.9 Hz, 1H), 6.96 (s, 2H), 6.57 (d, J = 9.8 Hz, 1H), 4.19 (s, 2H), 2.60 (s, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 9.8 Hz, 1H), 7.57 (d, J = 8.2) Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 5.0 Hz, 1H), 6.91 (s, 2H), 6.57 (d, J = 9.8 Hz, 1H), 4.33 ( s, 2H), 3.25 - 3.10 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 7.79 (d, J = 9.8 Hz, 1H), 7.62 (t, J = 7.8) Hz, 1H), 7.40 (dd, J = 23.8, 9.8 Hz, 2H), 7.24 (d, J = 4.9 Hz, 1H), 6.99 (s, 2H), 6.58 (d, J = 10.0 Hz, 1H), 4.24 (s, 2H), 2.65 (s, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.57 (d, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.38 (dd, J = 17.7, 9.3 Hz) , 2H), 7.31 (s, 1H), 7.18 (s, 1H) 7.05 (s, 1H), 6.95 (S, 1H) 6.58 (d, J = 10.1 Hz, 1H), 4.37 (s, 2H), 1.25 (m, 2H), 1.09 (t, J = 7.0 Hz, 3H)

[Example 54]: N -Cyclophyllophil- N- (2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydro chloride

LC-MS (ESI) calcd for C ₁₈ H ₁₇ FN ₄ O ₃ S [M + H] ⁺ 389.26, found m/z 389.3

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.55 (dd, J = 9.8, 2.7 Hz, 1H), 7.50 (t, J ) = 7.9 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 6.2 Hz, 2H), 7.24 (d, J = 4.8 Hz, 1H), 7.00 (s, 2H), 6.57 (d, J = 9.2 Hz, 1H), 4.22 (s, 2H), 2.64 (s, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 7.53 (dd, J = 9.7, 2.8 Hz, 1H), 7.45 (dt, J ) = 15.6, 7.2 Hz, 3H), 7.24 (d, J = 4.9 Hz, 1H), 6.58 (d, J = 9.8 Hz, 1H), 4.36 (s, 2H), 3.16 (q, J = 7.2 Hz, 2H) ), 1.09 (t, J = 7.1 Hz, 3H).

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

LC-MS (ESI) calcd for C ₁₈ H ₁₉ FN ₄ O ₃ S [M + H] ⁺ 391.25, found m/z 391.2

[Example 58]: N -Cyclophyllophil- N- (3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydro chloride

¹ H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 7.52 (dd, J = 9.7, 2.8 Hz, 1H), 7.45 (t, J ) = 7.7 Hz, 2H), 7.37 (s, 1H), 7.34 (d, J = 5.7 Hz, 2H), 7.23 (d, J = 4.9 Hz, 1H), 7.21 (s, 1H), 7.08 (s, 1H) ), 6.58 (d, J = 9.8 Hz, 1H), 4.39 (s, 2H), 0.64 (d, J = 5.1 Hz, 4H)

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.59 (d, J = 8.2) Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 4.9 Hz, 1H), 6.89 (s, 1H), 6.57 (d, J = 9.8 Hz, 1H), 5.11 ( q, J = 7.1 Hz, 1H), 2.52 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.71 (d, J = 5.4 Hz, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.56 ( d, J = 8.3 Hz, 2H), 7.51 (d, J = 5.4 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 5.26 (q, J = 7.1 Hz, 1H), 2.46 - 2.37 ( m, 1H), 1.85 (d, J = 7.1 Hz, 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).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.69 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.58 ( d, J = 8.2 Hz, 2H), 7.46 (d, J = 5.3 Hz, 1H), 6.85 (d, J = 9.6 Hz, 1H), 5.31 (q, J = 7.3 Hz, 1H), 2.67 (s, 3H), 1.69 (d, J = 7.0 Hz, 3H).

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

LC-MS (ESI) calcd for C ₁₇ H ₁₇ FN ₄ O ₃ S [M + H] ⁺ 376.10, found m/z 377.25

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

LC-MS (ESI) calcd for C17H17FN4O3S [M + H]+ 376.10, found m/z 377.28

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 9.8 Hz, 1H), 7.53 (d, J = 7.9) Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 6.99 (s, 2H), 6.56 (dd, J = 9.8 , 1.9 Hz, 1H), 4.60 (s, 4H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 9.8 Hz, 1H), 7.37 (d, J = 7.8) Hz, 1H), 7.34 - 7.27 (m, 2H), 7.20 (d, J = 5.0 Hz, 1H), 6.97 (s, 2H), 6.56 (d, J = 9.8 Hz, 1H), 4.30 (s, 2H) ), 3.33 (t, J = 5.9 Hz, 2H), 3.01 (t, J = 5.6 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.24 (brs, 1H), 8.64 (s, 1H), 8.16 (d, J = 6.5 Hz, 1H), 7.47 - 7.23 (m, 3H), 7.10 (d , J = 51.1 Hz, 1H), 6.82 (s, 1H), 6.57 (brs, 2H), 6.37 (d, J = 6.2 Hz, 1H), 4.00 (s, 2H), 3.12 (d, J = 7.2 Hz) , 2H), 2.82 (t, J = 7.4 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.46 ( d, J = 7.9 Hz, 2H), 7.27 (d, J = 4.9 Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H), 4.18 (s, 2H), 3.73 (s, 3H).

[Scheme 1-1]

4 (1.0 equiv) and RSO ₂ Cl in a round bottom flask (1.1 equivalents) was dissolved in dichloromethane (0.08 M), triethylamine (4.5 equivalents) was added thereto, and stirred at room temperature for 16 hours. After the reaction was completed, water was poured into the mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 9 (30-50% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.58 (d, J = 5.0 Hz, 1H), 7.95 (d, J = 9.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.50 ( d, J = 8.1 Hz, 2H), 7.25 (d, J = 5.0 Hz, 1H), 6.64 (d, J = 9.8 Hz, 1H), 4.37 (s, 2H), 2.94 (s, 3H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.56 (d, J = 4.9 Hz, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.43 ( d, J = 8.0 Hz, 2H), 7.40 - 7.34 (m, 4H), 7.20 (d, J = 5.0 Hz, 1H), 6.64 (d, J = 9.8 Hz, 1H), 4.17 (s, 2H), 2.41 (s, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 5.0 Hz, 1H), 7.70 (d, J = 9.8 Hz, 1H), 7.57 ( dd, J = 3.8, 1.3 Hz, 1H), 7.48 - 7.38 (m, 4H), 7.16 (dd, J = 8.1, 4.8 Hz, 2H), 6.58 (d, J = 9.8 Hz, 1H), 4.18 (s) , 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.57 (d, J = 5.0 Hz, 1H), 7.95 (d, J = 9.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.49 ( d, J = 8.1 Hz, 2H), 7.25 (d, J = 5.0 Hz, 1H), 6.64 (d, J = 9.8 Hz, 1H), 4.40 (s, 2H), 2.57 - 2.48 (m, 1H), 1.10 - 1.04 (m, 2H), 1.01 - 0.96 (m, 2H).

[Scheme 1-2]

After dissolving 4 (1.0 equiv.) in acetonite (0.08 M) in a round-bottom flask, bromotrimethylsillian (5.0 equiv.) was added to 0° C. and stirred at room temperature for 2 hours. After terminating the reaction with methanol, the residue obtained by filtration under reduced pressure was subjected to preparative HPLC to obtain 10 (14-20% yield).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 9.8 Hz, 1H), 7.53 (d, J = 8.2) Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 4.9 Hz, 1H), 6.56 (d, J = 9.8 Hz, 1H), 5.66 - 5.46 (m, 1H), 4.07 (dd, J = 12.1, 7.3 Hz, 2H), 3.97 - 3.88 (m, 3H), 1.20 (t, J = 7.1 Hz, 6H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 9.8 Hz, 1H), 7.47 (s, 4H), 7.21 (d, J = 4.9 Hz, 1H), 6.57 (dd, J = 9.8, 2.0 Hz, 1H), 4.00 (dd, J = 8.1, 7.1 Hz, 4H), 3.39 (s, 1H), 3.33 - 3.31 (m, 1H), 1.21 (t, J = 7.0 Hz, 6H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.55 - 7.39 (m, 4H) ), 7.20 (d, J = 4.9 Hz, 1H), 6.57 (d, J = 9.8 Hz, 1H), 4.04 - 3.81 (m, 2H), 3.19 (d, J = 21.6 Hz, 2H), 1.20 (t) , J = 7.1 Hz, 4H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.45 (d, J = 6.1) Hz, 4H), 7.19 (d, J = 4.9 Hz, 1H), 6.57 (d, J = 9.8 Hz, 1H), 3.51 (s, 1H), 3.08 (d, J = 21.6 Hz, 2H).

[Production Example 2]

Preparation Example 2 goes through a process of preparing product 3, product 4, product 7, or product 8.

Preparation Example 2:

[Scheme 2]

Step 1: In a round bottom flask 1 (1.0 equiv) with palladium(II) acetate (0.050 equiv), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv), 2 (1.3 equiv) and potassium carbonate (3.0 equiv) are dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) and refluxed under nitrogen for 16 hours. 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 obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 3 (40-60% yield).

Step 2: Add 3 (1.0 equiv.) to a round-bottom flask and add dichloromethane (0.040 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) is added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (60-80% yield).

Examples of the present invention prepared according to step 2 as described above are as follows.

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.94 (d, J = 8.7 Hz, 1H), 8.25 (d, J = 7.1 Hz, 1H), 7.56 (t, J = 7.9) Hz, 1H), 7.34 (d, J = 8.3 Hz, 3H), 7.25 (d, J = 7.4 Hz, 1H), 7.17 - 7.07 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 7.1 Hz, 1H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.72 (s, 1H), 8.45 (s, 3H), 8.18 (d, J = 6.7 Hz, 1H), 7.64 - 7.46 (m) , 2H), 7.45 - 7.30 (m, 2H), 6.81 (d, J = 6.7 Hz, 2H), 4.08 (d, J = 5.7 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.63 (s, 1H), 8.13 (d, J = 6.5 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.13 (s, 1H), 6.68 (s, 2H), 6.63 (d, J = 6.5 Hz, 1H), 4.11 (d, J = 3.9 Hz, 2H).

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

LC-MS (ESI) calcd for C ₁₆ H ₁₅ FN ₄ O [M + H] ⁺ 298.12, found m/z 299.24

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.05 (s, 2H), 8.85 (s, 1H), 8.19 (d, J = 6.8 Hz, 1H), 7.50 (t, J ) = 7.7 Hz, 1H), 7.32 (d, J = 12.0 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1H), 6.89 (s, 1H), 6.75 (d, J = 7.0 Hz, 1H), 3.16 (d, J = 3.9 Hz, 2H), 3.06 - 2.97 (m, 2H), 2.57 (t, J = 5.4 Hz, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.79 (s, 1H), 8.19 (d, J = 6.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 6.90 (s, 1H), 6.65 (d, J = 7.0 Hz, 1H), 4.04 (s, 4H)

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.85 (s, 1H), 8.49 (s, 3H), 8.23 (d, J = 6.9 Hz, 1H), 7.64 (d, J ) = 8.4 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.88 (s, 1H), 6.66 (d, J = 6.9 Hz, 1H), 4.07 (d, J = 5.7 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 2H), 8.73 (s, 1H), 8.21 (d, J = 6.6 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.81 (s, 1H), 6.70 (d, J = 6.7 Hz, 1H), 4.25 (s, 2H), 2.68 (s, 1H), 0.92 (t, J = 7.8 Hz, 2H), 0.76 (t, J = 7.8 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 10.04 (s, 2H), 8.81 (s, 1H), 8.20 (d, J = 6.7 Hz, 1H), 7.54 (d, J ) = 8.1 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 6.86 (s, 1H), 6.69 (d, J = 6.9 Hz, 1H), 4.54 (s, 4H) ).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.58 (s, 2H), 8.80 (s, 1H), 8.20 (d, J = 6.9 Hz, 1H), 7.37 (d, J ) = 8.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 6.67 (d, J = 6.9 Hz, 1H), 4.30 (s, 2H), 3.39 - 3.35 (m) , 2H), 3.06 (t, J = 6.1 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.53 (s, 2H), 8.70 (s, 1H), 8.20 (d, J = 6.2 Hz, 1H), 7.48 - 7.24 (m) , 2H), 6.79 (s, 1H), 6.29 (d, J = 4.3 Hz, 1H), 4.31 (s, 2H), 3.57 (m, 2H), 3.02 (t, J = 6.2 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.28 (s, 2H), 8.78 (s, 1H), 8.17 (d, J = 6.7 Hz, 1H), 7.45 (s, 1H) ), 7.39 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.73 (d, J = 6.8 Hz, 1H), 4.34 (s, 2H) ), 3.37 (s, 2H), 3.03 (d, J = 10.1 Hz, 2H), 1.90 (s, 2H).

Step 3: Put a solution of triethylamine (2.5 eq) in dichloromethane (0.1 M) in a round bottom flask. Then, 4 (1.0 equivalent) and 6 (1.1 equivalent) were added and stirred at room temperature for one day. When the reaction is completed, the mixture is concentrated under reduced pressure and dried, and the obtained residue is extracted using dichloromethane and water. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 7 (30-60% yield).

Step 4: Put 7 (1.0 equivalent) in a round-bottom flask, add dichloromethane (0.04 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2M) was added and stirred at room temperature for 16 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 8 (40-80% yield).

Examples of the present invention prepared according to step 4 as described above are as follows.

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.82 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 6.9 Hz, 1H), 7.42 (t, J ) = 8.0 Hz, 1H), 7.22 (s, 1H), 7.20 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H) ), 6.69 (d, J = 7.0 Hz, 1H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.76 (s, 1H), 8.17 (d, J = 6.8 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.19 (s, 1H), 6.86 (s, 1H), 6.70 (d, J ) = 6.9 Hz, 2H), 4.14 (s, 2H).

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

1H NMR (400 MHz, DMSO-d6) δ 9.32 (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).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.70 (s, 1H), 8.16 (d, J = 6.9 Hz, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.34 (d, J = 7.5 Hz, 2H), 7.21 (s, 1H), 6.86 (s, 1H), 6.73 (s, 1H), 6.63 (d, J = 6.9 Hz, 1H), 4.17 (s, 2H) ).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.85 (s, 1H), 8.17 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 14.4 Hz, 3H), 6.93 (s, 1H), 6.73 (d, J = 7.0 Hz, 1H), 6.58 (s, 2H), 3.19 - 3.10 (m, 2H), 2.85 (t) , J = 7.2 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.78 (d, J = 6.7 Hz, 1H), 8.15 (d, J = 7.0 Hz, 1H), 7.47 (t, J = 7.7) Hz, 1H), 7.34 - 7.20 (m, 3H), 6.89 (s, 1H), 6.74 (s, 1H), 6.70 (d, J = 7.0 Hz, 1H), 3.19 (dd, J = 12.6, 4.7 Hz) , 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.68 (s, 3H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.74 (s, 1H), 8.23 - 8.14 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.29 (s) , 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.01 - 6.85 (m, 1H), 6.73 (s, 1H), 6.69 (d, J = 6.9 Hz, 1H), 3.33 - 3.21 (m, 2H), 3.11 (q, J = 7.1 Hz, 2H), 2.89 (dd, J = 10.1, 5.1 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.69 (d, J = 9.3 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.36 - 7.29 (m, 1H), 7.04 (d, J = 9.4 Hz, 1H), 6.68 (dd, J = 7.1, 1.6 Hz, 1H), 3.32 - 3.28 (m, 2H) , 2.93 (t, J = 6.8 Hz, 2H).

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

LC-MS (ESI) calcd for C ₁₇ H ₁₈ FN ₅ O ₃ S [M + H] ⁺ 399.11, found m/z 392.35

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

¹ H NMR (400 MHz, DMSO-d6) δ 9.55 (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).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.63 (s, 1H), 8.13 (d, J = 6.5 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.13 (s, 1H), 6.68 (s, 2H), 6.63 (d, J = 6.5 Hz, 1H), 4.11 (d, J = 3.9 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.76 (d, J = 9.1 Hz, 1H), 8.18 (d, J = 6.6 Hz, 1H), 7.48 (d, J = 8.3) Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 51.0 Hz, 1H), 7.01 (s, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.66 ( d, J = 6.9 Hz, 1H), 4.32 (s, 2H), 2.41 - 2.21 (m, 1H), 0.58 (dd, J = 6.6, 5.1 Hz, 4H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.80 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 6.5 Hz, 1H), 7.69 (s, 1H), 7.49 (s, 2H), 7.44 (s, 1H), 7.31 - 7.27 (m, 1H), 7.18 (s, 1H), 6.86 (d, J = 9.3 Hz, 1H), 6.74 (s, 1H), 6.10 (d, J = 6.7 Hz, 1H), 4.17 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.65 (d, J = 6.7 Hz, 1H), 4.54 (s, 4H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.83 (d, J = 8.1 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 7.34 (d, J = 7.9) Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 6.99 (s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 7.1 Hz, 1H), 4.25 ( s, 2H), 3.31 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.8 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 7.33 (d, J = 8.0) Hz, 1H), 7.22 (dd, J = 11.8, 3.8 Hz, 2H), 6.89 (s, 1H), 6.79 (s, 1H), 6.69 (d, J = 7.0 Hz, 1H), 4.32 (s, 2H) ), 3.50 (s, 2H), 2.99 (d, J = 9.9 Hz, 2H), 1.82 (s, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.77 (s, 1H), 8.16 (d, J = 6.9 Hz, 1H), 7.37 (d, J = 25.5 Hz, 1H), 7.29 (d, J = 17.5 Hz, 1H), 7.14- (t, J = 17.2 Hz, 2H), 6.97 (s, 1H), 6.83 (s, 1H), 6.67 (d, J = 6.9 Hz, 1H) , 4.25 (s, 2H), 3.32 - 3.28 (m, 2H), 2.96 (t, J = 5.5 Hz, 2H).

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

LC-MS (ESI) calcd for C ₁₇ H ₁₆ FN ₅ O ₃ S [M + H] ⁺ 389.10, found m/z 390.23

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.76 (d, J = 6.4 Hz, 1H), 8.19 (d, J = 6.9 Hz, 1H), 7.37 (d, J = 11.0) Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 6.36 (dd, J = 6.7, 2.1 Hz, 1H), 4.27 (s, 2H) ), 3.30 (t, J = 5.8 Hz, 2H), 2.94 (d, J = 5.1 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.75 (s, 1H), 8.15 (d, J = 6.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 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 = 6.9 Hz, 2H), 4.23 - 4.04 (m) , 1H), 3.23 (dd, J = 15.8, 6.9 Hz, 2H), 3.03 - 2.80 (m, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.9 Hz, 1H), 7.37 (d, J = 9.8 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.09 ( s, 1H), 7.02 (d, J = 6.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.92 (s, 2H), 6.42 (d, J = 9.0 Hz, 1H), 4.15 ( s, 3H), 3.49 (s, 3H), 3.27 (s, 2H), 2.90 (s, 2H).

[Production Example 3]

Preparation Example 3 goes through a process of preparing product 3, product 4, product 7, or product 8.

Preparation Example 3:

[Scheme 3]

Step 1: Dissolve 1 (1.0 equiv.) and 2 (1.3 equiv) and N,N-diisopropylethylamine (3.0 equiv.) in n -butanol (0.1 M) in a round bottom flask and reflux for 16 hours. . After completion of the reaction, after cooling to room temperature, the settled solid was filtered to obtain 3 , or water was poured into the mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (1:10 MeOH:CH ₂ Cl ₂ ) to obtain 3 (40-60% yield).

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.79 (d, J = 9.7 Hz, 1H), 6.96 (d, J = 7.6) Hz, 1H), 6.75 (d, J = 5.6 Hz, 1H), 6.46 (d, J = 9.7 Hz, 1H), 2.89 (t, J = 11.8 Hz, 2H), 1.88 (d, J = 13.9 Hz, 2H), 1.70 - 1.54 (m, 3H), 1.40 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d6) δ 8.29 (d, J = 5.6 Hz, 1H), 8.02 (dd, J = 9.8, 1.2 Hz, 1H), 6.82 (d, J = 5.7 Hz, 1H), 6.57 (d, J = 9.7 Hz, 1H), 3.57 (d, J = 12.5 Hz, 2H), 3.04 (d, J = 6.6 Hz, 2H), 2.91 (t, J = 12.1 Hz, 2H), 1.87 ( d, J = 15.7 Hz, 2H), 1.77 - 1.63 (m, 1H), 1.55 - 1.47 (m, 2H), 1.45 (s, 9H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.25 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 9.7 Hz, 1H), 6.81 (t, J = 5.4) Hz, 1H), 6.74 (d, J = 5.6 Hz, 1H), 6.44 (d, J = 9.7 Hz, 1H), 3.41 (d, J = 12.2 Hz, 2H), 3.00 (q, J = 6.6 Hz, 2H), 2.80 (t, J = 11.8 Hz, 2H), 1.79 (d, J = 12.2 Hz, 2H), 1.53 - 1.33 (m, 14H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 5.5 Hz, 1H), 7.84 (d, J = 9.8 Hz, 1H), 6.92 (t, J = 5.8 Hz, 1H), 6.85 ( d, J = 5.6 Hz, 1H), 6.59 (d, J = 9.7 Hz, 1H), 3.64 (s, 3H), 3.42 (d, J = 11.3 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.82 (t, J = 11.9 Hz, 2H), 1.76 (d, J = 12.8 Hz, 2H), 1.64 - 1.51 (m, 1H), 1.44 - 1.34 (m, 11H).

Step 2: Add 3 (1.0 equivalent) to a round-bottom flask, add dichloromethane (0.04 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) is added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (60-80% yield).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 6.0 Hz, 1H), 8.17 (s, 3H), 7.91 (s, 1H), 6.87 (d, J = 6.0 Hz, 1H), 6.58 (s, 1H), 3.69 - 3.58 (m, 4H), 3.15 - 2.97 (m, 2H), 2.06 (d, J = 12.1 Hz, 2H), 1.84 - 1.69 (m, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.27 - 8.22 (m, 2H), 7.04 (d, J = 7.0 Hz, 1H), 6.86 (d, J = 9.4 Hz, 1H), 4.10 (d, J ) = 13.1 Hz, 2H), 3.41 (t, J = 12.7 Hz, 2H), 2.96 (d, J = 6.9 Hz, 2H), 2.13 - 2.05 (m, 1H), 2.06 - 1.97 (m, 2H), 1.67 - 1.54 (m, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.22 (dd, J = 8.2, 5.6 Hz, 2H), 7.01 (d, J = 7.0 Hz, 1H), 6.83 (d, J = 9.5 Hz, 1H), 4.06 (d, J = 13.1 Hz, 2H), 3.38 (t, J = 13.3 Hz, 2H), 3.04 (t, J = 7.9 Hz, 2H), 1.97 (d, J = 13.0 Hz, 2H), 1.89 - 1.78 (m, 1H), 1.71 (dt, J = 9.9, 7.1 Hz, 2H), 1.62 - 1.47 (m, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 2H), 8.26 (d, J = 6.9 Hz, 2H), 6.90 (d, J = 7.0 Hz, 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).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J = 9.5 Hz, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.89 ( d, J = 9.5 Hz, 1H), 3.88 - 3.73 (m, 4H), 3.47 (t, J = 7.4 Hz, 2H), 3.26 (s, 2H), 2.11 (t, J = 7.5 Hz, 2H), 2.02 - 1.89 (m, 4H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.20 (d, J = 6.9 Hz, 1H), 7.98 (d, J = 9.9 Hz, 1H), 7.12 (d, J = 6.9 Hz, 1H), 6.70 ( d, J = 9.9 Hz, 1H), 4.01 (d, J = 13.1 Hz, 2H), 3.76 (s, 3H), 3.42 - 3.34 (m, 2H), 2.96 (d, J = 6.8 Hz, 2H), 2.12 - 2.04 (m, 1H), 2.01 (d, J = 13.0 Hz, 2H), 1.67 - 1.51 (m, 2H).

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

Step 3: Put a solution of 4 (1.0 equiv.) and triethylamine (2.5 equiv) in dichloromethane (0.1 M) in a round bottom flask. Then, 6 (1.1 equivalents) is added. Stir at room temperature for one day. When the reaction is completed, the mixture is concentrated under reduced pressure and dried, and the obtained residue is extracted using dichloromethane and water. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 7 (30-60% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.30 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 9.7 Hz, 1H), 6.84 (d, J = 5.6 Hz, 1H), 6.59 ( d, J = 9.7 Hz, 1H), 3.57 - 3.41 (m, 3H), 3.03 (t, J = 11.7 Hz, 2H), 2.13 (d, J = 13.2 Hz, 2H), 1.92 - 1.76 (m, 2H) ), 1.48 (s, 9H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.25 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 9.7 Hz, 1H), 6.75 (d, J = 5.6) Hz, 1H), 6.44 (d, J = 9.7 Hz, 1H), 3.41 - 3.37 (m, 4H), 2.87 - 2.70 (m, 4H), 1.81 (d, J = 12.8 Hz, 2H), 1.68 - 1.58 (m, 1H), 1.37 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 9.7 Hz, 1H), 6.82 (d, J = 5.7 Hz, 1H), 6.57 ( d, J = 9.7 Hz, 1H), 3.61 - 3.51 (m, 2H), 3.09 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 12.0 Hz, 2H), 1.91 (d, J = 8.0) Hz, 2H), 1.73 - 1.65 (m, 1H), 1.60 (q, J = 6.9 Hz, 2H), 1.56 - 1.50 (m, 2H), 1.48 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.44 (d, J = 5.7 Hz, 1H), 8.04 (d, J = 9.7 Hz, 1H), 6.92 (d, J = 5.8 Hz, 1H), 6.68 ( d, J = 9.7 Hz, 1H), 3.82 (s, 3H), 3.60 - 3.54 (m, 2H), 3.02 (d, J = 6.7 Hz, 2H), 2.95 (t, J = 12.0 Hz, 2H), 1.98 (d, J = 13.0 Hz, 2H), 1.87 - 1.76 (m, 1H), 1.62 - 1.48 (m, 11H).

Step 4: Put 7 (1.0 equivalent) in a round-bottom flask, add dichloromethane (0.04 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2M) was added and stirred at room temperature for 16 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 8 (40-80% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J = 9.4 Hz, 1H), 8.20 (d, J = 7.3 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.91 ( d, J = 9.3 Hz, 1H), 4.12 (d, J = 13.7 Hz, 2H), 3.72 - 3.54 (m, 3H), 2.31 - 2.19 (m, 2H), 1.91 - 1.74 (m, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.21 (dd, J = 13.9, 8.1 Hz, 2H), 6.99 (d, J = 7.0 Hz, 1H), 6.82 (d, J = 9.4 Hz, 1H), 4.05 (d, J = 13.1 Hz, 2H), 3.38 (d, J = 13.4 Hz, 2H), 3.02 (d, J = 6.3 Hz, 2H), 2.08 - 1.90 (m, 3H), 1.53 (q, J ) = 12.3 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 6.3 Hz, 1H), 8.01 (s, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.70 - 6.40 (m, 4H) ), 3.78 - 3.69 (m, 2H), 3.15 - 3.08 (m, 2H), 2.96 (t, J = 7.2 Hz, 2H), 1.83 (d, J = 12.3 Hz, 2H), 1.76 - 1.64 (m, 1H), 1.50 (q, J = 7.0 Hz, 2H), 1.45 - 1.32 (m, 2H).

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

¹ H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J = 9.5 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.87 ( d, J = 9.5 Hz, 1H), 3.88 - 3.71 (m, 4H), 3.41 - 3.37 (m, 3H), 2.01 - 1.82 (m, 7H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.93 - 6.76 (m, 3H), 6.72 (d, J = 9.6 Hz, 1H), 3.93 (s, 2H), 3.54 (s, 2H), 3.33 (s, 2H), 3.30 - 3.26 (m, 2H), 2.04 (s, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.13 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 9.9 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.68 ( d, J = 9.9 Hz, 1H), 4.02 (d, J = 13.3 Hz, 2H), 3.75 (s, 3H), 3.40 (d, J = 12.8 Hz, 2H), 3.02 (d, J = 6.3 Hz, 2H), 2.08 - 1.92 (m, 3H), 1.62 - 1.43 (m, 2H).

[Production Example 4]

Preparation Example 4 goes through a process for preparing product 3, product 4, product 7, or product 8.

Preparation Example 4:

[Scheme 4]

Step 1: In a round bottom flask 1 (1.0 equiv) with palladium(II) acetate (0.050 equiv), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv), 2 (1.3 equiv) and potassium carbonate (3.0 equiv) are dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) and refluxed under nitrogen for 16 hours. 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 obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 3 (40-60% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.15 (d, J = 5.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.99 (d, J = 5.1 Hz, 1H), 4.29 (s, 2H), 2.94 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.45 (s, 9H).

Step 2: Add 3 (1.0 equiv.) to a round-bottom flask and add dichloromethane (0.040 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) is added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (60-80% yield).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.45 (t, J = 6.4 Hz, 1H), 7.36 (d, J = 3.9) Hz, 4H), 6.93 (d, J = 5.2 Hz, 1H), 4.18 (d, J = 6.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), 1.40 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J = 6.0 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.31 (d, J ) = 6.0 Hz, 1H), 3.06 (dd, J = 8.5, 6.6 Hz, 2H), 2.68 (dd, J = 8.5, 6.6 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J = 5.8 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.58 (s, 1H), 7.56 - 7.52 (m, 1H), 7.25 (d, J = 5.8 Hz, 1H), 4.23 (s, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.17 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 6.98 ( d, J = 5.2 Hz, 1H), 4.15 (s, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.32 ( d, J = 6.0 Hz, 1H), 3.08 (dd, J = 8.5, 6.6 Hz, 2H), 2.68 (dd, J = 8.5, 6.6 Hz, 2H), 1.80 (s, 6H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.68 (s, 2H), 8.19 (d, J = 5.2 Hz, 1H), 7.39 - 7.28 (m, 3H), 6.96 (d) , J = 5.3 Hz, 1H), 4.30 (s, 2H), 3.38 (s, 2H), 3.08 (t, J = 6.1 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.45 (t) , J = 7.5 Hz, 2H).

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

Step 3: Put a solution of triethylamine (2.5 eq) in dichloromethane (0.1 M) in a round bottom flask. Then, 4 (1.0 equivalent) and 6 (1.1 equivalent) were added and stirred at room temperature for one day. When the reaction is completed, the mixture is concentrated under reduced pressure and dried, and the obtained residue is extracted using dichloromethane and water. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 7 (30-60% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.15 (d, J = 5.2 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.31 - 7.27 (m, 1H), 7.02 (d, J = 5.2 Hz) , 1H), 4.17 (s, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.41 (s, 9H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.15 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.99 ( d, J = 5.1 Hz, 1H), 4.21 (s, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.45 (s, 9H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.52 (s, 1H), 8.15 (d, J = 5.1 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.23 (d , J = 7.7 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 4.53 (s, 2H), 3.57 (t, J = 5.9 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H) ), 2.85 (d, J = 7.9 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.33 (s, 9H).

Step 4: Put 7 (1.0 equivalent) in a round-bottom flask, add dichloromethane (0.04 M) to dissolve it. Then, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2M) was added and stirred at room temperature for 16 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 8 (40-80% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.23 (d, J = 6.0 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.36 - 7.30 (m, 3H), 7.15 (dt, J ) = 7.9, 1.2 Hz, 1H), 3.11 (t, J = 8.4, 6.6 Hz, 2H), 2.66 (dd, J = 8.4, 6.6 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J = 6.2 Hz, 1H), 7.60 - 7.53 (m, 3H), 7.41 (d, J = 6.3 Hz, 2H), 4.31 (s, 2H) ), 3.14 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.14 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0) Hz, 2H), 6.93 (d, J = 5.2 Hz, 1H), 4.13 (s, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J = 6.1 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 6.1 Hz, 1H), 7.32 - 7.25 (m, 2H), 4.36 (s, 2H), 3.10 (dd, J = 8.4, 6.6 Hz, 2H), 2.68 (t, J = 8.4, 6.6 Hz, 2H).

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

LC-MS (ESI) calcd for C ₁₆ H ₁₆ N ₄ O ₃ S [M + H] ⁺ 344.09, found m/z 345.35

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.26 (s, 1H), 7.85 (s, 1H), 7.31 - 7.21 (m, 1H), 7.08 (d, J = 17.5 Hz) , 2H), 6.96 (d, J = 7.4 Hz, 2H), 6.61 (d, J = 6.8 Hz, 1H), 4.22 (s, 2H), 3.29 (s, 1H), 2.93 (brs, 4H), 2.67 (t, J = 7.4 Hz, 2H).

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 12H), 7.24 (d, J = 7.2) Hz, 2H), 6.99 (d, J = 5.2 Hz, 2H), 4.27 - 4.22 (m, 2H), 3.31 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.44 (t, J = 7.5 Hz, 2H).

[Scheme 4-1]

4 (1.0 equiv) and RSO ₂ Cl in a round bottom flask (1.1 equivalents) was dissolved in dichloromethane (0.08 M), triethylamine (4.5 equivalents) was added thereto, and stirred at room temperature for 16 hours. After the reaction was completed, water was poured into the mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 9 (30-50% yield).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.16 (d, J = 5.1 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.42 (s, 1H), 7.33 (d, J = 6.9 Hz, 1H) ), 7.00 (d, J = 5.2 Hz, 1H), 4.33 (s, 2H), 2.95 (t, J = 7.6 Hz, 2H), 2.91 (s, 3H), 2.55 (t, J = 7.6 Hz, 2H) ).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.15 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.32 ( d, J = 7.8 Hz, 3H), 7.25 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 6.90 (d, J = 5.2 Hz, 1H), 4.15 (s, 2H), 2.86 ( t, J = 7.5 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H).

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

¹ H NMR (400 MHz, MeOD-d4) δ 8.15 (d, J = 5.2 Hz, 1H), 7.73 (dd, J = 5.0, 1.3 Hz, 1H), 7.56 (dd, J = 3.8, 1.3 Hz, 1H) ), 7.42 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H), 4.23 (s, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H).

[Experimental example]

The following experiment was performed on Examples 1-148 prepared as described above.

Experimental Example 1: ENPP1 enzyme assay with cGAMP substrate

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

The assay system final reaction mixture contains 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM CaCl ₂ , 1 μM ZnCl ₂ , 5% glycerol and 1% DMSO. Serially diluted ENPP1 inhibitors (typically in the range of 10 μM to 0.5 nM) are pre-stored with human recombinant ENPP1 enzyme (R & D systems) at 3 ng/reaction and room temperature (RT) conditions for 5-10 min. The reaction is started by addition of cGAMP (at a final concentration of 5 μM) and reacted at 37°C for 90 minutes. At the end of the reaction, 10 μl of AMP-Glo first reagent is added to stop the reaction, and then stored at room temperature for 1 hour. After the storage, 20 μl of the AMP detection solution (a mixture of AMP-Glo II reagent and Kinase-Glo 1: 100 ratio) is added and stored at room temperature for 1 hour. Luminescence signals are measured using a Victor® plate reader (Perkin Elmer). The maximal activity control (containing enzyme and substrate in the presence of 1% DMSO; MAX) and the lowest activity control (containing substrate and 1% DMSO; MIN) were evaluated simultaneously. In each experiment, serially diluted reference ENPP1 inhibitors were tested together. IC50 values for % residual activity versus compound concentration were determined by fitting inhibition curves using the 3-parameter parametric method of GraphPad Prism® software. Serially diluted samples of one compound were tested at least twice and the average IC50 value was calculated for each compound.

The experimental results were shown in Tables 1 and 2 below.

Example Enzyme activity One B 2 B 3 B 7 A 8 C 10 A 11 A 12 A 13 A 14 A 15 A 16 B 17 B 18 A 20 B 21 C 22 B 23 B 24 C 25 B 26 A 27 B 28 A 29 B 32 A 35 A 36 A 37 A 38 A 39 B 40 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 C 58 A 59 A 60 B 61 A 64 A 65 A 66 A 67 A 70 A 71 B 74 B 75 A 77 A 78 A 79 B 81 A 82 A 84 A 85 A 86 B 87 C 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 97 A 98 B 99 B 100 B 101 A 102 A 103 B 104 B 106 A 107 A 108 C 113 A 114 A 115 A 117 B 118 C 123 A 124 A 125 A 126 A 127 B 128 A 131 B 132 C 133 A 134 A 135 C 138 B 139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 B 147 A

Enzyme activity A B C NA IC ₅₀ (uM) activity < 1 μM 1 uM < activity < 10 uM activity > 10 uM No activity

[Experimental Example 2]

The following experiment was performed on the Examples prepared as described above.

Experimental Example 2: HCT116-dual cell Luciferase assay

HCT116-Dual ^TM 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 ^TM cell line was used to measure and monitor the activity of interferon regulatory factor 3 (IRF3), which is a type I interferon induction and subsequent signaling, and lucia secreted from the culture medium is used to generate luminescence in a luciferase reaction. .

Incubate HCT116-Dual ^TM cells in a 96-well plate at 2x10 ⁴ cells/well (93.4uL) in DMEM culture medium containing 10% FBS and 25mM HEPES (pH 7.2 - 7.5) for one day. Treat with 3.3uL of ENPP1 inhibitor (typically 10 μM) and 3.3uL of cGAMP (10 μM) to set the final dose to 100uL. (The final fraction of DMSO is 0.1%.) Cells treated with ENPP1 inhibitor and cGAMP are cultured at 37°C for 48 hours, and lucia luciferase activity is measured by adding 50uL of Quanti-Luc reaction solution to 20uL of cell culture medium. . The increase in interferon regulatory factor 3 (IRF3) by the compound compared to cGAMP was determined by fold.

The experimental results were shown in Tables 3 and 4 below.

Example cell activity 8 B 10 B 11 A 12 A 13 A 14 B 15 B 20 A 21 B 22 B 23 B 24 B 25 A 28 B 35 B 36 B 37 B 38 B 41 B 42 A 43 B 45 B 52 B 53 B 54 B 55 B 56 B 58 B 61 B 64 B 65 B 79 B 93 B 94 B 97 B 102 A 140 B 142 B 143 B 145 B

cell activity A B Drainage > 2 1< multiple <2

[Formulation example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation Example 1: Tablet (Direct Pressurization)

After 5.0 mg of the active ingredient was sieved, lactose 14.1 mg, crospovidone USNF 0.8 mg, and magnesium stearate 0.1 mg were mixed and pressurized to make tablets.

Formulation Example 2: Tablet (wet granulation)

After sieving 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 0.3 mg of polysorbate 80 in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation Example 3: Powder and Capsule

After sieving 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. Mix the mixture into a solid No. using a suitable device. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ ·12H ₂ O, and 2974 mg of distilled water.

In the above, embodiments of the present invention have been described, but those of ordinary skill in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without changing the technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (12)

A compound selected from a naphthyridinone derivative compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:
[Formula 1]

In Formula 1,
R ₁ is hydrogen; C ₁ -C ₁₃ alkyl group; or C ₃ -C ₁₀ cyclyl group; is,
R ₂ is -ZR ₃ -(R ₄ ) _m ,
Z is present or not, and 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 -, ; is
n is an integer from 0 to 8,
Wherein R ₃ is a C ₃ -C ₁₀ cyclyl group, a C ₃ -C ₁₀ heterocyclyl group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group,
wherein R ₄ is hydrogen; hydroxyl group; 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 ); amide group (-(C=O)NR ₅ R ₆ ); 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; sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₆ ); sulfamoylalkyl group (-(C _m H _m+2 )NR ₅ S(O) ₂ NHR ₆ ); sulfide group (-SR ₆ ); sulfone group (-S(O) ₂ R ₆ ); a phospyryl group (-P(O)R ₅ R ₆ ); connected to the same carbon as the carbon connected to R ₃ to form a 3 to 7 membered saturated ring; It is connected to the same carbon as the carbon connected to R ₃ to form a 3 to 7 membered hetero saturated ring containing one or more heteroatoms of N, O and S; It is connected to the carbon connected to R ₃ and the adjacent carbon to form a 3 to 7 membered saturated ring; or connected to the carbon connected to R ₃ and the adjacent carbon to form a 3 to 7 membered hetero saturated ring containing one or more heteroatoms of N, O and S;
m is an integer from 1 to 4,
The C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group, or C ₃ -C ₁₀ cyclyl group may include hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₅ R ₆ ); nitro group (-N(O) ₂ ); 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-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₅ R ₆ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it includes one or more substituents selected from the group consisting of C ₃ -C ₁₀ heterocyclyl group,
The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ₅ R ₆ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; a C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₅ R ₆ ); nitro group (-N(O) ₂ ); 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-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₅ R ₆ ); C ₆ -C ₁₀ aryl group; Containing one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group,
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 heterocyclyl group; or R ₅ together with the nitrogen or carbon atom connected to R ₆ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of, hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group, and Forms a 3 to 7 membered saturated ring that may be optionally substituted with at least one of a cyano group,
The C ₃ -C ₁₀ heteroaryl group and the C ₃ -C ₁₀ heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.
The method of claim 1,
R ₁ is hydrogen; Or a C ₁ -C ₅ alkyl group;
R ₃ is a C ₅ -C ₇ heterocyclyl group, a C ₆ -C ₈ aryl group, or a C ₅ -C ₁₀ heteroaryl group, a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof a compound selected from hydrates and stereoisomers thereof.
The method of claim 1,
R ₁ is hydrogen; Or a C ₁ -C ₃ alkyl group; and
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 phenathrene; 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 purines; substituted or unsubstituted cyclopropane; or substituted or unsubstituted cyclobutane;
A compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
R ₁ is hydrogen; Or a C ₁ -C ₃ alkyl group; and
R ₃ is substituted or unsubstituted benzene; or substituted or unsubstituted piperidine;
A compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
wherein R ₂ is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

sign,
A compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
6. The method of claim 5,
Wherein R ₄ is halogen, methyl group, 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),

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

sign,
A compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

The method of claim 1,
The compound is selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, characterized in that any one selected from the group consisting of the following compound numbers 1 to 148 compound:
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 number 6: 5-(3-(aminophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 7: 5-(3-(aminomethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 8: 5-(5-(amino-2-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 9: 5-(3-(aminomethyl)-4-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 10: 5-(4-(aminomethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 11: 5-(4-(aminomethyl)-2-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 12: 5-(4-(aminomethyl)-3-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound number 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound number 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound number 15: ( R )-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound number 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound number 17: ( R )-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 18: ( S )-5-(4-(1-(methylaminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 19: ( R )-5-(4-(1-(cyclopropylaminoethyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 20: 5-(4-((ethylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 21: 5-(2-fluoro-4-((isopropylamine)methyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 22: 5-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 23: 5-(3-fluoro-4-((methylamino)methyl)phenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 24: 5-(4-((ethylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 25: 5-(4-((cyclopropylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 26: 5-(Asoindorin-5-yl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound number 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 28: 5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2( 1H )-one hydrochloride;
Compound number 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1 H )-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 number 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)sulfa mide hydrochloride;
Compound No. 49: ( R )-( N- (1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfa mide 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 -Cyclophyllophil- 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 -Cyclophyllophil- 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)sulfa mide 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)sulfa mide hydrochloride;
Compound No. 63: ( R )- ( N- (1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfa mide hydrochloride;
Compound number 64: 5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindorin-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 (1 H )- 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 number 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 number 72: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;
Compound number 73: diethyl(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate;
Compound No. 74: Ethylhydrogen (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(1 H )-one dihydrochloride;
Compound No. 77: 5-((3-aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1 H )-one dihydrochloride;
Compound No. 78: 5-((3-aminomethyl)-4-fluorophenyl)amino)-1,8-naphthyridin-2(1 H )-one dihydrochloride;
Compound No. 79: 5-((5-(2-aminoethyl)-2-fluorophenyl)amino)-1,8-naphthyridin-2(1 H )-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(1 H )-one dihydrochloride;
Compound No. 82: 5-((4-(aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1 H )-one dihydrochloride;
Compound No. 83: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1 H )-one dihydrochloride;
Compound No. 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1 H )-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 di hydrochloride;
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)isoindorin-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-dihydroisoquinoline-2(1 H )-yl)sulfamide dihydrochloride;
Compound No. 106: (7-fluoro-6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2( 1 H )-yl)sulfamide dihydrochloride;
Compound No. 107: N- (5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-2,3-dihydro- 1H -indene-2- 1) sulfamide dihydrochloride;
Compound No. 108: (7- (methyl (7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl) amino) -3,4-dihydroisoquinoline-2 (1 H )- 1) 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(1 H )-one hydrochloride;
Compound No. 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1 H )-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(1 H )-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(1 H )-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)sulfa Moyl) 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-4yl)piperidin-4-yl)sulfamide;
Compound No. 124: N -((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)piperidin-4-yl)methyl)sulfamide;
Compound No. 125: N- (2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)piperidin-4-yl)ethyl)sulfamide;
Compound No. 126: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)-2,8-diazaspiro[4,5]decane-2-sulfamide;
Compound No. 127: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)-2,8-diazaspiro[4,5]decane-2-sulfamide;
Compound No. 128: N -((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4yl)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(1 H )-one hydrochloride;
Compound No. 133: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 134: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1 H )-one hydrochloride;
Compound No. 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1 H )-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-diisoquinoline-2(1) H )-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 (1 H )-sulfamide hydrochloride;
Compound No. 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoguanoline-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.
The method of claim 1,
The pharmaceutically acceptable salts include 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, a salt of an inorganic or organic acid selected from the group consisting of 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;
A compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
Claims 1 to 8, wherein the compound of any one of claims 1 to 8 is included as an active ingredient, cancer prevention, alleviation or prevention of cancer metastasis, anti-cancer vaccine efficacy enhancement, neo-reinforcement anti-cancer treatment efficacy enhancement, infection treatment, CAR-T anti-cancer effect enhancement , A pharmaceutical composition for promoting myocardial regeneration and enhancing cardiac function or treating hypophosphatemia.
Claims 1 to 8, which contains the compound of any one of claims 1 to 8 as an active ingredient, ENPP 1 inhibitor.
Claims 1 to 8, wherein the compound of any one of claims 1 to 8 is included as an active ingredient, STING pathway activator.
10. The method of claim 9,
The cancer is a cancer associated with inhibiting ENPP1, a pharmaceutical composition for preventing, alleviating or treating cancer.